WO2006046114A2

WO2006046114A2 - Osmotic dosage forms providing ascending drug release, and processes for their preparation

Info

Publication number: WO2006046114A2
Application number: PCT/IB2005/003183
Authority: WO
Inventors: Rajan Kumar Verma; Narayanan Badri Viswanathan; Rajeev Singh Raghuvanshi; Ashok Rampal
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2004-10-25
Filing date: 2005-10-25
Publication date: 2006-05-04
Also published as: WO2006046114A3

Abstract

The present invention discloses osmotic dosage forms that provide drug release at an ascending release rate. Further, processes for the preparation of the osmotic dosage forms are also disclosed.

Description

OSMOTIC DOSAGE FORMS PROVIDING ASCENDING DRUG RELEASE, AND PROCESSES FOR THEIR PREPARATION

Field of invention

The technical field of the present invention relates to osmotic dosage forms that provide drug release at an ascending release rate, and processes for preparation thereof.

Background of the invention

The development of osmotic drug delivery system was pioneered in part by Alza with the development of OROS®, an elementary oral osmotic system. These systems work on the principle of osmosis and deliver drugs in a near zero order profile. Osmotic drug delivery systems show better in vitro-in vivo correlation as their performance of osmotic drug delivery systems is reported to be independent of pH and contents of the gastrointestinal tract. Moreover, they are subject to various mechanical stresses encountered within the gut. Hence, properly designed osmotic systems may prove to be of paramount importance. Osmotic dosage forms, introduced by F. Theewas in J. Pharm. ScL, Vol. 64, 12,

1987-91 (1975), in them simplest versions take the form of a conventional coated tablet. The coated tablet includes a homogenous core tablet of drug coated with a semi-permeable wall/layer and an aperture created through the wall for the release of the contents from the core. Over time, Theewas's osmotic dosage forms have been improved by replacing the homogenous core with a multicompartment core comprising a separate drug layer and push layer, commonly known as "push-pull" osmotic systems.

U.S. Patent No. 4,111,202 assigned to Alza Corp. describes the fabrication of a "push-pull" (double compartment core) osmotic system wherein the core of the OROS^® system is replaced by a pull compartment containing a sparingly soluble drug composition and a push compartment containing water soluble osmotically active agents. The two compartments are separated by means of an elastic diaphragm. When in operation, the osmotic pressure that builds up in the push compartment causes an increase in its volume. This increase in volume expands the elastic diaphragm, which thereby forces the drug out of the pull compartment through an aperture. Though advantageous over the OROS^® system, manufacturing of "push-pull" systems is technically complicated and costly, requiring proper placement of the elastic diaphragm between the two compartments. Further, for sparingly soluble drugs having large therapeutic doses, unacceptably large sized "push-pull" systems are needed.

Variations of these "push-pull" systems are further disclosed in U.S. Patent Nos. 4,327,725, 4,612,008, 4,783,337, and 5,082,668, each of which is incorporated in its entirety by reference herein.

Nevertheless, the constant rate of drug release in these systems is known to be effective for most drugs. However, there are clinical situations in which patients being treated with dosage forms providing constant rates of drug release are subject to a decrease in the therapeutic effectiveness of the drug as they develop a tolerance to the drug. These situations may be improved by using dosage forms that dispense the drug at an ascending release rate.

PCT application WO 9806380 discloses "push-pull" osmotic dosage forms providing ascending drug release rates comprising a trilayer core composition; consisting of a first drug layer, a second drug layer, and a push layer.

U.S. Patent Application No. 20010012847 discloses "push-pull" osmotic dosage forms providing ascending drug release rates. The dosage forms include one or more drug layer and a push layer wherein the different layers are compressed together to provide a longitudinally compressed tablet core having a "capsule - shaped" configuration with a different layer at each narrow end. Such a compressed tablet core has the different layers compressed together along the longitudinal, width axis rather than the thickness axis. Such an unconventional core configuration ensures that, as the push layer expands longitudinally within the compartment formed by the semipermeable membrane, the surface area of the push layer in contact with the semipermeable membrane is increased more than when other configurations are used.

However, there still exists a need for osmotic dosage forms that dispense a drug at an ascending release rate but nonetheless have a conventional configuration and are economical to produce.

We have now developed an alternative approach to prepare an osmotic dosage form in which an ascending release rate of the drug may be achieved from simple bilayered "push-pull" osmotic systems by using polyethylene oxide having a molecular weight greater than 200,000 in the drug layer.

Summary of the Invention

In one general aspect there is provided an osmotic dosage form configured to dispense a drug at an ascending release rate. The dosage form consists of a core, a semipermeable membrane, and at least one passageway. The core has a longitudinal width dimension and a thickness dimension and includes a drug layer and a push layer. The drug layer and the push layer are joined along the thickness dimension. The semipermeable membrane surrounds the core. The at least one passageway is in the semipermeable membrane.

Embodiments of the dosage form may include one or more of the following features. For example, the drug may be one or more of central nervous system stimulants, opioids, antidiabetics, antineoplastic agents, antihypertensives, hypnotics, barbiturates, psychostimulants, cannabinoids, catecholamines, cardiovascular agents, platelet aggregation inhibitors, analgesics, antimicrobials, diuretics, and spasmolytics. The drug may be one or more of methylphenidate, amphetamines, glipizide, doxazosin, isradipine, nifedipine, nisoldipine, bendroflumethazide, chlorpropamide, hydrocortisone, ibuprofen, diclofenac, and oxycodone.

The drug may be dispensed at an ascending release rate for at least 4 hours. The drug layer may further include polyethylene oxide having a molecular weight greater than 200,000. The molecular weight may be, for example, between 300,000 and 600,000.

The push layer may include one or more of water swellable polymers, alginic acid and its derivatives or salts, water insoluble, water swellable copolymers produced by forming a dispersion of a finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, butylene or isobutylene cross-linked with a saturated cross-linking agent of saturated cross-linking agent per mole of maleic anhydride in the copolymer, acidic carboxy polymers, polyacrylamides, cross-linked water swellable indenemaleic anhydride polymers, and polyacrylic acid. The water swellable polymers may be one or more of polyethylene oxide, hydroxypropyl methylcellulose, and poly(hydroxy alkyl methacrylate). The drug layer and/ or the push layer may be one or more of osmotic agents comprising magnesium chloride or magnesium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, water soluble salts of organic acids, non ionic organic compounds with high water solubility, water-soluble amino acids, and urea and urea derivatives.

The water soluble salts of organic acids may be one or more of sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, and sodium ascorbate. The non ionic organic compounds with high water solubility may be one or more carbohydrates. The water-soluble amino acids may be one or more of glycine, leucine, alanine, and methionine.

The osmotic dosage form may further include one or more pharmaceutically acceptable inert excipients comprising osmotic agents, binders, diluents, surfactants, pH modifiers, lubricants/glidants, stabilizers, plasticizers, and coloring agents.

The semipermeable membrane may include one or more membrane forming polymers, including cellulose derivatives, polymeric epoxides, copolymers of alkylene oxides and alkyl glycidyl ethers, polyglycols or polylactic acid derivatives, and copolymers of acrylic acid ethyl ester or methacrylic acid methyl ester. The cellulose derivatives may be one or more of cellulose acetate, ethyl cellulose, cellulose triacetate, agar acetate, amylose acetate, cellulose acetate ethyl carbamate, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate ethyl carbonate, cellulose acetate chloroacetate, cellulose acetate ethyl oxalate, cellulose acetate methyl sulphonate, cellulose acetate butyl sulphonate, cellulose acetate propionate, cellulose acetate diethylamino-acetate, cellulose acetate octate, cellulose acetate laurate, cellulose acetate p-toluenesulphonate, and cellulose acetate butyrate.

In another general aspect there is provided a process for the preparation of an osmotic dosage form configured to dispense a drug at an ascending release rate. The process includes the steps of: (a) combining the components of a drug layer by blending of a drug with polyethylene oxide of molecular weight greater than 200,000, and at least one pharmaceutically acceptable inert excipient and optionally granulating the blend;

(b) combining the components of a push layer by blending of at least one water swellable polymer with one or more pharmaceutical acceptable excipients and optionally granulating the blend;

(c) combining the granules/ blends of Steps (a) and (b) and processing into a conventional bilayer core tablet, the core tablet have a longitudinal width dimension and a thickness dimension, the drug layer and the push layer being joined along the thickness dimension;

(d) applying a coating composition comprising a solution or dispersion of the semipermeable membrane-forming polymer and other coating additives over the bilayered core tablet to form a semipermeable membrane coating; and

(e) optionally creating at least one passageway in the semipermeable membrane.

Embodiments of the process may include one or more of the following features or those described above. For example, either or both of the blends may be granulated using a wet granulation or dry granulation technique. The drug layer further comprises polyethylene oxide having a molecular weight greater than 200,000. In another general aspect there is provided a method of treating a condition in a mammal by administering to the mammal in need thereof an osmotic dosage form configured to dispense a drug at an ascending release rate. The dosage form consists of a core, a semipermeable membrane, and at least one passageway. The core has a longitudinal width dimension and a thickness dimension and includes a drug layer and a push layer. The drug layer and the push layer are joined along the thickness dimension. The semipermeable membrane surrounds the core. The at least one passageway is in the semipermeable membrane.

Embodiments of the method may include one or more of the following features or those described above. For example, the drug may be one or more of central nervous system stimulants, opioids, antidiabetics, antineoplastic agents, antihypertensives, hypnotics, barbiturates, psychostimulants, cannabinoids, catecholamines, cardiovascular agents, platelet aggregation inhibitors, analgesics, antimicrobials, diuretics, and spasmolytics. The drug layer may further include polyethylene oxide having a molecular weight greater than 200,000. The details of one or more embodiments are set forth in the description below.

Other features, objects and advantages of the invention will be apparent from the description and claims.

Detailed Description of the Invention

Figure 1 is a graphical representation of the cumulative in vitro release of the drug from the tablets of Examples 1 and 2.

Figure 2 is a graphical representation of the in vitro release rate of the drug from the tablet of Examples 1 and 2.

Figure 3 is a graphical representation of the cumulative in vitro release of the drug from the tablets of Examples 3 and 4. Figure 4 is a graphical representation of the in vitro release rate of the drug from the tablet of Examples 3 and 4.

Detailed Description of the Invention

The present inventions are not limited to particular process steps and materials disclosed herein, but are extended to equivalents thereof as would be recognized by those ordinarily skilled in the relevant art. It should also be understood that terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting.

The core tablets may have a configuration of a conventional tablet, wherein the drug and push layers are placed along the thickness of the tablets. In other words, if a core tablet has a longitudinal, width axis or dimension and a thickness axis or dimension, the two layers are compressed together with a plane being formed along the thickness axis rather than, for example, the width or longitudinal axis.

Further, osmotic dosage form has a drug layer and a push layer, wherein the drug layer includes of polyethylene oxide having high molecular weight, approximately greater than 200,000. The in vitro release profile of the osmotic dosage forms thus developed has a gradually increasing release rate over time. This characteristic release rate is mainly attributed to the use of high molecular weight polyethylene oxide having a molecular weight hat is greater than approximately 200,000. Further, the present dosage forms can be prepared using simple conventional solid dosage form manufacturing techniques, avoiding the extra fabrication cost for the development of a core having more than two layers.

The term "core" as used herein covers any bilayer compact composition having at least one drug layer and push layer, with a defined shape such as tablet, mold, capsule and the like.

The drug layer may be made up of drug, polyethylene oxide of molecular weight greater than 200,000, and the push layer may be made up of one or more water swellable polymers, in addition to an osmotic agent in one or both of the layers.

The term "drug" as used herein includes any drug for which an ascending release rate is desired or is of some benefit. The drug may be in the form of pharmaceutically acceptable salts, solvates, enantiomers, ester, and mixtures thereof. Suitable examples include drugs belonging to the class of central nervous system stimulants, opioids, antidiabetics, antineoplastic agents, antihypertensives, hypnotics, barbiturates, psychostimulants, cannabinoids, catecholamines, cardiovascular agents, platelet aggregation inhibitors, analgesics, antimicrobials, diuretics, and spasmolytics although other classes may be used as desired. Specific examples include methylphenidate, amphetamines, glipizide, doxazosin, isradipine, nifedipine, nisoldipine, bendroflumethazide, chlorpropamide, hydrocortisone, ibuprofen, diclofenac, oxycodone, and the like. The drug constitutes from about 1% to about 50% of the drug layer by weight. In particular, it may constitute from about 3% to about 25% of the drug layer by weight.

Polyethylene oxide used in the drug layer is marketed by Dow under the trade name POLYOX™. It is available in various grades depending on its molecular weight, which may range from greater than 200,000. In particular, the molecular weight of polyethylene oxide may vary from about 200,000 to about 8,000,000 and more particularly from about 200,000 to about 2,000,000. Examples of suitable grades of polyethylene oxide that may be used in the drug layer include POLYOX™ WSR N-80 (MW - 200,000), WSR N-750 (MW - 300,000), WSR-205 (MW - 600,000), WSR-1105 (MW - 900,000), WSR N-12K (MW - 1,000,000), WSR N-60K (MW - 2,000,000), WSR-301 (MW - 4,000,000), WSR Coagulant (MW - 5,000,000), and WSR-303 (MW - 7,000,000). The polyethylene oxide constitutes from about 20% to about 80% of the drug layer by weight. In particular, it may constitute from about 30% to about 60% of the drug layer by weight.

The term "osmotic agent" as used herein includes all pharmaceutically acceptable inert water soluble compounds suitable for inducing osmosis, referred to in the Pharmacoepias, or in "Hager" as well as in Remington's Pharmaceutical sciences. Examples of compounds suitable as osmotic agents include water soluble salts of inorganic acids such as magnesium chloride or magnesium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate; water soluble salts of organic acids such as sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, and sodium ascorbate; non ionic organic compounds with high water solubility, e.g., carbohydrates such as mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, and raffinose; water- soluble amino acids such as glycine, leucine, alanine, or methionine; urea and urea derivatives; and the like. The amount of osmotic agent used may vary from about 1% to about 50% by weight of the total weight of the drug layer or push layer.

The composition of the push layer includes a water swellable polymer such as polyethylene oxide having a weight average molecular weight of 100,000 to 6,000,000, hydroxypropyl methylcellulose, poly(hydroxy alkyl methacrylate); poly(vinyl)alcohol, having a low acetal residue, which is cross-linked with glyoxal, formaldehyde or glutaraldehyde and having a degree of polymerization of from 200 to 30,000; a mixture of methyl cellulose, cross-linked agar and carboxymethyl cellulose; alginic acid and its derivatives/salts such as sodium alginate, and potassium alginate; a water insoluble, water swellable copolymer produced by forming a dispersion of a finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, butylene or isobutylene cross-linked with saturated cross-linking agent of saturated cross-linking agent per mole of maleic anhydride in the copolymer; Carbopol™ acidic carboxy polymers having a molecular weight of 450,000 to 4,000,000; Cyanamer™ polyacrylamides; cross-linked water swellable indenemaleic anhydride polymers; Goodrite™ polyacrylic acid having a molecular weight of 80,000 to 200,000; starch graft copolymers; Aqua-Keeps™ acrylate polymer polysaccharides composed of condensed glucose units such as diester cross- linked polyglucan and the like. Other polymers, which form hydrogels, are described in U.S. Patent Nos. 3,865,108; 4,002,173 and 4,207,893 all of which are incorporated by reference. The pharmaceutically acceptable, water swellable polymers may be employed in an effective amount that will control the swelling of the push layer. These amounts will generally be from about 30% to 90%, preferably from about 40% to 75% based on the weight of the push layer.

Besides the above, the drug and push layer may further comprise one or more pharmaceutically acceptable inert excipients. The term "pharmaceutically acceptable inert excipients" as used herein includes all excipients used in the art of manufacturing osmotic controlled dosage forms and described in the literature. Specific examples include binders, diluents, surfactants, pH modifiers, lubricants/glidants, stabilizers, plasticizers, coloring agents, and the like.

Specific examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.

Specific examples of diluents include calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like.

Specific examples of surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical compositions. These include polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol -20 glyceryl stearate; alcohol - oil transesterification products, for example polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides for example glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example polyethylene glycol - 20 cetyl ether, polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyl carnitine; and the like.

The pH modifiers are substances which help in maintaining the pH of the local environment surrounding the drug at a value favorable for dissolution of drug. Specific examples of pH modifiers include dibasic sodium phosphate, sodium ascorbate, meglumine, sodium citrate, trimethanolamine, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium oxide, magnesium hydroxide, ammonia, tertiary sodium phosphate, diethanolamine, ethylenediamine, L-lysine and the like.

Specific examples of lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.

Specific examples of plasticizers include acetylated triacetin, triethylcitrate, tributylcitrate, glyceroltributyrate, monoglyceride, rape oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethyl phthalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, and the like.

Stabilizers include antioxidants, buffers, acids, and the like. Coloring agents include any FDA approved colors for oral use.

The term "Semipermeable membrane" as used herein is a membrane or coating, which allows movement of water molecules through it, but does not allow contents of the core to pass through. Semipermeable membrane comprises membrane forming polymers and other pharmaceutically acceptable coating additives.

Membrane forming polymers are those which are not metabolized in the gastrointestinal tract, i.e., are ejected unchanged from the body in feces. Membrane forming polymers include those known in the art for fabrication of semipermeable membrane and described in the literature, e.g., in U.S. Patent Nos. 3,916, 899 and 3,977,404. Examples of semipermeable membrane forming polymers include cellulose derivatives such as cellulose acetate, ethyl cellulose, cellulose triacetate, agar acetate, amylose acetate, cellulose acetate ethyl carbamate, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate ethyl carbonate, cellulose acetate chloroacetate, cellulose acetate ethyl oxalate, cellulose acetate methyl sulphonate, cellulose acetate butyl sulphonate, cellulose acetate propionate, cellulose acetate diethylamino-acetate, cellulose acetate octate, cellulose acetate laurate, cellulose acetate p-toluenesulphonate, and cellulose acetate butyrate; polymeric epoxides; copolymers of alkylene oxides and alkyl glycidyl ethers; polyglycols or polylactic acid derivatives; copolymers of acrylic acid ethyl ester and methacrylic acid methyl ester; and the like. Controlling membrane thickness also helps to control the permeability of the membrane, which generally may vary from about 3% to about 25% weight build up over the weight of the bilayered core tablet. The term "coating additives" as used herein includes all conventional coating additives used in the art of coating technology and described in the literature. Examples include flux enhancers as well as those described above under pharmaceutically acceptable inert excipients.

Flux enhancers are water soluble substances which aid in drawing water from the surrounding media and are thereby helpful in manipulating the semipermeable membrane's permeability. Specific examples include hydroxymethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, hydroxypropylcellulose, propylene glycol, polyvinylpyrrolidone, and the like.

The term "passageway" as used herein covers any suitable means for releasing the contents of the core into the surrounding media. The term includes passages, apertures, bores, holes, openings and the like, that are created through the semipermeable membrane and form a connection between the core and the surrounding media. The passageway may be created by mechanical drilling or laser drilling, or formed in response to the osmotic pressure acting on the drug delivery system. Based on the nature of the desired drug release profile, the number and diameter of the passageways may be adjusted. However, the diameter of the passageway should not be large enough to allow body fluids to enter the drug delivery system by the process of convection.

The bilayer core of the osmotic dosage form may be prepared by combining the granule or blend compositions of the drug and the push layers.

In one of the embodiments, the process for the preparation of a bilayered core of osmotic dosage form that dispenses drug at an ascending release rate includes the steps of: (a) Combining the components of the drug layer by blending of a drug with polyethylene oxide of molecular weight greater than 200,000, binder, and other pharmaceutically acceptable inert excipient and; optionally granulating the blend; (b) Combining the components of the push layer by blending of at least one water swellable polymer with one or more pharmaceutical acceptable excipients and; optionally granulating the blend; and (c) Combining the granules/ blends of steps (a) and (b) and processing into a conventional bilayer core tablet. The granules in any of the above embodiments may be prepared using dry or wet granulation techniques.

The osmotic dosage prepared in any of the above embodiments may be further coated with a coating composition comprising a solution / dispersion of the semipermeable membrane a forming polymer, plasticizers and optionally other coating additives. The semipermeable layer may be applied using conventional coating techniques well known in the art such as spray coating in a conventional coating pan, or fluidized bed processor, dip coating, melt coating, and the like. In particular a spray coating technique may be used. Examples of granulating fluids or solvents for preparing the solution/dispersion of coating composition include aqueous or organic solvents, and mixtures thereof such as water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetone and the like.

Additionally the osmotic dosage prepared in any of the above embodiments may further be processed to form at least one passageway in the semipermeable membrane using a 0.8 mm mechanical drill. The osmotic dosage form further may be coated with an immediate release layer of drug. The drug in the immediate release layer may be same or different from the drug present in the drug layer surrounded by semipermeable membrane.

The invention is further illustrated by the following examples, which are provided for illustrative purposes only and should not be construed as limiting the scope of the inventions in any way.

Examples Core Tablet Composition

Equivalent to 4 mg doxazosin (+10% overage), MW - 4,000,000, MW - 2,000,000 Semipermeable layer

Procedure

Preparation of co-processed doxazosin

1. Polyethylene glycol 6000 was melted and doxazosin added into it with constant stirring.

2. The melted mixture of step 1 was cooled to form a solid mass.

3. The solid mass of step 2 was crushed and sized through a # 44 sieve (BSS) to provide co-processed doxazosin.

Preparation of core tablet 1. The Co-processed doxazosin was blended with all other ingredients of the drug layer and sized through a #22 sieve (BSS).

2. The ingredients of the push layer were blended and sized through a #22 sieve (BSS).

3. The blends of step 1 and 2 were compressed into conventional bilayered core tablets.

Coatinε of core tablet with semipermeable membrane

1. The bilayered core tablets were coated with the semipermeable membrane- forming coating solution of cellulose acetate and polyethylene glycol, up to a weight gain of about 12-14%. 2. An orifice (0.6 to 0.8 mm) was drilled through the semipermeable membrane towards the drug layer using mechanical drill.

The in vitro release of drug (doxazosin) from the osmotic dosage forms prepared as per Examples 1 and 2 was studied in 900 ml phosphate buffer (pH 6.8, containing 0.5% sodium lauryl sulphate) using USP II dissolution apparatus, at a paddle speed of 50 rpm. The results of the study are incorporated herein for reference in Fig. 1. The in vitro release rate of doxazosin during different time intervals was calculated and plotted as Fig. 2. Figure 2 clearly indicates an ascending release rate of doxazosin between 4 to 16 hours from the dosage forms of Example 1, and between 6 to 16 hours from the dosage forms of Example 2.

Core Tablet Composition

Semipermeable layer

Preparation of core tablet 1. Glipizide was blended with all other ingredients of the drug layer and sized through a #22 sieve (BSS).

3. The blends of step 1 and 2 were compressed into conventional bilayered core tablets using standard round concave punches.

Coatins of core tablet with semipermeable membrane

1. The bilayered core tablets were coated with the semipermeable membrane-forming coating solution of cellulose acetate and polyethylene glycol, until reading a weight gain of about 7-10%. 2. An orifice (0.8-10 mm) was drilled through the semipermeable membrane towards the drug layer using mechanical drill.

The in vitro release of drug (glipizide) from the osmotic dosage forms prepared as per Examples 3 and 4 were studied in 900 ml phosphate buffer (pH 7.5) using USP II dissolution apparatus, at a paddle speed of 50 rpm. The results of the study are provided in Fig. 3.

The in vitro release rate of glipizide during different time intervals was calculated and plotted as Fig. 4. Figure 4 clearly indicates an ascending release rate of glipizide between 4 to 16 hours from these dosage forms of Example 3, and between 6 to 16 hours from dosage forms of Example 4. While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text and claims can be made without departing from the spirit and scope of the invention. For example, use of high molecular weight polymers such as hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, alginic acid derivatives, carbopols, etc., instead of polyethylene oxide in the drug layer may also provide ascending drug release profiles. Another useful modification is illustrated in the following example wherein an osmotic core composition comprising methylphenidate is disclosed. The core may be surrounded by a semipermeable membrane, and an optional immediate release layer of methylphenidate, and one or more passageways may be drilled through the semipermeable membrane. The osmotic dosage form thus formed would provide an optional immediate dose of methylphenidate followed by ascending release rate of methylphenidate delivery.

An osmotic dosage form of methylphenidate that dispenses methylphenidate at an ascending release rate may have the following composition ranges.

Core tablet composition

Claims

We Claim: 1. An osmotic dosage form configured to dispense a drug at an ascending release rate, the dosage form consisting essentially of: a core having a longitudinal width dimension and a thickness dimension and comprising a drug layer and a push layer, the drug layer and the push layer being joined along the thickness dimension; a semipermeable membrane surrounding the core; and at least one passageway in the semipermeable membrane. 2. The osmotic dosage form according to claim 1, wherein the drug comprises one or more of central nervous system stimulants, opioids, antidiabetics, antineoplastic agents, antihypertensives, hypnotics, barbiturates, psychostimulants, cannabinoids, catecholamines, cardiovascular agents, platelet aggregation inhibitors, analgesics, antimicrobials, diuretics, and spasmolytics. 3. The osmotic dosage form according to claim 1, wherein the drug comprises one or more of methylphenidate, amphetamines, glipizide, doxazosin, isradipine, nifedipine, nisoldipine, bendrofiumethazide, chlorpropamide, hydrocortisone, ibuprofen, diclofenac, and oxycodone. 4. The osmotic dosage form according to claim 1 , wherein the drug layer further comprises polyethylene oxide having a molecular weight greater than 200,000. 5. The osmotic dosage form according to claim 1, wherein the push layer comprises one or more of water swellable polymers, alginic acid and its derivatives or salts, water insoluble, water swellable copolymers produced by forming a dispersion of a finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, butylene or isobutylene cross-linked with a saturated cross-linking agent of saturated cross-linking agent per mole of maleic anhydride in the copolymer, acidic carboxy polymers, polyacrylamides, cross-linked water swellable indenemaleic anhydride polymers, and polyacrylic acid. 6. The osmotic dosage form according to claim 5, wherein the water swellable polymers comprise one or more of polyethylene oxide, hydroxypropyl methylcellulose, and poly(hydroxy alkyl methacrylate). 7. The osmotic dosage form according to claim 1, wherein the drug layer and/ or the push layer comprises one or more of osmotic agents comprising magnesium chloride or magnesium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, water soluble salts of organic acids, non ionic organic compounds with high water solubility, water-soluble amino acids, and urea and urea derivatives. 8. The osmotic dosage form according to claim 7, wherein the water soluble salts of organic acids comprise one or more of sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, and sodium ascorbate. 9. The osmotic dosage form according to claim 7, wherein the non ionic organic compounds with high water solubility comprise one or more carbohydrates. 10. The osmotic dosage form according to claim 7, wherein the water-soluble amino acids comprise one or more of glycine, leucine, alanine, and methionine. 11. The osmotic dosage form according to claim 1, wherein the dosage form further comprises one or more pharmaceutically acceptable inert excipients comprising osmotic agents, binders, diluents, surfactants, pH modifiers, lubricants/glidants, stabilizers, plasticizers, and coloring agents. 12. The osmotic dosage form according to claim 1, wherein the semipermeable membrane comprises one or more membrane forming polymers comprising cellulose derivatives, polymeric epoxides, copolymers of alkylene oxides and alkyl glycidyl ethers, polyglycols or polylactic acid derivatives, and copolymers of acrylic acid ethyl ester or methacrylic acid methyl ester. 13. The osmotic dosage form according to claim 12, wherein the cellulose derivatives comprise one or more of cellulose acetate, ethyl cellulose, cellulose triacetate, agar acetate, amylose acetate, cellulose acetate ethyl carbamate, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate ethyl carbonate, cellulose acetate chloroacetate, cellulose acetate ethyl oxalate, cellulose acetate methyl sulphonate, cellulose acetate butyl sulphonate, cellulose acetate propionate, cellulose acetate diethylamino-acetate, cellulose acetate octate, cellulose acetate laurate, cellulose acetate p-toluenesulphonate, and cellulose acetate butyrate. 14. The osmotic dosage form according to claim 1, wherein the drug is dispensed at an ascending release rate for at least 4 hours. 15. A process for the preparation of an osmotic dosage form configured to dispense a drug at an ascending release rate, the process comprising the steps of: (a) combining the components of a drug layer by blending of a drug with polyethylene oxide of molecular weight greater than 200,000, and at least one pharmaceutically acceptable inert excipient and optionally granulating the blend; (b) combining the components of a push layer by blending of at least one water swellable polymer with one or more pharmaceutical acceptable excipients and optionally granulating the blend; (c) combining the granules/ blends of Steps (a) and (b) and processing into a conventional bilayer core tablet, the core tablet have a longitudinal width dimension and a thickness dimension, the drug layer and the push layer being joined along the thickness dimension; (d) applying a coating composition comprising a solution or dispersion of the semipermeable membrane-forming polymer and other coating additives over the bilayered core tablet to form a semipermeable membrane coating; and (e) optionally creating at least one passageway in the semipermeable membrane. 16. The process according to claim 15, wherein either or both of the blends are granulated using a wet granulation or dry granulation technique. 17. The process according to claim 15, wherein the drug layer further comprises polyethylene oxide having a molecular weight greater than 200,000. 18. A method of treating a condition in a mammal by administering to the mammal in need thereof an osmotic dosage form configured to dispense a drug at an ascending release rate, the dosage form consisting essentially of: a core having a longitudinal width dimension and a thickness dimension and comprising a drug layer and a push layer, the drug layer and the push layer being joined along the thickness dimension; a semipermeable membrane surrounding the core; and at least one passageway in the semipermeable membrane. 19. The method according to claim 18, wherein the drug comprises one or more of central nervous system stimulants, opioids, antidiabetics, antineoplastic agents, antihypertensives, hypnotics, barbiturates, psychostimulants, cannabinoids, catecholamines, cardiovascular agents, platelet aggregation inhibitors, analgesics, antimicrobials, diuretics, and spasmolytics. 20. The method according to claim 18, wherein the drug layer further comprises polyethylene oxide having a molecular weight greater than 200,000.