WO2006022996A2

WO2006022996A2 - Dosage form containing multiple drugs

Info

Publication number: WO2006022996A2
Application number: PCT/US2005/020499
Authority: WO
Inventors: Viswanathan Srinivasan; Ralph Brown; David Brown; Himanshu Patel; Juan Carlos Menendez; Venkatesh Balasubramanian; Somphet Peter Suphasawud
Original assignee: Sovereign Pharmaceuticals, Ltd.
Priority date: 2004-08-04
Filing date: 2005-06-13
Publication date: 2006-03-02
Also published as: WO2006022996A3

Abstract

A pharmaceutical dosage form comprising a first drug and a second drug, both of which are selected from decongestants, antitussives, expectorants, analgesics and antihistamines. The dosage form provides a plasma concentration within a therapeutic range of the second drug over a period which is coextensive with at least about 70% of a period over which the dosage form provides a plasma concentration within a therapeutic range of the first drug.

Description

DOSAGE FORM CONTAINING MULTIPLE DRUGS

BACKGROUND OF THE INVENTION

1. Field of the Invention

[0001] The present invention relates to a pharmaceutical dosage form which comprises a first drug and a second drug, both of which are selected from decongestants, antitussives, expectorants, analgesics and antihistamines. The dosage form releases the first drug and the second drug so as to provide pharmaceutically effective plasma concentrations of these drugs over similar periods of time. The present invention also relates to a process for manufacturing the dosage form and to methods for alleviating conditions which can be alleviated by a combination of these drugs.

2. Discussion of Background Information

[0002] Conditions such as colds and allergies are accompanied by a variety of symptoms which frequently can not satisfactorily be ameliorated or treated with a single drug but require the administration of two or more drugs. Drugs which are indicated for the amelioration of cold and allergy related symptoms often belong to at least one of the following classes: antihistamines, decongestants, antitussives, expectorants and analgesics. To facilitate and simplify the administration of the different drugs that are required for the amelioration of the various symptoms that a patient is experiencing it would be expedient to administer all of these drugs in a single dosage form, or at least in as few dosage forms as possible. However, in many cases these different drags have significantly different pharmacokinetic properties. For example, a single dose of a first indicated drug may provide a therapeutically effective plasma concentration for a period of time which is significantly longer than the therapeutically effective plasma concentration that is provided by a single dose of a second indicated drug. As a result, there appears to be virtually no benefit in combining the first drug and the second drug in a single dosage form because with a corresponding combination, the first drug would still provide the desired therapeutic effect when the other drug has ceased to be effective and would have to be administered again.

[0003] Accordingly, it would be desirable if patients suffering from symptoms for which a first drug is indicated would also obtain relief, over a similar time period, from one or more symptoms for which one or more second drugs are indicated, by administering a single dose of a dosage form such as, e.g., a tablet, liquid, syrup, suspension, gel, capsule, suppository and the like. In other words, it would be desirable to have available a dosage form which provides the therapeutic effects of drugs with significantly different pharmacokinetic properties over a similar period of time.

SUMMARY OF THE INVENTION

[0004] The present invention provides a pharmaceutical dosage form which comprises a first drug and a second drug, both of which are selected from decongestants, antitussives, expectorants, analgesics and antihistamines and preferably belong to different classes of drugs. The dosage form provides a plasma concentration within the therapeutic range of the second drug over a period which is coextensive with at least about 70 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug.

[0005] In one aspect of the dosage form, the first drug may comprise a decongestant. By way of non-limiting example, the decongestant may comprise phenylephrine and/or pseudoephedrine and/or one or more pharmaceutically acceptable salts of one or both of two decongestants.

[0006] In another aspect of the dosage form, the first drug may comprise an antitussive. By way of non-limiting example, the antitussive may comprise one or more of a morphine derivative such as, e.g., codeine, dihydrocodeine, hydrocodone and hydromorphone, dextromethorphan, carbetapentane, chlophedianol, benzonatate, caramiphen, noscapine and/or one or more pharmaceutically acceptable salts of one or more of these antitussive drugs. [0007] In another aspect of the dosage form, the first drug may comprise an antihistamine. Non-limiting examples of antihistamines for use in the present invention include acrivastine, astemizole, azatadine, azelastine, bromodiphenhydramine, brompheniramine, carbinoxamine, carebastine, cetirizine, chlophedianol, chlorcyclizine, clemastine, chlorothen, chlorpheniramine, cyclizine, cyproheptadine, descarboethoxyloratadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimethindene, diphenhydramine, diphenylpyraline, doxylamine, ebastine, epanastine, efletirizine, fexofenadine, hydroxyzine, isothipendyl, ketotifen, loratadine, meclizine, methapyrilene, mizolastine, mequitazine, mianserin, montelukast, noberastine, norastemizole, picumast, phenindamine, pheniramine, phenyltoloxamine, promethazine, prophenpyridamine, pyrilamine, temelastine, terfenadine, thenyldiamine, thonzylamine, trimeprazine, tripelennamine, triprolidine, and pharmaceutically acceptable salts thereof. By way of non-limiting example, the antihistamine may comprise at least one of promethazine, diphenhydramine, chlorpheniramine, carbinoxamine and pharmaceutically acceptable salts thereof. [0008] In yet another aspect of the dosage form, the first drug may comprise an analgesic.

By way of non-limiting example, the analgesic may comprise one or more of aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, hydrocodone, oxycodone, morphine, meperidine and fentanyl.

[0009] In a still further aspect of the dosage form of the present invention, the first drug may comprise an expectorant such as, e.g., guaifenesin and/or a pharmaceutically acceptable salt thereof.

[0010] In another aspect of the dosage form of the present invention, the second drug may comprise a decongestant and/or an antitussive and/or an antihistamine and/or an analgesic and/or an expectorant. Non-limiting specific examples of these drugs include those which are given above as non-limiting examples of the first drug.

[0011] In another aspect of the dosage form, the plasma half-life of the second drug may differ from the plasma half-life of the first drug by at least about 2 hours, e.g., by at least about 3 hours, or by at least about 4 hours.

[0012] In yet another aspect of the dosage form of the present invention, the plasma concentration within the therapeutic range of the second drug may be coextensive with at least about 80 %, e.g., at least about 90 %, or at least about 95 %, of the period of a plasma concentration within the therapeutic range of the first drug.

[0013] In a still further aspect of the dosage form, the dosage form may comprise a tablet such as, e.g., a bi-layered tablet. By way of non-limiting example, the tablet may comprise a matrix which comprises the first drag or the second drug and has dispersed therein particles which comprise the other one of the first drug and the second drug.

[0014] In another aspect of the dosage form, the dosage form may comprise a solution or a suspension.

[0015] The present invention also provides a bi-layered tablet which comprises a first layer and a second layer. The first layer comprises a first drug which is selected from decongestants, antitussives, expectorants, analgesics and antihistamines, and the second layer comprising a second drug which is also selected from decongestants, antitussives, expectorants, analgesics and antihistamines but is different from the first drug and preferably belongs to a different class than the first drug. The bi-layered tablet provides a plasma concentration within the therapeutic range of the second drug over a period which is coextensive with at least about 70 % of the period over which the bi-layered tablet provides a plasma concentration within the therapeutic range of the first drug. [0016] In one aspect of the bi-layered tablet of the present invention, the first layer and/or the second layer may comprise at least one drug that is selected from phenylephrine, pseudoephedrine, codeine, dihydrocodeine, hydrocodone, dextromethorphan, carbetapentane, chlophedianol, benzonatate, caramiphen, noscapine, guaifenesin, acrivastine, astemizole, azatadine, azelastine, bromodiphenhydramine, brompheniramine, carbinoxamine, carebastine, cetirizine, chlophedianol, chlorcyclizine, clemastine, chlorothen, chlorpheniramine, cyclizine, cyproheptadine, descarboethoxyloratadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimethindene, diphenhydramine, diphenylpyraline, doxylamine, ebastine, epanastine, efletirizine, fexofenadine, hydroxyzine, isothipendyl, ketotifen, loratadine, meclizine, methapyrilene, mizolastine, mequitazine, mianserin, montelukast, noberastine, norastemizole, picumast, phenindamine, pheniramine, phenyltoloxamine, promethazine, prophenpyridamine, pyrilamine, temelastine, terfenadine, thenyldiamine, thonzylamine, trimeprazine, tripelennamine, triprolidine and pharmaceutically acceptable salts thereof, aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, hydrocodone, oxycodone, morphine, meperidine and fentanyl. [0017] In another aspect of the bi-layered tablet, the period of a plasma concentration within the therapeutic range of the second drug may be coextensive with at least about 80 %, e.g., at least about 90 %, or at least about 95 %, of the period of a plasma concentration within the therapeutic range of the first drug.

[0018] In yet another aspect of the bi-layered tablet, the plasma half-life of the second drug may differ from the plasma half-life of the first drug by at least about 2 hours, for example, by at least about 3 hours.

[0019] In a still further aspect of the bi-layered tablet, the first or the second layer may be an immediate release layer, or the first and the second layers may both be controlled release layers.

[0020] The present invention also provides a multi-layered tablet which comprises at least a first layer and a second layer. The first layer comprises a first drug which is selected from decongestants, antitussives, expectorants, analgesics and antihistamines and the second layer is a controlled release layer and comprises a second drug which is selected from decongestants, antitussives, expectorants, analgesics and antihistamines and is different from the first drug and preferably belongs to a different class than the first drug. [0021] In one aspect of the multi-layered tablet, the first layer may be an immediate release layer and/or the second layer may be a controlled release layer. [0022] In another aspect of the multi-layered tablet, the second drug may have a plasma half-life which differs from the plasma half-life of the first drug by at least about 2 hours, for example, by at least about 3 hours.

[0023] In yet another aspect of the multi-layered tablet, the tablet may provide a plasma concentration within the therapeutic range of the second drug over a period which is coextensive with at least about 90 % of the period over which the tablet provides a plasma concentration within the therapeutic range of the first drug.

[0024] In a still further aspect of the multi-layered tablet, the layers thereof may be discrete zones which are arranged adjacent to each other, or one of the first and second layers may be partially or completely surrounded by the other one of the first and second layers. [0025] The present invention also provides a pharmaceutical dosage form which comprises a first drug which is selected from antihistamines and has a first plasma half-life, and a second drug which is selected from decongestants, antitussives, analgesics and expectorants and has a second plasma half-life that differs from the first plasma half-life by at least about 3 hours. The dosage form provides a plasma concentration within the therapeutic range of the second drug over a period which is coextensive with at least about 80 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug. [0026] In one aspect of the dosage form, the first plasma half-life may be longer by at least about 4 hours, e.g., longer by at least about 6 hours, than the second plasma half-life. In another aspect, the first plasma half-life may be at least about 8 hours. [0027] In another aspect of the dosage form of the present invention, the period of a plasma concentration within the therapeutic range of the at least one second drug may be coextensive with at least about 90 %, e.g., at least about 95 %, or about 100 % of the period of a plasma concentration within the therapeutic range of the first drug.

[0028] In yet another aspect, the dosage form may be associated with instructions to administer the dosage form three or fewer times per day, e.g., once or twice per day. [0029] In a still further aspect, the dosage form may comprise a tablet. [0030] In another aspect of the dosage form, the second drug may comprise a decongestant. [0031] In another aspect, the antihistamine may be selected from acrivastine, astemizole, azatadine, azelastine, bromodiphenhydramine, brompheniramine, carbinoxamine, carebastine, cetirizine, chlorcyclizine, clemastine, chlorothen, chlorpheniramine, cyclizine, cyproheptadine, descarboethoxyloratadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimethindene, diphenhydramine, diphenylpyraline, doxylamine, ebastine, epanastine, efletirizine, fexofenadine, hydroxyzine, isothipendyl, ketotifen, loratadine, meclizine, methapyrilene, mizolastine, mequitazine, mianserin, montelukast, noberastine, norastemizole, picumast, phenindamine, pheniramine, phenyltoloxamine, promethazine, prophenpyridamine, pyrilamine, temelastine, terfenadine, thenyldiamine, thonzylamine, trimeprazine, tripelennamine, triprolidine, and pharmaceutically acceptable salts thereof.

[0032] The present invention also provides dosage forms as set forth above, including the various aspects thereof, which dosage forms are substantially free of antihistamines. [0033] The present invention also provides a method of alleviating a condition which can be alleviated by administration of an antihistamine and at least one other condition which can be alleviated by administration of a drug which is at least one of a decongestant, an antitussive, an expectorant and an analgesic, wherein the method comprises administering a dosage form of the present invention, including the various aspects thereof, to a subject in need thereof. [0034] The present invention also provides a process of making a pharmaceutical dosage form of the present invention, wherein the method comprises preparing a first composition which comprises the first drug and a second composition which comprises the second drug, and combining the first and the second compositions, for example, by using a tablet press. [0035] The pharmaceutical dosage forms of the present invention comprise at least two drugs, i.e., a first drug and a second drug. It is noted that the terms "a first drug" and "a second drug" do not exclude, but rather include the presence of more than one first or second drug. For example, the dosage form may comprise one first drug and two or more (e.g., three, four, five, etc.) second drugs. In this case, the dosage form desirably provides plasma concentrations within the therapeutic ranges of all of the second drugs over periods of time which individually are coextensive with at least about 70 % (e.g., at least about 80 %, at least about 90 %, at least about 95 %, or at least about 100 %) of the period of time over which the dosage form provides a plasma concentration within the therapeutic range of the first drug. Moreover, in cases where the dosage form comprises more than one first drug and more than one second drug, the first drug with the longest period of a plasma concentration with the therapeutic range is the standard, i.e., preferably all other drugs that are present in the dosage form show plasma concentrations within the therapeutic ranges thereof over periods of time which are coextensive with at least about 70 % (e.g., at least about 80 %, at least about 90 %, at least about 95 %, or at least about 100 %) of the period for the first drug with the longest period of a plasma concentration with the therapeutic range.

[0036] The pharmaceutical dosage form which constitutes one aspect of the present invention comprises first and second drugs which may be present in the form of a pharmaceutically acceptable salt thereof. The term "pharmaceutically acceptable salt" as used herein and in the appended claims refers to those salts of a particular drug that are not substantially toxic at the dosage administered to achieve the desired effect and do not independently possess significant pharmacological activity. The salts included within the scope of this term are pharmaceutically acceptable acid addition salts of a suitable inorganic or organic acid. Non-limiting examples of suitable inorganic acids are, for example hydrochloric, hydrobromic, sulfuric and phosphoric acids. Non-limiting examples of suitable organic acids include carboxylic acids, such as acetic, propionic, tannic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, cyclamic, ascorbic, maleic, hydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranillic, cinnamic, salicylic, 4-aminosalicyclic, 2-phenoxybenzoic, 2-acetoxybenzoic and mandelic acids, as well as sulfonic acids, such as methanesulfonic, ethanesulfonic, and β- hydroxyethanesulfonic acids.

[0037] Non-limiting examples of drugs for use in the present invention in the form of their pharmaceutically acceptable salts include codeine phosphate, codeine sulfate, hydrocodone bitartrate, dihydrocodeine bitartrate, carbetapentane citrate, pseudoephedrine hydrochloride, phenephrine hydrochloride, azatadine maleate, bromodiphenhydramine HCl, brompheniramine maleate, carbinoxamine maleate, cetirizine HCl, chlorcyclizine HCl, clemastine fumarate, chlorothen citrate, chlorpheniramine maleate, dimethindene maleate, diphenhydramine HCl, fexofenadine HCl, hydroxyine HCl, isothipendyl HCl (theruhistin), methapyrilene fumarate, methapyrilene HCl, montelukast sodium, phenindamine tartrate, pheniramine maleate, phenyltoloxamine citrate, promethazine hydrochloride, prophenpyridamine maleate, pyrilamine maleate, thenyldiamine HCl, trimeprazine tartrate, tripelennamine HCl and triprolidine HCl.

[0038] The dosage form of the present invention will usually provide a plasma concentration within the therapeutic range of the second drug over a period which is coextensive with (overlaps) at least about 70 %, more preferred at least about 80 %, e.g., at least about 90 %, at least about 95 %, or about 100 %, of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug. The term "therapeutic range" as used herein and in the appended claims refers to the range of drug levels (including active metabolite levels) within which most patients will experience a significant therapeutic effect (including alleviation of symptoms) without an undesirable degree of adverse reactions. It is noted that the term "coextensive with" does not exclude, but rather includes, cases where a part of the period over which the plasma concentration of the second drug (and/or active metabolites thereof) is within the therapeutic range is outside the period over which the plasma concentration of the first drug is within the therapeutic range. In other words, even if the corresponding period for the second drug is to overlap, for example, 70 % of the corresponding period of the first drug, a certain percentage (preferably not more than about 30 %, e.g., not more than about 20 %, not more than about 10 % or even not more than about 5 %) of the total period over which the plasma concentration of the second drug is within the therapeutic range may be outside the period over which the plasma concentration of the first drug is within the therapeutic range.

[0039] The period over which the therapeutic range of a particular drug may be provided in a given case depends, at least in part, on the plasma half-life of the drug and/or active metabolites thereof. The term "plasma half-life" as used herein and in the appended claims refers to the time required for the plasma drug concentration to decline by 50 %. The shorter the plasma half-life of a particular drug, the shorter will be the period within the therapeutic range of the drug which is provided by a single administered dose of the drug. In one preferred aspect of the dosage form of the present invention, the plasma half-life of the second drug will be shorter than the plasma half-life of the first drug by at least about 2 hours, e.g., by at least about 3 hours, by at least about 4 hours, by at least about 5 hours, by at least about 6 hours, by at least about 8 hours, or even by at least about 10 hours. [0040] A preferred, although non-limiting, embodiment of the dosage form of the present invention is a tablet, in particular, a bi-layered tablet. Non-limiting examples of other embodiments of the dosage form of the invention are capsules, pills, chewable tablets, suspensions, solutions, syrups, and suppositories.

[0041] The bi-layered tablet which forms one of the aspects of the present invention comprises two layers. The first layer comprises a first drug which is selected from decongestants, antitussives, expectorants, analgesics and antihistamines. The second layer comprises a second drug which is different from the first drug and is selected from decongestants, antitussives, expectorants, analgesics and antihistamines. Specific and non- limiting examples of such drugs are given above. Particularly for the treatment of conditions which are associated with thick tenacious mucus exudates it is preferred for the bi-layered tablet or any other dosage form of the present invention to be substantially antihistamine-free, i.e., neither the first nor the second drug comprise more than insignificant amounts of antihistamines or any other drugs which have a substantial drying action. [0042] The layers of the bi-layered tablet of the present invention may individually be immediate release layers or controlled release layers. The term "controlled release layer" as used herein and in the appended claims refers to any layer that is not an immediate release layer, i.e., does not release all of the active ingredients contained therein within a relatively short time (for example, within less than 1 hour, e.g., less than 0.5 hours, following ingestion of the dosage form). Accordingly, this term is a generic term which encompasses, e.g., sustained (extended) release layers, pulsed release layers, delayed release layers, and the like. Preferably, the controlled release layer releases the one or more drugs contained therein continuously or intermittently and, preferably, in approximately equal amounts per time unit (e.g., zero order release rate), over an extended period of time such as, e.g., at least about 2 hours, at least about 3 hours, at least about 4 hours, or at least about 6 hours. The desirable length of the time period of continuous or intermittent (e.g., pulsed) release depends, inter alia, on the plasma half-life of the drug and/or an active metabolite thereof. [0043] The first and second layers of the bi-layered tablet of the present invention will usually contain the first and second drugs in amounts which are commensurate with the intended duration of action but will not give rise to overdosing when present in the intended form (e.g., a particular pharmaceutically acceptable salt) and the intended release matrix (e.g., immediate release, controlled release, etc.). In this regard, it is noted that a drug may be present in both the first layer and the second layer (and any additional layer, if present), for example, in order to obtain an as fast as possible release and, thus action of the drug (e.g., by using an immediate release matrix) and to at the same time extend the duration of the action of the drug (e.g., by using a controlled release matrix that releases the drug at a lower rate and/or at a later time than the immediate release layer). In the following, preferred ranges of amounts of selected drugs for use in the bi-layered tablet and other dosage forms of the present invention are given for illustrative purposes only.

[0044] Promethazine: at least about 0.1 mg, e.g., at least about 5 mg, at least about 6 mg, at least about 8 mg, at least about 12 mg, or at least about 25 mg, but not more than about 90 mg, e.g., not more than about 75 mg, not more than about 70 mg, not more than about 60 mg, or not more than about 50 mg of promethazine hydrochloride, or an equivalent amount (on a molar basis) of promethazine and/or any other pharmaceutically acceptable salt thereof. [0045] Chlorpheniramine: at least about 0.1 mg, e.g., at least about 2 mg, or at least about 4 mg, but not more than about 16 mg, e.g., not more than about 12 mg of chlorpheniramine maleate, or an equivalent amount of chlorpheniramine and/or any other pharmaceutically acceptable salt thereof. [0046] Carbinoxamine: at least about 0.1 mg, e.g., at least about 6 mg, but not more than about 32 mg, e.g., not more than about 24 mg of carbinoxamine maleate, or an equivalent amount of carbinoxamine and/or any other pharmaceutically acceptable salt thereof.

[0047] Diphenhydramine: at least about 10 mg, e.g., at least about 15 mg, at least about 20 mg, at least about 40 mg, at least about 70 mg, or at least about 90 mg, but not more than about 200 mg, e.g., not more than about 150 mg, not more than about 120 mg, or not more than about 100 mg of diphenhydramine hydrochloride, or an equivalent amount of diphenhydramine and/or any other pharmaceutically acceptable salt thereof.

[0048] Carbetapentane: at least about 1 mg, e.g., at least about 5 mg, at least about 10 mg, at least about 25 mg, or at least about 50 mg, but not more than about 120 mg, e.g., not more than about 100 mg, not more than about 70 mg, or not more than about 60 mg, of carbetapentane citrate, or an equivalent amount of carbetapentane and/or any other pharmaceutically acceptable salt thereof.

[0049] Codeine: at least about 1 mg, e.g., at least about 10 mg, at least about 25 mg, or at least about 30 mg, but not more than about 120 mg, e.g., not more than about 80 mg, not more than about 60 mg, or not more than about 45 mg, of codeine phosphate, or an equivalent amount of codeine and/or any other pharmaceutically acceptable salt thereof.

[0050] Dihydrocodeine: at least about 1 mg, e.g., at least about 5 mg, but not more than about 30 mg, e.g., not more than about 20 mg, of dihydrocodeine bitartrate, or an equivalent amount of dihydrocodeine and/or any other pharmaceutically acceptable salt thereof.

[0051] Hydrocodone: at least about 1 mg, e.g., at least about 5 mg, but not more than about

20 mg, e.g., not more than about 15 mg, of hydrocodone bitartrate, or an equivalent amount of hydrocodone and/or any other pharmaceutically acceptable salt thereof.

[0052] Phenylepherine: at least about 1 mg, e.g., at least about 10 mg, or at least about 15 mg, but not more than about 125 mg, e.g., not more than about 100 mg, not more than about

90 mg, not more than about 75 mg, not more than about 50 mg, or not more than about 25 mg of phenylephrine hydrochloride, or an equivalent amount of phenylephrine and/or any other pharmaceutically acceptable salt thereof.

[0053] Pseudoephedrine: at least about 1 mg, e.g., at least about 10 mg, at least about 25 mg, or at least about 50 mg, but not more than about 240 mg, e.g., not more than about 150 mg, not more than about 100 mg, or not more than about 70 mg of pseudoephedrine hydrochloride, or an equivalent amount of pseudoephedrine and/or any other pharmaceutically acceptable salt thereof. [0054] Guaifenesin: at least about 1 mg, e.g., at least about 10 mg, at least about 25 mg, at least about 50 mg, or at least about 100 mg, but not more than about 2400 mg, e.g., not more than about 1600 mg, not more than about 1500 mg, not more than about 1200 mg, not more than about 1000 mg, not more than about 600 mg, or not more than about 500 mg of guaifenesin, or an equivalent amount of a pharmaceutically acceptable salt thereof. [0055] Acetaminophen: at least about 10 mg, e.g., at least about 50 mg, or at least about 100 mg, but not more than about 1000 mg, e.g., not more than about 500 mg, or not more than about 250 mg of acetaminophen.

[0056] Another aspect of the present invention is a multi-layered tablet which comprises at least a first layer and a second layer, but may optionally comprise a third, fourth, fifth, etc. layer. The first layer may be an immediate release layer or a controlled release layer, depending on the drug(s) contained therein and the desired release characteristics thereof, and comprises at least one first drug which is selected from decongestants, antitussives, expectorants, analgesics and antihistamines. The mandatory second layer may also be an immediate release layer or a controlled release layer, depending on the drug(s) contained therein and the desired release characteristics thereof, and comprises at least one second drug which is different from the first drug and is selected from decongestants, antitussives, expectorants, analgesics and antihistamines. If more than two drugs are to be incorporated in the tablet, the first and/or the second layer may contain all of the additional drugs. Alternatively, separate additional layers may be provided for the additional drugs, for example, in cases where it would be difficult to design a controlled release layer which provides a desired release rate for both the first or second drug and/or the additional drug(s). Of course, a fourth, fifth, etc. layer may be provided for, e.g., a third or fourth additional drug, and so on. Alternatively and by way of non-limiting example, the second and a third layer may contain the same drug or drugs, but in different (relative) concentrations and/or incorporated in a different controlled release formulation.

[0057] The multi-layered tablet of the present invention will usually be made up of two or more distinct layers or discrete zones of granulation compressed together with the individual layers lying on top of one another. Layered tablets have the appearance of a sandwich because the edges of each layer or zone are exposed. Such conventional layered tablets are generally prepared by compressing a granulation onto a previously compressed granulation. The operation may be repeated to produce multi-layered tablets of more than two layers. In a preferred embodiment of the multi-layered tablet of the present invention, the tablet consists of two layers. [0058] It is to be noted that it is not necessary for the two or more individual layers of the multi-layered tablet of the present invention to lie on top of one another. By way of non- limiting example, a second layer (e.g., sustained release layer) may be partially or completely surrounded by a first layer (e.g., an immediate release layer). For example, the second layer may be coated with the first layer. In the case of three layers, for example, the third layer may be partially or completely coated with the second layer, which in turn may be partially or completely coated with the first layer. Of course, these are but a few examples of the many different ways in which the various layers of the multi-layered tablet of the present invention can be arranged relative to each other. Moreover, it is to be understood that the tablets of the present invention are not limited to such multi-layered tablets. By way of non-limiting example, the tablet may comprise an immediate release matrix which comprises one or more first drugs, which matrix has dispersed therein particles of one or more sustained release formulations which have the one or more second drugs and any of the additional desired drug(s) incorporated therein.

[0059] In another aspect of the multi-layered tablet, the at least one drug in the second layer (and/or in the additional layers) may have a plasma half-life which is shorter by at least about 3 hours, e.g., shorter by at least about 4 hours, or shorter by at least about 6 hours, than the plasma half-life of the first drug or the first drug with the longest plasma half-life, respectively.

[0060] In another aspect of the multi-layered tablet, the tablet may provide a plasma concentration within a therapeutic range of the drug(s) in the second layer over a period which is coextensive with at least about 80 %, e.g., at least about 90 %, of the period over which the multi-layered tablet provides a plasma concentration within the therapeutic range of the drug(s) in the first layer.

[0061] Another aspect of the present invention is formed by a liquid dosage form, preferably a suspension, which comprises (a) a first drug which is selected from decongestants, expectorants, antitussives, analgesics and antihistamines and (b) a second drug which is selected from decongestants, expectorants, antitussives, analgesics and antihistamines and is different from the first drug. This liquid dosage form provides a plasma concentration within the therapeutic range of component (b) over a period which is coextensive with at least about 70 %, preferably at least 80 %, e.g., at least 90 %, of the period over which the liquid dosage form provides a plasma concentration within the therapeutic range of component (a). This may be accomplished in various ways. By way of non-limiting example, component (b) may be incorporated into a solid controlled release formulation. For example, particles of component (b) may be provided with a controlled release coating (e.g. a controlled release coating comprising an organic polymer such as, e.g., a polyacrylate). This formulation may then be comminuted, if necessary, in an appropriate manner (e.g., by milling) to form particles of a size which is small enough to be suitable for being suspended in a pharmaceutically acceptable liquid carrier. Component (a), on the other hand, may be used as such or incorporated in a solid immediate release formulation, comminuted and incorporated into the liquid carrier as well. A non-limiting example of a corresponding procedure is described in the Examples below.

[0062] Prior to incorporating components (a) and (b) into a pharmaceutically acceptable liquid carrier to form a liquid dosage form according to the present invention, at least a part of component (a) and/or at least a part of component (b) may be converted into a complex with a complexing agent. Non-limiting examples of suitable complexing agents comprise ion- exchange resins such as, e.g., (sodium) polystyrene sulfonate.

[0063] The dosage forms of the present invention can be manufactured by processes which are well known to those of skill in the art. For example, for the manufacture of bi-layered tablets, the active ingredients may be dispersed uniformly into a mixture of excipients, for example, by high shear granulation, low shear granulation, fluid bed granulation, or by blending for direct compression. Excipients may include diluents, binders, disintegrants, dispersants, lubricants, glidants, stabilizers, surfactants and colorants. Diluents, also termed "fillers", are typically used to increase the bulk of a tablet so that a practical size is provided for compression. Non-limiting examples of diluents include lactose, cellulose, microcrystalline cellulose, mannitol, dry starch, hydrolyzed starches, powdered sugar, talc, sodium chloride, silicon dioxide, titanium oxide, dicalcium phosphate dihydrate, calcium sulfate, calcium carbonate, alumina and kaolin. Binders impart cohesive qualities to a tablet formulation and are used to ensure that a tablet remains intact after compression. Non-limiting examples of suitable binders include starch (including corn starch and pregelatinized starch), gelatin, sugars (e.g., glucose, dextrose, sucrose, lactose and sorbitol), celluloses, polyethylene glycol, waxes, natural and synthetic gums, e.g., acacia, tragacanth, sodium alginate, and synthetic polymers such as polymethacrylates and polyvinylpyrrolidone. Lubricants facilitate tablet manufacture; non-limiting examples thereof include magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and polyethylene glycol. Disintegrants facilitate tablet disintegration after administration, and non-limiting examples thereof include starches, alginic acid, crosslinked polymers such as, e.g., crosslinked polyvinylpyrrolidone, croscarmellose sodium, potassium or sodium starch glycolate, clays, celluloses, starches, gums and the like. Non-limiting examples of suitable glidants include silicon dioxide, talc and the like. Stabilizers inhibit or retard drug decomposition reactions, including oxidative reactions. Surfactants may be anionic, cationic, amphoteric or nonionic. If desired, the tablets may also contain minor amounts of nontoxic auxiliary substances such as pH buffering agents, preservatives, e.g., antioxidants, wetting or emulsifying agents, solubilizing agents, coating agents, flavoring agents, and the like.

[0064] Extended/sustained release formulations may be made by choosing the right combination of excipients that slow the release of the active ingredients by coating or temporarily bonding or decreasing the solubility of the active ingredients. Examples of these excipients include cellulose ethers such as hydroxypropylmethylcellulose (e.g., Methocel K4M), polyvinylacetate-based excipients such as, e.g., Kollidon SR, and polymers and copolymers based on methacrylates and methacrylic acid such as, e.g., Eudragit NE 3OD. [0065] There are several commercially available tablet presses capable of making bi-layered tablets. For example, Manesty RotaPress Diamond, a 45 station D tooling press, is capable of making bi-layered tablets described in this application. Non-limiting examples of presses for the manufacture of bi-layered tablets include Fette America Model No. PT 3090; Maneklal Global Exports (Mumbai, India) Models JD and DH series; Niro Pharma Systems, Model R292F; and Korsch AG Models XL 800 and XL 400.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0066] The particulars shown herein are by way of example and for purposes of illustrative discussion of the embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the present invention. In this regard, no attempt is made to show details of the present invention in more detail than is necessary for the fundamental understanding of the present invention, the description making apparent to those skilled in the art how the several forms of the present invention may be embodied in practice.

Example 1: Liquid Formula:

[0067] A liquid dosage form in accordance with the present invention which comprises promethazine hydrochloride, dihydrocodeine bitartrate and phenylephrine hydrochloride is illustrated as follows: Ingredients . Per 5 mL Per 425 L

Promethazine Hydrochloride USP 12.5 mg 1.063 kg

Dihydrocodeine Bitartrate USP 10.0 mg 0.850 kg

Phenylephrine Hydrochloride USP 10.0 mg 0.850 kg

Methyl Paraben USP 9.0 mg 0.765 kg

Propyl Paraben USP 1.0 mg 0.085 kg

Propylene Glycol USP 259 mg 22.016 kg

Saccharin Sodium USP 3.18 mg 0.270 kg

Citric Acid USP 5.0 mg 0.425 kg

Strawberry Flavor 10 mg 0.850 kg

Banana Flavor 10 mg 0.850 kg

Sorbitol Solution 70% USP 3212.5 mg 273.1 kg

Purified Water, as required to q.s. to 5.O mL 425 L

[0068] Manufacturing process for 425 L batch size: In a suitably sized stainless steel vessel, dissolve methyl paraben and propyl paraben in approximately 50L of warm (about 45 ⁰C), purified water. Add about half of the propylene glycol and mix for about 1 hr. In a separate 1000 L stainless steel tank equipped with a suitably sized agitator, add about 50 L of purified water. With the agitator on, add phenylephrine hydrochloride, promethazine hydrochloride, saccharin sodium and citric acid and dissolve.Add the previously prepared paraben/propylene glycol solution to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinsate to the 1000 L tank. Add the remaining propylene glycol to a suitably sized stainless steel vessel and dissolve the strawberry and banana flavors. Transfer this to the 1000 L tank. Rinse the container with 2 L of purified water and transfer to the 1000 L tank. With the agitator on, add the sorbitol solution 70% to the 1000 L tank. In a suitably sized stainless steel vessel, dissolve the dihydrocodeine bitartrate in about 5 L of purified water and transfer to the 1000 L tank. Rinse the container with about 2 L of purified water and transfer to the 1000 L tank. Stop the agitator and let the solution stand for 15 minutes. QS to 425 L with purified water. Filter product through a 1 micron filter and fill in appropriately sized containers.

[0069] To make products with other antihistamines, decongestants, antitussives, or expectorants, one or more combinations of each of the ingredients in a range as described in Table 1 below can be made depending on the specific therapeutic effect desired. Example 2: Suspension Formula

[0070] A suspension formula in accordance with the present invention which comprises promethazine hydrochloride and phenylephrine tannate is illustrated as follows:

Ingredients g/100mL kg/batch

=120 g =1000 kg

Promethazine Hydrochloride 0.500 4.167

Phenylepherine Tannate 0.800 6.667

Silica, colloidal anhydrous, NF 1.73 14.417

Hydroxyethylcellulose, NF 0.05 0.417

Sorbitol Solution 70% (non-crystallizing), NF 34.00 283.333

Glycerol 14.75 122.917

Xylitol, NF 16.00 133.333

Sodium Citrate, USP 2.00 16.667

Saccharin Sodium cryst, USP, 0.01 0.083

Sodium Benzoate, NF 0.15 1.250

Citric Acid Monohydrate, USP 0.16 1.333

Strawberry Flavor 0.15 1.250

Banana Flavor 0.15 1.250

Purified Water 49.55 412.917

Total Amount 120.000 g 1000.000 kg

[0071] Manufacturing process for 1000 kg batch: In a suitably sized stainless steel vessel, dissolve saccharin sodium, sodium benzoate, citric acid, and sodium citrate in approximately 50L of warm (about 45 deg C), purified water. In another large stainless steel drum mix the silica, promethazine hydrochloride and micronized phenylephrine tannate until a uniform and consistent mixture is obtained. In a separate 1000 L stainless steel tank equipped with a suitably sized homogenizer/disperser add about 100 L of purified water. With the homogenizer on, add the silica mixture containing phenylephrine tannate and promethazine hydrochloride. Add the previously prepared solution of saccharin sodium, sodium benzoate, citric acid, and sodium citrate to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinsate to the 1000 L tank. Add the remaining ingredients and homogenize for 15 minutes. Filter product through a 10 micron filter and fill in appropriately sized containers.

[0072] To make products with other antihistamines, decongestants, antitussives, or expectorants, one or more combinations of each of the ingredients in a range as described in Table 1 below can be made depending on the specific therapeutic effect desired.

Example 3: Bi-layered Tablet (Direct Compression)

[0073] A bi-layered tablet in accordance with the present invention which comprises promethazine hydrochloride in one layer and phenylephrine hydrochloride and chlorpheniramine maleate in the other layer is illustrated as follows:

Manufacturing process

[0074] (a) Immediate release layer: Screen all ingredients through a USP sieve size # 30.

Blend promethazine hydrochloride (45.5 gms), silicified microcrystalline cellulose (207.3 gms) and sodium starch glycolate (18.2 gms) in a twin shell blender for 20 minutes. Add magnesium stearate (1.8 gms), which acts as a lubricant, to the above blend and mix for 3 minutes.

[0075] (b) Sustained release layer: Screen all ingredients through a USP sieve size # 30.

Preblend a portion of the Kollidon SR (145 gms) and all the chlorpheniramine maleate (14.5 gms) for 15 minutes. Add the remaining Kollidon SR (313.2 gms), phenylephrine hydrochloride (36.4 gms), lactose monohydrate (90.9 gms) and dicalcium phosphate (90.9 gms) to the above preblend and mix for an additional 20 minutes. Add stearic acid (27.3 gms) and magnesium stearate (9.1 gms) to the above blend and mix for three minutes.

[0076] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet the immediate release layer is 150 mgs and the sustained release layer is 400 mgs.

[0077] By using the process described above, a bi-layered tablet of the following composition may be manufactured by using direct compression:

Example 4: Bi-layered Tablet (Wet Granulation):

[0078] A bi-layered tablet in accordance with the present invention which comprises promethazine hydrochloride in one layer and pseudoephedrine hydrochloride and chlorpheniramine maleate in the other layer is illustrated as follows:

Manufacturing process

[0079] (a) Immediate release layer: Screen all ingredients through a USP sieve size # 30. Blend promethazine hydrochloride (35.7 gms), silicified microcrystalline cellulose (158.6 gms) and croscarmellose sodium (14.3 gms) in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (4.3 gms povidone in 14.3 gms purified water). Dry the granulation until the loss on drying (LOD) is less than 2.0 %. Screen the dried granulation through a USP sieve size # 14. Add the screened granulation and the prescreened magnesium stearate (1.4 gms) to the above blend and mix for 3 minutes. [0080] (b) Sustained release layer: Screen all ingredients through a USP sieve size # 30. Blend the pseudoephedrine hydrochloride (87.5 gms), chlorpheniramine maleate (11.4 gms), microcrystalline cellulose PH 102 (42.9 gms), lactose monohydrate (142.9 gms), dicalcium phosphate (142.9gms), Methocel K4M Premium (302.9 gms) and stearic acid (28.6 gms) in a high shear mixer/granulator for 10 minutes.Granulate the above blend using a 30 % povidone solution (21.4 gms povidone in 71.3 gms purified water). Dry the granulation till the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add granules and the prescreened magnesium stearate (7.1 gms) to the above blend and mix for 3 minutes. [0081] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet the immediate release layer is 150 mgs and the sustained release layer is 550 nigs. [0082] By using the process described above, a bi-layered tablet of the following composition may be manufactured by using wet granulation:

[0083] The above examples illustrate how to manufacture a bi-layered tablet containing an antihistamine, i.e., promethazine hydrochloride, in one layer and an antihistamine and/or a decongestant and/or an antitussive and/or an expectorant in the other layer. For the layer that does not contain promethazine hydrochloride, combinations of one or more of each of the non-limiting examples of possible ingredients in an exemplary range as described in the following Table 1 can be made depending on the specific therapeutic effect desired.

Table 1

Example 5: Extended Release Suspension

[0084] The formula described above serves as a non-limiting example. Any active drug which is in the form of a salt, such as promethazine hydrochloride, codeine phosphate, pseudoephedrine hydrochloride, morphine sulfate, or meperidine hydrochloride can be incorporated as an ion-exchange resin complex.

Procedure:

[0085] (1) Add the appropriate amount of sodium polystyrene sulphonate USP (e.g. Amberlite® IRP 69) to a hydrocodone bitartarate, dexchlorpheniramine maleate and phenylephrine HCl solution.

(2) Stir the mix for 12 hrs to allow complete drug/resin complex formation.

(3) Separate and dry the insoluble drug/resin complex.

(4) Granulate the drug/resin complex with a delayed release/enteric polymer (e.g. Eugragit® L 100, Kollidon® MAE, Aquacoa®t cPD) and dry the granules.

(5) Mill the granules, if needed.

(6) To an appropriate amount of water add the following ingredients and dissolve: Carbomer (e.g., Carbopol® 974), glycerin, polysorbate 80, methyl paraben, propyl paraben, artificial grape flavor, FD&C red # 40 dye.

(7) Add milled granules.

(8) Add water to make up to a final volume.

(9) Agitate at suitable rate to avoid settling of the suspension and maintain a homogeneous product mixture.

(10) Fill in suitable containers ensuring that the product is homogeneous throughout the filling operation. Example 6: Bi-layered Tablet (Wet Granulation)

[0086] A bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and codeine phosphate and pseudoephedrine hydrochloride in a second sustained release layer is illustrated as follows:

Procedure:

[0087] (a) Sustained release layer #1: Mix the guaifenesin, Methocel®K15M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD (weight loss on drying) is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0088] (b) Sustained release layer #2: Screen all ingredients through a USP sieve size # 30. Mix the codeine phosphate, pseudoephedrine HCl, microcrystalline cellulose PH 102, and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0089] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 800 mgs and layer #2 is 375 mgs. Capsules may be manufactured by filling the same proportions into capsules.

Example 7: Bi-layered Tablet (Wet Granulation)

[0090] A bi-layered tablet in accordance with the present invention which comprises promethazine hydrochloride in an immediate release layer and codeine phosphate and pseudoephedrine hydrochloride in a sustained release layer is illustrated as follows:

Procedure:

[0091] (a) Immediate release layer #1: Mix the promethazine HCl, silicified microcrystalline cellulose and croscarmellose sodium, in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (3.0 gms povidone in 10.0 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0092] (b) Sustained release layer #2: Mix the codeine phosphate, pseudoephedrine HCl, microcrystalline cellulose PH 102, dicalcium phosphate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (15.0 gms povidone in 50.0 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0093] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 150 mgs and layer #2 is 525 mgs. Capsules may be manufactured by filling the same proportions into capsules. Example 8: Bi-layered Tablet (Wet Granulation)

[0094] A bi-layered tablet in accordance with the present invention which comprises phenylephrine hydrochloride and carbinoxamine maleate in a first sustained release layer and codeine phosphate in a second sustained release layer is illustrated as follows:

Procedure:

[0095] (a) Sustained release layer #1: Mix the phenylephrine HCl, carbinoxamine maleate, Methocel®K4M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0096] (b) Sustained release layer #2: Screen all ingredients through a USP sieve size # 30. Mix the codeine phosphate, microcrystalline cellulose PH 102, and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0097] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 190 mgs and layer #2 is 215 mgs. Capsules may be manufactured by filling the same proportions into capsules.

Example 9: Bi-layered Tablet (Wet Granulation)

[0098] A bi-layered tablet in accordance with the present invention which comprises pseudoephedrine hydrochloride and chlorpheniramine maleate in a first sustained release layer and codeine phosphate in a second sustained release layer is illustrated as follows:

Procedure:

[0099] (a) Sustained release layer #1: Mix the pseudoephedrine HCl, chlorpheniramine maleate, Methocel®K4M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0100] (b) Sustained release layer #2: Screen all ingredients through a USP sieve size # 30. Mix the codeine phosphate, microcrystalline cellulose PH 102, and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0101] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 260 mgs and layer #2 is 215 mgs. Capsules may be manufactured by filling the same proportions into capsules.

Example 10: Bi-layered Tablet (Wet Granulation)

[0102] A bi-layered tablet in accordance with the present invention which comprises carbinoxamine maleate in a first sustained release layer and codeine phosphate in a second sustained release layer is illustrated as follows:

Procedure:

[0103] (a) Sustained release layer #1: Mix the carbinoxamine maleate, Methocel®K4M, lactose monohydrate and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0104] (b) Sustained release layer #2: Screen all ingredients through a USP sieve size # 30. Mix the codeine phosphate, microcrystalline cellulose PH 102, and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0105] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 200 mgs and layer #2 is 215 mgs. Capsules may be manufactured by filling the same proportions into capsules.

Example 11: Bi-layered Tablet (Direct Compression)

[0106] A bi-layered tablet in accordance with the present invention which comprises promethazine hydrochloride (longer half-life drug) in an immediate release layer and codeine phosphate (shorter half-life drug) in a sustained release layer is illustrated as follows:

Procedure:

[0107] (a) Immediate release layer #1: Screen all ingredients through a USP sieve size # 30.

Blend the promethazine hydrochloride, microcrystalline cellulose and sodium starch glycolate for 20 minutes. Add magnesium stearate to the above blend and mix for an additional time of three minutes.

[0108] (b) Sustained release layer #2: Blend the codeine phosphate, lactose monohydrate, dicalcium phosphate and Kollidon® SR for 20 minutes. Add stearic acid and magnesium stearate to the above blend and mix for an additional time of three minutes.

[0109] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet the immediate release layer #1 is 150 mgs and the sustained release layer #2 is 400 mgs.

Capsules may be manufactured by filling the same proportions into capsules.

Example 12: Bi-layered Tablet (Wet Granulation):

[0110] A bi-layered tablet in accordance with the present invention which comprises pseudoephedrine tannate and chlorpheniramine tannate in an immediate release layer and codeine phosphate in a sustained release layer is illustrated as follows:

Procedure:

[0111] (a) Immediate release layer #1: Mix the pseudoephedrine tannate, chlorpheniramine tannate, silicified microcrystalline cellulose and croscarmellose sodium, in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution

(3.0 gms povidone in 10.0 gms purified water). Dry the granulation until the LOD is less than

2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0112] (b) Sustained release layer #2: Mix the codeine phosphate, microcrystalline cellulose

PH 102, lactose monohydrate, dicalcium phosphate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (15.0 gms povidone in 50.0 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0113] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 190 mgs and layer #2 is 510 mgs. Capsules may be manufactured by filling the same proportions into capsules.

Example 13: Bi-layered Tablet (Wet Granulation):

[0114] A bi-layered tablet in accordance with the present invention which comprises promethazine hydrochloride in an immediate release layer and codeine phosphate and phenylephrine hydrochloride in a sustained release layer is illustrated as follows:

Procedure:

[0115] (a) Immediate release layer #1: Mix the promethazine hydrochloride, silicified microcrystalline cellulose and croscarmellose sodium, in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (3.0 gms povidone in

10.0 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0116] (b) Sustained release layer #2: Mix the codeine phosphate, phenylephrine HCl, microcrystalline cellulose PH 102, dicalcium phosphate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (15.0 gms povidone in 50.0 grns purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0117] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 125 mgs and layer #2 is 325 mgs. Capsules may be manufactured by filling the same proportions into capsules.

Example 14: Bi-layered Tablet (Direct Compression)

[0118] A bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and codeine phosphate in a second sustained release layer is illustrated as follows:

Procedure:

[0119] (a) Sustained release layer #1: Screen all ingredients through a USP sieve size # 30.

Blend the guaifenesin, Methocel® Kl 5M and silicified microcrystalline cellulose for 25 minutes. Add magnesium stearate to the above blend and mix for an additional time of three minutes.

[0120] (b) Sustained release layer #2: Blend the codeine phosphate, lactose monohydrate, dicalcium phosphate and Kollidon® SR for 20 minutes. Add stearic acid and magnesium stearate to the above blend and mix for an additional time of three minutes.

[0121] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 880 mgs and layer #2 is 320 mgs. Capsules may be manufactured by filling the same proportions into capsules.

Example 15: Bi-layered Tablet (Wet Granulation)

[0122] A bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and codeine phosphate and phenylephrine hydrochloride in a second sustained release layer is illustrated as follows:

Procedure:

[0123] (a) Sustained release layer #1: Mix the guaifenesin, Methocel®K15M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0124] (b) Sustained release layer #2: Screen all ingredients through a USP sieve size # 30. Mix the codeine phosphate, phenylephrine HCl, microcrystalline cellulose PH 102, dicalcium phosphate and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Add the Methocel® K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0%. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0125] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 800 mgs and layer #2 is 275 mgs. Capsules may be manufactured by filling the same proportions into capsules.

Example 16: Bi-layered Tablet (Wet Granulation)

A bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and codeine phosphate and phenylephrine hydrochloride in a second sustained release layer is illustrated as follows:

Procedure:

[0126] (a) Sustained release layer #1: Mix the guaifenesin, Methocel®K15M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0127] (b) Sustained release layer #2: Screen all ingredients through a USP sieve size # 30. Mix the codeine phosphate, phenylephrine HCl, microcrystalline cellulose PH 102, dicalcium phosphate and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0128] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 1300 mgs and layer #2 is 275 mgs. Capsules may be manufactured by filling the same proportions into capsules.

Example 17: Bi-layered Tablet (Direct Compression)

[0129] A bi-layered tablet in accordance with the present invention which comprises codeine phosphate in a first sustained release layer and phenylephrine hydrochloride and chlorpheniramine maleate in a second sustained release layer is illustrated as follows:

Procedure:

[0130] (a) Sustained release Layer #1: Screen all ingredients through a USP sieve size # 30.

Preblend a portion of the Kollidon SR (145 gms) and all the codeine phosphate for 15 minutes. Add lactose monohydrate (90.9 gms) and dicalcium phosphate (90.9 gms) to the above preblend and mix for an additional 20 minutes. Add stearic acid (27.3 gms) and magnesium stearate (9.1 gms) to the above blend and mix for three minutes.

[0131] (b) Sustained release layer #2: Screen all ingredients through a USP sieve size # 30.

[0132] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet the immediate release layer is 150 mgs and the sustained release layer is 400 mgs.

Example 18: Bi-layered Tablet (Direct Compression)

[0133] By using the process described in Example 17, a bi-layered tablet which contains codeine phosphate in an immediate release layer and codeine phosphate, phenylephrine hydrochloride and chlorpheniramine maleate in a sustained release layer may be manufactured by using direct compression:

Example 19: Bi-layered Tablet (Wet Granulation)

[0134] A bi-layered tablet in accordance with the present invention which comprises codeine phosphate in an immediate release layer and codeine phosphate, pseudoephedrine hydrochloride and chlorpheniramine maleate in a sustained release layer is illustrated as follows:

Procedure:

[0135] (a) Immediate release layer #1 : Screen all ingredients through a USP sieve size # 30. Blend the codeine phosphate (11.9 grams), silicified microcrystalline cellulose (158.6 grams), and croscarmellose sodium in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (4.3 gms povidone in 14.3 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add granules and the prescreened magnesium stearate (1.4 gms) to the above blend and mix for 3 minutes.

[0136] (b) Sustained release layer #2: Screen all ingredients through a USP sieve size # 30. Blend the pseudoephedrine hydrochloride (87.5 gms), chlorpheniramine maleate (11.4 gms), codeine phosphate (37.5 gms), microcrystalline cellulose PH 102 (42.9 gms), lactose monohydrate (142.9 gms), dicalcium phosphate (142.9gms), Methocel K4M Premium (302.9 gms) and stearic acid (28.6 gms) in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (21.4 gms povidone in 71.3 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add granules and the prescreened magnesium stearate (7.1 gms) to the above blend and mix for 3 minutes.

[0137] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet the immediate release layer is 150 mgs and the sustained release layer is 550 mgs.

Example 20: Bi-layered Tablet (Wet Granulation)

[0138] By using the process described in Example 19, a bi-layered tablet containing codeine phosphate in an immediate release layer and pseudoephedrine hydrochloride and chlorpheniramine maleate in a sustained release layer may be manufactured by using wet granulation:

[0139] The above examples 6-20 illustrate how to manufacture a bi-layered tablet containing an antitussive, i.e., codeine phosphate in (at least) a first layer and an antihistamine and/or a decongestant and/or an expectorant in (at least) a second layer. Non-limiting examples of possible active ingredients (in addition to the antitussive morphine derivative) in an exemplary range as described in the above Table 1 can be employed depending on the specific therapeutic effect desired. Example 21: Extended Release Suspension (Gel)

[0140] An extended release suspension (in the form of a gel) in accordance with the present invention which contains a codeine phosphate ion-exchange complex and promethazine hydrochloride is illustrated as follows (note that the codeine phosphate is used in a controlled release form since it has a shorter half-life than the promethazine hydrochloride):

Procedure:

[0141] (1) Add the appropriate amount of sodium polystyrene sulphonate USP (e.g.

Amberlite® IRP 69) to a codeine phosphate solution.

(2) Stir the mix for 12 hrs to allow complete drug/resin complex formation.

(3) Separate and dry the insoluble drug/resin complex.

(4) Granulate the drug/resin complex with a delayed release/enteric polymer (e.g. Eudragit® L 100, Kollidon® MAE, Aquacoat® cPD) and dry the granules.

(5) Mill the granules, if needed.

(6) To an appropriate amount of water add the following ingredients and dissolve: promethazine hydrochloride, Carbomer (e.g., Carbopol® 974), glycerin, polysorbate 80, methyl paraben, propyl paraben, artificial grape flavor, FD&C red # 40 dye. (7) Add milled granules.

(8) Add water to 95 % of final volume.

(10) Neutralize the solution to form a gel using a IN sodium hydroxide solution. Add water to make final volume.

(11) Fill in suitable containers ensuring that the product is homogeneous throughout the filling operation.

Example 22: Extended Release Suspension (Liquid)

[0142] An extended release suspension (in the form of a liquid) in accordance with the present invention which contains a codeine phosphate ion-exchange complex and promethazine hydrochloride is illustrated as follows:

Manufacturing process for 1000 L batch:

[0143] Add the appropriate amount of sodium polystyrene sulphonate USP (e.g.

Amberlite® IRP 69) to a codeine phosphate solution. Stir the mix for 12 hrs to allow complete drug/resin complex formation. Separate and dry the insoluble drug/resin complex. Granulate the drug/resin complex with a delayed release/enteric polymer (e.g. Eudragit® L 100, Kollidon® MAE, Aquacoat® CPD) and dry the granules. Mill the granules, if needed. [0144] In a suitably sized stainless steel vessel, dissolve saccharin sodium, sodium benzoate, citric acid, and sodium citrate in approximately 5OL of warm (about 45 ⁰C), purified water. In another large stainless steel drum mix the silica, codeine phosphate ion-exchange complex, and promethazine hydrochloride until a uniform and consistent mixture is obtained. In a separate 1000 L stainless steel tank equipped with a suitably sized homogenizer/disperser add about 100 L of purified water. With the homogenizer on, add the silica mixture containing codeine phosphate ion-exchange complex, and promethazine hydrochloride. Add the previously prepared solution of saccharin sodium, sodium benzoate, citric acid, and sodium citrate to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinsate to the 1000 L tank. Add the remaining ingredients and homogenize for 15 minutes.

Example 23: Extended Release Suspension (Liquid)

[0145] An extended release suspension (in the form of a liquid) in accordance with the present invention which contains a codeine phosphate ion-exchange complex, pseudoephedrine tannate and chlorpheniramine tannate is illustrated as follows:

Manufacturing process for 1000 kg batch:

[0146] Add the appropriate amount of sodium polystyrene sulphonate USP (e.g. Amberlite® IRP 69) to a codeine phosphate solution. Stir the mix for 12 hrs to allow complete drug/resin complex formation. Separate and dry the insoluble drug/resin complex. Granulate the drug/resin complex with a delayed release/enteric polymer (e.g. Eudragit® L 100, Kollidon® MAE, Aquacoat® CPD) and dry the granules. Mill the granules, if needed. [0147] In a suitably sized stainless steel vessel, dissolve saccharin sodium, sodium benzoate, citric acid, and sodium citrate in approximately 5OL of warm (about 45 ⁰C), purified water. In another large stainless steel drum mix the silica, codeine phosphate ion-exchange complex, pseudoephedrine tannate, and the chlorpheniramine tannate until a uniform and consistent mixture is obtained. In a separate 1000 L stainless steel tank equipped with a suitably sized homogenizer/disperser add about 100 L of purified water. With the homogenizer on, add the silica mixture containing codeine phosphate ion-exchange complex, pseudoephedrine tannate, and the chlorpheniramine tannate. Add the previously prepared solution of saccharin sodium, sodium benzoate, citric acid, and sodium citrate to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinsate to the 1000 L tank. Add the remaining ingredients and homogenize for 15 minutes.

Example 24: Extended Release Suspension

[0148] An extended release suspension which contains a hydrocodone bitartrate ion- exchange complex, a dexchlorpheniramine maleate ion-exchange complex and a phenylephrine hydrochloride ion-exchange complex is illustrated as follows:

[0149] The formula described above serves as a non-limiting example. Any active drug which is in the form of a salt, such as codeine, or dihydrocodeine, or hydrocodone can be incorporated as an ion-exchange resin complex.

Procedure:

[0150] (1) Add the appropriate amount of sodium polystyrene sulphonate USP (e.g. Amberlite® IRP 69) to a codeine phosphate, dexchlorpheniramine maleate and phenylephrine HCl solution.

(2) Stir the mix for 12 hrs to allow complete drug/resin complex formation.

(3) Separate and dry the insoluble drug/resin complex.

(5) Mill the granules, if needed.

(7) Add milled granules.

(8) Add water to make up to a final volume.

(9) Agitate at suitable rate to avoid settling of the suspension and maintain a homogeneous product mixture. (10) Fill in suitable containers ensuring that the product is homogeneous throughout the filling operation.

Example 25: Suspension Formula

[0151] A suspension formula which comprises codeine phosphate and phenylephrine tannate is illustrated as follows:

Ingredients g/100mL kg/batch

=120 g =1000 kg

Codeine Phosphate 0.500 4.167

Phenylephrine Tannate 0.800 6.667

Silica, colloidal anhydrous, NF 1.73 14.417

Hydroxyethylcellulose, NF 0.05 0.417

Sorbitol Solution 70% (non-crystallizing), NF 34.00 283.333

Glycerol 14.75 122.917

Xylitol, NF 16.00 133.333

Sodium Citrate, USP 2.00 16.667

Saccharin Sodium cryst, USP, 0.01 0.083

Sodium Benzoate, NF 0.15 1.250

Citric Acid Monohydrate, USP 0.16 1.333

Strawberry Flavor 0.15 1.250

Banana Flavor 0.15 1.250

Purified Water 49.55 412.917

Total Amount 120.000 g 1000.000 kg

Manufacturing process for 1000 kg batch:

[0152] In a suitably sized stainless steel vessel, dissolve saccharin sodium, sodium benzoate, citric acid, and sodium citrate in approximately 5OL of warm (about 45 ⁰C), purified water. In another large stainless steel drum mix the silica, codeine phosphate, and micronized phenylephrine tannate until a uniform and consistent mixture is obtained. In a separate 1000 L stainless steel tank equipped with a suitably sized homogenizer/disperser add about 100 L of purified water. With the homogenizer on, add the silica mixture containing phenylephrine tannate and codeine phosphate. Add the previously prepared solution of saccharin sodium, sodium benzoate, citric acid, and sodium citrate to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinsate to the 1000 L tank. Add the remaining ingredients and homogenize for 15 minutes. Filter product through a 10 micron filter and fill in appropriately sized containers.

[0153] To make products with other agents such as antihistamines, decongestants, or expectorants, one or more combinations of each of the ingredients in a range as described in Table 1 below can be made depending on the specific therapeutic effect desired.

Example 26: Liquid Formula:

[0154] A liquid dosage form which comprises codeine phosphate and phenylephrine hydrochloride is illustrated as follows:

Ingredients Per 5 mL Per 425 L

Codeine Phosphate USP 30 mg 2.550 kg

Phenylepherine Hydrochloride USP 10.0 mg 0.850 kg

Methyl Paraben USP 9.0 mg 0.765 kg

Propyl Paraben USP 1.0 mg 0.085 kg

Propylene Glycol USP 259 mg 22.016 kg

Saccharin Sodium USP 3.18 mg 0.270 kg

Citric Acid USP 5.0 mg 0.425 kg

Strawberry Flavor 10 mg 0.850 kg

Banana Flavor 10 mg 0.850 kg

Sorbitol Solution 70% USP 3212.5 mg 273.1 kg

Purified Water, as required to q.s. to 5.O mL 425 L

Manufacturing process for 425 L batch size:

[0155] In a suitably sized stainless steel vessel, dissolve methyl paraben and propyl paraben in approximately 5OL of warm (about 45 ⁰C), purified water. Add about half of the propylene glycol and mix for about 1 hr. In a separate 1000 L stainless steel tank equipped with a suitably sized agitator, add about 50 L of purified water. With the agitator on, add phenylephrine hydrochloride, codeine phosphate, saccharin sodium and citric acid and dissolve. Add the previously prepared paraben/propylene glycol solution to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinsate to the 1000 L tank. Add the remaining propylene glycol to a suitably sized stainless steel vessel and dissolve the strawberry and banana flavors. Transfer this to the 1000 L tank. Rinse the container with 2 L of purified water and transfer to the 1000 L tank. With the agitator on, add the sorbitol solution 70 % to the 1000 L tank. In a suitably sized stainless steel vessel, dissolve the codeine phosphate in about 5 L of purified water and transfer to the 1000 L tank. Rinse the container with about 2 L of purified water and transfer to the 1000 L tank. Stop the agitator and let the solution stand for 15 minutes. QS to 425 L with purified water. Filter product through a 1 micron filter and fill in appropriately sized containers.

[0156] To make products with other antihistamines, decongestants, or expectorants, one or more combinations of each of the ingredients in a range as described in Table 1 above can be made depending on the specific therapeutic effect desired.

Example 27: Bi-layered Tablet (Wet Granulation)

[0157] A bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and carbetapentane citrate and pseudoephedrine hydrochloride in a second sustained release layer is illustrated as follows:

Procedure:

[0158] (a) Sustained release layer #1: Mix the guaifenesin, Methocel®K15M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Dry the granulation until the LOD (weight loss on drying) is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0159] (b) Sustained release layer #2: Screen all ingredients through a USP sieve size # 30.

Mix the carbetapentane citrate, pseudoephedrine HCl, microcrystalline cellulose PH 102, and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0160] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 800 mgs and layer #2 is 375 mgs. Capsules may be manufactured by filling the same proportions into capsules.

Example 28: Bi-layered Tablet (Wet Granulation)

[0161] A bi-layered tablet in accordance with the present invention which comprises promethazine hydrochloride in an immediate release layer and carbetapentane citrate and pseudoephedrine hydrochloride in a sustained release layer is illustrated as follows:

Procedure:

[0162] (a) Immediate release layer #1: Mix the promethazine HCl, silicified microcrystalline cellulose and croscarmellose sodium, in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (3.0 gms povidone in 10.0 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0163] (b) Sustained release layer #2: Mix the carbetapentane citrate, pseudoephedrine HCl, microcrystalline cellulose PH 102, dicalcium phosphate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (15.0 gms povidone in 50.0 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0164] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 150 mgs and layer #2 is 525 mgs. Capsules may be manufactured by filling the same proportions into capsules.

Example 29: Bi-layered Tablet (Wet Granulation)

[0165] A bi-layered tablet in accordance with the present invention which comprises phenylephrine hydrochloride and carbinoxamine maleate in a first sustained release layer and carbetapentane citrate in a second sustained release layer is illustrated as follows:

Procedure:

[0166] (a) Sustained release layer #1: Mix the phenylephrine HCl, carbinoxamine maleate,

Methocel®K4M and silicified microcrystalline cellulose in a high shear mixer/granulator for

10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0167] (b) Sustained release layer #2: Screen all ingredients through a USP sieve size # 30.

Mix the carbetapentane citrate, microcrystalline cellulose PH 102, and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30

%). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14.

Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for

3 minutes.

[0168] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 190 mgs and layer #2 is 215 mgs. Capsules may be manufactured by filling the same proportions into capsules.

Example 30: Bi-layered Tablet (Wet Granulation)

[0169] A bi-layered tablet in accordance with the present invention which comprises pseudoephedrine hydrochloride and chlorpheniramine maleate in a first sustained release layer and carbetapentane citrate in a second sustained release layer is illustrated as follows:

Procedure:

[0170] (a) Sustained release layer #1: Mix the pseudoephedrine HCl, chlorpheniramine maleate, Methocel®K4M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0171] (b) Sustained release layer #2: Screen all ingredients through a USP sieve size # 30. Mix the carbetapentane citrate, microcrystalline cellulose PH 102, and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0172] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 260 mgs and layer #2 is 215 mgs. Capsules may be manufactured by filling the same proportions into capsules.

Example 31: Bi-layered Tablet (Wet Granulation)

[0173] A bi-layered tablet in accordance with the present invention which comprises carbinoxamine maleate in a first sustained release layer and carbetapentane citrate in a second sustained release layer is illustrated as follows:

Procedure:

[0174] (a) Sustained release layer #1: Mix the carbinoxamine maleate, Methocel®K4M, lactose monohydrate and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0175] (b) Sustained release layer #2: Screen all ingredients through a USP sieve size # 30. Mix the carbetapentane citrate, microcrystalline cellulose PH 102, and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0176] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 200 mgs and layer #2 is 215 mgs. Capsules may be manufactured by filling the same proportions into capsules.

Example 32: Bi-layered Tablet (Direct Compression)

[0177] A bi-layered tablet in accordance with the present invention which comprises promethazine hydrochloride (longer half-life drug) in an immediate release layer and carbetapentane citrate (shorter half-life drug) in a sustained release layer is illustrated as follows:

Procedure:

[0178] (a) Immediate release layer #1 : Screen all ingredients through a USP sieve size # 30.

[0179] (b) Sustained release layer #2: Blend the carbetapentane citrate, lactose monohydrate, dicalcium citrate and Kollidon® SR for 20 minutes. Add stearic acid and magnesium stearate to the above blend and mix for an additional time of three minutes.

[0180] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet the immediate release layer #1 is 150 mgs and the sustained release layer #2 is 400 mgs.

Capsules may be manufactured by filling the same proportions into capsules.

Example 33: Bi-layered Tablet (Wet Granulation):

[0181] A bi-layered tablet in accordance with the present invention which comprises pseudoephedrine tannate and chlorpheniramine tannate in an immediate release layer and carbetapentane tannate in a sustained release layer is illustrated as follows:

Procedure:

[0182] (a) Immediate release layer #1: Mix the pseudoephedrine tannate, chlorpheniramine tannate, silicified microcrystalline cellulose and croscarmellose sodium, in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (3.0 gms povidone in 10.0 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0183] (b) Sustained release layer #2: Mix the carbetapentane tannate, microcrystalline cellulose PH 102, lactose monohydrate, dicalcium phosphate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (15.0 gms povidone in 50.0 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0184] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 190 mgs and layer #2 is 510 mgs. Capsules may be manufactured by filling the same proportions into capsules.

Example 34: Bi-layered Tablet (Wet Granulation):

[0185] A bi-layered tablet in accordance with the present invention which comprises diphenhydramine hydrochloride in an immediate release layer and carbetapentane citrate and phenylephrine hydrochloride in a sustained release layer is illustrated as follows:

Procedure: [0186] (a) Immediate release layer #1: Mix the diphenhydramine hydrochloride, silicified microcrystalline cellulose and croscarmellose sodium in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (3.0 gms povidone in 10.0 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0187] (b) Sustained release layer #2: Mix the carbetapentane citrate, phenylephrine HCl, microcrystalline cellulose PH 102, dicalcium phosphate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (15.0 gms povidone in 50.0 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0188] Manufacture bi-layered tablets using a rotaiy bi-layer tablet press where in each tablet layer #1 is 125 mgs and layer #2 is 325 mgs. Capsules may be manufactured by filling the same proportions into capsules.

Example 35: Bi-layered Tablet (Direct Compression)

[0189] A bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and carbetapentane citrate in a second sustained release layer is illustrated as follows:

Procedure:

[0190] (a) Sustained release layer #1: Screen all ingredients through a USP sieve size # 30.

Blend the guaifenesin, Methocel® K15M and silicified microcrystalline cellulose for 25 minutes. Add magnesium stearate to the above blend and mix for an additional time of three minutes.

[0191] (b) Sustained release layer #2: Blend the carbetapentane citrate, lactose monohydrate, dicalcium citrate and Kollidon® SR for 20 minutes. Add stearic acid and magnesium stearate to the above blend and mix for an additional time of three minutes.

[0192] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 880 mgs and layer #2 is 320 mgs. Capsules may be manufactured by filling the same proportions into capsules.

Example 36: Bi-layered Tablet (Wet Granulation)

[0193] A bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and carbetapentane citrate and phenylephrine hydrochloride in a second sustained release layer is illustrated as follows:

Procedure:

[0194] (a) Sustained release layer #1: Mix the guaifenesin, Methocel®K15M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0195] (b) Sustained release layer #2: Screen all ingredients through a USP sieve size # 30. Mix the carbetapentane citrate, phenylephrine HCl, microcrystalline cellulose PH 102, dicalcium phosphate and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0%. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0196] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 800 mgs and layer #2 is 275 mgs. Capsules may be manufactured by filling the same proportions into capsules. Example 37: Bi-layered Tablet (Wet Granulation)

[0197] A bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and carbetapentane citrate and phenylephrine hydrochloride in a second sustained release layer is illustrated as follows:

Procedure:

[0198] (a) Sustained release layer #1: Mix the guaifenesin, Methocel®K15M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0199] (b) Sustained release layer #2: Screen all ingredients through a USP sieve size # 30. Mix the carbetapentane citrate, phenylephrine HCl, macrocrystalline cellulose PH 102, dicalcium phospate and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0200] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 1300 mgs and layer #2 is 300 mgs. Capsules may be manufactured by filling the same proportions into capsules.

Example 38: Bi-layered Tablet (Direct Compression)

[0201] By using the process described in Example 37, a bi-layered tablet which contains carbetapentane citrate in an immediate release layer and carbetapentane citrate, phenylephrine hydrochloride and chlorpheniramine maleate in a sustained release layer may be manufactured by using direct compression:

Example 39: Bi-layered Tablet (Wet Granulation)

[0202] A bi-layered tablet in accordance with the present invention which comprises carbetapentane citrate in an immediate release layer and carbetapentane citrate, pseudoephedrine hydrochloride and chlorpheniramine maleate in a sustained release layer is illustrated as follows:

Procedure:

[0203] (a) Immediate release layer #1: Screen all ingredients through a USP sieve size # 30. Blend the carbetapentane citrate, silicified microcrystalline cellulose, and croscarmellose sodium in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (4.1 gms povidone in 13.7 gms of solution). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add granules and the prescreened magnesium stearate (1.4 gms) to the above blend and mix for 3 minutes. [0204] (b) Sustained release layer #2: Screen all ingredients through a USP sieve size # 30. Blend the pseudoephedrine hydrochloride (87.5 gms), chlorpheniramine maleate, carbetapentane citrate, microcrystalline cellulose PH 102, lactose monohydrate, dicalcium citrate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (20.7 gms povidone in 69 gms of solution). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add granules and the prescreened magnesium stearate (6.9 gms) to the above blend and mix for 3 minutes.

[0205] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet the immediate release layer is 135 mgs and the sustained release layer is 590 mgs. Example 40: Bi-layered Tablet (Wet Granulation)

[0206] By using the process described in Example 39, a bi-layered tablet containing carbetapentane citrate in an immediate release layer and carbetapentane citrate, pseudoephedrine hydrochloride and chlorpheniramine maleate in a sustained release layer may be manufactured by using wet granulation:

[0207] The above examples 21-40 illustrate how to manufacture a bi-layered tablet containing an antitussive, i.e., carbetapentane citrate, in (at least) a first layer and an antihistamine and/or a decongestant and/or an expectorant in (at least) a second layer. Non- limiting examples of possible active ingredients (in addition to carbetapentane) in an exemplary range as described in the above Table 1 can be employed depending on the specific therapeutic effect desired.

Example 41: Extended Release Suspension (Gel)

[0208] An extended release suspension (in the form of a gel) in accordance with the present invention which contains a carbetapentane citrate ion-exchange complex and promethazine hydrochloride is illustrated as follows (note that the carbetapentane citrate is used in a controlled release form since it has a shorter half-life than the promethazine hydrochloride):

Procedure:

[0209] (1) Add the appropriate amount of sodium polystyrene sulphonate USP (e.g.

Amberlite® IRP 69) to a carbetapentane citrate solution.

(2) Stir the mix for 12 hrs to allow complete drug/resin complex formation.

(3) Separate and dry the insoluble drug/resin complex.

(5) Mill the granules, if needed.

(6) To an appropriate amount of water add the following ingredients and dissolve: promethazine hydrochloride, Carbomer (e.g., Carbopol® 974), glycerin, polysorbate 80, methyl paraben, propyl paraben, artificial grape flavor, FD&C red # 40 dye.

(7) Add milled granules.

(8) Add water to 95 % of final volume.

(10) Neutralize the solution to form a gel using a IN sodium hydroxide solution to a pH of 5 to 8. Add water to make final volume. (11) Fill in suitable containers ensuring that the product is homogeneous throughout the filling operation.

Example 42: Extended Release Suspension (Liquid)

[0210] An extended release suspension (in the form of a liquid) in accordance with the present invention which contains a carbetapentane tannate ion-exchange complex and promethazine hydrochloride is illustrated as follows:

Manufacturing process for 1000 L batch:

[0211] Add the appropriate amount of sodium polystyrene sulphonate USP (e.g.

Amberlite® IRP 69 or Amberlite® 88N) to a carbetapentane tannate solution. Stir the mix for

12 hrs to allow complete drug/resin complex formation. Separate and dry the insoluble drug/resin complex. Granulate the drug/resin complex with a delayed release/enteric polymer

(e.g. Eudragit® L 100, Kollidon® MAE, Aquacoat® CPD) and dry the granules. Mill the granules, if needed.

[0212] In a suitably sized stainless steel vessel, dissolve saccharin sodium, sodium benzoate, citric acid, and sodium citrate in approximately 50 L of warm (about 45 ⁰C), purified water. In another large stainless steel drum mix the silica, carbetapentane tannate ion- exchange complex, and promethazine hydrochloride until a uniform and consistent mixture is obtained. In a separate 1000 L stainless steel tank equipped with a suitably sized homogenizer/disperser add about 100 L of purified water. With the homogenizer on, add the silica mixture containing carbetapentane tannate ion-exchange complex, and promethazine hydrochloride. Add the previously prepared solution of saccharin sodium, sodium benzoate, citric acid, and sodium citrate to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinsate to the 1000 L tank. Add the remaining ingredients and homogenize for 15 minutes.

Example 43: Extended Release Suspension (Liquid)

[0213] An extended release suspension (in the form of a liquid) in accordance with the present invention which contains a carbetapentane citrate ion-exchange complex, pseudoephedrine tannate and chlorpheniramine tannate is illustrated as follows:

Manufacturing process for 1000 kg batch: [0214] Add the appropriate amount of sodium polystyrene sulphonate USP (e.g.

Amberlite® IRP 69or Amberlite® 188N) to a carbetapentane citrate solution. Stir the mix for 12 hrs to allow complete drug/resin complex formation. Separate and dry the insoluble drug/resin complex. Granulate the drug/resin complex with a delayed release/enteric polymer (e.g. Eudragit® L 100, Kollidon® MAE, Aquacoat® CPD) and dry the granules. Mill the granules, if needed.

[0215] In a suitably sized stainless steel vessel, dissolve saccharin sodium, sodium benzoate, citric acid, and sodium citrate in approximately 50 L of warm (about 45 ⁰C), purified water. In another large stainless steel drum mix the silica, carbetapentane citrate ion- exchange complex, pseudoephedrine tannate, and the chlorpheniramine tannate until a uniform and consistent mixture is obtained. In a separate 1000 L stainless steel tank equipped with a suitably sized homogenizer/disperser add about 100 L of purified water. With the homogenizer on, add the silica mixture containing carbetapentane citrate ion-exchange complex, pseudoephedrine tannate, and the chlorpheniramine tannate. Add the previously prepared solution of saccharin sodium, sodium benzoate, citric acid, and sodium citrate to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinsate to the 1000 L tank. Add the remaining ingredients and homogenize for 15 minutes.

Example 44: Extended Release Gel

[0216] An extended release suspension which contains a carbetapentane citrate ion- exchange complex, a dexchlorpheniramine maleate ion-exchange complex and a phenylephrine hydrochloride ion-exchange complex is illustrated as follows:

[0217] The formula described above serves as a non-limiting example. Any active drug which is in the form of a salt can be incorporated as an ion-exchange resin complex.

Procedure:

[0218] (1) Add the appropriate amount of sodium polystyrene sulphonate USP (e.g. Amberlite® IRP 69 or Amberlite® 188N) to a carbetapentane citrate, dexchlorpheniramine maleate and phenylephrine HCl solution.

(2) Stir the mix for 12 hrs to allow complete drug/resin complex formation.

(3) Separate and dry the insoluble drug/resin complex.

(5) Mill the granules, if needed.

(7) Add milled granules.

(8) Add water to 95% of the final volume.

(10) Neutralize the solution to form a gel using a IN sodium hydroxide solution to a pH of 5 to 8. Add enough water to make up to the final volume.

Example 45: Suspension Formula [0219] A suspension formula which comprises carbetapentane citrate and phenylephrine tannate is illustrated as follows:

Ingredients g/100niL kg/batch

=120 g =1000 kg

Carbetapentane Citrate 0.500

Phenylepherine Tannate 0.800 6.667

Silica, colloidal anhydrous, NF 1.73 14.417

Hydroxyethylcellulose, NF 0.05 0.417

Sorbitol Solution 70% (non-crystallizing), NF 34.00 283.333

Glycerol 14.75 122.917

Xylitol, NF 16.00 133.333

Sodium Citrate, USP 2.00 16.667

Saccharin Sodium cryst, USP, 0.01 0.083

Sodium Benzoate, NF 0.15 1.250

Citric Acid Monohydrate, USP 0.16 1.333

Strawberry Flavor 0.15 1.250

Banana Flavor 0.15 1.250

Purified Water 49.55 412.917

Total Amount 120.000 g 1000.000 kg

Manufacturing process for 1000 kg batch: bbb

[0220] In a suitably sized stainless steel vessel, dissolve saccharin sodium, sodium benzoate, citric acid, and sodium citrate in approximately 50 L of warm (about 45 ⁰C), purified water. In another large stainless steel drum mix the silica, carbetapentane citrate, and micronized phenylephrine tannate until a uniform and consistent mixture is obtained. In a separate 1000 L stainless steel tank equipped with a suitably sized homogenizer/disperser add about 100 L of purified water. With the homogenizer on, add the silica mixture containing phenylephrine tannate and carbetapentane citrate. Add the previously prepared solution of saccharin sodium, sodium benzoate, citric acid, and sodium citrate to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinsate to the 1000 L tank. Add the remaining ingredients and homogenize for 15 minutes. Filter product through a 10 micron filter and fill in appropriately sized containers.

[0221] To make products with other agents such as antihistamines, decongestants, or expectorants, one or more combinations of each of the ingredients in a range as described in Table 1 above can be made depending on the specific therapeutic effect desired.

Example 46: Liquid Formula:

[0222] A liquid dosage form which comprises carbetapentane citrate and phenylephrine hydrochloride is illustrated as follows:

Ingredients Per 5 mL Per 425 L

Carbetapentane Citrate USP 30 mg 2.55 kg

Phenylepherine Hydrochloride USP 10.0 mg 0.850 kg

Methyl Paraben USP 9.0 mg 0.765 kg

Propyl Paraben USP 1.0 mg 0.085 kg

Propylene Glycol USP 259 mg 22.016 kg

Saccharin Sodium USP 3.18 mg 0.270 kg

Citric Acid USP 5.0 mg 0.425 kg

Strawberry Flavor 10 mg 0.850 kg

Banana Flavor 10 mg 0.850 kg

Sorbitol Solution 70% USP 3212.5 mg 273.1 kg

Purified Water, as required to q.s. to 5.O mL 425 L

Manufacturing process for 425 L batch size:

[0223] In a suitably sized stainless steel vessel, dissolve methyl paraben and propyl paraben in approximately 50 L of warm (about 45 ⁰C), purified water. Add about half of the propylene glycol and mix for about 1 hr. In a separate 1000 L stainless steel tank equipped with a suitably sized agitator, add about 50 L of purified water. With the agitator on, add phenylephrine hydrochloride, carbetapentane citrate, saccharin sodium and citric acid and dissolve. Add the previously prepared paraben/propylene glycol solution to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinsate to the 1000 L tank. Add the remaining propylene glycol to a suitably sized stainless steel vessel and dissolve the strawberry and banana flavors. Transfer this to the 1000 L tank. Rinse the container with 2 L of purified water and transfer to the 1000 L tank. With the agitator on, add the sorbitol solution 70 % to the 1000 L tank. In a suitably sized stainless steel vessel, dissolve the carbetapentane citrate in about 5 L of purified water and transfer to the 1000 L tank. Rinse the container with about 2 L of purified water and transfer to the 1000 L tank. Stop the agitator and let the solution stand for 15 minutes. QS to 425 L with purified water. Filter product through a 1 micron filter and fill in appropriately sized containers.

[0224] To make products with other antihistamines, decongestants, or expectorants, one or more combinations of each of the ingredients in a range as described in Table 1 above can be made depending on the specific therapeutic effect desired.

Example 47: Bi-layered Tablet (Wet Granulation)

[0225] A bi-layered tablet in accordance with the present invention which comprises phenylephrine hydrochloride in a first sustained release layer and guaifenesin in a second sustained release layer is illustrated as follows:

Procedure:

[0226] (a) Sustained release layer #1: Mix phenylephrine hydrochloride in Methocel®K15M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes.

Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD

(weight loss on drying) is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0227] (b) Sustained release layer #2: Screen all ingredients through a US sieve size # 30.

Mix guaifenesin, microcrystalline cellulose PH 102, and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %).

Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0228] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 260 mg and layer #2 is 825 mg. Capsules may be manufactured by filling the same proportions into capsules.

Example 48: Bi-layered Tablet (Wet Granulation)

[0229] A bi-layered tablet in accordance with the present invention which comprises promethazine hydrochloride in an immediate release layer and phenylephrine hydrochloride in a sustained release layer is illustrated as follows:

Procedure:

[0230] (a) Immediate release layer #1: Mix the promethazine HCl, silicified microcrystalline cellulose and croscarmellose sodium, in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (3.0 g povidone in 10.0 g purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0231] (b) Sustained release layer #2: Mix the phenylephrine hydrochloride, microcrystalline cellulose PH 102, dicalcium phosphate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (15.0 g povidone in 50.0 g purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0232] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 200 mg and layer #2 is 350 mg. Capsules may be manufactured by filling the same proportions into capsules.

Example 49: Bi-layered Tablet (Wet Granulation)

[0233] A bi-layered tablet in accordance with the present invention which comprises phenylephrine hydrochloride and carbinoxamine maleate in a first sustained release layer and phenylephrine hydrochloride in a second sustained release layer is illustrated as follows:

Procedure: [0234] (a) Sustained release layer #1 : Mix the phenylephrine HCl, carbinoxamine maleate, Methocel®K4M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0235] (b) Sustained release layer #2: Screen all ingredients through a US sieve size # 30. Mix the phenylephrine hydrochloride, microcrystalline cellulose PH 102, and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0236] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 250 mg and layer #2 is 250 mg. Capsules may be manufactured by filling the same proportions into capsules.

Example 50: Bi-layered Tablet (Wet Granulation)

[0237] A bi-layered tablet in accordance with the present invention which comprises phenylephrine hydrochloride and diphenhydramine hydrochloride in a first sustained release layer and codeine phosphate in a second sustained release layer is illustrated as follows:

Procedure:

[0238] (a) Sustained release layer #1: Mix the phenylephrine HCl, diphenhydramine hydrochloride, Methocel®K4M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0239] (b) Sustained release layer #2: Screen all ingredients through a US sieve size # 30. Mix the codeine phosphate, microcrystalline cellulose PH 102, and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0240] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 390 mg and layer #2 is 260 mg. Capsules may be manufactured by filling the same proportions into capsules.

Example 51: Bi-layered Tablet (Wet Granulation)

[0241] A bi-layered tablet in accordance with the present invention which comprises carbinoxamine maleate in a first sustained release layer and phenylephrine hydrochloride in a second sustained release layer is illustrated as follows:

Procedure:

[0242] (a) Sustained release layer #1: Mix the carbinoxamine maleate, Methocel®K4M, lactose monohydrate and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0243] (b) Sustained release layer #2: Screen all ingredients through a US sieve size # 30.

Mix the phenylephrine hydrochloride, microcrystalline cellulose PH 102, and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE

(30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0244] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 200 mg and layer #2 is 215 mg. Capsules may be manufactured by filling the same proportions into capsules.

Example 52: Bi-layered Tablet (Direct Compression)

[0245] A bi-layered tablet in accordance with the present invention which comprises promethazine hydrochloride (longer half-life drug) in an immediate release layer and phenylephrine hydrochloride (shorter half-life drug) in a sustained release layer is illustrated as follows:

Procedure:

[0246] (a) Immediate release layer #1: Screen all ingredients through a US sieve size # 30. Blend the promethazine hydrochloride, microcrystalline cellulose and sodium starch glycolate for 20 minutes. Add magnesium stearate to the above blend and mix for an additional time of three minutes.

[0247] (b) Sustained release layer #2: Blend the phenylephrine hydrochloride, lactose monohydrate, dicalcium phosphate and Kollidon® SR for 20 minutes. Add stearic acid and magnesium stearate to the above blend and mix for an additional time of three minutes. [0248] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet the immediate release layer #1 is 150 mg and the sustained release layer #2 is 400 mg. Capsules may be manufactured by filling the same proportions into capsules.

Example 53: Bi-layered Tablet (Wet Granulation):

[0249] A bi-layered tablet in accordance with the present invention which comprises phenylephrine tannate and chlorpheniramine tannate in an immediate release layer and phenylephrine tannate in a sustained release layer is illustrated as follows:

Procedure:

[0250] (a) Immediate release layer #1: Mix the phenylephrine tannate, chlorpheniramine tannate, silicified microcrystalline cellulose and croscarmellose sodium, in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (3.0 Kg povidone in 7.0 Kg purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0251] (b) Sustained release layer #2: Mix the Phenylepherine tannate, microcrystalline cellulose PH 102, dicalcium phosphate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (15.0 Kg povidone in 35.0 Kg purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0252] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 290 mg and layer #2 is 410 mg. Capsules may be manufactured by filling the same proportions into capsules.

Example 54: Bi-layered Tablet (Wet Granulation):

[0253] A bi-layered tablet in accordance with the present invention which comprises diphenhydramine hydrochloride in an immediate release layer and phenylephrine hydrochloride in a sustained release layer is illustrated as follows:

Procedure:

[0254] (a) Immediate release layer #1: Mix the diphenydramine hydrochloride, silicified microcrystalline cellulose and croscarmellose sodium, in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (3.O g povidone in 10.0 g purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0255] (b) Sustained release layer #2: Mix the phenylephrine hydrochloride, microcrystalline cellulose PH 102, dicalcium phosphate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (15.0 g povidone in 50.0 g purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0256] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 200 mg and layer #2 is 350 mg. Capsules may be manufactured by filling the same proportions into capsules. Example 55: Bi-layered Tablet (Direct Compression)

[0257] A bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and phenylephrine hydrochloride in a second sustained release layer is illustrated as follows:

Procedure:

[0258] (a) Sustained release layer #1: Screen all ingredients through a US sieve size # 30.

Blend the guaifenesin, Methocel® Kl 5M and silicified microcrystalline cellulose for 25 minutes. Add magnesium stearate to the above blend and mix for an additional time of three minutes. [0259] (b) Sustained release layer #2: Blend the phenylephrine hydrochloride, dicalcium phosphate and Kollidon® SR for 20 minutes. Add stearic acid and magnesium stearate to the above blend and mix for an additional time of three minutes.

[0260] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 880 mg and layer #2 is 320 mg. Capsules may be manufactured by filling the same proportions into capsules.

Example 56: Bi-layered Tablet (Wet Granulation)

[0261] A bi-layered tablet in accordance with the present invention which comprises brompheniramine maleate in a first sustained release layer and phenylephrine hydrochloride in a second sustained release layer is illustrated as follows:

Procedure: [0262] (a) Sustained release layer #1: Mix the brompheniramine maleate, MethoceI®K15M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0263] (b) Sustained release layer #2: Screen all ingredients through a US sieve size # 30. Mix the phenylephrine hydrochloride, microcrystalline cellulose PH 102, dicalcium phosphate and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0%. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0264] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 200 mg and layer #2 is 250 mg. Capsules may be manufactured by filling the same proportions into capsules.

Example 57: Bi-layered Tablet (Wet Granulation)

A bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and phenylephrine hydrochloride in a second sustained release layer is illustrated as follows:

Procedure:

[0265] (a) Sustained release layer #1: Mix the guaifenesin, Methocel®K15M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0

%. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0266] (b) Sustained release layer #2: Screen all ingredients through a US sieve size # 30.

Mix the phenylephrine HCl, microcrystalline cellulose PH 102 and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %).

[0267] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 1300 mg and layer #2 is 210 mg. Capsules may be manufactured by filling the same proportions into capsules.

Example 58: Bi-layered Tablet (Direct Compression)

[0268] A bi-layered tablet in accordance with the present invention which comprises phenylephrine hydrochloride in a first immediate release layer and phenylephrine hydrochloride and diphenhydramine hydrochloride in a second sustained release layer is illustrated as follows:

Procedure:

[0269] (a) Immediate release Layer #1: Screen all ingredients through a US sieve size # 30.

Preblend a portion (about a third of the total) of the silicified microcrystalline cellulose and all the phenylephrine hydrochloride for the immediate release layer for 15 minutes. Add sodium starch glycolate and mix for additional 10 minutes. Add magnesium stearate to the above blend and mix for three minutes.

[0270] (b) Sustained release layer #2: Screen all ingredients through a US sieve size # 30.

Preblend a portion of the Kollidon SR (about a third of the total) and all the diphenhydramine hydrochloride for 15 minutes. Add the remaining Kollidon SR, phenylephrine hydrochloride and dicalcium phosphate to the above preblend and mix for additional 20 minutes. Add stearic acid and magnesium stearate to the above blend and mix for three minutes. [0271] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet the immediate release layer is 200 mg and the sustained release layer is 460 mg.

Example 59: Bi-layered Tablet (Direct Compression)

[0272] By using the process described in Example 58, a bi-layered tablet which contains phenylephrine hydrochloride in an immediate release layer and phenylephrine hydrochloride and dexbrompheniramine maleate in a sustained release layer (see the formula below) may be manufactured by using direct compression:

Example 60: Bi-layered Tablet (Wet Granulation) [0273] A bi-layered tablet in accordance with the present invention which comprises phenylephrine hydrochloride in an immediate release layer and phenylephrine hydrochloride and chlorpheniramine maleate in a sustained release layer is illustrated as follows:

Procedure: [0274] (a) Immediate release layer #1: Screen all ingredients through a US sieve size # 30. Blend the phenylephrine hydrochloride, silicified microcrystalline cellulose, and croscarmellose sodium in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (4.3 Kg povidone in 10.0 Kg purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add granules and the prescreened magnesium stearate to the above blend and mix for 3 minutes.

[0275] (b) Sustained release layer #2: Screen all ingredients through a US sieve size # 30. Blend the phenylephrine hydrochloride, chlorpheniramine maleate, microcrystalline cellulose PH 102, dicalcium phosphate and Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (15.0 Kg povidone in 35.0 Kg purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add granules and the prescreened magnesium stearate to the above blend and mix for 3 minutes.

[0276] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet the immediate release layer is 135 mg and the sustained release layer is 450 mg.

Example 61: Bi-layered Tablet (Wet Granulation)

[0277] By using the process described in Example 60, a bi-layered tablet containing phenylephrine hydrochloride in an immediate release layer and phenylephrine hydrochloride and chlorpheniramine maleate in a sustained release layer may be manufactured by using wet granulation:

Example 62: Bi-layered Tablet (Wet Granulation)

[0278] A bi-layered tablet in accordance with the present invention which comprises phenylephrine hydrochloride in a sustained release layer and carbetapentane citrate in a immediate release layer is illustrated as follows:

Procedure

[0279] Sustained Release Layer (Layer 1)

1. Set aside 0.5 kg of Purified Water to be used in step 4.

2. Prepare a solution using the scale up amounts of Povidone K-30, and the remaining Purified Water from step 1.

3. Blend the pre-blend scale up amounts of Phenylephrine HCl USP, Calcium Phosphate Dibasic Dihydrate, and Prosolv SMCC 90 with a high shear mixer/granulator for 10 minutes.

4. With the mixer/granulator on, pump the solution prepared in step 2 in to the mixer/granulator. After completion, stop the mixer/granulator and rinse the container with the Purified water set aside in step 1. Pump the rinse water to the mixer/granulator with mixer on. Turn off mixer when completed.

5. Charge the pre-blend scale up amount of Methocel K4M premium to the mixer/granulator and mix for 1 minute.

6. Dry the granulation until the LOD is 4% or less.

7. Pass the dried granulation through a Fitzpatrick Fitzmill fitted with a 14 mesh screen.

8. Screen the final blend scale up amount of Methocel K4M premium through a 14 mesh screen. 9. Blend the milled granulation from step 7 and the screened materials from step 8 using a V-blender for 20 minutes.

10. Screen the lube scale up amount of Magnesium Stearate using a 30 mesh screen.

11. Transfer the screened Magnesium Stearate to the V-blender and blend for 3 minutes. When completed discharge into drums double lined with polyethylene bags.

[0280] Immediate Release Layer (Layer 2)

1. Set aside 0.5 kg of Purified Water to be used in step 4.

2. Prepare a solution using the scale up amounts Povidone K-30, and the remaining Purified Water from step 1.

3. Blend the pre-blend scale up amounts of Carbetapentane Citrate, Prosolv SMCC 90, Lactose Monohydrate #316, Sodium Starch Glycolate, and FD&C Blue #1 Aluminum Lake using a high shear mixer/granulator for 10 minutes.

4. With the mixer/granulator on, pump the solution prepared in step 2 in to the mixer/granulator. After completion, stop the mixer/granulator and rinse the container with the Purified Water set aside in step 1. Pump the rinse water to the mixer/granulator with mixer on. Allow mixture to mix for an additional minute then turn mixer/granulator off.

5. Dry the granulation until the LOD is 4% or less.

6. Pass the dried granulation through a Fitzpatrick Fitzmill fitted with a 14 mesh screen.

7. Screen the final blend scale up amounts of Prosolv SMCC 90, Lactose Monohydrate #316, Sodium Starch Glycolate, and FD&C Blue #1 Aluminum Lake through a 14 mesh screen.

8. Blend the milled granulation from step 6 and the screened materials from step 7 using a V-blender for 20 minutes.

9. Screen the lube scale up amount of Magnesium Stearate using a 30 mesh screen.

10. Transfer the screened Magnesium Stearate to the V-blender and blend for 3 minutes. When completed discharge into proper drums double lined with polyethylene bags.

[0281] Compress bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer 1 is 400.0 mg and layer 2 is 400 mg.

[0282] The above examples 41-62 illustrate how to manufacture a bi-layered tablet containing a decongestant, i.e., phenylephrine hydrochloride, in (at least) a first layer and an antihistamine and/or a decongestant and/or an expectorant in (at least) a second layer. Non- limiting examples of other possible active ingredients in an exemplary range as described in the above Table 1 can be employed depending on the specific therapeutic effect desired.

Example 63: Bi-layered Tablet (Wet Granulation)

[0283] A bi-layered tablet in accordance with the present invention which contains phenylephrine hydrochloride in both an immediate release layer and a sustained release layer and carbetapentane citrate in both an immediate release layer and a sustained release layer is illustrated as follows:

Procedure:

[0284] (a) Immediate release layer #1: Mix the prescreened (# 30 mesh) phenylephrine hydrochloride,carbetapentane citrate, silicified microcrystalline cellulose and croscarmellose sodium, in a V shaped blender for 20 minutes. Add prescreened (# 40 mesh) magnesium stearate in a V shaped blender and mix for 3 minutes. [0285] (b) Sustained release layer #2: Mix the phenylephrine hydrochloride, carbetapentane citrate, Methocel K4M Premium and microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (12.0 Kg povidone in 28.0 Kg purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.

[0286] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 115 mg and layer #2 is 270 mg.

Example 64: Bi-layered Tablet (Wet granulation)

[0287] A bi-layered tablet in accordance with the present invention which comprises phenylephrine hydrochloride and guaifenesin in two different sustained release layers is illustrated as follows:

[0288] Procedure

1. Set aside 0.5 kg of purified water to be used as a rinse in step 4.

2. Prepare a solution using the scale up amounts of Povidone K-30, and the remaining Purified Water. 3. Blend the pre-blend scale up amounts of Guaifenesin USP, Phenylephrine HCl USP, and Calcium Phosphate Dibasic Anhydrous using a high sheer mixer/granulator for 10 minutes.

4. With the mixer/granulator on, pump the solution prepared in step 2 in to the mixer/granulator. After completion, stop the mixer/granulator and rinse the container with the 0.5 kg of Purified water set aside in step 1. Pump the rinse water to the mixer/granulator with mixer on. Turn off mixer when completed.

6. Dry the granulation until the LOD is 1% or less.

7. Pass the dried granulation through a Fitzpatrick Fitzmill fitted with a 109 screen.

8. Screen the final blend raw materials through a 12 mesh screen.

9. Blend the milled granulation from step 7 and the screened materials from step 8 using a V-blender for 20 minutes.

10. Screen the lube blend material through a 30 mesh screen.

11. Charge the screened material from step 10 to the V-blender and blend for 2 minutes.

12. Discharge half of the blended product into proper drums double lined with polyethylene bags and set aside for step 16.

13. Screen the color blend material through a 30 mesh screen.

14. Charge the screened color blend material to the V-blender and blend for 1 minute.

15. Discharge into proper drums double lined with polyethylene bags and set aside for step 16.

16. Compress bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer 1 is 400.0 mg's and layer 2 is 400.0 mg's.

Example 65: Extended Release Suspension (Gel)

[0289] An extended release suspension (in the form of a gel) in accordance with the present invention which contains a phenylephrine hydrochloride ion-exchange complex and promethazine hydrochloride is illustrated as follows (the phenylephrine hydrochloride is used in a controlled release form since it has a shorter half-life than the promethazine hydrochloride):

Procedure:

[0290] (1) Add the appropriate amount of sodium polystyrene sulphonate USP (e.g.

Amberlite® IRP 69) to a phenylephrine hydrochloride solution.

(2) Stir the mix for 12 hrs to allow complete drug/resin complex formation.

(3) Separate and dry the insoluble drug/resin complex.

(5) Mill the granules, if needed.

(7) Add milled granules.

(8) Add water to 80 % of final volume.

(10) Neutralize the solution to a pH of 6.5 (range 5.5 to 7.5) to form a gel using a IN sodium hydroxide solution. QS with water to make final volume of 5 ml per dose.

(11) Fill in suitable containers. Example 66: Extended Release Suspension (Liquid)

[0291] An extended release suspension (in the form of a liquid) in accordance with the present invention which contains a phenylephrine hydrochloride ion-exchange complex and promethazine hydrochloride is illustrated as follows:

Manufacturing process for 1000 L batch:

[0292] Add the appropriate amount of sodium polystyrene sulphonate USP (e.g.

Amberlite® IRP 69) to a phenylephrine hydrochloride solution. Stir the mix for 12 hrs to allow complete drug/resin complex formation. Separate and dry the insoluble drug/resin complex. Granulate the drug/resin complex with a delayed release/enteric polymer (e.g. Eudragit® L 100, Kollidon® MAE, Aquacoat® CPD) and dry the granules. Mill the granules, if needed.

[0293] In a suitably sized stainless steel vessel, dissolve saccharin sodium, sodium benzoate, citric acid, and sodium citrate in approximately 50L of warm (about 45 ⁰C), purified water. In another large stainless steel drum mix the silica, phenylephrine hydrochloride ion- exchange complex, and promethazine hydrochloride until a uniform and consistent mixture is obtained. In a separate 1000 L stainless steel tank equipped with a suitably sized homogenizer/disperser add about 100 L of purified water. With the homogenizer on, add the silica mixture containing phenylephrine hydrochloride ion-exchange complex, and promethazine hydrochloride. Add the previously prepared solution of saccharin sodium, sodium benzoate, citric acid, and sodium citrate to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinsate to the 1000 L tank. Add the remaining ingredients and homogenize for 15 minutes.

Example 67: Extended Release Suspension (Liquid)

[0294] An extended release suspension (in the form of a liquid) in accordance with the present invention which contains a codeine phosphate ion-exchange complex, phenylephrine tannate and chlorpheniramine tannate is illustrated as follows:

Manufacturing process for 1000 Kg batch:

[0295] Add the appropriate amount of sodium polystyrene sulphonate USP (e.g. Amberlite® IRP 69) to a codeine phosphate solution. Stir the mix for 12 hrs to allow complete drug/resin complex formation. Separate and dry the insoluble drug/resin complex. Granulate the drug/resin complex with a delayed release/enteric polymer (e.g. Eudragit® L 100, Kollidon® MAE, Aquacoat® CPD) and dry the granules. Mill the granules, if needed. [0296] In a suitably sized stainless steel vessel, dissolve saccharin sodium, sodium benzoate, citric acid, and sodium citrate in approximately 5OL of warm (about 45 ⁰C), purified water. In another large stainless steel drum mix the silica and the codeine phosphate ion- exchange complex, phenylephrine tannate, and the chlorpheniramine tannate until a uniform and consistent mixture is obtained. In a separate 1000 L stainless steel tank equipped with a suitably sized homogenizer/disperser add about 100 L of purified water. With the homogenizer on, add the silica mixture containing the codeine phosphate ion-exchange complex, the phenylephrine tannate, and the chlorpheniramine tannate. Add the previously prepared solution of saccharin sodium, sodium benzoate, citric acid, and sodium citrate to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinse to the 1000 L tank. Add the remaining ingredients and homogenize for 15 minutes.

Example 68: Extended Release Suspension

[0297] An extended release suspension which contains a hydrocodone bitartrate ion- exchange complex, a dexchlorpheniramine maleate ion-exchange complex and a phenylephrine hydrochloride ion-exchange complex is illustrated as follows:

[0298] The formula described above serves as a non-limiting example. Any active drug which is in the form of a salt, such as an antihistamine, codeine, or dihydrocodeine, can be incorporated as an ion-exchange resin complex.

Procedure:

[0299] (1) Add the appropriate amount of sodium polystyrene sulphonate USP (e.g. Amberlite® IRP 69) to a dexchlorpheniramine maleate, hydrocodone bitartrate and phenylephrine HCl solution.

(2) Stir the mix for 12 hrs to allow complete drug/resin complex formation.

(3) Separate and dry the insoluble drug/resin complex.

(5) Mill the granules, if needed.

(7) Add milled granules.

(8) Add water to make up to a final volume.

(10) Fill in suitable containers ensuring that the product is homogeneous throughout the filling operation.

Example 69: Suspension Formula

[0300] A suspension formula which comprises codeine phosphate and phenylephrine tannate is illustrated as follows:

Ingredients g/100mL kg/batch Codeine Phosphate 0.20 1.667

Phenylephrine Tannate 0.80 6.667

Silica, colloidal anhydrous, NF 1.73 14.417

Hydroxyethylcellulose, NF 0.05 0.417

Sorbitol Solution 70% (non-crystallizing), NF 34.00 283.333

Glycerol 14.75 122.917

Xylitol, NF 16.00 133.333

Sodium Citrate, USP 2.00 16.667

Saccharin Sodium cryst, USP, 0.01 0.083

Sodium Benzoate, NF 0.15 1.250

Citric Acid Monohydrate, USP 0.16 1.333

Strawberry Flavor 0.15 1.250

Banana Flavor 0.15 1.250

Purified Water 49.55 412.917

Total Amount 120.00 1000.000

Manufacturing process for 1000 kg batch:

[0301] In a suitably sized stainless steel vessel, dissolve saccharin sodium, sodium benzoate, citric acid, and sodium citrate in approximately 50L of warm (about 45 ⁰C), purified water. In another large stainless steel drum mix the silica, codeine phosphate and micronized phenylephrine tannate until a uniform and consistent mixture is obtained. In a separate 1000 L stainless steel tank equipped with a suitably sized homogenizer/disperser add about 100 L of purified water. With the homogenizer on, add the silica mixture containing phenylephrine tannate and codeine phosphate Add the previously prepared solution of saccharin sodium, sodium benzoate, citric acid, and sodium citrate to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinse to the 1000 L tank. Add the remaining ingredients and homogenize for 15 minutes. Filter product through a 10 micron filter and fill in appropriately sized containers. [0302] To make products with other agents such as antihistamines, decongestants, or expectorants, one or more combinations of each of the ingredients in a range as described in Table 1 below can be made depending on the specific therapeutic effect desired.

Example 70: Liquid Formula:

[0303] A liquid dosage form which comprises phenylephrine hydrochloride is illustrated as follows:

Ingredients Per 5 mL Per 425 L

Codeine Phosphate USP 30 mg 2.550 kg

Phenylepherine Hydrochloride USP 10.0 mg 0.850 kg

Methyl Paraben USP 9.0 mg 0.765 kg

Propyl Paraben USP 1.0 mg 0.085 kg

Propylene Glycol USP 259 mg 22.016 kg

Saccharin Sodium USP 3.18 mg 0.270 kg

Citric Acid USP 5.0 mg 0.425 kg

Strawberry Flavor 10 mg 0.850 kg

Banana Flavor 10 mg 0.850 kg

Sorbitol Solution 70% USP 3212.5 mg 273.1 kg

Purified Water, as required to q.s. to 5.O mL 425 L

Manufacturing process for 425 L batch size:

[0304] In a suitably sized stainless steel vessel, dissolve methyl paraben and propyl paraben in approximately 5OL of warm (about 45 ⁰C), purified water. Add about half of the propylene glycol and mix for about 1 hr. In a separate 1000 L stainless steel tank equipped with a suitably sized agitator, add about 50 L of purified water. With the agitator on, add phenylephrine hydrochloride, codeine phosphate, saccharin sodium and citric acid and dissolve. Add the previously prepared paraben/propylene glycol solution to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinsate to the 1000 L tank. Add the remaining propylene glycol to a suitably sized stainless steel vessel and dissolve the strawberry and banana flavors. Transfer this to the 1000 L tank. Rinse the container with 2 L of purified water and transfer to the 1000 L tank. With the agitator on, add the sorbitol solution 70 % to the 1000 L tank. In a suitably sized stainless steel vessel, dissolve the codeine phosphate in about 5 L of purified water and transfer to the 1000 L tank. Rinse the container with about 2 L of purified water and transfer to the 1000 L tank. Stop the agitator and let the solution stand for 15 minutes. QS to 425 L with purified water. Filter product through a 1 micron filter and fill in appropriately sized containers.

[0305] To make products with other antihistamines, decongestants, or expectorants, one or more combinations of each of the ingredients in a range as described in Table 1 above can be made depending on the specific therapeutic effect desired.

Example 71: Liquid Formula:

[0306] A liquid dosage form in accordance with the present invention which comprises diphenhydramine hydrochloride, dihydrocodeine bitartrate and phenylephrine hydrochloride is illustrated as follows:

Ingredients Per 5 mL Per 425 L

Diphenhydramine Hydrochloride USP 12.5 mg 1.063 kg

Dihydrocodeine Bitartrate USP 10.0 mg 0.850 kg

Phenylephrine Hydrochloride USP 10.0 mg 0.850 kg

Methyl Paraben USP 9.0 mg 0.765 kg

Propyl Paraben USP 1.0 mg 0.085 kg

Propylene Glycol USP 259 mg 22.016 kg

Saccharin Sodium USP 3.18 mg 0.270 kg

Citric Acid USP 5.0 mg 0.425 kg

Strawberry Flavor 10 mg 0.850 kg

Banana Flavor 10 mg 0.850 kg

Sorbitol Solution 70% USP 3212.5 mg 273.1 kg

Purified Water, as required to q.s. to 5.O mL 425 L

[0307] Manufacturing process for 425 L batch size: In a suitably sized stainless steel vessel, dissolve methyl paraben and propyl paraben in approximately 50L of warm (about 45 ⁰C), purified water. Add about half of the propylene glycol and mix for about 1 hr. In a separate 1000 L stainless steel tank equipped with a suitably sized agitator, add about 50 L of purified water. With the agitator on, add phenylephrine hydrochloride, diphenhydramine hydrochloride, saccharin sodium and citric acid and dissolve. Add the previously prepared paraben/propylene glycol solution to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinsate to the 1000 L tank. Add the remaining propylene glycol to a suitably sized stainless steel vessel and dissolve the strawberry and banana flavors. Transfer this to the 1000 L tank. Rinse the container with 2 L of purified water and transfer to the 1000 L tank. With the agitator on, add the sorbitol solution 70% to the 1000 L tank. In a suitably sized stainless steel vessel, dissolve the dihydrocodeine bitartrate in about 5 L of purified water and transfer to the 1000 L tank. Rinse the container with about 2 L of purified water and transfer to the 1000 L tank. Stop the agitator and let the solution stand for 15 minutes. Adjust pH to 3.5 to 5.5 with either HCl or NaOH, qs to 425 L with purified water. Filter product through a 1 micron filter and fill in appropriately sized containers.

[0308] To make products with other analgesics, decongestants, antitussives or expectorants, one or more combinations of each of the ingredients in a range as described in Table 1 below can be made depending on the specific therapeutic effect desired.

Example 72: Suspension Formula

[0309] A suspension formula in accordance with the present invention which comprises diphenhydramine hydrochloride and phenylephrine tannate is illustrated as follows:

Ingredients 10OmL 833.33 L

Diphenhydramine Hydrochloride 0.250 2.083

Phenylepherine Tannate 0.800 6.667

Silica, colloidal anhydrous, NF 1.73 14.417

Hydroxyethylcellulose, NF 0.05 0.417

Sorbitol Solution 70% (non-crystallizing), NF 34.00 283.333

Glycerol 15.00 125.000

Xylitol, NF 16.00 133.333

Sodium Citrate, U.S. Patent No. 2.00 16.667

Saccharin Sodium cryst, USP, 0.01 0.083

Sodium Benzoate, NF 0.15 1.250

Citric Acid Monohydrate, USP 0.16 1.333

Strawberry Flavor 0.15 1.250 Banana Flavor 0.15 1.250

Purified Water QS QS

Total Amount 10O mL 833.33 L

[0310] Manufacturing process for 833.33 L batch: In a suitably sized stainless steel vessel, dissolve saccharin sodium, sodium benzoate, citric acid, and sodium citrate in approximately 50 L of warm (about 45 ⁰C), purified water. In another large stainless steel drum mix the silica, diphenhydramine hydrochloride and micronized phenylephrine tannate until a uniform and consistent mixture is obtained. In a separate 1000 L stainless steel tank equipped with a suitably sized homogenizer/disperser add about 100 L of purified water. With the homogenizer on, add the silica mixture containing phenylephrine tannate and diphenhydramine hydrochloride. Add the previously prepared solution of saccharin sodium, sodium benzoate, citric acid, and sodium citrate to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinsate to the 1000 L tank. Add the remaining ingredients, qs to 833.33 L and homogenize for 15 minutes. Filter product through a 10 micron filter and fill in appropriately sized containers.

[0311] To make products with other antihistamines, decongestants, antitussives, or expectorants, one or more combinations of each of the ingredients in a range as described in Table 1 below can be made depending on the specific therapeutic effect desired.

Example 73: Bi-layered Tablet (Direct Compression)

[0312] A bi-layered tablet in accordance with the present invention which comprises diphenhydramine hydrochloride in one layer and phenylephrine hydrochloride and diphenhydramine hydrochloride in the other layer is illustrated as follows:

Manufacturing process

[0313] (a) Immediate release layer: Screen all ingredients through a USP sieve size # 30.

Blend diphenhydramine hydrochloride, silicifϊed microcrystalline cellulose and sodium starch glycolate in a twin shell blender for 20 minutes. Add magnesium stearate which acts as a lubricant, to the above blend and mix for 3 minutes.

[0314] (b) Sustained release layer: Screen all ingredients through a USP sieve size # 30.

Preblend a portion (about 1/3) of the Kollidon SR and all the diphenydramine hydrochloride for 15 minutes. Add the remaining Kollidon SR, phenylephrine hydrochloride, lactose monohydrate and dicalcium phosphate to the above preblend and mix for an additional 20 minutes. Add stearic acid and magnesium stearate to the above blend and mix for three minutes.

[0315] Manufacture bi-layered tablets using a rotary bi-Iayer tablet press where in each tablet the immediate release layer is 225 mg and the sustained release layer is 500 mg.

[0316] By using the process described above, a bi-layered tablet of the following composition may be manufactured through direct compression:

Example 74: Bi-layered Tablet (Wet Granulation):

[0317] A bi-layered tablet in accordance with the present invention which comprises diphenhydramine hydrochloride in one layer and pseudoephedrine hydrochloride and diphenhydramine hydrochloride in the other layer is illustrated as follows:

Manufacturing process

[0318] (a) Immediate release layer: Screen all ingredients through a USP sieve size # 30. Blend diphenhydramine hydrochloride, silicified microcrystalline cellulose and croscarmellose sodium in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (4.3 gms povidone in 14.3 gms purified water). Dry the granulation until the loss on drying (LOD) is less than 2.0 %. Screen the dried granulation through a USP sieve size # 14. Add the screened granulation and the prescreened magnesium stearate to the above blend and mix for 3 minutes.

[0319] (b) Sustained release layer: Screen all ingredients through a USP sieve size # 30. Blend the pseudoephedrine hydrochloride , diphenhydramine hydrochloride, Prosolv® (silicified microcrystalline cellulose), lactose monohydrate, dicalcium phosphate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add granules and the prescreened magnesium stearate to the above blend and mix for 3 minutes.

[0320] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet the immediate release layer is 225 mgs and the sustained release layer is 575 mgs. [0321] By using the process described above, a bi-layered tablet of the following composition may be manufactured through wet granulation:

[0322] The above examples 63-74 illustrate how to manufacture a bi-layered tablet containing an antihistamine, i.e., diphenhydramine hydrochloride in one layer and a decongestant and/or an antitussive and/or an expectorant and/or an analgesic in the other layer (optionally in combination with diphenhydramine hydrochloride). One or more of the non- limiting examples of active ingredients which may be used in combination with diphenhydramine hydrochloride depending on the specific therapeutic effect desired are listed in the above Table 1 together with exemplary ranges thereof.

Example 75: Extended Release Suspension

[0323] The formula described above serves as a non-limiting example. Any active drug which is in the form of a salt, such as diphenhydramine hydrochloride, codeine phosphate, pseudoephedrine hydrochloride, morphine sulfate, or meperidine hydrochloride can be incorporated as an ion-exchange resin complex.

Procedure:

[0324] (1) Add the appropriate amount of sodium polystyrene sulphonate USP (e.g.

Amberlite® IRP 88N) to a diphenhydramine hydrochloride and phenylephrine HCl solution.

(2) Stir the mix for 12 hrs to allow complete drug/resin complex formation.

(3) Separate and dry the insoluble drug/resin complex.

(4) Granulate the drug/resin complex with a delayed release/enteric polymer (e.g. Eugragit® L 100, Kollidon® MAE, Aquacoat® PD) and dry the granules.

(5) Mill the granules, if needed. (6) To an appropriate amount of water add the following ingredients and dissolve: Carbomer (e.g., Carbopol® 974), glycerin, polysorbate 80, methyl paraben, propyl paraben, artificial grape flavor, FD&C red # 40 dye.

(7) Add milled granules.

(8) Add water to make up to a final volume.

(9) Adjust pH to the desired viscosity to keep all the solid materials in suspension.

(10) Agitate at suitable rate to avoid settling of the suspension and maintain a homogeneous product mixture.

Example 76: Bi-layered Tablet (Wet granulation)

[0325] A bilayered tablet in accordance with the present invention which comprises diphenhydramine hydrochloride and guaifenesin in both layers as sustained release layers is illustrated as follows.

[0326] Procedure

1. Set aside 0.5 kg of purified water to be used as a rinse in step 4.

2. Prepare a solution using the scale up amounts of Povidone K-30, and the remaining Purified Water. 3. Blend the pre-blend scale up amounts of Guaifenesin USP, Diphenhydramine HCl USP, and Calcium Phosphate Dibasic Anhydrous using a high shear mixer/granulator for 10 minutes.

6. Dry the granulation until the LOD is 1% or less.

8. Screen the final blend raw materials through a 12 mesh screen.

10. Screen the lube blend material through a 30 mesh screen.

12. Discharge half of the blended product into properly labeled drums double lined with polyethylene bags and set aside for step 16.

13. Screen the color blend material through a 30 mesh screen.

15. Discharge into properly labeled drums double lined with polyethylene bags and set aside for step 16.

16. Compress bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer 1 is 450 mg and layer 2 is 475 mg.

Example 77: Bi-layered Tablet (Wet granulation)

[0327] A bilayered tablet in accordance with the present invention which comprises diphenhydramine hydrochloride in a sustained release layer and carbetapentane in an immediate release layer is illustrated as follows.

Formula

Amounts

Procedure

[0328] Sustained Release Layer (Layer 1^*)

1. Set aside 0.5 kg of purified water to be used in step 4.

3. Blend the pre-blend scale up amounts of Diphenhydramine HCl USP, Calcium Phosphate Dibasic Dihydrate, and Prosolv SMCC 90 with a high shear mixer/granulator for 10 minutes.

6. Dry the granulation until the LOD is 4% or less.

8. Screen the final blend scale up amount of Methocel K4M premium through a 14 mesh screen.

11. Transfer the screened Magnesium Stearate to the V-blender and blend for 3 minutes. When completed discharge into properly identified drums double lined with polyethylene bags.

[0329] Immediate Release Layer (Layer 2)

1. Set aside 0.5 kg of purified water to be used in step 4.

2. Prepare a solution using the scale up amount of Povidone K-30, and the remaining purified water from step 1.

5. Dry the granulation until the LOD is 4% or less.

8. Blend the milled granulation from step 6 and the screened materials from step 7 using a V-blender for 20 minutes. 9. Screen the lube scale up amount of Magnesium Stearate using a 30 mesh screen.

10. Transfer the screened Magnesium Stearate to the V-blender and blend for 3 minutes. When completed discharge into properly identified drums double lined with polyethylene bags.

11. Compress bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer 1 is 400.0 mg and layer 2 is 400 mg.

Example 78: Once-A-Day Dosage Form

[0330] A bi-layered tablet for administration every 24 hours which comprises 100 mg of promethazine hydrochloride is illustrated as follows:

[0331] Manufacturing process: The active ingredients and excipients are mixed in a high shear mixer/granulator for about 10 minutes. The granulation solution, water and PovidoneK30 (polyvinyl pyrrolidone) are pumped into the contents of the granulator to wet the powder. After the solution is added the post mix sustained release matrix ingredient Methocel K4M premium (hydroxypropyl methylcellulose) is added and the contents are mixed until a uniform granulation is developed. Upon completion of the granulation process, the wet mass is dried at 45 ⁰C. The dried granulation powder is milled using a Fitzmill and blended in a V-B lender with other excipients. The dye is added to one half of the granulation powder. This granulation material in powder form is ready for compression on a bi-layer tablet press. Final tablet weight is 350 mg.

Example 79: Once-A-Day Dosage Form

[0332] A bi-layered tablet for once-a-day administration which comprises 100 mg of promethazine hydrochloride in an immediate release layer and 240 mg of pseudoephedrine hydrochloride in a sustained release layer is illustrated as follows:

Immediate Release Layer

Sustained Release Layer

Manufacturing process:

[0333] Promethazine HCl (^"Immediate Release Layer)

1. Blend the dry mix amounts of Promethazine HCI, Calcium Phosphate Dibasic Dihydrate, and Prosolv SMCC 90 with a high sheer mixer/granulator for 10 minutes.

2. With the mixer/granulator on, pump the Eudragit RS 30D into the mixer/granulator. After completion, stop the mixer/granulator and rinse the container with Purified Water. Pump the rinse water to the mixer/granulator with mixer on. Turn off mixer when completed.

3. Charge the post mix amount of Methocel K4M premium to the mixer/granulator and mix for 1 minute.

4. Dry the granulation until the LOD (loss on Drying) is 4% or less.

5. Resize the dried granulation through a number 14 mesh screen.

6. Mix approximately 30% of the remaining Methocel K4M premium with the Colloidal Silicon Dioxide in an appropriate bag. Screen through a 30 mesh screen.

7. Screen the remaining amount of Methocel K4M premium through a number 14 mesh screen.

8. Blend the screened materials from steps 5, 6 and 7 using a V-blender for 20 minutes.

9. Screen the Magnesium Stearate using a number 30 mesh screen. 10. Transfer the screened Magnesium Stearate to the V-blender and blend for 3 minutes. When completed discharge and set aside for step 11 below.

[0334] Pseudoephedrine HCl (Sustained release laver)

1. Prepare a solution using the Povidone K-30, and Purified Water.

2. Blend the Pseudoephedrine HCl, Calcium Phosphate Dibasic USP Dihydrate, FD&C Blue #1 Aluminum Lake, and Prosolv SMCC 90 with a high sheer mixer/granulator for 10 minutes.

3. With the mixer/granulator on, pump the solution prepared in step 1 in to the mixer/granulator. After completion, stop the mixer/granulator and rinse the container with Purified Water. Pump the rinse water to the mixer/granulator with mixer on. Allow mixture to mix for an additional minute then turn mixer/granulator off.

4. Charge the post mix amount of Methocel K4M premium to the mixer/granulator and mix for 1 minute.

5. Dry the granulation until the LOD is 4% or less.

6. Resize the dried granulation through a number 14 mesh screen.

7. Screen the final blend amount of Methocel K4M premium through a number 14 mesh screen.

8. Screen the final blend amounts of Stearic Acid and FD&C Blue #1 Aluminum Lake through a number 30 mesh screen.

9. Blend the screened materials from step 6, 7, and 8 using a V-blender for 20 minutes.

10. Screen the lube amount of Magnesium Stearate using a number 30 mesh screen.

11. Transfer the screened Magnesium Stearate to the V-blender and blend for 3 minutes. When completed discharge and set aside for step 10.

12. Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer 1 is 300.0 mg and layer 2 is 450.0 mg.

Example 80: Bi-Layered Tablet

[0335] A bi-layered tablet for once-a-day administration which comprises 200 mg of diphenhydramine hydrochloride in a first layer and 240 mg of pseudoephedrine hydrochloride in a second layer is illustrated as follows: Diphenhydramine Layer

* Aqueous suspension (30 % b. w.); water is removed during drying stage

Pseudoephedrine Layer

Aqueous suspension (30 % b. w.); water is removed during ry ng stage

[0336] Manufacturing Process: Each layer is processed separately until the final compression. The dry mix components are blended in a Lodige mixer for ten minutes (mixer blades on). The sustained release agent (Eudragit dispersion) is then pumped into the dry mix (the suspension is stirred all times before and during pumping to avoid solids settlement). The postmix component (Methocel K4M Premium) is added into the Lodige mixer, the choppers are turned on and the blend is kept for another minute. The product is discharged and poured onto trays for drying in an oven for 18 hours at 45 ⁰C. The granules as well as the final blend components are milled at high speed in a Fitzmill (knives forward) through a US # 14 screen and loaded into a "V"-blender. The product is blended for 15 minutes; the lube blend component (Magnesium stearate) is passed through an oscillating granulator (US # 30 screen) and is then added to the "V"-blender for a final blend of 3 minutes. The layer formulations are poured into different hoppers of the tableting machine to compress bi-layered tablets at 700 mg of tablet weight.

[0337] It is noted that the foregoing examples have been provided merely for the purpose of explanation and are in no way to be construed as limiting of the present invention. While the present invention has been described with reference to exemplary embodiments, it is understood that the words which have been used herein are words of description and illustration, rather than words of limitation. Changes may be made, within the purview of the appended claims, as presently stated and as amended, without departing from the scope and spirit of the present invention in its aspects. Although the present invention has been described herein with reference to particular means, materials and embodiments, the present invention is not intended to be limited to the particulars disclosed herein; rather, the present invention extends to all functionally equivalent structures, methods and uses, such as are within the scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical dosage form comprising (a) a first drug which is selected from decongestants, antitussives, expectorants, analgesics and antihistamines, and (b) a second drug which is selected from decongestants, antitussives, expectorants, analgesics and antihistamines, wherein the dosage form provides a plasma concentration within the therapeutic range of the second drug over a period which is coextensive with at least about 70 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug.

2. The dosage form of claim 1, wherein the first drug comprises a decongestant.

3. The dosage form of claim 2, wherein the decongestant comprises at least one of phenylephrine, pseudoephedrine and pharmaceutically acceptable salts thereof.

4. The dosage form of claim 3, wherein the decongestant comprises at least one of phenylephrine and a pharmaceutically acceptable salt thereof.

5. The dosage form of claim 3, wherein the decongestant comprises at least one of pseudoephedrine and a pharmaceutically acceptable salt thereof.

6. The dosage form of claim 1, wherein the first drug comprises an antitussive.

7. The dosage form of claim 6, wherein the antitussive comprises at least one of a morphine derivative, dextromethorphan, carbetapentane, chlophedianol, benzonatate, caramiphen, noscapine and pharmaceutically acceptable salts thereof.

8. The dosage form of claim 7, wherein the antitussive comprises at least one of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof.

9. The dosage form of claim 7, wherein the antitussive comprises at least one of carbetapentane and a pharmaceutically acceptable salt thereof.

10. The dosage form of claim 7, wherein the antitussive comprises at least one of chlophedianol and a pharmaceutically acceptable salt thereof.

11. The dosage form of claim 1, wherein the first drug comprises an antihistamine.

12. The dosage form of claim 11, wherein the antihistamine comprises at least one of astemizole, azatadine, azelastine, bromodiphenhydramine, brompheniramine, carbinoxamine, cetirizine, chlorcyclizine, clemastine, chlorothen, chlorpheniramine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexbrompheniramine, dimethindene, diphenhydramine, diphenylpyraline, doxylamine, fexofenadine, hydroxyzine, isothipendyl, loratadine, methapyrilene, montelukast, phenindamine, pheniramine, phenyltoloxamine, promethazine, prophenpyridamine, pyrilamine, terfenadine, thenyldiamine, thonzylamine, trimeprazine, tripelennamine, triprolidine, and pharmaceutically acceptable salts thereof.

13. The dosage form of claim 11, wherein the antihistamine comprises at least one of promethazine, diphenhydramine, chlorpheniramine and pharmaceutically acceptable salts thereof.

14. The dosage form of claim 11, wherein the antihistamine comprises at least one of carbinoxamine and a pharmaceutically acceptable salt thereof.

15. The dosage form of claim 1, wherein the first drug comprises an analgesic.

16. The dosage form of claim 15, wherein the analgesic comprises at least one of aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, hydrocodone, oxycodone, morphine, meperidine, and fentanyl.

17. The dosage form of claim 1, wherein the first drug comprises an expectorant.

18. The dosage form of claim 17, wherein the expectorant comprises at least one of guaifenesin and a pharmaceutically acceptable salt thereof.

19. The dosage form of claim 2, wherein the second drug comprises an antitussive.

20. The dosage form of claim 19, wherein the antitussive comprises at least one of a morphine derivative, dextromethorphan, carbetapentane, chlophedianol, benzonatate, caramiphen, noscapine and pharmaceutically acceptable salts thereof.

21. The dosage form of claim 19, wherein the antitussive comprises at least one of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof.

22. The dosage form of claim 2, wherein the second drug comprises an antihistamine.

23. The dosage form of claim 22, wherein the antihistamine comprises at least one of astemizole, azatadine, azelastine, bromodiphenhydramine, brompheniramine, carbinoxamine, cetirizine, chlorcyclizine, clemastine, chlorothen, chlorpheniramine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexbrompheniramine, dimethindene, diphenhydramine, diphenylpyraline, doxylamine, fexofenadine, hydroxyzine, isothipendyl, loratadine, methapyrilene, montelukast, phenindamine, pheniramine, phenyltoloxamine, promethazine, prophenpyridamine, pyrilamine, terfenadine, thenyldiamine, thonzylamine, trimeprazine, tripelennamine, triprolidine, and pharmaceutically acceptable salts thereof.

24. The dosage form of claim 22, wherein the antihistamine comprises at least one of promethazine, diphenhydramine, chlorpheniramine and pharmaceutically acceptable salts thereof.

25. The dosage form of claim 22, wherein the antihistamine comprises at least one of carbinoxamine and a pharmaceutically acceptable salt thereof.

26. The dosage form of claim 2, wherein the second drug comprises an analgesic.

27. The dosage form of claim 26, wherein the analgesic comprises at least one of aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, hydrocodone, oxycodone, morphine, meperidine, and fentanyl.

28. The dosage form of claim 2, wherein the second drug comprises an expectorant.

29. The dosage form of claim 28, wherein the expectorant comprises at least one of guaifenesin and a pharmaceutically acceptable salt thereof.

30. The dosage form of claim 7, wherein the second drug comprises a decongestant.

31. The dosage form of claim 30, wherein the decongestant comprises at least one of phenylephrine, pseudoephedrine and pharmaceutically acceptable salts thereof.

32. The dosage form of claim 6, wherein the second drug comprises an antihistamine.

33. The dosage form of claim 32, wherein the antihistamine comprises at least one of astemizole, azatadine, azelastine, bromodiphenhydramine, brompheniramine, carbinoxamine, cetirizine, chlorcyclizine, clemastine, chlorothen, chlorpheniramine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexbrompheniramine, dimethindene, diphenhydramine, diphenylpyraline, doxylamine, fexofenadine, hydroxyzine, isothipendyl, loratadine, methapyrilene, montelukast, phenindamine, pheniramine, phenyltoloxamine, promethazine, prophenpyridamine, pyrilamine, terfenadine, thenyldiamine, thonzylamine, trimeprazine, tripelennamine, triprolidine, and pharmaceutically acceptable salts thereof.

34. The dosage form of claim 32, wherein the antihistamine comprises at least one of promethazine, diphenhydramine, chlorpheniramine and pharmaceutically acceptable salts thereof.

35. The dosage form of claim 32, wherein the antihistamine comprises at least one of carbinoxamine and a pharmaceutically acceptable salt thereof.

36. The dosage form of claim 6, wherein the second drug comprises an analgesic.

37. The dosage form of claim 36, wherein the analgesic comprises at least one of aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, hydrocodone, oxycodone, morphine, meperidine, and fentanyl.

38. The dosage form of claim 6, wherein the second drug comprises an expectorant.

39. The dosage form of claim 38, wherein the expectorant comprises at least one of guaifenesin and a pharmaceutically acceptable salt thereof.

40. The dosage form of claim 12, wherein the second drug comprises a decongestant.

41. The dosage form of claim 40, wherein the decongestant comprises at least one of phenylephrine, pseudoephedrine and pharmaceutically acceptable salts thereof.

42. The dosage form of claim 12, wherein the second drug comprises an antitussive.

43. The dosage form of claim 42, wherein the antitussive comprises at least one of a morphine derivative, dextromethorphan, carbetapentane, chlophedianol, benzonatate, caramiphen, noscapine and pharmaceutically acceptable salts thereof.

44. The dosage form of claim 42, wherein the antitussive comprises at least one of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof.

45. The dosage form of claim 11, wherein the second drug comprises an analgesic.

46. The dosage form of claim 45, wherein the analgesic comprises at least one of aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, hydrocodone, oxycodone, morphine, meperidine, and fentanyl.

47. The dosage form of claim 11, wherein the second drug comprises an expectorant.

48. The dosage form of claim 47, wherein the expectorant comprises at least one of guaifenesin and a pharmaceutically acceptable salt thereof.

49. The dosage form of claim 16, wherein the second drug comprises a decongestant.

50. The dosage form of claim 49, wherein the decongestant comprises at least one of phenylephrine, pseudoephedrine and pharmaceutically acceptable salts thereof.

51. The dosage form of claim 16, wherein the second drug comprises an antitussive.

52. The dosage form of claim 51, wherein the antitussive comprises at least one of a morphine derivative, dextromethorphan, carbetapentane, chlophedianol, benzonatate, caramiphen, noscapine and pharmaceutically acceptable salts thereof.

53. The dosage form of claim 51, wherein the antitussive comprises at least one of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof.

54. The dosage form of claim 16, wherein the second drug comprises an antihistamine.

55. The dosage form of claim 54, wherein the antihistamine comprises at least one of astemizole, azatadine, azelastine, bromodiphenhydramine, brompheniramine, carbinoxamine, cetirizine, chlorcyclizine, clemastine, chlorothen, chlorpheniramine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimethindene, diphenhydramine, diphenylpyraline, doxylamine, fexofenadine, hydroxyzine, isothipendyl, loratadine, methapyrilene, montelukast, phenindamine, pheniramine, phenyltoloxamine, promethazine, prophenpyridamine, pyrilamine, terfenadine, thenyldiamine, thonzylamine, trimeprazine, tripelennamine, triprolidine, and pharmaceutically acceptable salts thereof.

56. The dosage form of claim 54, wherein the antihistamine comprises at least one of promethazine, diphenhydramine, chlorpheniramine and pharmaceutically acceptable salts thereof.

57. The dosage form of claim 54, wherein the antihistamine comprises promethazine.

58. The dosage form of claim 15, wherein the second drug comprises at least one of carbinoxamine and a pharmaceutically acceptable salt thereof.

59. The dosage form of claim 58, wherein the expectorant comprises at least one of guaifenesin and a pharmaceutically acceptable salt thereof.

60. The dosage form of any one of claims 1 to 59, wherein the plasma half-life of the second drug differs from the plasma half-life of the first drug by at least about 2 hours.

61. The dosage form of any one of claims 1 to 60, wherein the plasma half-life of the second drug differs from the plasma half-life of the first drug by at least about 3 hours.

62. The dosage form of any one of claims 1 to 61, wherein the plasma half-life of the second drug differs from the plasma half-life of the first drug by at least about 4 hours.

63. The dosage form of any one of claims 1 to 62, wherein the period of a plasma concentration within the therapeutic range of the second drug is coextensive with at least about 80 % of the period of a plasma concentration within the therapeutic range of the first drug.

64. The dosage form of any one of claims 1 to 63, wherein the period of a plasma concentration within the therapeutic range of the second drug is coextensive with at least about 90 % of the period of a plasma concentration within the therapeutic range of the first drug.

65. The dosage form of any one of claims 1 to 64, wherein the period of a plasma concentration within the therapeutic range of the second drug is coextensive with at least about 95 % of the period of a plasma concentration within the therapeutic range of the first drug.

66. The dosage form of any one of claims 1 to 65, wherein the period of a plasma concentration within the therapeutic range of the second drug is substantially coextensive with the period of a plasma concentration within the therapeutic range of the first drug.

67. The dosage form of any one of claims 1 to 66, wherein the dosage form comprises a tablet.

68. The dosage form of claim 67, wherein the tablet comprises a matrix which comprises one of the first drug and the second drug and has dispersed therein particles which comprise the other one of the first drug and the second drug.

69. The dosage form of any one of claims 1 to 66, wherein the dosage form comprises a solution or a suspension.

70. A bi-layered tablet which comprises a first layer and a second layer, the first layer comprising a first drug which is selected from decongestants, antitussives, expectorants, analgesics and antihistamines, and the second layer comprising a second drug which is selected from decongestants, antitussives, expectorants, analgesics and antihistamines and is different from the first drug, wherein the bi-layered tablet provides a plasma concentration within the therapeutic range of the second drug over a period which is coextensive with at least about 70 % of the period over which the bi-layered tablet provides a plasma concentration within the therapeutic range of the first drug.

71. The bi-layered tablet of claim 70, wherein the first drug comprises one or more of phenylephrine, pseudoephedrine, codeine, dihydrocodeine, hydrocodone, dextromethorphan, carbetapentane, chlophedianol, benzonatate, caramiphen, noscapine, guaifenesin, astemizole, azatadine, azelastine, bromodiphenhydramine, brompheniramine, carbinoxamine, cetirizine, chlorcyclizine, clemastine, chlorothen, chlorpheniramine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimethindene, diphenhydramine, diphenylpyraline, doxylamine, fexofenadine, hydroxyzine, isothipendyl, loratadine, methapyrilene, montelukast, phenindamine, pheniramine, phenyltoloxamine, promethazine, prophenpyridamine, pyrilamine, terfenadine, thenyldiamine, thonzylamine, trimeprazine, tripelennamine, triprolidine, and pharmaceutically acceptable salts thereof, aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, hydrocodone, oxycodone, morphine, meperidine, and fentanyl.

72. The bi-layered tablet of claim 71, wherein the second drug is different from the first drug and comprises one or more of phenylephrine, pseudoephedrine, codeine, dihydrocodeine, hydrocodone, dextromethorphan, carbetapentane, chlophedianol, benzonatate, caramiphen, noscapine, guaifenesin, astemizole, azatadine, azelastine, bromodiphenhydramine, brompheniramine, carbinoxamine, cetirizine, chlorcyclizine, clemastine, chlorothen, chlorpheniramine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimethindene, diphenhydramine, diphenylpyraline, doxylamine, fexofenadine, hydroxyzine, isothipendyl, loratadine, methapyrilene, montelukast, phenindamine, pheniramine, phenyltoloxamine, promethazine, prophenpyridamine, pyrilamine, terfenadine, thenyldiamine, thonzylamine, trimeprazine, tripelennamine, triprolidine, and pharmaceutically acceptable salts thereof, aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, hydrocodone, oxycodone, morphine, meperidine, and fentanyl.

73. The bi-layered tablet of any one of claims 70 to 72, wherein the period of a plasma concentration within the therapeutic range of the second drug is coextensive with at least about 80 % of the period of a plasma concentration within the therapeutic range of the first drug.

74. The bi-layered tablet of any one of claims 70 to 73, wherein the period of a plasma concentration within the therapeutic range of the second drug is coextensive with at least about 90 % of the period of a plasma concentration within the therapeutic range of the first drug.

75. The bi-layered tablet of any one of claims 70 to 74, wherein the period of a plasma concentration within the therapeutic range of the second drug is coextensive with at least about 95 % of the period of a plasma concentration within the therapeutic range of the first drag.

76. The bi-layered tablet of any one of claims 70 to 75, wherein the period of a plasma concentration within the therapeutic range of the second drug is substantially coextensive with the period of a plasma concentration within the therapeutic range of the first drug.

77. The bi-layered tablet of any one of claims 70 to 76, wherein the plasma half-life of the second drug differs from the plasma half-life of the first drug by at least about 2 hours.

78. The bi-layered tablet of any one of claims 70 to 77, wherein the plasma half-life of the second drug differs from the plasma half-life of the first drug by at least about 3 hours.

79. The bi-layered tablet of any one of claims 70 to 78, wherein one of the first and second layers is an immediate release layer.

80. The bi-layered tablet of any one of claims 70 to 78, wherein the first and second layers are controlled release layers.

81. A multi-layered tablet which comprises at least a first layer and a second layer, wherein the first layer comprises a first drug which is selected from decongestants, antitussives, expectorants, analgesics and antihistamines and the second layer is a controlled release layer and comprises a second drug which is selected from decongestants, antitussives, expectorants, analgesics and antihistamines and is different from the first drug.

82. The multi-layered tablet of claim 81, wherein the first layer is an immediate release layer.

83. The multi-layered tablet of any one of claims 81 and 82, wherein the second layer is a controlled release layer.

84. The multi-layered tablet of any one of claims 81 to 83, wherein the second drug has a plasma half-life which differs from the plasma half-life of the first drug by at least about 3 hours.

85. The multi-layered tablet of any one of claims 81 to 84, wherein the tablet provides a plasma concentration within the therapeutic range of the second drug over a period which is coextensive with at least about 90 % of the period over which the tablet provides a plasma concentration within the therapeutic range of the first drug.

86. The multi-layered tablet of any one of claims 81 to 85, wherein the layers are discrete zones which are arranged adjacent to each other.

87. The multi-layered tablet of any one of claims 81 to 85, wherein one of the first and second layers is partially or completely surrounded by the other one of the first and second layers.

88. A pharmaceutical dosage form which comprises (a) a first drug which is selected from antihistamines and has a first plasma half-life and (b) a second drug which is selected from decongestants, antitussives, analgesics and expectorants and has a second plasma half-life that differs from the first plasma half-life by at least about 3 hours, wherein the dosage form provides a plasma concentration within the therapeutic range of the second drug over a period which is coextensive with at least about 80 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug.

89. The dosage form of claim 88, wherein the first plasma half-life is longer by at least about 4 hours than the second plasma half-life.

90. The dosage form of any one of claims 88 and 89, wherein the first plasma half-life is longer by at least about 6 hours than the second plasma half-life.

91. The dosage form of any one of claims 88 to 90, wherein the first plasma half-life is at least about 8 hours.

92. The dosage form of any one of claims 88 to 91, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 90 % of the period of a plasma concentration within the therapeutic range of the first drug.

93. The dosage form of any one of claims 88 to 92, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 95 % of the period of a plasma concentration within the therapeutic range of the first drug.

94. The dosage form of any one of claims 88 to 93, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is substantially coextensive with the period of a plasma concentration within the therapeutic range of the first drug.

95. The dosage form of any one of claims 88 to 94, wherein the dosage form is associated with instructions to administer the dosage form three or fewer times per day.

96. The dosage form of any one of claims 88 to 95, wherein the dosage form is associated with instructions to administer the dosage form once or twice per day.

97. The dosage form of any one of claims 88 to 96, wherein the dosage form comprises a tablet.

98. The dosage form of any one of claims 88 to 97, wherein the second drug comprises a decongestant.

99. The dosage form of any one of claims 88 to 98, wherein the antihistamine is selected from astemizole, azatadine, azelastine, bromodiphenhydramine, brompheniramine, carbinoxamine, cetirizine, chlorcyclizine, clemastine, chlorothen, chlorpheniramine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimethindene, diphenhydramine, diphenylpyraline, doxylamine, fexofenadine, hydroxyzine, isothipendyl, loratadine, methapyrilene, montelukast, phenindamine, pheniramine, phenyltoloxamine, promethazine, prophenpyridamine, pyrilamine, terfenadine, thenyldiamine, thonzylamine, trimeprazine, tripelennamine, triprolidine, and pharmaceutically acceptable salts thereof.

100. The dosage form of any one of claims 88 to 99, wherein the antihistamine comprises at least one of promethazine, diphenhydramine, chlorpheniramine and pharmaceutically acceptable salts thereof.

101. The dosage form of any one of claims 88 to 100, wherein the antihistamine comprises carbinoxamine.

102. The dosage form of any one of claims 88 to 101, wherein the second drug comprises a decongestant.

103. The dosage form of claim 102, wherein the decongestant comprises at least one of phenylephrine, pseudoephedrine and pharmaceutically acceptable salts thereof.

104. The dosage form of any one of claims 88 to 103, wherein the second drug comprises an antitussive.

105. The dosage form of claim 104, wherein the antitussive comprises at least one of a morphine derivative, dextromethorphan, carbetapentane, chlophedianol, benzonatate, caramiphen, noscapine and pharmaceutically acceptable salts thereof.

106. The dosage form of claim 104, wherein the antitussive comprises at least one of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof.

107. The dosage form of any one of claims 88 to 106, wherein the second drug comprises an analgesic.

108. The dosage form of claim 107, wherein the analgesic comprises at least one of aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, hydrocodone, oxycodone, morphine, meperidine, and fentanyl.

109. The dosage form of any one of claims 88 to 108, wherein the second drug comprises an expectorant.

110. The dosage form of claim 109, wherein the expectorant comprises at least one of guaifenesin and a pharmaceutically acceptable salt thereof.

111. A method of alleviating a condition which can be alleviated by administration of an antihistamine and at least one other condition which can be alleviated by administration of a drug which is at least one of a decongestant, antitussive, expectorant, and analgesic, wherein the method comprises administering the dosage form of any one of claims 88 to 110 to a subject in need thereof.

112. A process of making the pharmaceutical dosage form of claim 1, wherein the method comprises preparing a first composition which comprises the first drug and a second composition which comprises the second drug, and combining the first and the second compositions.

113. The process of claim 112, wherein the first and second compositions are combined by using a tablet press.

114. A pharmaceutical dosage form comprising (a) a first drug which is selected from decongestants, antitussives, expectorants and analgesics, and (b) a second drug which is selected from decongestants, antitussives, expectorants and analgesics and is different from the first drug, wherein the dosage form provides a plasma concentration within a therapeutic range of the second drug over a period which is coextensive with at least about 70 % of a period over which the dosage form provides a plasma concentration within a therapeutic range of the first drug and wherein the dosage form is substantially free of antihistamines.

115. The dosage form of claim 114, wherein the first drug comprises a decongestant.

116. The dosage form of claim 115, wherein the decongestant comprises at least one of phenylephrine, pseudoephedrine and pharmaceutically acceptable salts thereof.

117. The dosage form of claim 114, wherein the first drug comprises an antitussive.

118. The dosage form of claim 117, wherein the antitussive comprises at least one of a morphine derivative, dextromethorphan, carbetapentane, chlophedianol, benzonatate, caramiphen, noscapine and pharmaceutically acceptable salts thereof.

119. The dosage form of claim 117, wherein the antitussive comprises at least one of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof.

120. The dosage form of claim 117, wherein the antitussive comprises at least one of carbetapentane and a pharmaceutically acceptable salt thereof.

121. The dosage form of claim 114, wherein the first drug comprises an analgesic.

122. The dosage form of claim 121, wherein the analgesic comprises at least one of aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, hydrocodone, oxycodone, morphine, meperidine, and fentanyl.

123. The dosage form of claim 121, wherein the analgesic comprises a NSAID.

124. The dosage form of claim 114, wherein the first drug comprises an expectorant.

125. The dosage form of claim 124, wherein the expectorant comprises at least one of guaifenesin and a pharmaceutically acceptable salt thereof.

126. The dosage form of claim 115, wherein the second drug comprises an antitussive.

127. The dosage form of claim 126, wherein the antitussive comprises at least one of a morphine derivative, dextromethorphan, carbetapentane, chlophedianol, benzonatate, caramiphen, noscapine and pharmaceutically acceptable salts thereof.

128. The dosage form of claim 127, wherein the antitussive comprises at least one of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof.

129. The dosage form of claim 115, wherein the second drug comprises an analgesic.

130. The dosage form of claim 129, wherein the analgesic comprises at least one of aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, hydrocodone, oxycodone, morphine, meperidine, and fentanyl.

131. The dosage form of claim 129, wherein the analgesic comprises a NSAID.

132. The dosage form of claim 115, wherein the second drug comprises an expectorant.

133. The dosage form of claim 132, wherein the expectorant comprises at least one of guaifenesin and a pharmaceutically acceptable salt thereof.

134. The dosage form of claim 117, wherein the second drug comprises an analgesic.

135. The dosage form of claim 134, wherein the analgesic comprises at least one of aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, hydrocodone, oxycodone, morphine, meperidine, and fentanyl.

136. The dosage form of claim 134, wherein the analgesic comprises a NSAID.

137. The dosage form of claim 117, wherein the second drug comprises an expectorant.

138. The dosage form of claim 137, wherein the expectorant comprises at least one of guaifenesin and a pharmaceutically acceptable salt thereof.

139. The dosage form of claim 121, wherein the second drug comprises an expectorant.

140. The dosage form of claim 139, wherein the expectorant comprises at least one of guaifenesin and a pharmaceutically acceptable salt thereof.

141. The dosage form of any one of claims 114 to 140, wherein the plasma half-life of the second drug differs from the plasma half-life of the first drug by at least about 2 hours.

142. The dosage form of any one of claims 114 to 141, wherein the period of a plasma concentration within the therapeutic range of the second drug is substantially coextensive with the period of a plasma concentration within the therapeutic range of the first drug.

143. The dosage form of any one of claims 114 to 142, wherein the dosage form comprises a tablet.

144. A bi-layered tablet which comprises a first layer and a second layer, the first layer comprising a first drug which is selected from decongestants, antitussives, expectorants and analgesics, and the second layer comprising a second drug which is different from the first drug and is selected from decongestants, antitussives, expectorants and analgesics, wherein the bi-layered tablet provides a plasma concentration within a therapeutic range of the second drug over a period which is coextensive with at least about 70 % of a period over which the bi-layered tablet provides a plasma concentration within a therapeutic range of the first drug and wherein the bi-layered tablet is substantially free of antihistamines.

145. The bi-layered tablet of claim 144, wherein the first drug is selected from one or more of phenylephrine, pseudoephedrine, codeine, dihydrocodeine, hydrocodone, dextromethorphan, carbetapentane, chlophedianol, benzonatate, caramiphen, noscapine, guaifenesin, and pharmaceutically acceptable salts thereof, aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, hydrocodone, oxycodone, morphine, meperidine, and fentanyl.

146. The bi-layered tablet of claim 145, wherein the second drug is different from the first drug and is selected from one or more of phenylephrine, pseudoephedrine, codeine, dihydrocodeine, hydrocodone, dextromethorphan, carbetapentane, chlophedianol, benzonatate, caramiphen, noscapine, guaifenesin, and pharmaceutically acceptable salts thereof, aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, hydrocodone, oxycodone, morphine, meperidine, and fentanyl.

147. The bi-layered tablet of any one of claims 144 to 146, wherein the period of a plasma concentration within the therapeutic range of the second drug is substantially coextensive with the period of a plasma concentration within the therapeutic range of the first drug.

148. The bi-layered tablet of any one of claims 144 to 147, wherein the plasma half-life of the second drug differs from the plasma half-life of the first drug by at least about 2 hours.

149. The bi-layered tablet of any one of claims 144 to 148, wherein one of the first and second layers is an immediate release layer.

150. The bi-layered tablet of any one of claims 144 to 148, wherein the first and second layers are controlled release layers.

151. A method of alleviating a condition which can be alleviated by administration of at least two drugs which are selected form decongestants, antitussives, expectorants and analgesics, wherein the method comprises administering the dosage form of any one of claims 114 to 143 to a subject in need thereof.

152. The dosage form of claim 1, wherein the dosage form comprises at least one of carbinoxamine and a pharmaceutically acceptable salt thereof as a first drug and at least one of pseudoephedrine and a pharmaceutically acceptable salt thereof as a second drug.

153. The bi-layered tablet of claim 70, wherein the dosage form comprises at least one of carbinoxamine and a pharmaceutically acceptable salt thereof as a first drug and at least one of pseudoephedrine and a pharmaceutically acceptable salt thereof as a second drug.

154. The dosage form of claim 114, wherein the dosage form comprises an NSAID as a first drug and at least one of pseudoephedrine, phenylephrine, guaifenesin, codeine, dihydrocodeine, hydrocodone, carbetapentane and pharmaceutically acceptable salts thereof as a second drug.

155. The dosage form of claim 154, wherein the NSAID comprises at least one of ibuprofen, ketoprofen, naproxen and sodium naproxen.

156. The bi-layered tablet of claim 144, wherein the dosage form comprises an NSAID as a first drug and at least one of pseudoephedrine, phenylephrine, guaifenesin, codeine, dihydrocodeine, hydrocodone, carbetapentane and pharmaceutically acceptable salts thereof as a second drug.

157. A pharmaceutical dosage form which comprises (a) a first drug which is at least one of promethazine and a pharmaceutically acceptable salt thereof and (b) at least one second drug, wherein the dosage form provides a plasma concentration within the therapeutic range of the at least one second drug over a period which is coextensive with at least about 70 % of the period over which the dosage form provides a plasma concentration within a therapeutic range of the first drug.

158. The dosage form of claim 157, wherein the at least one second drug is selected from decongestants, antitussives, expectorants, mucus thinning drugs, analgesics and antihistamines.

159. The dosage form of any one of claims 157 and 158, wherein the first drug comprises promethazine hydrochloride.

160. The dosage form of any one of claims 157 to 159, wherein the at least one second drug comprises an antitussive.

161. The dosage form of claim 160, wherein the antitussive comprises one or more of codeine, dihydrocodeine, hydrocodone, dextromethorphan and pharmaceutically acceptable salts thereof.

162. The dosage form of any one of claims 157 to 161, wherein the at least one second drug comprises a decongestant.

163. The dosage form of any one of claims 157 to 162, wherein the second drug comprises one or more of phenylepherine, pseudoephedrine and pharmaceutically acceptable salts thereof.

164. The dosage form of any one of claims 157 to 163, wherein the at least one second drug comprises an antihistamine.

165. The dosage form of claim 164, wherein the antihistamine comprises at least one of chlorpheniramine and pharmaceutically acceptable salts thereof.

166. The dosage form of any one of claims 157 to 165, wherein the at least one second drug comprises an expectorant.

167. The dosage form of claim 166, wherein the expectorant comprises guaifenesin.

168. The dosage form of any one of claims 157 to 167, wherein the plasma half-life of the at least one second drug is shorter than the plasma half-life of the first drug by at least about 3 hours.

169. The dosage form of any one of claims 157 to 168, wherein the plasma half-life of the at least one second drug is shorter than the plasma half-life of the first drug by at least about 4 hours.

170. The dosage form of any one of claims 157 to 169, wherein the plasma half-life of the at least one second drug is shorter than the plasma half-life of the first drag by at least about 6 hours.

171. The dosage form of any one of claims 157 to 170, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 80 % of the period of a plasma concentration within the therapeutic range of the first drug.

172. The dosage form of any one of claims 157 to 171, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 90 % of the period of a plasma concentration within the therapeutic range of the first drug.

173. The dosage form of any one of claims 157 to 172, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 95 % of the period of a plasma concentration within the therapeutic range of the first drug.

174. The dosage form of any one of claims 157 to 173, wherein the dosage form comprises a tablet.

175. The dosage form of claim 174, wherein the tablet has at least two layers.

176. The dosage form of claim 174, wherein the tablet is a bi-layered tablet.

177. The dosage form of claim 174, wherein the tablet comprises a matrix which comprises the first drug and has dispersed therein particles which comprise the at least one second drug.

178. The dosage form of claim 177, wherein the matrix has dispersed therein particles which comprise a second drug and a third drug.

179. The dosage form of claim 177, wherein the matrix has dispersed therein particles which comprise a second drug, a third drug and a fourth drug.

180. The dosage form of claim 177, wherein the matrix provides an immediate release of the first drug and the particles provide a controlled release of the at least one second drug.

181. The dosage form of any one of claims 157 to 173, wherein the dosage form comprises one of a solution and a suspension.

182. The dosage form of claim 181, wherein the dosage form comprises a suspension having particles therein which provide a controlled release of the at least one second drug.

183. A bi-layered tablet which comprises a first layer and a second layer, the first layer comprising a first drug which is at least one of promethazine and a pharmaceutically acceptable salt thereof, and the second layer comprising at least one second drug which is selected from decongestants, antitussives, expectorants, mucus thinning drugs, analgesics and antihistamines, wherein the bi-layered tablet provides a plasma concentration within the therapeutic range of the at least one second drug over a period which is coextensive with at least about 70 % of the period over which the bi-layered tablet provides a plasma concentration within the therapeutic range of the first drug.

184. The bi-layered tablet of claim 183, wherein the second layer comprises one or more of phenylephrine, pseudoephedrine, chlorpeniramine and pharmaceutically acceptable salts thereof.

185. The bi-layered tablet of any one of claims 183 and 184, wherein the first layer comprises promethazine hydrochloride and the second layer comprises at least two of phenylephrine, pseudoephedrine, chlorpeniramine and pharmaceutically acceptable salts thereof.

186. The bi-layered tablet of any one of claims 183 to 185, wherein the first layer comprises only promethazine or a pharmaceutically acceptable salt thereof as the active ingredient.

187. The bi-layered tablet of any one of claims 183 to 186, wherein the first layer comprises only promethazine hydrochloride as an active ingredient.

188. The bi-layered tablet of any one of claims 183 to 187, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 80 % of the period of a plasma concentration within the therapeutic range of the first drug.

189. The bi-layered tablet of any one of claims 183 to 188, wherein the period of a plasma concentration within a therapeutic range of the at least one second drug is coextensive with at least about 90 % of the period of a plasma concentration within a therapeutic range of the first drug.

190. The bi-layered tablet of any one of claims 183 to 189, wherein the first layer is an immediate release layer.

191. The bi-layered tablet of any one of claims 183 to 190, wherein the second layer is a controlled release layer.

192. The bi-layered tablet of any one of claims 183 to 191, wherein the first layer contains from about 0.1 mg to about 90 mg of promethazine hydrochloride.

193. The bi-layered tablet of any one of claims 183 to 192, wherein the first layer contains from about 25 mg to about 50 mg of promethazine hydrochloride.

194. The bi-layered tablet of any one of claims 183 to 193, wherein the second layer is a controlled release layer and contains at least one of (i) from about 0.1 mg to about 16 mg of chlorpheniramine maleate or an equivalent amount of at least one other pharmaceutically acceptable salt of chlorpheniramine; (ii) from about 1 mg to about 90 mg of phenylepherine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of phenylepherine; and (iii) from about 1 mg to about 240 mg of pseudoephedrine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of pseudoephedrine .

195. A multi-layered tablet which comprises at least a first layer and a second layer, wherein the first layer comprises at least one of promethazine and a pharmaceutically acceptable salt thereof and the second layer is a controlled release layer and comprises at least one drug which is selected from decongestants, antitussives, expectorants, mucus thinning drugs, analgesics and antihistamines.

196. The multi-layered tablet of claim 195, wherein the first layer is an immediate release layer.

197. The multi-layered tablet of any one of claims 195 and 196, wherein the first layer comprises promethazine hydrochloride.

198. The multi-layered tablet of any one of claims 195 to 197, wherein the first layer does not contain any active ingredient which is different from promethazine or a pharmaceutically acceptable salt thereof.

199. The multi-layered tablet of any one of claims 195 to 198, wherein the second layer comprises one or more of codeine, dihydrocodeine, hydrocodone, dextromethorphan, phenylepherine, pseudoephedrine, guaifenesin, chlorpheniramine and pharmaceutically acceptable salts thereof.

200. The multi-layered tablet of any one of claims 195 to 199, wherein the second layer comprises at least two of codeine, dihydrocodeine, hydrocodone, dextromethorphan, phenylepherine, pseudoephedrine, guaifenesin, chlorpheniramine and pharmaceutically acceptable salts thereof.

201. The multi-layered tablet of any one of claims 195 to 200, wherein the at least one drug in the second layer has a plasma half-life which is shorter by at least about 3 hours than the plasma half-life of the at least one of promethazine and a pharmaceutically acceptable salt thereof in the first layer.

202. The multi-layered tablet of any one of claims 195 to 201, wherein the first layer comprises promethazine hydrochloride and the tablet provides a plasma concentration within the therapeutic range of the at least one drug in the second layer over a period which is coextensive with at least about 80 % of the period over which the multi-layered tablet provides a plasma concentration within the therapeutic range of promethazine hydrochloride.

203. The multi -layered tablet of any one of claims 195 to 202, wherein the at least one drug in the second layer comprises one or more of phenylepherine, pseudoephedrine, chlorpheniramine and pharmaceutically acceptable salts thereof.

204. The multi-layered tablet of any one of claims 195 to 203, wherein the layers are discrete zones which are arranged adjacent to each other.

205. The multi-layered tablet of any one of claims 195 to 203, wherein the second layer is partially or completely surrounded by the first layer.

206. The multi-layered tablet of any one of claims 195 to 204, wherein the second layer is coated with the first layer.

207. A liquid dosage form which comprises (a) at least one of promethazine and a pharmaceutically acceptable salt thereof and (b) at least one drug which is selected from decongestants, expectorants, mucus thinning drugs, antitussives, analgesics and antihistamines, wherein the liquid dosage form provides a plasma concentration within the therapeutic range of component (b) over a period which is coextensive with at least about 70 % of the period over which the liquid dosage form provides a plasma concentration within the therapeutic range of component (a).

208. The liquid dosage form of claim 207, wherein the liquid dosage form comprises a suspension.

209. The liquid dosage form of any one of claims 207 and 208, wherein at least a part of component (b) is present as a complex with a complexing agent.

210. The liquid dosage form of any one of claims 207 to 209, wherein at least a part of component (a) is present as a complex with a complexing agent.

211. The liquid dosage form of any one of claims 209 and 210, wherein the complexing agent comprises an ion-exchange resin.

212. The suspension of claim 211, wherein the ion-exchange resin comprises sodium polystyrene sulfonate.

213. The suspension of claim 208, wherein the suspension comprises particles of a complex of at least a part of component (b) with an ion-exchange resin, which particles are provided, at least in part, with a controlled release coating.

214. The suspension of claim 213, wherein the controlled release coating comprises an organic polymer.

215. The suspension of claim 214, wherein the organic polymer comprises a polyacrylate.

216. A method of concurrently alleviating a condition which can be alleviated by administration of promethazine and at least one other condition which can be alleviated by administration of a drug which is at least one of a decongestant, antitussive, expectorant, mucus thinning drug, analgesic and antihistamine, wherein the method comprises administering the pharmaceutical dosage form of any one of claims 157 to 182 to a subject in need thereof.

217. A method of concurrently alleviating a condition which can be alleviated by administration of promethazine and at least one other condition which can be alleviated by administration of a drug which is at least one of a decongestant, antitussive, expectorant, mucus thinning drug, analgesic and antihistamine, wherein the method comprises administering the multi-layered tablet of any one of claims 195 to 206 to a subject in need thereof.

218. The method of claim 217, wherein the condition which can be alleviated by administration of promethazine comprises an allergic reaction.

219. The method of any one of claims 217 and 218, wherein the multi-layered tablet is administered not more than about three times per day.

220. The method of 217 and 218, wherein the multi-layered tablet is administered not more than about twice per day.

221. A method of concurrently alleviating a condition which can be alleviated by administration of promethazine and at least one other condition which can be alleviated by administration of a drug which is at least one of a decongestant, antitussive, expectorant, mucus thinning drug, analgesic and antihistamine, wherein the method comprises administering the liquid dosage form of any one of claims 207 to 215 to a subject in need thereof.

222. A process of making the pharmaceutical dosage form of claim 1, wherein the method comprises preparing a first composition which comprises the first drug and a second composition which comprises the at least one second drug, and combining the first and the second compositions to form the dosage form.

223. The process of claim 222, wherein the first and second compositions are combined by using a tablet press.

224. A pharmaceutical dosage form which comprises (a) a first drug which is an antihistamine and has a first plasma half-life and (b) at least one second drug which is selected from decongestants, antitussives, expectorants, mucus thinning drugs, analgesics and antihistamines and has a second plasma half-life which differs from the first plasma half-life by at least about 3 hours, wherein the dosage form provides a plasma concentration within the therapeutic range of the at least one second drug over a period which is coextensive with at least about 70 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug.

225. The dosage form of claim 224, wherein the first plasma half-life is longer by at least about 4 hours than the plasma half-life of the at least one second drug.

226. The dosage form of any one of claims 224 and 225, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 80 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug.

227. The dosage form of any one of claims 224 to 226, wherein the dosage form comprises a bi-layered tablet.

228. The dosage form of any one of claims 224 to 227, wherein the first plasma half-life is at least about 8 hours.

229. The dosage form of any one of claims 224 to 228, wherein the dosage form is associated with instructions to administer the dosage form three or fewer times per day.

230. A pharmaceutical dosage form which comprises (a) a first drug which comprises at least one morphine derivative having antitussive activity and (b) at least one second drug, wherein the dosage form provides a plasma concentration within the therapeutic range of the at least one second drug over a period which is coextensive with at least about 70 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug.

231. The dosage form of claim 230, wherein the at least one of morphine derivative comprises at least one of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof.

232. The dosage form of any one of claims 230 and 231, wherein the first drug comprises at least one of codeine phosphate, dihydrocodeine bitartrate and hydrocodone bitartrate.

233. The dosage form of any one of claims 230 to 232, wherein the first drug comprises codeine phosphate.

234. The dosage form of any one of claims 230 to 233, wherein the at least one second drug comprises at least one of a decongestant, expectorant, mucus thinning drug, and antihistamine.

235. The dosage form of any one of claims 230 to 234, wherein the at least one second drug comprises a decongestant.

236. The dosage form of any one of claims 230 to 235, wherein the second drug comprises at least one of phenylepherine, pseudoephedrine and pharmaceutically acceptable salts thereof.

237. The dosage form of any one of claims 230 to 236, wherein the at least one second drug comprises an antihistamine.

238. The dosage form of claim 237, wherein the antihistamine comprises at least one of chlorpheniramine, promethazine, carbinoxamine and pharmaceutically acceptable salts thereof.

239. The dosage form of any one of claims 230 to 238, wherein the at least one second drug comprises an expectorant.

240. The dosage form of claim 239, wherein the expectorant comprises guaifenesin.

241. The dosage form of any one of claims 230 to 240, wherein the plasma half-life of the at least one second drug differs from the plasma half-life of the first drug by at least about 2 hours.

242. The dosage form of any one of claims 230 to 241, wherein the plasma half-life of the at least one second drug differs from the plasma half-life of the first drug by at least about 3 hours.

243. The dosage form of any one of claims 230 to 242, wherein the plasma half-life of the at least one second drug differs from the plasma half-life of the first drug by at least about 4 hours.

244. The dosage form of any one of claims 230 to 243, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 80 % of the period of a plasma concentration within the therapeutic range of the first drug.

245. The dosage form of any one of claims 230 to 244, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 90 % of the period of a plasma concentration within the therapeutic range of the first drug.

246. The dosage form of any one of claims 230 to 245, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 95 % of the period of a plasma concentration within the therapeutic range of the first drug.

247. The dosage form of any one of claims 230 to 246, wherein the dosage form comprises a tablet.

248. The dosage form of claim 247, wherein the tablet comprises at least two layers.

249. The dosage form of claim 247, wherein the tablet is a bi-layered tablet.

250. The dosage form of claim 247, wherein the tablet comprises a matrix which comprises the first drug and has dispersed therein particles which comprise the at least one second drug.

251. The dosage form of any one of claims 230 to 246, wherein the dosage form comprises a solution or a suspension.

252. A bi-layered tablet which comprises a first layer and a second layer, the first layer comprising a first drug which comprises at least one morphine derivative having antitussive activity, and the second layer comprising at least one second drug which is selected from decongestants, expectorants, mucus thinning drugs, and antihistamines, wherein the bi-layered tablet provides a plasma concentration within the therapeutic range of the at least one second drug over a period which is coextensive with at least about 70 % of the period over which the bi-layered tablet provides a plasma concentration within the therapeutic range of the first drug.

253. The bi-layered tablet of claim 252, wherein the first layer comprises one or more of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof.

254. The bi-layered tablet of any one of claims 252 and 253, wherein the second layer comprises one or more of phenylepherine, pseudoephedrine, chlorpheniramine, carbinoxamine, promethazine, guaifenesin and pharmaceutically acceptable salts thereof.

255. The bi-layered tablet of any one of claims 252 to 254, wherein the tablet comprises at least two of phenylepherine, pseudoephedrine, chlorpheniramine, carbinoxamine, promethazine, guaifenesin and pharmaceutically acceptable salts thereof.

256. The bi-layered tablet of any one of claims 252 to 255, wherein the first layer only comprises one or more of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof as active ingredient(s).

257. The bi-layered tablet of any one of claims 252 to 256, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 80 % of the period of a plasma concentration within the therapeutic range of the first drug.

258. The bi-layered tablet of any one of claims 252 to 257, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 90 % of the period of plasma concentration within the therapeutic range of the first drug.

259. The bi-layered tablet of any one of claims 252 to 258, wherein at least one of the first and second layers is an immediate release layer.

260. The bi-layered tablet of any one of claims 252 to 259, wherein the first layer is an immediate release layer.

261. The bi-layered tablet of any one of claims 252 to 260, wherein the second layer is an immediate release layer.

262. The bi-layered tablet of any one of claims 252 to 258, wherein both of the first and second layers are controlled release layers.

263. The bi-layered tablet of any one of claims 252 to 262, wherein the first layer comprises a total of from about 0.1 mg to about 120 mg of at least one of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof.

264. The bi-layered tablet of any one of claims 252 to 263, wherein the first layer comprises a total of from about 5 mg to about 90 mg of at least one of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof.

265. The bi-layered tablet of any one of claims 252 to 264, wherein the first layer comprises a total of from about 25 mg to about 50 mg of at least one of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof.

266. The bi-layered tablet of any one of claims 252 to 265, wherein the second layer comprises at least one of (i) from about 0.1 mg to about 16 mg of chlorpheniramine maleate or an equivalent amount of at least one other pharmaceutically acceptable salt of chlorpheniramine; (ii) from about 1 mg to about 90 mg of phenylepherine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of phenylepherine; (iii) from about 1 mg to about 240 mg of pseudoephedrine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of pseudoephedrine; (iv) from about 0.1 mg to about 75 mg of promethazine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of promethazine; (v) from about 0.1 mg to about 32 mg of carbinoxamine maleate or an equivalent amount of at least one other pharmaceutically acceptable salt of carbinoxamine; and (vi) form about 1 mg to about 2400 mg of guaifenesin or an equivalent amount of at least one pharmaceutically acceptable salt of guaifenesin.

267. The bi-layered tablet of any one of claims 252 to 266, wherein the first layer comprises at least one of (i) from about 1 mg to about 90 mg of phenylepherine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of phenylepherine; and (ii) from about 1 mg to about 240 mg of pseudoephedrine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of pseudoephedrine, and the second layer comprises at least one of an antihistamine and an expectorant.

268. A multi-layered tablet which comprises at least a first layer and a second layer, wherein the first layer comprises at least one of codeine, dihydrocodeine, hydrocodone and a pharmaceutically acceptable salt thereof and the second layer comprises at least one drug which is selected from decongestants, expectorants, mucus thinning drugs, analgesics and antihistamines.

269. The multi-layered tablet of claim 268, wherein the first layer is an immediate release layer.

270. The multi-layered tablet of claim 268, wherein the first layer is a controlled release layer.

271. The multi-layered tablet of any one of claims 268 to 270, wherein the second layer is a controlled release layer.

272. The multi-layered tablet of any one of claims 268 to 271, wherein the first layer comprises at least one of codeine phosphate, dihydrocodeine bitartrate and hydrocodone bitartrate.

273. The multi-layered tablet of any one of claims 268 to 272, wherein the first layer does not contain any active ingredient which is different from codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof.

274. The multi-layered tablet of any one of claims 268 to 273, wherein the tablet comprises at least one of dextromethorphan, phenylepherine, pseudoephedrine, guaifenesin, chlorpheniramine, carbinoxamine, promethazine and pharmaceutically acceptable salts thereof.

275. The multi-layered tablet of any one of claims 268 to 274, wherein the tablet comprises at least two of dextromethorphan, phenylepherine, pseudoephedrine, guaifenesin, chlorpheniramine, carbinoxamine, promethazine and pharmaceutically acceptable salts thereof.

276. The multi-layered tablet of any one of claims 268 to 275, wherein the at least one drug in the second layer has a plasma half-life which differs by at least about 1 hour from the plasma half-life of the at least one of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof.

277. The multi-layered tablet of any one of claims 268 to 276, wherein the tablet provides a plasma concentration within the therapeutic range of the at least one drug in the second layer over a period which is coextensive with at least about 80 % of the period over which the tablet provides a plasma concentration within the therapeutic range of the at least one of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof.

278. The multi-layered tablet of any one of claims 268 to 277, wherein the at least one drug in the second layer comprises one or more of phenylepherine, pseudoephedrine, chlorpheniramine and pharmaceutically acceptable salts thereof.

279. The multi-layered tablet of any one of claims 268 to 278, wherein the layers are discrete zones which are arranged adjacent to each other.

280. The multi-layered tablet of any one of claims 268 to 278, wherein the second layer is partially or completely surrounded by the first layer.

281. The multi-layered tablet of any one of claims 268 to 279, wherein the second layer is coated with the first layer.

282. A liquid dosage form which comprises (a) at least one of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof and (b) at least one drug which is selected from decongestants, expectorants, mucus thinning drugs, and antihistamines, wherein the liquid dosage form provides a plasma concentration within a therapeutic range of (b) over a period which is coextensive with at least about 70 % of a period over which the liquid dosage form provides a plasma concentration within the therapeutic range of (a).

283. The liquid dosage form of claim 282, wherein the liquid dosage form comprises a suspension.

284. The liquid dosage form of claim 283, wherein the suspension comprises a gel.

285. The liquid dosage form of any one of claims 282 to 284, wherein at least a part of (b) is present as a complex with a complexing agent.

286. The liquid dosage form of any one of claims 282 to 285, wherein at least a part of (a) is present as a complex with a complexing agent.

287. The liquid dosage form of any one of claims 285 and 286, wherein the complexing agent comprises an ion-exchange resin.

288. The liquid dosage form of claim 287, wherein the ion-exchange resin comprises sodium polystyrene sulfonate.

289. The liquid dosage form of any one of claims 283 and 284, wherein the suspension comprises particles of a complex of at least a part of component (b) with an ion-exchange resin, which particles are provided, at least in part, with a controlled release coating.

290. The liquid dosage form of claim 289, wherein the controlled release coating comprises an organic polymer.

291. The liquid dosage form of claim 290, wherein the organic polymer comprises a polyacrylate.

292. A method of concurrently alleviating a condition which can be alleviated by administering codeine, dihydrocodeine, or hydrocodone and at least one other condition which can be alleviated by administering a drug which is at least one of a decongestant, expectorant, mucus thinning drug, and antihistamine, wherein the method comprises administering the pharmaceutical dosage form of any one of claims 230 to 251 to a subject in need thereof.

293. A method of concurrently alleviating a condition which can be alleviated by administering codeine, dihydrocodeine, or hydrocodone and at least one other condition which can be alleviated by administering a drug which is at least one of a decongestant, expectorant, mucus thinning drug, and antihistamine, wherein the method comprises administering the multi-layered tablet of any one of claims 268 to 281 to a subject in need thereof.

294. The method of any one of claims 292 and 293, wherein the condition which can be alleviated by administering codeine, dihydrocodeine, or hydrocodone comprises coughing.

295. The method of claim 292, wherein the dosage form is administered not more than about three times per day.

296. The method of claim 293, wherein the multi-layered tablet is administered not more than about twice per day.

297. A method of concurrently alleviating a condition which can be alleviated by administering codeine, dihydrocodeine, or hydrocodone and at least one other condition which can be alleviated by administering a drug which is at least one of a decongestant, expectorant, mucus thinning drug, and antihistamine, wherein the method comprises administering the liquid dosage form of any one of claims 282 to 291 to a subject in need thereof.

298. A process of making the pharmaceutical dosage form of claim 230, wherein the method comprises preparing a first composition which comprises the first drug and a second composition which comprises the at least one second drug, and combining the first and the second compositions to form the dosage form.

299. The process of claim 298, wherein the first and second compositions are combined by using a tablet press.

300. A pharmaceutical dosage form which comprises (a) a first drug which comprises at least one of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof and has a first plasma half-life and (b) at least one second drug which is selected from decongestants, expectorants, mucus thinning drugs, and antihistamines and has a second plasma half-life which differs from the first plasma half-life by at least about 2 hours, wherein the dosage form provides a plasma concentration within the therapeutic range of the at least one second drug over a period which is coextensive with at least about 80 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug.

301. The dosage form of claim 300, wherein the first plasma half-life differs by at least about 3 hours from the second plasma half-life.

302. The dosage form of any one of claims 300 and 301, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 90 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug.

303. The dosage form of any one of claims 300 to 302, wherein the dosage form comprises a multi-layered tablet.

304. The dosage form of any one of claims 300 to 303, wherein the dosage form is associated with instructions to administer the dosage form three or fewer times per day..

305. The dosage form of any one of claims 300 to 304, wherein the dosage form is associated with instructions to administer the dosage form once or twice per day.

306. A pharmaceutical dosage form which comprises (a) at least one first morphine derivative in a first form or layer and (b) at least one second morphine derivative in a second form or layer which is different from the first form or layer, wherein the dosage form releases the at least one first morphine derivative at least one of over a different period and at a different rate than the at least one second morphine derivative.

307. The dosage form of claim 306, wherein the at least one first morphine derivative and the at least one second morphine derivative are the same.

308. The dosage form of any one of claims 306 and 307, wherein the at least one first morphine derivative and the at least one second morphine derivative are independently selected from codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof.

309. The dosage form of any one of claims 306 to 308, wherein the at least one first morphine derivative and the at least one second morphine derivative comprise at least one of codeine phosphate, dihydrocodeine bitartrate and hydrocodone bitartrate.

310. The dosage form of any one of claims 306 to 309, wherein the dosage form comprises codeine phosphate.

311. The dosage form of any one of claims 306 to 310, wherein the first form or layer is an immediate release form or layer and the second form or layer is a controlled release form or layer.

312. The dosage form of any one of claims 306 to 311 , wherein the dosage form is a multi- layered tablet which comprises at least one immediate release layer and at least one controlled release layer which independently comprise at least one of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof.

313. The dosage form of claim 312, wherein the dosage form further comprises at least one additional drug which is selected from decongestants, expectorants, mucus thinning drugs, and antihistamines.

314. The dosage form of claim 313, wherein at least the immediate release layer thereof comprises the at least one additional drug.

315. The dosage form of claim 313, wherein at least the controlled release layer thereof comprises the at least one additional drug.

316. The dosage form of any one of claims 306 to 310, wherein the dosage form is a liquid which comprises the at least one first morphine derivative in a free form and the at least one second morphine derivative as a complex with a complexing agent.

317. The dosage form of claim 316, wherein the at least one first morphine derivative and the at least one second morphine derivative are the same.

318. The dosage form of any one of claims 316 and 317, wherein the complexing agent comprises an ion-exchange resin.

319. The dosage form of any one of claims 316 to 318, wherein the liquid comprises a suspension.

320. The dosage form of any one of claims 306 to 319, wherein the dosage form releases the at least one first morphine derivative over a different period and at a different rate than the at least one second morphine derivative.

321. The dosage form of any one of claims 306 to 319, wherein the dosage form releases the at least one first morphine derivative over a different period than the at least second morphine derivative.

322. The dosage form of any one of claims 306 to 321, wherein the dosage form releases the at least one first morphine derivative over a first period and the at least one second morphine derivative over a second period and not more than about 30 % of the second period are coextensive with all or a part of the first period.

323. The dosage form of claim 322, wherein there is substantially no overlap between the first and second periods.

324. The dosage form of any one of claims 306 to 323, wherein the dosage form releases the at least one first morphine derivative at a different rate than the at least second morphine derivative.

325. The dosage form of claim 306, wherein not more than about 30 % of the period over which a plasma concentration within the therapeutic range of the morphine derivative is provided by (b) is coextensive with all or a part of the period over which (a) provides a plasma concentration within the therapeutic range, provided that the plasma concentrations provided by (a) and (b) together at any time following ingestion of the dosage form are not higher than a maximum plasma concentration of the therapeutic range of the morphine derivative.

326. The dosage form of claim 325, wherein not more than about 10 % of the period over which a plasma concentration within the therapeutic range is provided by (b) is coextensive with all or a part of the period over which (a) provides a plasma concentration within the therapeutic range.

327. A pharmaceutical dosage form which comprises (a) a first drug which is selected from phenylephrine and pharmaceutically acceptable salts thereof and (b) at least one second drug, wherein the dosage form provides a plasma concentration within the therapeutic range of the at least one second drug over a period which is coextensive with at least about 70 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of phenylephrine.

328. The dosage form of claim 327, wherein the first drug comprises at least one pharmaceutically acceptable salt of phenylephrine.

329. The dosage form of any one of claims 327 and 328, wherein the first drug comprises phenylephrine hydrochloride.

330. The dosage form of any one of claims 327 to 329, wherein the at least one second drug comprises one or more of an expectorant, a mucus thinning drug, an antihistamine, an antitussive drug and an analgesic.

331. The dosage form of any one of claims 327 to 330, wherein the at least one second drug comprises an antitussive drug.

332. The dosage form of any one of claims 327 to 331 wherein the second drug comprises at least one drug selected from codeine, hydrocodone, dihydrocodeine, carbetapentane, and pharmaceutically acceptable salts thereof.

333. The dosage form of any one of claims 327 to 332, wherein the second drug comprises at least one of codeine phosphate, hydrocodone bitartrate, dihydrocodeine bitartrate and carbetapentane citrate.

334. The dosage form of any one of claims 327 to 333, wherein the at least one second drug comprises an antihistamine.

335. The dosage form of claim 334, wherein the antihistamine comprises at least one compound selected from astemizole, zatadine, bromodiphenhydramine, brompheniramine, carbinoxamine, cetirizine, chlorcyclizine, clemastine, chlorothen, chlorpheniramine, cyclizine, cyproheptadine, desloratadine, dimethindene, diphenhydramine, diphenylpyraline, doxylamine, fexofenadine, hydroxyine, isothipendyl, loratadine, methapyrilene, montelukast, phenindamine, pheniramine, phenyltoloxamine, promethazine, prophenpyridamine, pyrilamine, terfenadine, thenyldiamine, thonzylamine, trimeprazine, tripelennamine, triprolidine, and pharmaceutically acceptable salts thereof.

336. The dosage form of claim 334, wherein the antihistamine comprises at least one of astetnizole, zatadine maleate, bromodiphenhydramine HCl, brompheniramine maleate, carbinoxamine maleate, cetirizine HCl, chlorcyclizine HCl, clemastine fumarate, chlorothen citrate, chlorpheniramine maleate, cyclizine, cyproheptadine, desloratadine, dimethindene maleate, diphenhydramine HCl, diphenylpyraline, doxylamine, fexofenadine HCl, hydroxyine HCl, isothipendyl HCl (theruhistin), loratadine, methapyrilene fumarate, methapyrilene HCl, montelukast sodium, phenindamine tartrate, pheniramine maleate, phenyltoloxamine citrate, promethazine hydrochloride, prophenpyridamine maleate, pyrilamine maleate, terfenadine, thenyldiamine HCl, thonzylamine, trimeprazine tartrate, tripelennamine HCl and triprolidine HCl.

337. The dosage form of any one of claims 327 to 336, wherein the at least one second drug comprises an expectorant.

338. The dosage form of claim 337, wherein the expectorant comprises guaifenesin.

339. The dosage form of any one of claims 327 to 338, wherein the plasma half-life of the at least one second drug differs from the plasma half-life of phenylephrine by at least about 2 hours.

340. The dosage form of any one of claims 327 to 339, wherein the plasma half-life of the at least one second drug differs from the plasma half-life of phenylephrine by at least about 3 hours.

341. The dosage form of any one of claims 327 to 340, wherein the plasma half-life of the at least one second drug differs from the plasma half-life of phenylephrine by at least about 4 hours.

342. The dosage form of any one of claims 327 to 341, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 80 % of the period of a plasma concentration within the therapeutic range of phenylephrine.

343. The dosage form of any one of claims 327 to 342, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 90 % of the period of a plasma concentration within the therapeutic range of phenylephrine.

344. The dosage form of any one of claims 327 to 343, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least 'about 95 % of the period of a plasma concentration within the therapeutic range of phenylephrine.

345. The dosage form of any one of claims 327 to 344, wherein the dosage form comprises a tablet.

346. The dosage form of claim 345, wherein the tablet comprises at least two layers.

347. The dosage form of claim 345, wherein the tablet is a bi-layered tablet.

348. The dosage form of claim 345, wherein the tablet comprises a matrix which comprises one of the first drug and the at least one second drug and has dispersed therein particles which comprise the other one of the first drug and the at least one second drug.

349. The dosage form of any one of claims 327 to 344, wherein the dosage form comprises one of a solution and a suspension.

350. A bi-layered tablet which comprises a first layer and a second layer, the first layer comprising a first drug which is selected from phenylephrine and pharmaceutically acceptable salts thereof, and the second layer comprising at least one second drug which is selected from antitussives, expectorants, mucus thinning drugs, analgesics, and antihistamines, wherein the bi-layered tablet provides a plasma concentration within the therapeutic range of the at least one second drug over a period which is coextensive with at least about 70 % of the period over which the bi-layered tablet provides a plasma concentration within a therapeutic range of phenylephrine.

351. The bi-layered tablet of claim 350, wherein the first layer comprises at least one of phenylephrine hydrochloride and phenylephrine tannate.

352. The bi-layered tablet of any one of claims 350 and 351, wherein the second layer comprises at least one compound which is selected from dextromethorphan, carbetapentane, codeine, dihydrocodeine, hydrocodone, guaifenesin, astemizole, azatadine, bromodiphenhydramine, brompheniramine, carbinoxamine, cetirizine, chlorcyclizine, chlorpheniramine, clemastine, chlorothen, cyclizine, cyproheptadine, desloratadine, dimethindene, diphenhydramine, diphenylpyraline, doxylamine, fexofenadine, hydroxyine, isothipendyl, loratadine, methapyrilene, methapyrilene, montelukast, phenindamine, pheniramine, phenyltoloxamine, promethazine thonzylamine, trimeprazine, tripelennamine, triprolidine, acetaminophen, ibuprofen, and pharmaceutically acceptable salts thereof.

353. The bi-layered tablet of any one of claims 350 to 352, wherein the second layer comprises at least one of dextromethorphan hydrobromide, carbetapentane citrate, codeine phosphate, dihydrocodeine bitartrate, hydrocodone bitartrate, guaifenesin HBr, astemizole, azatadine maleate, bromodiphenhydramine HCl, brompheniramine maleate, carbinoxamine maleate, cetirizine HCl, chlorcyclizine HCl, chlorpheniramine maleate, clemastine fumarate, chlorothen citrate, cyclizine, cyproheptadine, desloratadine, dimethindene maleate, diphenhydramine HCl, diphenylpyraline, doxylamine, fexofenadine HCl, hydroxyine HCl, isothipendyl HCl (theruhistin), loratadine, methapyrilene fumarate, methapyrilene HCl, montelukast sodium, phenindamine tartrate, pheniramine maleate, phenyltoloxamine citrate, promethazine thonzylamine, trimeprazine tartrate, tripelennamine HCl, triprolidine HCl, acetaminophen and ibuprofen.

354. The bi-layered tablet of any one of claims 350 to 353, wherein the tablet comprises at least two of dextromethorphan hydrobromide, carbetapentane citrate, codeine phosphate, dihydrocodeine bitartrate, hydrocodone bitartrate, guaifenesin HBr, astemizole, azatadine maleate, bromodiphenhydramine HCl, brompheniramine maleate, carbinoxamine maleate, cetirizine HCl, chlorcyclizine HCl, chlorpheniramine maleate, clemastine fumarate, chlorothen citrate, cyclizine, cyproheptadine, desloratadine, dimethindene maleate, diphenhydramine HCl, diphenylpyraline, doxylamine, fexofenadine HCl, hydroxyine HCl, isothipendyl HCl (theruhistin), loratadine, methapyrilene fumarate, methapyrilene HCl, montelukast sodium, phenindamine tartrate, pheniramine maleate, phenyltoloxamine citrate, promethazine HCl, prophenpyridamine maleate, pyrilamine maleate, terfenadine, thenyldiamine HCl, thonzylamine, trimeprazine tartrate, tripelennamine HCl, triprolidine HCl, acetaminophen and ibuprofen.

355. The bi-layered tablet of any one of claims 350 to 354, wherein the first layer comprises the first drug as the only active ingredient in the first layer.

356. The bi-layered tablet of any one of claims 350 to 355, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 80 % of the period of a plasma concentration within the therapeutic range of phenylepherine.

357. The bi-layered tablet of any one of claims 350 to 356, wherein the period of a plasma concentration within a therapeutic range of the at least one second drug is coextensive with at least about 90 % of the period of a plasma concentration within a therapeutic range of phenylepherine.

358. The bi-layered tablet of any one of claims 350 to 357, wherein one of the first and second layers is an immediate release layer.

359. The bi-layered tablet of any one of claims 350 to 358, wherein the first layer is an immediate release layer.

360. The bi-layered tablet of any one of claims 350 to 359, wherein the second layer is an immediate release layer.

361. The bi-layered tablet of any one of claims 350 to 357, wherein the first and second layers are controlled release layers.

362. The bi-layered tablet of any one of claims 350 to 361, wherein the tablet comprises a total of from about 1 mg to about 100 mg of phenylephrine or an equivalent amount of at least one pharmaceutically acceptable salt of phenylephrine.

363. The bi-layered tablet of any one of claims 350 to 362, wherein the tablet comprises a total of from about 10 mg to about 75 mg of phenylephrine or an equivalent amount of at least one pharmaceutically acceptable salt of phenylephrine.

364. The bi-layered tablet of any one of claims 350 to 363, wherein the tablet comprises at least one of (i) from about 0.1 mg to about 16 mg of chlorpheniramine maleate or an equivalent amount of at least one other pharmaceutically acceptable salt of chlorpheniramine; (ii) about 0.1 mg to about 120 mg of at least one of codeine, dihydrocodeine, hydrocodone and pharmaceutically acceptable salts thereof; (iii) from about 1 mg to about 240 mg of diphenhydramine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of diphenhydramine; (iv) from about 0.1 mg to about 75 mg of promethazine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of promethazine; (v) from about 0.1 mg to about 32 mg of carbinoxamine maleate or an equivalent amount of at least one other pharmaceutically acceptable salt of carbinoxamine; and (vi) from about 1 mg to about 2400 mg of guaifenesin.

365. The bi-layered tablet of any one of claims 350 to 364, wherein the first layer comprises from about 1 mg to about 75 mg of phenylephrine or an equivalent amount of at least one pharmaceutically acceptable salt of phenylepherine, and at least one of (i) from about 1 mg to about 75 mg of codeine phosphate or an equivalent amount of at least one other pharmaceutically acceptable salt of codeine, (ii) from about 10 mg to about 30 mg of dihydrocodeine bitartrate or an equivalent amount of at least one other pharmaceutically acceptable salt of dihydrocodeine, (iii) from about 5 mg to about 30 mg of hydrocodone bitartrate or an equivalent amount of at least one other pharmaceutically acceptable salt of hydrocodone, and the second layer comprises at least one of an antihistamine, an expectorant and an analgesic.

366. The bi-layered tablet of any one of claims 350 to 365, wherein the first layer comprises from about 1 mg to about 75 mg of phenylepherine or an equivalent amount of at least one pharmaceutically acceptable salt of phenylepherine, and at least one drug which is selected from carbinoxamine, diphenhydramine, chlorpheniramine, dexbrompheniramine, carbetapentane and pharmaceutically acceptable salts thereof.

367. A multi-layered tablet which comprises at least a first layer and a second layer, wherein the first layer comprises phenylephrine or a pharmaceutically acceptable salt thereof and the second layer comprises at least one drug which is selected from expectorants, mucus thinning drugs, analgesics, antitussives and antihistamines.

368. The multi-layered tablet of claim 367, wherein the first layer is an immediate release layer.

369. The multi-layered tablet of claim 367, wherein the first layer is a controlled release layer.

370. The multi-layered tablet of any one of claims 367 to 369, wherein the second layer is a controlled release layer.

371. The multi-layered tablet of any one of claims 367 to 370, wherein the first layer does not contain any pharmaceutically active ingredient which is different from phenylepherine or a pharmaceutically acceptable salt thereof.

372. The multi-layered tablet of any one of claims 367 to 371, wherein the tablet comprises, in addition to phenylephrine or a pharmaceutically acceptable salt thereof, at least one of dextromethorphan hydrobromide, carbetapentane citrate, codeine phosphate, dihydrocodeine bitartrate, hydrocodone bitartrate, guaifenesin HBr, astemizole, azatadine maleate, bromodiphenhydramine HCl, brompheniramine maleate, carbinoxamine maleate, cetirizine HCl, chlorcyclizine HCl, chlorpheniramine maleate, clemastine fumarate, chlorothen citrate, cyclizine, cyproheptadine, desloratadine, dimethindene maleate, diphenhydramine HCl, diphenylpyraline, doxylamine, fexofenadine HCl, hydroxyine HCl, isothipendyl HCl (theruhistin), loratadine, methapyrilene fumarate, methapyrilene HCl, montelukast sodium, phenindamine tartrate, pheniramine maleate, phenyltoloxamine citrate, promethazine HCl, prophenpyridamine maleate, pyrilamine maleate, terfenadine, thenyldiamine HCl, thonzylamine, trimeprazine tartrate, tripelennamine HCl, triprolidine HCl, acetaminophen and ibuprofen.

373. The multi-layered tablet of any one of claims 367 to 372, wherein the at least one drug in the second layer has a plasma half-life which differs by at least about 1 hour from the plasma half-life of phenylephrine.

374. The multi-layered tablet of any one of claims 367 to 373, wherein the tablet provides a plasma concentration within the therapeutic range of the at least one drug in the second layer over a period which is coextensive with at least about 80 % of the period over which the tablet provides a plasma concentration within the therapeutic range of phenylephrine.

375. The multi-layered tablet of any one of claims 367 to 374, wherein the second layer comprises one or more compounds selected from dextromethorphan, carbetapentane, codeine, dihydrocodeine, hydrocodone, guaifenesin, astemizole, azatadine, bromodiphenhydramine, brompheniramine, carbinoxamine, cetirizine, chlorcyclizine, chlorpheniramine, clemastine, chlorothen, cyclizine, cyproheptadine, desloratadine, dimethindene, diphenhydramine, diphenylpyraline, doxylamine, fexofenadine, hydroxyine, isothipendyl, loratadine, methapyrilene, methapyrilene, montelukast, phenindamine, pheniramine, phenyltoloxamine, promethazine, prophenpyridamine, pyrilamine, terfenadine, thenyldiamine, thonzylamine, trimeprazine, tripelennamine, triprolidine, acetaminophen, ibuprofen, and pharmaceutically acceptable salts thereof.

376. The multi-layered tablet of any one of claims 367 to 375, wherein the layers are discrete zones which are arranged adjacent to each other.

377. The multi-layered tablet of any one of claims 367 to 375, wherein one of the first and second layers is partially or completely surrounded by the other one of the first and second layers.

378. The multi-layered tablet of any one of claims 367 to 375, wherein one of the first and second layers is partially or completely coated with the other one of the first and second layers.

379. A liquid dosage form which comprises (a) at least one of phenylephrine and a pharmaceutically acceptable salt thereof and (b) at least one drug which is selected from antitussives, expectorants, mucus thinning drugs, analgesics, and antihistamines, wherein the liquid dosage form provides a plasma concentration within the therapeutic range of (b) over a period which is coextensive with at least about 70 % of the period over which the liquid dosage form provides a plasma concentration within the therapeutic range of (a).

380. The liquid dosage form of claim 379, wherein the liquid dosage form comprises a suspension.

381. The liquid dosage form of claim 380, wherein the suspension comprises a gel.

382. The liquid dosage form of any one of claims 379 to 381, wherein at least a part of (b) is present as a complex with a complexing agent.

383. The liquid dosage form of any one of claims 379 to 382, wherein at least a part of (a) is present as a complex with a complexing agent.

384. The liquid dosage form of any one of claims 382 and 383, wherein the complexing agent comprises an ion-exchange resin.

385. The liquid dosage forms of claim 384, wherein the ion-exchange resin comprises sodium polystyrene sulfonate.

386. The liquid dosage form of any one of claims 380 and 381, wherein the suspension comprises particles of a complex of at least a part of at least one of component (a) and component (b) with an ion-exchange resin, which particles are provided, at least in part, with a controlled release coating.

387. The liquid dosage form of claim 386, wherein the controlled release coating comprises an organic polymer.

388. The liquid dosage forms of claim 387, wherein the organic polymer comprises a polyacrylate.

389. A method of concurrently alleviating a condition which can be alleviated by administering phenylephrine and at least one other condition which can be alleviated by administering at least one of an antitussive, expectorant, mucus thinning drug, analgesic or antihistamine, wherein the method comprises administering the pharmaceutical dosage form of any one of claims 327 to 349 to a subject in need thereof.

390. A method of concurrently alleviating a condition which can be alleviated by administering phenylephrine and at least one other condition which can be alleviated by administering at least one of an antitussive, expectorant, mucus thinning drug or antihistamine, wherein the method comprises administering the multi-layered tablet of any one of claims 367 to 378 to a subject in need thereof.

391. The method of any one of claims 389 and 390, wherein the condition which can be alleviated by administering phenylephrine comprises respiratory congestion.

392. The method of any one of claims 389 to 391, wherein the dosage form is administered not more than about three times per day.

393. The method of claim 390, wherein the multi-layered tablet is administered not more than about twice per day.

394. A method of concurrently alleviating a condition which can be alleviated by administering phenylepherine and at least one other condition which can be alleviated by administering at least one of an antitussive, expectorant, mucus thinning drug, analgesic or antihistamine, wherein the method comprises administering the liquid dosage form of any one of claims 380 to 388 to a subject in need thereof.

395. A process for making the pharmaceutical dosage form of claim 327, wherein the method comprises preparing a first composition which comprises the first drug and a second composition which comprises the at least one second drug, and combining the first and the second compositions to form the dosage form.

396. The process of claim 395, wherein the first and second compositions are combined by using a tablet press.

397. A pharmaceutical dosage form which comprises (a) a first drug which comprises phenylephrine or a pharmaceutically acceptable salt thereof and has a first plasma half-life and (b) at least one second drug which is selected from antitussives, expectorants, mucus thinning drugs, analgesics, and antihistamines and has a second plasma half-life which differs from the first plasma half-life by at least about 2 hours, wherein the dosage form provides a plasma concentration within the therapeutic range of the at least one second drug over a period which is coextensive with at least about 80 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug.

398. The dosage form of claim 397, wherein the first plasma half-life differs by at least about 3 hours from the second plasma half-life.

399. The dosage form of any one of claims 397 and 398, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 90 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug.

400. The dosage form of any one of claims 397 to 399, wherein the dosage form comprises a multi-layered tablet.

401. The dosage form of any one of claims 397 to 400, wherein the dosage form is associated with instructions to administer the dosage form three or fewer times per day.

402. The dosage form of any one of claims 397 to 401, wherein the dosage form is associated with instructions to administer the dosage form once or twice per day.

403. A pharmaceutical dosage form which comprises (a) phenylephrine or a pharmaceutically acceptable salt thereof in a first form or layer and (b) phenylephrine or a pharmaceutically acceptable salt thereof in a second form or layer which is different from the first form or layer, wherein the dosage form releases the phenylephrine (b) over a different period and at a different rate than the phenylephrine (a).

404. The dosage form of claim 403, wherein the first form or layer is an immediate release form or layer and the second form or layer is a controlled release form or layer.

405. The dosage form of any one of claims 403 and 404, wherein the dosage form is a multi-layered tablet which comprises at least one immediate release layer and at least one controlled release layer which independently comprise at least phenylephrine or a pharmaceutically acceptable salt thereof and wherein at least one of the layers comprises an additional drug.

406. The dosage form of claim 405, wherein the at least one additional drug is selected from antitussives, expectorants, mucus thinning drugs, analgesics and antihistamines.

407. The dosage form of any one of claims 405 and 406, wherein at least the immediate release layer thereof comprises the at least one additional drug.

408. The dosage form of any one of claims 405 and 406, wherein the at least one controlled release layer thereof comprises the at least one additional drug.

409. The dosage form of any one of claims 403 and 404, wherein the dosage form comprises a liquid which comprises phenylephrine or a pharmaceutically acceptable salt thereof in uncomplexed form and phenylephrine or a pharmaceutically acceptable salt thereof as a complex with a complexing agent.

410. The dosage form of claim 409, wherein the complexing agent comprises an ion- exchange resin.

411. The dosage form of any one of claims 409 and 410, wherein the liquid comprises a suspension.

412. The dosage form of any one of claims 403 to 411, wherein the dosage form releases phenylephrine or a pharmaceutically acceptable salt thereof independently over a first period and over a second period and not more than about 30% of the second period is coextensive with all or a part of the first period.

413. The dosage form of claim 412, wherein there is substantially no overlap between the first and second periods.

414. A pharmaceutical dosage form which comprises (a) a first drug which is selected from carbetapentane and pharmaceutically acceptable salts thereof, and (b) at least one second drug, wherein the dosage form provides a plasma concentration within the therapeutic range of the at least one second drug over a period which is coextensive with at least about 70 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of carbetapentane.

415. The dosage form of claim 414, wherein the first drug comprises at least one pharmaceutically acceptable salt of carbetapentane.

416. The dosage form of any one of claims 414 and 415, wherein the first drug comprises carbetapentane citrate.

417. The dosage form of any one of claims 414 to 416, wherein the at least one second drug comprises one or more of a decongestant, an expectorant, a mucus thinning drug, and an antihistamine.

418. The dosage form of any one of claims 414 to 417, wherein the at least one second drug comprises a decongestant.

419. The dosage form of any one of claims 414 to 418, wherein the at least one second drug comprises at least one of phenylepherine, pseudoephedrine and pharmaceutically acceptable salts thereof.

420. The dosage form of any one of claims 414 to 419, wherein the at least one second drug comprises an antihistamine.

421. The dosage form of claim 420, wherein the antihistamine comprises at least one of chlorpheniramine, promethazine, carbinoxamine, diphenhydramine and pharmaceutically acceptable salts thereof.

422. The dosage form of any one of claims 414 to 421, wherein the at least one second drug comprises an expectorant.

423. The dosage form of claim 422, wherein the expectorant comprises guaifenesin.

424. The dosage form of any one of claims 414 to 423, wherein the plasma half-life of the at least one second drug differs from the plasma half-life of carbetapentane by at least about 2 hours.

425. The dosage form of any one of claims 414 to 424, wherein the plasma half-life of the at least one second drug differs from the plasma half-life of carbetapentane by at least about 3 hours.

426. The dosage form of any one of claims 414 to 425, wherein the plasma half-life of the at least one second drug differs from the plasma half-life of carbetapentane by at least about 4 hours.

427. The dosage form of any one of claims 414 to 426, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 80 % of the period of a plasma concentration within the therapeutic range of carbetapentane.

428. The dosage form of any one of claims 414 to 427, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 90 % of the period of a plasma concentration within the therapeutic range of carbetapentane.

429. The dosage form of any one of claims 414 to 428, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 95 % of the period of a plasma concentration within the therapeutic range of carbetapentane.

430. The dosage form of any one of claims 414 to 429, wherein the dosage form comprises a tablet.

431. The dosage form of claim 430, wherein the tablet comprises at least two layers.

432. The dosage form of claim 430, wherein the tablet is a bi-layered tablet.

433. The dosage form of claim 430, wherein the tablet comprises (a) a matrix which comprises the first drug and has dispersed therein particles which comprise the at least one second drug, or (b) a matrix which comprises the at least one second drug and has dispersed therein particles which comprise the first drug.

434. The dosage form of any one of claims 414 to 429, wherein the dosage form comprises a solution or a suspension.

435. A bi-layered tablet which comprises a first layer and a second layer, the first layer comprising a first drug which is selected from carbetapentane and pharmaceutically acceptable salts thereof, and the second layer comprising at least one second drug which is selected from decongestants, expectorants, mucus thinning drugs, and antihistamines, wherein the bi-layered tablet provides a plasma concentration within the therapeutic range of the at least one second drug over a period which is coextensive with at least about 70 % of the period over which the bi-layered tablet provides a plasma concentration within the therapeutic range of carbetapentane.

436. The bi-layered tablet of claim 435, wherein the first layer comprises one or more of carbetapentane citrate and carbetapentane tannate.

437. The bi-layered tablet of any one of claims 435 and 436, wherein the second layer comprises at least one drug selected from phenylephrine, pseudoephedrine, chlorpheniramine, carbinoxamine, promethazine, diphenhydramine, guaifenesin and pharmaceutically acceptable salts thereof.

438. The bi-layered tablet of any one of claims 435 to 437, wherein the tablet comprises at least one drug selected from phenylepherine, pseudoephedrine, guaifenesin and pharmaceutically acceptable salts thereof, and at least one other drug selected from chlorpheniramine, carbinoxamine, promethazine, diphenhydramine and pharmaceutically acceptable salts thereof.

439. The bi-layered tablet of any one of claims 435 to 438, wherein the .first layer comprises at least one of carbetapentane and a pharmaceutically acceptable salt thereof as the only active ingredient in the first layer.

440. The bi-layered tablet of any one of claims 435 to 439, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 80 % of the period of a plasma concentration within the therapeutic range of carbetapentane.

441. The bi-layered tablet of any one of claims 435 to 440, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 90 % of the period of a plasma concentration within the therapeutic range of carbetapentane.

442. The bi-layered tablet of any one of claims 435 to 441, wherein at least one of the first and second layers is a controlled release layer.

443. The bi-layered tablet of any one of claims 435 to 442, wherein the second layer is an immediate release layer.

444. The bi-layered tablet of any one of claims 435 to 442, wherein both of the first and second layers are controlled release layers.

445. The bi-layered tablet of any one of claims 435 to 443, wherein at least one of the tablet and the first layer comprises a total of from about 0.1 mg to about 120 mg of the first drug.

446. The bi-layered tablet of any one of claims 435 to 445, wherein at least one of the tablet and the first layer comprises a total of from about 5 mg to about 90 mg of the first drug.

447. The bi-layered tablet of any one of claims 435 to 446, wherein at least one of the tablet and the first layer comprises a total of from about 25 mg to about 60 mg of the first drug.

448. The bi-layered tablet of any one of claims 435 to 447, wherein at least one of the tablet and the second layer comprises one or more of (i) from about 0.1 mg to about 16 mg of chlorpheniramine maleate or an equivalent amount of at least one other pharmaceutically acceptable salt of chlorpheniramine; (ii) from about 1 mg to about 90 mg of phenylepherine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of phenylepherine; (iii) from about 1 mg to about 240 mg of pseudoephedrine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of pseudoephedrine; (iv) from about 0.1 mg to about 75 mg of promethazine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of promethazine; (v) from about 0.1 mg to about 32 mg of carbinoxamine maleate or an equivalent amount of at least one other pharmaceutically acceptable salt of carbinoxamine; (vi) from about 0.1 mg to about 300 mg of diphenhydramine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of diphenhydramine; and (vii) from about 1 mg to about 2400 mg of guaifenesin or an equivalent amount of at least one pharmaceutically acceptable salt of guaifenesin.

449. The bi-layered tablet of any one of claims 435 to 448, wherein at least one of the tablet and the first layer comprises at least one of (i) from about 1 mg to about 90 mg of phenylepherine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of phenylepherine; and (ii) from about 1 mg to about 240 mg of pseudoephedrine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of pseudoephedrine.

450. The bi-layered tablet of any one of claims 435 to 449, wherein the second layer comprises at least one of (i) from about 0.1 mg to about 16 mg of chlorpheniramine maleate or an equivalent amount of at least one other pharmaceutically acceptable salt of chlorpheniramine; (ii) from about 0.1 mg to about 75 mg of promethazine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of promethazine; (iii) from about 0.1 mg to about 32 mg of carbinoxamine maleate or an equivalent amount of at least one other pharmaceutically acceptable salt of carbinoxamine; (iv) from about 0.1 mg to about 300 mg of diphenhydramine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of diphenhydramine; and (v) form about 1 mg to about 2400 mg of guaifenesin or an equivalent amount of at least one pharmaceutically acceptable salt of guaifenesin.

451. A multi-layered tablet which comprises at least a first layer and a second layer, wherein the first layer comprises at least one of carbetapentane and a pharmaceutically acceptable salt thereof and the second layer comprises at least one drug which is selected from decongestants, expectorants, mucus thinning drugs and antihistamines.

452. The multi-layered tablet of claim 451, wherein the first layer is a controlled release layer.

453. The multi-layered tablet of any one of claims 451 and 452, wherein the second layer is a controlled release layer.

454. The multi-layered tablet of any one of claims 451 and 452, wherein the second layer is an immediate release layer.

455. The multi-layered tablet of any one of claims 451 to 454, wherein the first layer comprises at least one of carbetapentane citrate and carbetapentane tannate.

456. The multi-layered tablet of any one of claims 451 to 455, wherein the second layer comprises at least one of dextromethorphan, phenylepherine, pseudoephedrine, guaifenesin, chlorpheniramine, carbinoxamine, promethazine, diphenhydramine and pharmaceutically acceptable salts thereof.

457. The multi-layered tablet of any one of claims 451 to 456, wherein the tablet comprises at least two of dextromethorphan, phenylepherine, pseudoephedrine, guaifenesin, chlorpheniramine, carbinoxamine, promethazine, diphenhydramine and pharmaceutically acceptable salts thereof.

458. The multi-layered tablet of any one of claims 451 to 457 wherein the at least one drug in the second layer has a plasma half-life which differs by at least about 2 hours from the plasma half-life of carbetapentane.

459. The multi-layered tablet of any one of claims 451 to 458, wherein the tablet provides a plasma concentration within a therapeutic range of the at least one drug in the second layer over a period which is coextensive with at least about 80 % of the period over which the tablet provides a plasma concentration within the therapeutic range of carbetapentane.

460. The multi-layered tablet of any one of claims 451 to 459, wherein the at least one drug in the second layer comprises one or more drugs selected from chlorpheniramine, promethazine, carbinoxamine, diphenhydramine, guaifensin and pharmaceutically acceptable salts thereof.

461. The multi-layered tablet of any one of claims 451 to 460, wherein the layers are discrete zones which are arranged adjacent to each other.

462. The multi-layered tablet of any one of claims 451 to 460, wherein one of the first and second layers is partially or completely surrounded by the other one of the first and second layers.

463. The multi-layered tablet of any one of claims 451 to 460, wherein one of the first and second layers is coated by the other one of the first and second layers.

464. A liquid dosage form which comprises (a) at least one of carbetapentane and a pharmaceutically acceptable salt thereof and (b) at least one additional drug which is selected from decongestants, expectorants, mucus thinning drugs, and antihistamines, wherein the liquid dosage form provides a plasma concentration within the therapeutic range of the at least one additional drug over a period which is coextensive with at least about 70 % of a period over which the liquid dosage form provides a plasma concentration within a therapeutic range of carbetapentane.

465. The liquid dosage form of claim 464, wherein the liquid dosage form comprises a suspension.

466. The liquid dosage form of claim 465, wherein the suspension comprises a gel.

467. The liquid dosage form of any one of claims 464 to 466, wherein at least a part of (a) is present as a complex with a complexing agent.

468. The liquid dosage form of any one of claims 464 to 467, wherein at least a part of (b) is present as a complex with a complexing agent.

469. The liquid dosage form of any one of claims 467 to 468, wherein the complexing agent comprises an ion-exchange resin.

470. The liquid dosage form of claim 469, wherein the ion-exchange resin comprises sodium polystyrene sulfonate.

471. The liquid dosage form of any one of claims 465 and 466, wherein the suspension comprises particles of a complex of at least a part of (a) with an ion-exchange resin, which particles are provided, at least in part, with a controlled release coating.

472. The liquid dosage form of claim 471, wherein the controlled release coating comprises an organic polymer.

473. The liquid dosage form of claim 472, wherein the organic polymer comprises a polyacrylate.

474. A method of concurrently alleviating a condition which can be alleviated by administering carbetapentane and at least one other condition which can be alleviated by administering a drug which is at least one of a decongestant, an expectorant, a mucus thinning drug, and an antihistamine, wherein the method comprises administering the pharmaceutical dosage form of any one of claims 414 to 434 to a subject in need thereof.

475. A method of concurrently alleviating a condition which can be alleviated by administering carbetapentane and at least one other condition which can be alleviated by administering a drug which is at least one of a decongestant, an expectorant, a mucus thinning drug, and an antihistamine, wherein the method comprises administering the multi-layered tablet of any one of claims 451 to 463 to a subject in need thereof.

476. A method of concurrently alleviating a condition which can be alleviated by administering carbetapentane and at least one other condition which can be alleviated by administering a drug which is at least one of a decongestant, an expectorant, a mucus thinning drug, and an antihistamine, wherein the method comprises administering the liquid dosage form of any one of claims 464 to 473 to a subject in need thereof.

477. The method of any one of claims 474 to 476, wherein the condition which can be alleviated by administering carbetapentane comprises coughing.

478. The method of claim 474, wherein the dosage form is administered not more than about three times per day.

479. The method of claim 475, wherein the multi-layered tablet is administered not more than about twice per day.

480. A process of making the pharmaceutical dosage form of claim 414, wherein the method comprises preparing a first composition which comprises the first drug and a second composition which comprises the at least one second drug, and combining the first and the second compositions to form the dosage form.

481. The process of claim 480, wherein the first and second compositions are combined by using a tablet press.

482. A pharmaceutical dosage form which comprises (a) a first drug which is selected from carbetapentane and pharmaceutically acceptable salts thereof and (b) at least one second drug which is selected from decongestants, expectorants, mucus thinning drugs, and antihistamines and has a plasma half-life which differs from the plasma half-life of carbetapentane by at least about 2 hours, wherein the dosage form provides a plasma concentration within the therapeutic range of the at least one second drug over a period which is coextensive with at least about 80 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of carbetapentane.

483. The dosage form of claim 482, wherein the plasma half-life of (b) differs by at least about 3 hours from the plasma half-life of carbetapentane.

484. The dosage form of any one of claims 482 and 483, wherein the plasma half-life of (b) is longer than the plasma half-life of carbetapentane.

485. The dosage form of any one of claims 482 to 484, wherein the plasma half-life of (b) is shorter than the plasma half-life of carbetapentane.

486. The dosage form of any one of claims 482 to 485, wherein the dosage form is associated with instructions to administer the dosage form three or fewer times per day.

487. The dosage form of any one of claims 482 to 486, wherein the dosage form is associated with instructions to administer the dosage form once or twice per day.

488. A pharmaceutical dosage form which comprises at least a first release form of carbetapentane and a second release form of carbetapentane, wherein the first form releases the carbetapentane at least one of over a different period and at a different rate than the second form.

489. The dosage form of claim 488, wherein the first form is an immediate release form and the second form is a controlled release form.

490. The dosage form of any one of claims 488 and 489, which comprises a solid dosage form.

491. The dosage form of any one of claims 488 to 490, wherein the dosage form comprises a tablet.

492. The dosage form of any one of claims 488 to 491, wherein the dosage form comprises a multi-layered tablet.

493. The dosage form of claim 492, wherein the multi-layered tablet comprises at least (a) an immediate release layer which comprises at least one of carbetapentane and a pharmaceutically acceptable salt thereof and (b) a controlled release layer which comprises at least one of carbetapentane and a pharmaceutically acceptable salt thereof.

494. The dosage form of any one of claims 488 to 493, wherein the dosage form comprises at least one of carbetapentane citrate and carbetapentane tannate.

495. The dosage form of any one of claims 488 to 494, wherein the dosage form comprises a bi-layered tablet.

496. The dosage form of any one of claims 488 to 495, wherein the dosage form further comprises at least one additional drug which is selected from decongestants, expectorants, mucus thinning drugs, and antihistamines.

497. The dosage form of claim 496, wherein at least an immediate release layer thereof comprises the at least one additional drug.

498. The dosage form of claim 496, wherein at least a controlled release layer thereof comprises the at least one additional drug.

499. The dosage form of any one of claims 496 to 498, wherein the dosage form provides a plasma concentration within the therapeutic range of the at least one additional drug over a period which is coextensive with at least about 70 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of carbetapentane.

500. The dosage form of any one of claims 488 to 490, 494, 496 and 499 which comprises a liquid dosage form.

501. The dosage form of claim 500, wherein the dosage form comprises at least one of carbetapentane and a pharmaceutically acceptable salt thereof in an uncomplexed form and as a complex with a complexing agent.

502. The liquid dosage form of claim 501, wherein the complexing agent comprises an ion- exchange resin.

503. The liquid dosage form of claim 502, wherein the ion-exchange resin comprises sodium polystyrene sulfonate.

504. The dosage form of any one of claims 500 to 503, wherein the dosage form comprises a suspension.

505. The dosage form of any one of claims 500 to 504, wherein the dosage form further comprises at least one additional drug which is selected from decongestants, expectorants, mucus thinning drugs, and antihistamines.

506. The dosage form of claim 505, wherein the dosage form provides a plasma concentration within the therapeutic range of the at least one additional drug over a period which is coextensive with at least about 70 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of carbetapentane.

507. The dosage form of any one of claims 488 to 506, wherein the first release form releases the carbetapentane over a different period and at a different rate than the second release form.

508. The dosage form of any one of claims 488 to 506, wherein the first release form releases the carbetapentane over a different period than the second release form.

509. The dosage form of claim 507, wherein the first release form releases the carbetapentane over a first period and the second release form releases the carbetapentane over a second period and not more than about 30 % of the second period are coextensive with all or a part of the first period.

510. The dosage form of claim 509, wherein there is substantially no overlap between the first and second periods.

511. The dosage form of claim 488, wherein not more than about 30 % of a period over which the plasma concentration within the therapeutic range of carbetapentane is provided by (b) is coextensive with all or a part of the period over which (a) provides a plasma concentration within the therapeutic range, provided that the plasma concentrations provided by (a) and (b) together at any time following ingestion of the dosage form are not higher than the maximum plasma concentration of the therapeutic range of carbetapentane.

512. The dosage form of claim 511, wherein not more than about 10 % of the period over which a plasma concentration within the therapeutic range is provided by (b) is coextensive with all or a part of the period over which (a) provides a plasma concentration within the therapeutic range.

513. A method of concurrently alleviating a condition which can be alleviated by administering carbetapentane and at least one other condition which can be alleviated by administering a drug which is at least one of a decongestant, an expectorant, a mucus thinning drug, and an antihistamine, wherein the method comprises administering the pharmaceutical dosage form of any one of claims 496 to 499, 505 and 506 to a subject in need thereof.

514. A pharmaceutical dosage form which comprises (a) a first drug which is at least one of diphenhydramine and a pharmaceutically acceptable salt thereof and (b) at least one second drug, wherein the dosage form provides a plasma concentration within the therapeutic range of the at least one second drug over a period which is coextensive with at least about 60 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug.

515. The dosage form of claim 514, wherein the at least one second drug is selected from decongestants, antitussives, expectorants, mucus thinning drugs and analgesics.

516. The dosage form of any one of claims 514 and 515, wherein the first drug comprises diphenhydramine hydrochloride.

517. The dosage form of any one of claims 514 to 516, wherein the at least one second drug comprises an antitussive.

518. The dosage form of claim 517, wherein the antitussive comprises at least one of codeine, dihydrocodeine, hydrocodone, dextromethorphan, carbetapentane and pharmaceutically acceptable salts thereof.

519. The dosage form of any one of claims 514 to 518, wherein the at least one second drug comprises a decongestant.

520. The dosage form of any one of claims 514 to 519, wherein the second drug comprises one or more of phenylepherine, pseudoephedrine and pharmaceutically acceptable salts thereof.

521. The dosage form of any one of claims 514 to 520, wherein the at least one second drug comprises an analgesic.

522. The dosage form of claim 521, wherein the analgesic comprises at least one of acetaminophen, aspirin, ibuprofen, naproxen, hydrocodone, oxycodone, morphine and hydromorphone.

523. The dosage form of any one of claims 514 to 522, wherein the at least one second drug comprises an expectorant.

524. The dosage form of claim 523, wherein the expectorant comprises guaifenesin.

525. The dosage form of any one of claims 514 to 524, wherein the plasma half-life of the at least one second drug is shorter or longer than the plasma half-life of the first drug by at least about 1 hour.

526. The dosage form of any one of claims 514 to 525, wherein the plasma half-life of the at least one second drug is shorter or longer than the plasma half-life of the first drug by at least about 4 hours.

527. The dosage form of any one of claims 514 to 526, wherein the plasma half-life of the at least one second drug is shorter than the plasma half-life of the first drug by at least about 6 hours.

528. The dosage form of any one of claims 514 to 527, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 80 % of the period of a plasma concentration within the therapeutic range of the first drug.

529. The dosage form of any one of claims 514 to 528, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 90 % of the period of a plasma concentration within the therapeutic range of the first drug.

530. The dosage form of any one of claims 514 to 529, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 95 % of the period of a plasma concentration within the therapeutic range of the first drug.

531. The dosage form of any one of claims 514 to 530, wherein the dosage form comprises a tablet.

532. The dosage form of any one of claims 514 to 531, wherein the dosage form comprises a matrix which comprises the first drug and has dispersed therein particles which comprise the at least one second drug.

533. The dosage form of claim 532, wherein the matrix provides an immediate release of the first drug and the particles provide a controlled release of the at least one second drug.

534. The dosage form of any one of claims 514 to 531, wherein the dosage form comprises a matrix which comprises the at least one second drug and has dispersed therein particles which comprise the first drug.

535. The dosage form of claim 534, wherein the matrix provides an immediate release of the at least one second drug and the particles provide a controlled release of the first drug.

536. The dosage form of any one of claims 514 to 530, wherein the dosage form comprises a liquid or semi-liquid dosage form.

537. The dosage form of claim 536, wherein the dosage form comprises a solution or a suspension.

538. The dosage form of any one of claims 536 and 537, wherein the dosage form comprises a suspension having particles therein which provide a controlled release of at least one of the first drug and the at least one second drug.

539. A bi-layered tablet which comprises a first layer and a second layer, the first layer comprising a first drug which is at least one of diphenhydramine and a pharmaceutically acceptable salt thereof, and the second layer comprising at least one second drug which is selected from decongestants, antitussives, expectorants, mucus thinning drugs and analgesics, wherein the bi-layered tablet provides a plasma concentration within the therapeutic range of the at least one second drug over a period which is coextensive with at least about 60% of the period over which the bi-layered tablet provides a plasma concentration within the therapeutic range of the first drug.

540. The bi-layered tablet of claim 539, wherein the second layer comprises one or more of phenylepherine, pseudoephedrine, carbetapentane, guaifenesin, hydrocodone, dihydrocodeine, oxycodone, hydromorphone, dextromethorphan, acetaminophen, aspirin, ibuprofen, naproxen, morphine and pharmaceutically acceptable salts thereof.

541. The bi-layered tablet of any one of claims 539 and 540, wherein the first layer comprises diphenhydramine hydrochloride and the second layer comprises at least two of phenylepherine, pseudoephedrine, carbetapentane, diphenhydramine, guaifenesin, hydrocodone, dihydrocodeine, oxycodone, hydromorphone, dextromethorphan, acetaminophen, aspirin, ibuprofen, naproxen, morphine and pharmaceutically acceptable salts thereof.

542. The bi-layered tablet of any one of claims 539 to 541, wherein the first layer comprises only diphenhydramine or a pharmaceutically acceptable salt thereof as an active ingredient.

543. The bi-layered tablet of any one of claims 539 to 542, wherein the first layer comprises only diphenhydramine hydrochloride as an active ingredient.

544. The bi-layered tablet of any one of claims 539 to 543, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 80 % of the period of a plasma concentration within the therapeutic range of the first drug.

545. The bi-layered tablet of any one of claims 539 to 544, wherein the first layer is an immediate release layer.

546. The bi-layered tablet of any one of claims 539 to 545, wherein the second layer is a controlled release layer.

547. The bi-layered tablet of any one of claims 539 to 544 and 546, wherein the first layer is a controlled release layer.

548. The bi-layered tablet of any one of claims 539 to 547, wherein the first layer comprises from about 1 mg to about 300 mg of diphenhydramine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of diphenhydramine.

549. The bi-layered tablet of any one of claims 539 to 548, wherein the second layer comprises from about 1 mg to about 300 mg of diphenhydramine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of diphenhydramine.

550. The bi-layered tablet of any one of claims 539 to 549, wherein the second layer is a controlled release layer and comprises one or more of (i) from about 1 mg to about 120 mg of phenylephrine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of phenylepherine; (ii) from about 1 mg to about 240 mg of pseudoephedrine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of pseudoephedrine; (iii) from about 1 mg to about 120 mg of carbetapentane citrate or an equivalent amount of at least one other pharmaceutically acceptable salt of carbetapentane; (iv) from about 1 mg to about 120 mg of codeine phosphate or an equivalent amount of at least one other pharmaceutically acceptable salt of codeine; (v) from about 1 mg to about 30 mg of dihydrocodeine bitartrate or an equivalent amount of at least one other pharmaceutically acceptable salt of dihydrocodeine; (vi) from about 1 mg to about 20 mg of hydrocodone bitartrate or an equivalent amount of at least one other pharmaceutically acceptable salt of hydrocodone; (vii) from about 10 mg to about 1000 mg of acetaminophen; and (viii) from about 10 mg to about 1500 mg of guaifenesin.

551. The bi-layered tablet of any one of claims 539 to 550, wherein the second layer is a controlled release layer and comprises one or more of (i) from about 1 mg to about 120 mg of phenylephrine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of phenylepherine; (ii) from about 1 mg to about 240 mg of pseudoephedrine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of pseudoephedrine; (iii) from about 1 mg to about 120 mg of carbetapentane citrate or an equivalent amount of at least one other pharmaceutically acceptable salt of carbetapentane; (iv) from about 1 mg to about 120 mg of codeine phosphate or an equivalent amount of at least one other pharmaceutically acceptable salt of codeine; (v) from about 1 mg to about 30 mg of dihydrocodeine bitartrate or an equivalent amount of at least one other pharmaceutically acceptable salt of dihydrocodeine; (vi) from about 1 mg to about 20 mg of hydrocodone bitartrate or an equivalent amount of at least one other pharmaceutically acceptable salt of hydrocodone; (vii) from about 10 mg to about 1000 mg of acetaminophen; and (viii) from about 10 mg to about 1500 mg of guaifenesin.

552. A multi-layered tablet which comprises at least a first layer and a second layer, wherein the first layer comprises at least one of diphenhydramine and a pharmaceutically acceptable salt thereof and the second layer is a controlled release layer and comprises at least one drug which is selected from decongestants, antitussives, expectorants, mucus thinning drugs and analgesics.

553. The multi-layered tablet of claim 552, wherein the first layer is an immediate release layer.

554. The multi-layered tablet of any one of claims 552 and 553, wherein the first layer does not contain any active ingredient which is different from diphenhydramine or a pharmaceutically acceptable salt thereof.

555. The multi-layered tablet of any one of claims 552 to 554, wherein the second layer comprises at least one of codeine, dihydrocodeine, hydrocodone, dextromethorphan, phenylepherine, pseudoephedrine, guaifenesin and pharmaceutically acceptable salts thereof.

556. The multi-layered tablet of any one of claims 552 to 555, wherein the second layer comprises at least two of codeine, dihydrocodeine, hydrocodone, dextromethorphan, phenylepherine, pseudoephedrine, guaifenesin and pharmaceutically acceptable salts thereof.

557. The multi-layered tablet of any one of claims 552 to 556, wherein the at least one drug in the second layer has a plasma half-life which is longer or shorter by at least about 1 hour than the plasma half-life of diphenhydramine.

558. The multi-layered tablet of any one of claims 552 to 557, wherein the first layer comprises diphenhydramine hydrochloride and the tablet provides a plasma concentration within the therapeutic range of the at least one drug in the second layer over a period which is coextensive with at least about 80 % of the period over which the multi-layered tablet provides a plasma concentration within the therapeutic range of diphenhydramine hydrochloride.

559. The multi-layered tablet of any one of claims 552 to 558, wherein the at least one drug in the second layer comprises one or more of codeine, dihydrocodeine, hydrocodone, dextromethorphan, phenylepherine, pseudoephedrine, guaifenesin and pharmaceutically acceptable salts thereof.

560. The multi-layered tablet of any one of claims 552 to 559, wherein the layers are discrete zones which are arranged adjacent to each other.

561. The multi-layered tablet of any one of claims 552 to 559, wherein one of the first and second layers is partially or completely surrounded by the other one of the first and second layers.

562. The multi-layered tablet of any one of claims 552 to 559, wherein one of the first and second layers is coated with the other one of the first and second layers.

563. A liquid dosage form which comprises (a) at least one of diphenhydramine and a pharmaceutically acceptable salt thereof and (b) at least one drug which is selected from decongestants, expectorants, mucus thinning drugs, antitussives and analgesics, wherein the liquid dosage form provides a plasma concentration within the therapeutic range of component (b) over a period which is coextensive with at least about 60 % of the period over which the liquid dosage form provides a plasma concentration within the therapeutic range of component (a).

564. The liquid dosage form of claim 563, wherein the liquid dosage form comprises a suspension.

565. The liquid dosage form of any one of claims 563 and 564, wherein at least a part of component (a) is present as a complex with a complexing agent.

566. The liquid dosage form of any one of claims 563 to 565, wherein at least a part of component (b) is present as a complex with a complexing agent.

567. The liquid dosage form of any one of claims 563 and 564, wherein at least one of component (a) and component (b) comprises a complexing agent and the complexing agent comprises an ion-exchange resin.

568. The suspension of claim 567, wherein the ion-exchange resin comprises sodium polystyrene sulfonate.

569. The suspension of claim 564, wherein the suspension comprises particles of a complex of at least one of component (a) and component (b) with an ion-exchange resin, which particles are provided, at least in part, with a controlled release coating.

570. The suspension of claim 569, wherein the controlled release coating comprises an organic polymer.

571. The suspension of claim 570, wherein the organic polymer comprises at least one of a polyacrylate and an alkylcellulose.

572. A method of concurrently alleviating a condition which can be alleviated by administration of diphenhydramine and at least one other condition which can be alleviated by administration of a drug which is at least one of a decongestant, an antitussive, an expectorant, a mucus thinning drug and an analgesic, wherein the method comprises administering the pharmaceutical dosage form of any one of claims 514 to 538 to a subject in need thereof.

573. A method of concurrently alleviating a condition which can be alleviated by administration of diphenhydramine and at least one other condition which can be alleviated by administration of a drug which is at least one of a decongestant, antitussive, expectorant, mucus thinning drug and analgesic, wherein the method comprises administering the multi- layered tablet of any one of claims 552 to 562 to a subject in need thereof.

574. The method of any one of claims 572 and 573, wherein the condition which can be alleviated by administration of diphenhydramine comprises an allergic reaction.

575. The method of any one of claims 573 and 574, wherein the multi-layered tablet is administered not more than about three times per day.

576. The method of any one of claims 573 to 575, wherein the multi-layered tablet is administered not more than about twice per day.

577. A method of concurrently alleviating a condition which can be alleviated by administration of diphenhydramine and at least one other condition which can be alleviated by administration of a drug which is at least one of a decongestant, antitussive, expectorant, mucus thinning drug and analgesic, wherein the method comprises administering the liquid dosage form of any one of claims 563 to 571 to a subject in need thereof.

578. A process of manufacturing the pharmaceutical dosage form of claim 514, wherein the method comprises preparing a first composition which comprises the first drug and a second composition which comprises the at least one second drug, and combining the first and the second compositions to form the dosage form.

579. The process of claim 578, wherein the first and second compositions are combined by using a tablet press.

580. A pharmaceutical dosage form which comprises (a) a first drug which is diphenhydramine or a pharmaceutically acceptable salt thereof and has a first plasma half-life and (b) at least one second drug which is selected from decongestants, antitussives, expectorants, mucus thinning drugs and analgesics and has a second plasma half-life which differs from the first plasma half-life by at least about 1 hour, wherein the dosage form provides a plasma concentration within the therapeutic range of the at least one second drug over a period which is coextensive with at least about 70 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug.

581. The dosage form of claim 580, wherein the first plasma half- life is longer or shorter by at least about 2 hours than the second plasma half-life.

582. The dosage form of any one of claims 580 and 581, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 80 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug.

583. The dosage form of any one of claims 580 to 582, wherein the dosage form comprises a bi-layered tablet.

584. The dosage form of any one of claims 580 to 583, wherein the dosage form is associated with instructions to administer the dosage form three or fewer times per day.

585. The dosage form of any one of claims 580 to 584, wherein the dosage form is associated with instructions to administer the dosage form three or fewer times per day.

586. A pharmaceutical dosage form which comprises (a) at least one of diphenhydramine and a pharmaceutically acceptable salt thereof in a first form or layer and (b) at least one of diphenhydramine and a pharmaceutically acceptable salt thereof in a second form or layer which is different from the first form or layer, wherein the dosage form releases the diphenhydramine (b) at least one of over a different period and at a different rate than the diphenhydramine (a).

587. A pharmaceutical dosage form which comprises (a) a first drug which is an antihistamine and has a first plasma half-life and (b) at least one second drug which is selected from decongestants, antitussives, expectorants, mucus thinning drugs, analgesics and antihistamines and has a second plasma half-life that differs from the first plasma half-life by at least about 3 hours, wherein the dosage form provides a plasma concentration within the therapeutic range of the at least one second drug over a period which is coextensive with at least about 70 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug.

588. The dosage form of claim 587, wherein the first drug is selected from promethazine and pharmaceutically acceptable salts thereof.

589. The dosage form of any one of claims 587 and 588, wherein the first drug comprises promethazine hydrochloride.

590. The dosage form of any one of claims 587 to 589, wherein the at least one second drug comprises at least one of codeine, dihydrocodeine, hydrocodone, dextromethorphan, phenylepherine, pseudoephedrine and pharmaceutically acceptable salts thereof, aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, oxycodone, morphine, meperidine and fentanyl.

591. The dosage form of any one of claims 587 to 589, wherein the at least one second drug comprises an antitussive.

592. The dosage form of any one of claims 587 to 591, wherein the at least one second drug comprises at least one of codeine, dihydrocodeine, hydrocodone, dextromethorphan and pharmaceutically acceptable salts thereof.

593. The dosage form of any one of claims 587 to 592, wherein the at least one second drug comprises at least one of dextromethorphan and pharmaceutically acceptable salts thereof.

594. The dosage form of any one of claims 587 to 593, wherein the at least one second drug comprises a decongestant.

595. The dosage form of any one of claims 587 to 594, wherein the at least one second drug comprises at least one of phenylepherine, pseudoephedrine and pharmaceutically acceptable salts thereof.

596. The dosage form of any one of claims 587 to 595, wherein the second drug comprises phenylepherine hydrochloride.

597. The dosage form of any one of claims 587 to 596, wherein the second drug comprises pseudoephedrine hydrochloride.

598. The dosage form of any one of claims 587 to 597, wherein the at least one second drug comprises an analgesic.

599. The dosage form of any one of claims 587 to 598, wherein the second drug comprises at least one of aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, hydrocodone, oxycodone, morphine, meperidine and fentanyl.

600. The dosage form of any one of claims 587 to 599, wherein the second drug comprises at least one of ibuprofen and ketoprofen.

601. The dosage form of any one of claims 587 to 600, wherein the second drag comprises at least one of naproxen and sodium naproxen.

602. The dosage form of any one of claims 587 to 601, wherein the dosage form comprises one second drug.

603. The dosage form of any one of claims 587 to 601, wherein the dosage form comprises two second drugs.

604. The dosage form of any one of claims 587 to 601, wherein the dosage form comprises three second drugs.

605. The dosage form of any one of claims 587 to 604, wherein the first plasma half-life is longer by at least about 4 hours than the second plasma half-life.

606. The dosage form of any one of claims 587 to 605, wherein the first plasma half-life is longer by at least about 6 hours than the second plasma half-life.

607. The dosage form of any one of claims 587 to 606, wherein the first plasma half-life is at least about 8 hours.

608. The dosage form of any one of claims 587 to 607, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 80 % of the period of a plasma concentration within the therapeutic range of the first drug.

609. The dosage form of any one of claims 587 to 608, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 90 % of the period of a plasma concentration within the therapeutic range of the first drug.

610. The dosage form of any one of claims 587 to 609, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 95 % of the period of a plasma concentration within the therapeutic range of the first drug.

611. The dosage form of any one of claims 587 to 610, wherein the dosage form is associated with instructions to administer the dosage form three or fewer times per day.

612. The dosage form of any one of claims 587 to 611, wherein the dosage form is associated with instructions to administer the dosage form once per day.

613. The dosage form of any one of claims 587 to 612, wherein the dosage form is associated with instructions to administer the dosage form twice per day.

614. The dosage form of any one of claims 587 to 613, wherein the dosage form comprises a tablet.

615. A bi-layered tablet which comprises a first layer and a second layer, the first layer comprising a first drug which is an antihistamine and has a first plasma half-life, and the second layer comprising at least one second drug which has a second plasma half-life that differs from the first plasma half-life by at least about 3 hours and is selected from decongestants, antitussives, expectorants, mucus thinning drugs, analgesics and antihistamines, wherein the bi-layered tablet provides a plasma concentration within the therapeutic range of the at least one second drug over a period which is coextensive with at least about 70 % of the period over which the bi-layered tablet provides a plasma concentration within the therapeutic range of the first drug.

616. The bi-layered tablet of claim 615, wherein the first drug comprises at least one of promethazine and a pharmaceutically acceptable salt thereof.

617. The bi-layered tablet of any one of claims 615 and 616, wherein the first drug comprises promethazine hydrochloride.

618. The bi-layered tablet of any one of claims 615 to 617, wherein the second layer comprises one or more of codeine, dihydrocodeine, hydrocodone, dextromethorphan and pharmaceutically acceptable salts thereof.

619. The bi-layered tablet of any one of claims 615 to 618, wherein the second layer comprises one or more of phenylepherine, pseudoephedrine and pharmaceutically acceptable salts thereof.

620. The bi-layered tablet of any one of claims 615 to 619, wherein the second layer comprises pseudoephedrine hydrochloride.

621. The bi-layered tablet of any one of claims 615 to 620, wherein the second layer comprises at least one of aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, hydrocodone, oxycodone, morphine, meperidine and fentanyl.

622. The bi-layered tablet of any one of claims 615 to 621, wherein the second layer comprises ibuprofen.

623. The bi-layered tablet of any one of claims 615 to 622, wherein the first plasma half- life is longer by at least about 4 hours than the second plasma half-life.

624. The bi-layered tablet of any one of claims 615 to 623, wherein the period of a plasma concentration within the therapeutic range of the at least one second drug is coextensive with at least about 80 % of the period of a plasma concentration within the therapeutic range of the first drug.

625. The bi-layered tablet of any one of claims 615 to 624, wherein the period of a plasma concentration within a therapeutic range of the at least one second drug is coextensive with at least about 90 % of the period of a plasma concentration within the therapeutic range of the first drug.

626. The bi-layered tablet of any one of claims 615 to 625, wherein the period of a plasma concentration within a therapeutic range of the at least one second drug is coextensive with at least about 95 % of the period of a plasma concentration within the therapeutic range of the first drug.

627. The bi-layered tablet of any one of claims 615 to 626, wherein the first plasma half- life is at least about 8 hours.

628. The bi-layered tablet of any one of claims 615 to 627, wherein the first layer is an immediate release layer.

629. The bi-layered tablet of any one of claims 615 to 628, wherein the second layer is a controlled release layer.

630. The bi-layered tablet of any one of claims 615 to 629, wherein the second layer comprises at least one of (i) from about 1 mg to about 90 mg of phenylephrine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of phenylepherine; and (ii) from about 1 mg to about 240 mg of pseudoephedrine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of pseudoephedrine.

631. The bi-layered tablet of any one of claims 615 to 630, wherein the second layer comprises from about 1 mg to about 240 mg of pseudoephedrine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of pseudoephedrine.

632. A bi-layered tablet which comprises a first layer and a second layer, the first layer being an immediate release layer and comprising a first drug which is an antihistamine and has a first plasma half-life, and the second layer being a controlled release layer and comprising at least one second drug which has a second plasma half-life that differs from the first plasma half-life by at least about 3 hours and is selected from codeine, dihydrocodeine, hydrocodone, dextromethorphan, phenylepherine, pseudoephedrine and pharmaceutically acceptable salts thereof, aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, oxycodone, morphine, meperidine and fentanyl, wherein the bi-layered tablet provides a plasma concentration within the therapeutic range of the at least one second drug over a period which is coextensive with at least about 95% of the period over which the bi-layered tablet provides a plasma concentration within the therapeutic range of the first drug.

633. The bi-layered tablet of claim 632, wherein the first plasma half-life is longer by at least about 4 hours than the second plasma half-life.

634. The bi-layered tablet of any one of claims 632 and 633, wherein the first plasma half- life is at least about 8 hours.

635. A method of concurrently alleviating a condition which can be alleviated by administration of an antihistamine and at least one other condition which can be alleviated by administration of a drug which is at least one of a decongestant, antitussive, expectorant, mucus thinning drug and analgesic, wherein the method comprises administering the dosage form of any one of claims 587 to 614 to a subject in need thereof.

636. A method of concurrently alleviating a condition which can be alleviated by administration of an antihistamine and at least one other condition which can be alleviated by administration of a drug which is at least one of a decongestant, antitussive, expectorant, mucus thinning drug and analgesic, wherein the method comprises administering the bi- layered tablet of any one of claims 615 to 634 to a subject in need thereof.

637. A process of making the pharmaceutical dosage form of claim 587, wherein the method comprises preparing a first composition which comprises the first drug and a second composition which comprises the at least one second drug, and combining the first and the second compositions to form the dosage form.

638. The process of claim 637, wherein the first and second compositions are combined by using a tablet press.

639. A pharmaceutical dosage form which comprises at least one of promethazine and a pharmaceutically acceptable salt thereof, wherein the dosage form is capable of providing a promethazine plasma concentration within the therapeutic range for at least about 24 hours per single dose.

640. The dosage form of claim 639, wherein the dosage form is capable of providing relief from allergy symptoms in a patient in need thereof for at least about 24 hours per single dose.

641. The dosage form of any one of claims 639 and 640, wherein the dosage form comprises at least two promethazine formulations which exhibit different release profiles.

642. The dosage form of any one of claims 639 to 641, wherein the dosage form comprises an immediate release formulation.

643. The dosage form of any one of claims 639 to 642, wherein the dosage form comprises a controlled release formulation.

644. The dosage form of any one of claims 639 to 643, wherein the dosage form comprises a solid dosage form.

645. The dosage form of claim 644, wherein the solid dosage form is selected from tablets, capsules and caplets.

646. The dosage form of claim 644, wherein the dosage form comprises a bi-layered tablet.

647. The dosage form of claim 646, wherein the bi-layered tablet comprises an immediate release layer and a controlled release layer.

648. The dosage form of claim 647, wherein each of the immediate release layer and the controlled release layer comprises at least about 25 mg of promethazine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of promethazine.

649. The dosage form of any one of claims 646 to 648, wherein the bi-layered tablet comprises a total of at least about 70 mg of promethazine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of promethazine.

650. The dosage form of any one of claims 646 to 649, wherein at least one of the controlled release layer and the immediate release layer comprises at least about 40 mg of promethazine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of promethazine.

651. The dosage form of any one of claims 639 to 650, wherein the dosage form comprises at least about 70 mg of promethazine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of promethazine.

652. The dosage form of any one of claims 639 to 651, wherein the dosage form comprises at least about 90 mg of promethazine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of promethazine.

653. The dosage form of any one of claims 639 to 652, wherein the dosage form is capable of providing a promethazine plasma concentration within the therapeutic range within not more than about 1 hour following administration thereof.

654. The dosage form of any one of claims 639 to 653, wherein the dosage form comprises at least one further drug.

655. The dosage form of claim 654, wherein the at least one further drug is selected from decongestants, antitussives, expectorants, mucus thinning drugs and analgesics.

656. The dosage form of any one of claims 654 and 655, wherein the dosage form is capable of providing a plasma concentration of the at least one further drug within the therapeutic range for at least about 24 hours per single dose.

657. The dosage form of any one of claims 654 to 656, wherein the at least one further drug is selected from one or more of phenylephrine, pseudoephedrine, phenylephrine, pseudoephedrine, codeine, dihydrocodeine, hydrocodone, dextromethorphan, carbetapentane, guaifenesin, acetaminophen, aspirin, ibuprofen, naproxen, oxycodone, morphine and hydromorphone and pharmaceutically acceptable salts thereof.

658. The dosage form of any one of claims 654 to 657, wherein the dosage form is capable of providing a plasma concentration within the therapeutic range of promethazine over a period which is coextensive with at least about 70 % of the period over which the dosage form is capable of providing a plasma concentration within the therapeutic range of the at least one further drug.

659. The dosage form of any one of claims 654 to 658, wherein the plasma half-life of the at least one further drug is shorter than the plasma half-life of promethazine by at least about 3 hours.

660. The dosage form of any one of claims 654 to 659, wherein the period of a plasma concentration within the therapeutic range of the at least one further drug is coextensive with at least about 90 % of the period of a plasma concentration within the therapeutic range of promethazine.

661. A pharmaceutical dosage form which comprises (a) at least one of promethazine and a pharmaceutically acceptable salt thereof in a first form or layer and (b) at least one of promethazine and a pharmaceutically acceptable salt thereof in a second form or layer which is different from the first form or layer, wherein the dosage form releases the promethazine (b) at least one of over a different period and at a different rate than the promethazine (a) and wherein the dosage form is capable of providing a promethazine plasma concentration within the therapeutic range for at least about 24 hours per single dose.

662. The dosage form of claim 661, wherein the dosage form is a multi-layered tablet which comprises at least one immediate release layer and at least one controlled release layer and at least one of these layers comprises at least one of promethazine and a pharmaceutically acceptable salt thereof, and wherein at least one of the layers of the multi-layered tablet comprises at least one further drug.

663. A pharmaceutical dosage form which comprises at least one of promethazine and a pharmaceutically acceptable salt thereof and at least one of pseudoephedrine and a pharmaceutically acceptable salt thereof, wherein the dosage form is capable of providing plasma concentrations within therapeutic ranges of both promethazine and pseudoephedrine for at least about 24 hours per single dose.

664. The dosage form of claim 663, wherein the dosage form comprises a solid dosage form.

665. The dosage form of claim 663, wherein the dosage form comprises a multi-layered tablet.

666. The dosage form of any one of claims 663 to 665, wherein the dosage form is capable of providing promethazine and pseudoephedrine plasma concentrations within therapeutic ranges within not more than about 1 hour following administration thereof.

667. The dosage form of any one of claims 663 to 666, wherein the dosage form comprises promethazine hydrochloride and pseudoephedrine hydrochloride.

668. The dosage form of any one of claims 663 to 667, wherein the dosage form comprises at least about 70 mg of promethazine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of promethazine.

669. The dosage form of any one of claims 663 to 668, wherein the dosage form comprises at least about 180 mg of pseudoephedrine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of pseudoephedrine per single dose.

670. The dosage form of any one of claims 663 to 669, wherein the dosage form comprises at least one further drug.

671. The dosage form of any one of claims 639 to 670, wherein the dosage form is associated with instructions to administer the dosage form once every 24 hours.

672. A method of alleviating a condition which can be alleviated by administration of promethazine and optionally a drug which is at least one of a decongestant, an antitussive, an expectorant, a mucus thinning drug and an analgesic, wherein the method comprises administering the pharmaceutical dosage form of any one of claims 639 to 671 to a subject in need thereof.

673. The method of claim 672, wherein the condition that can be alleviated by administration of promethazine comprises an allergic reaction.

674. The method of any one of claims 672 and 673, wherein the dosage form is administered not more than about once every 24 hours.

675. A process for making the pharmaceutical dosage form of claim 663, wherein the process comprises preparing a first composition which comprises promethazine or a pharmaceutically acceptable salt thereof and a second composition which comprises pseudoephedrine or a pharmaceutically acceptable salt thereof, and combining the first and second compositions.

676. The process of claim 675, wherein the compositions are combined by a method which comprises use of a tablet press.

677. A pharmaceutical dosage form which comprises at least one of diphenhydramine and a pharmaceutically acceptable salt thereof, wherein the dosage form is capable of providing a diphenhydramine plasma concentration within the therapeutic range for at least about 24 hours per single dose.

678. The dosage form of claim 677, wherein the dosage form is capable of providing relief from allergy symptoms in a patient in need thereof for at least about 24 hours per single dose.

679. The dosage form of any one of claims 677 and 678, wherein the dosage form comprises at least two diphenhydramine formulations which exhibit different release profiles.

680. The dosage form of any one of claims 677 to 679, wherein the dosage form comprises an immediate release formulation.

681. The dosage form of any one of claims 677 to 680, wherein the dosage form comprises a controlled release formulation.

682. The dosage form of any one of claims 677 to 681, wherein the dosage form comprises a solid dosage form.

683. The dosage form of claim 682, wherein the solid dosage form is selected from tablets, capsules and caplets.

684. The dosage form of claim 682, wherein the dosage form comprises a bi-layered tablet.

685. The dosage form of claim 684, wherein the bi-layered tablet comprises an immediate release layer and a controlled release layer.

686. The dosage form of claim 685, wherein at least one of the immediate release layer and the controlled release layer comprises at least about 70 mg of diphenhydramine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of diphenhydramine .

687. The dosage form of any one of claims 684 to 686, wherein the bi-layered tablet comprises a total of at least about 100 mg of diphenhydramine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of diphenhydramine.

688. The dosage form of any one of claims 677 to 687, wherein at least one of the controlled release layer and the immediate release layer comprises at least about 100 mg of diphenhydramine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of diphenhydramine.

689. The dosage form of any one of claims 677 to 688, wherein the dosage form comprises at least about 100 mg of diphenhydramine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of diphenhydramine.

690. The dosage form of any one of claims 677 to 689, wherein the dosage form comprises at least about 150 mg of diphenhydramine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of diphenhydramine.

691. The dosage form of any one of claims 677 to 690, wherein the dosage form is capable of providing a diphenhydramine plasma concentration within the therapeutic range within not more than about 1 hour following administration thereof.

692. The dosage form of any one of claims 677 to 691, wherein the dosage form comprises at least one further drug.

693. The dosage form of claim 692, wherein the at least one further drug is selected from decongestants, antitussives, expectorants, mucus thinning drugs and analgesics.

694. The dosage form of any one of claims 692 and 693, wherein the dosage form is capable of providing a plasma concentration of the at least one further drug within the therapeutic range for at least about 24 hours per single dose.

695. The dosage form of any one of claims 692 to 694, wherein the at least one further drug is selected from one or more of phenylephrine, pseudoephedrine, phenylephrine, pseudoephedrine, codeine, dihydrocodeine, hydrocodone, dextromethorphan, carbetapentane, guaifenesin, acetaminophen, aspirin, ibuprofen, naproxen, oxycodone, morphine and hydromorphone and pharmaceutically acceptable salts thereof.

696. The dosage form of any one of claims 692 to 695, wherein the dosage form is capable of providing a plasma concentration within the therapeutic range of diphenhydramine over a period which is coextensive with at least about 70 % of the period over which the dosage form is capable of providing a plasma concentration within the therapeutic range of the at least one further drug.

697. The dosage form of any one of claims 692 to 696, wherein the plasma half-life of the at least one further drug differs from the plasma half-life of diphenhydramine by at least about 2 hours.

698. The dosage form of any one of claims 692 to 697, wherein the period of a plasma concentration within the therapeutic range of the at least one further drug is coextensive with at least about 90 % of the period of a plasma concentration within the therapeutic range of diphenhydramine.

699. A pharmaceutical dosage form which comprises (a) at least one of diphenhydramine and a pharmaceutically acceptable salt thereof in a first form or layer and (b) at least one of diphenhydramine and a pharmaceutically acceptable salt thereof in a second form or layer which is different from the first form or layer, wherein the dosage form releases the diphenhydramine (b) at least one of over a different period and at a different rate than the diphenhydramine (a) and wherein the dosage form is capable of providing a diphenhydramine plasma concentration within the therapeutic range for at least about 24 hours per single dose.

700. The dosage form of claim 699, wherein the dosage form is a multi-layered tablet which comprises at least one immediate release layer and at least one controlled release layer and at least one of these layers comprises at least one of diphenhydramine and a pharmaceutically acceptable salt thereof, and wherein at least one of the layers of the multi- layered tablet comprises at least one further drug.

701. A pharmaceutical dosage form which comprises at least one of diphenhydramine and a pharmaceutically acceptable salt thereof and at least one of pseudoephedrine and a pharmaceutically acceptable salt thereof, wherein the dosage form is capable of providing plasma concentrations within therapeutic ranges of both diphenhydramine and pseudoephedrine for at least about 24 hours per single dose.

702. The dosage form of claim 701, wherein the dosage form comprises a solid dosage form.

703. The dosage form of claim 701, wherein the dosage form comprises a multi-layered tablet.

704. The dosage form of any one of claims 701 to 703, wherein the dosage form is capable of providing diphenhydramine and pseudoephedrine plasma concentrations within therapeutic ranges within not more than about 1 hour following administration thereof.

705. The dosage form of any one of claims 701 to 704, wherein the dosage form comprises diphenhydramine hydrochloride and pseudoephedrine hydrochloride.

706. The dosage form of any one of claims 701 to 705, wherein the dosage form comprises at least about 70 mg of diphenhydramine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of diphenhydramine.

707. The dosage form of any one of claims 701 to 706, wherein the dosage form comprises at least about 180 mg of pseudoephedrine hydrochloride or an equivalent amount of at least one other pharmaceutically acceptable salt of pseudoephedrine per single dose.

708. The dosage form of any one of claims 701 to 707, wherein the dosage form comprises at least one further drug.

709. The dosage form of any one of claims 677 to 708, wherein the dosage form is associated with instructions to administer the dosage form once every 24 hours.

710. A method of alleviating a condition which can be alleviated by administration of diphenhydramine and optionally a drug which is at least one of a decongestant, an antitussive, an expectorant, a mucus thinning drug and an analgesic, wherein the method comprises administering the pharmaceutical dosage form of any one of claims 677 to 709 to a subject in need thereof.

711. The method of claim 710, wherein the condition that can be alleviated by administration of diphenhydramine comprises an allergic reaction.

712. The method of any one of claims 710 and 711, wherein the dosage form is administered not more than about once every 24 hours.

713. A process for making the pharmaceutical dosage form of claim 701, wherein the process comprises preparing a first composition which comprises diphenhydramine or a pharmaceutically acceptable salt thereof and a second composition which comprises pseudoephedrine or a pharmaceutically acceptable salt thereof, and combining the first and second compositions.

714. The process of claim 713, wherein the compositions are combined by a method which comprises the use of a tablet press.

715. A pharmaceutical dosage form which comprises at least about 37 mg of phenylephrine or an equivalent amount of a pharmaceutically acceptable salt thereof.

716. The dosage form of claim 715, wherein the dosage form comprises at least about 40 mg of phenylephrine or an equivalent amount of a pharmaceutically acceptable salt thereof.

717. The dosage form of claim 715, wherein the dosage form comprises at least about 45 mg of phenylephrine or an equivalent amount of a pharmaceutically acceptable salt thereof.

718. The dosage form of claim 715, wherein the dosage form comprises at least about 50 mg of phenylephrine or an equivalent amount of a pharmaceutically acceptable salt thereof.

719. The dosage form of any one of claims 715 to 718, wherein the dosage form comprises one or more controlled release forms or layers of at least one of phenylephrine and a pharmaceutically acceptable salt thereof.

720. The dosage form of claim 719, wherein the dosage form additionally comprises an immediate release form or layer of at least one of phenylepherine and a pharmaceutically acceptable salt thereof.

721. The dosage form of any one of claims 715 to 720, wherein the dosage form comprises at least one additional drug.

722. The dosage form of claim 721, wherein the at least one additional drug comprises at least one of an expectorant, an antihistamine, an antitussive drug and an analgesic.

723. The dosage form of any one of claims 715 to 722, wherein the dosage form comprises a solid dosage form.

724. The dosage form of claim 723, wherein the dosage form comprises a tablet.

725. The dosage form of claim 724, wherein the dosage form comprises a multilayered tablet.

726. The dosage form of any one of claims 715 to 722, wherein the dosage form comprises a liquid dosage form.

727. The dosage form of claim 726, wherein the dosage form comprises a suspension.

728. A pharmaceutical dosage form which comprises at least one controlled release form or layer of phenylephrine or a pharmaceutically acceptable salt thereof, wherein the dosage form is associated with instructions to administer the dosage form to a subject in need thereof every x hours and wherein the resultant amount of phenylepherine or pharmaceutically acceptable salt thereof thereby administered every x hours divided by x is at least about 5 mg of phenylephrine or an equivalent amount of a pharmaceutically acceptable salt thereof.

729. The dosage form of claim 728, wherein the amount thereby administered is at least about 6 mg of phenylephrine or an equivalent amount of a pharmaceutically acceptable salt thereof.

730. The dosage form of claim 728, wherein the amount thereby administered is at least about 7 mg of phenylephrine or an equivalent amount of a pharmaceutically acceptable salt thereof.

731. The dosage form of claim 728, wherein the amount thereby administered is at least about 8 mg of phenylephrine or an equivalent amount of a pharmaceutically acceptable salt thereof.

732. The dosage form of any one of claims 728 to 731, wherein the dosage form additionally comprises an immediate release form or layer of at least one of phenylepherine and a pharmaceutically acceptable salt thereof.

733. The dosage form of any one of claims 728 to 732, wherein the dosage form comprises at least one additional drug.

734. The dosage form of claim 733, wherein the at least one additional drug comprises one or more of an expectorant, a mucus thinning drug, an antihistamine, an antitussive drug and an analgesic.

735. The dosage form of any one of claims 728 to 734, wherein the dosage form comprises a solid dosage form.

736. The dosage form of claim 735, wherein the dosage form comprises a tablet.

737. The dosage form of claim 736, wherein the dosage form comprises a multilayered tablet.

738. The dosage form of any one of claims 728 to 734, wherein the dosage form comprises a liquid dosage form.

739. The dosage form of claim 738, wherein the dosage form comprises a suspension.

740. A method of alleviating a condition which can be alleviated by administering phenylephrine, wherein the method comprises administering to a subject in need thereof in intervals of x hours, a pharmaceutical dosage form which comprises phenylepherine or a pharmaceutically acceptable salt thereof, wherein x is at least about 4 and the amount of phenylephrine or pharmaceutically acceptable salt thereof administered per interval, expressed as mg of phenylepherine free base, is at least about 5-x.

741. The method of claim 740, wherein x is at least about 6.

742. The method of claim 740, wherein x is at least about 8.

743. The method of claim 740, wherein x is at least about 8.

744. The method of any one of claims 740 to 743, wherein the amount is at least about 6-x.

745. The method of any one of claims 740 to 743, wherein the amount is at least about 7-x.

746. The method of any one of claims 740 to 743, wherein the amount is at least about 8-x.

747. The method of any one of claims 740 to 746, wherein the condition which can be alleviated by administering phenylephrine comprises respiratory congestion.

748. The method of any one of claims 740 to 747, wherein the dosage form comprises at least one controlled release form or layer of the phenylepherine or pharmaceutically acceptable salt thereof.

749. The method of any one of claims 740 to 748, wherein the dosage form comprises at least one additional drug.

750. The method of claim 749, wherein the at least one additional drug comprises at least one of an expectorant, a mucus thinning drug, an antihistamine, an antitussive drug and an analgesic.

751. The method of any one of claims 740 to 750, wherein the dosage form comprises a tablet.

752. The method of claim 751, wherein the dosage form comprises a multilayered tablet.

753. The method of any one of claims 740 to 750, wherein the dosage form comprises a liquid dosage form.

754. The method of claim 753, wherein the dosage form comprises a suspension.

755. A method of dosing phenylephrine or a pharmaceutically acceptable salt thereof when present in a dosage form for administration in intervals of not less than about 4 hours, wherein the method comprises administering the dosage form every x hours in a quantity which is equivalent to at least 5 -x milligrams of phenylepherine free base.