CA1205381A - Extended action controlled release compositions - Google Patents
Extended action controlled release compositionsInfo
- Publication number
- CA1205381A CA1205381A CA000430797A CA430797A CA1205381A CA 1205381 A CA1205381 A CA 1205381A CA 000430797 A CA000430797 A CA 000430797A CA 430797 A CA430797 A CA 430797A CA 1205381 A CA1205381 A CA 1205381A
- Authority
- CA
- Canada
- Prior art keywords
- tablet
- salt
- base
- weight
- active
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
Abstract
A B S T R A C T
Extended action controlled release compositions are formed by incorporating into a controlled release matrix for a medication a mixture of the salt form of the medication and the free base form of the medication in a proportion of 75%-25% by weight of the salt form to 25%-75% by weight of the free base form, the weight amounts being calculated with respect to the active base.
Extended action controlled release compositions are formed by incorporating into a controlled release matrix for a medication a mixture of the salt form of the medication and the free base form of the medication in a proportion of 75%-25% by weight of the salt form to 25%-75% by weight of the free base form, the weight amounts being calculated with respect to the active base.
Description
~z0s3~
EXTENDED ACTION CONTROLLED RE:LE~SE COMPOSITIONS
It is known in the pharmaceutical art to prepare a compo-sitions which provide for slow release of pharmacologically active substances contained in said compositions after oral administration to humans and animals in order to delay absorption of a medicament until it has reached certain portions of the alimentary tract and to further maintain à desired concentration of the medicament in the blood stream for a longer duration than would occur if conventional rapid release dosage forms are administered.
lo Some slow release formulations provide for related sequen-tial release of a single dose of an active compound at predetermined periods a~ter administration.
- It is the intent of all slow release preparations to pro- j vide a longer period of pharmacological response after the administra-tion of a drug than is ordinarily experienced after the administration of the rapid release dosage forms.
Another critical role for extended acting medications is in therapy of cardiovascular diseases whereby optimal peak blood levels of a medicament must be maintained at the steady state level to 20 achieve the desired therapeutic effect. -The prior art teaching of the preparation and use of compo-sitions providing the slow release of an active compound from a car-rier is basically concerned with the release of the active substance into the physiologic fluids of the alimentary tract. However, it is generally recognized that the mere presence of an active drug sub-stance in the gastrointestinal fluids does not, by itself, insure ~2~
bioavailability. Bioavailability is the availability of a drug sub-stance to the bloodstream and to the receptor site to achieve a desired pharmacologic action. Bioavailability~ in a more meaningful sense, is the degree (or amount) to which a drug substance is bsorbed to be available to a target tissue site after administration of a unit dosage form.
To be absorbed, an active drug substance must be in solu-tion. The time required for a given proportion of an active drug substance contained in unit dosage form to enter into solution in lo appropriate physiologic fluids, is known as the dissolution time. , The dissolution time of an active substance from a unit dosage form is determined as the proportion of the amount of active drug substance released from a unit dosage form over a specified time base by a test method conducted under standardized conditions. The physiologic fluids of the gastrointestinal tract are the media for determining dissolution time.
Although there are many diverse factors which influenee the dissolution of a drug substance from its carrier, the dissolution time determined for a pharmacologically active substance from the specific composition is relatively constant and reproducible. Among the different factors affecting the dissolution time are the surface area of the drug substance presented to the dissolution solvent medium, the pH of solution, the solubility of the substance in the specific solvent medium, and the driving forces of the saturation concentration of dissolved materials in the solvent medium. Thus, the dissolution concentration of an active drug substance is dynam-ically modified in its steady state as components are removed from ~z~
the dissolution medium through absorption across the tissue site.
Under physiologic conditions, the saturation level of the dissolved materials is replenished from the dosage form reserves to maintain a relatively uniform and constant dissolution concentration in the solvent medium providing for a steady state absorption.
The prior art teaches that the absorption of drugs is influenced by the degree of electrical charges borns by the drug at the absorption site. Drugs which are present in an electrically uncharged form more readily cross the tissue absorption barrier than lo drugs in a dissociated or electrically charged state. F~rthermore, the intrinsic oil-water partition coefficient for a substance which ' favors the oil phase is another characteristic leading to an in-creased rapid absorption of the drug substance across the alimentary tract and a slowed absorption of a drug substance is observed with an increased ionization strength o the substance. These relation- ,~
ships are well established in the art through findings that absorb- '-able materials must pass through a lipoid-like barrier when pene-trating membranes at the absorption site. - ~
Notwithstanding the diverse factors influencing both ,-dissolution and absorption of a drug substan~e, a strong correlation has been established between the in-vitro dissolution time determined -for a dosage form and in the in-vivo bioavailability. This correla~ ', tion is so firmly established in the art that dissolution time has become generally descriptive of bioavailability potential for the active component of the particular unit dosage composition. In view of this relationship it is clear that the dissolution time determined for a composition is one of the important undamental eharacteristics for consideration when evaluating slow release eompositions.
This invention relates to pharmaeeutical compositions with an extended and improved controlled rate of drug release providing for an extended bioavailability of the active materials incorporated therein. In particular, it provides for novel slow release composi-tions comprising a balanced combination of a salt of a pharmacolog-ically active substance and the free active base moiety of said pharmacologically active salt in specific proportion to eaeh other lo which, when incorporated into a slow release composition seleetively modified the period of release of said pharmacologically active eom-ponent from said slow release composition to materially affeet the bioavailability of said pharmaeologieally aetive substanee~
The present invention mainly comprises an ~xtended eon- S
trolled release pharmaceutical eomposition comprising a slow release matrix having dispersed therein both the pharmaeologieally active salt form of a medication and the free base form of the same medi- -eation in a proportion of 25-75 parts by weight of said salt form to-25-75 parts by weight of said free base form, ealeulated with respeet 20 to the pharmacologically active non salt moiety.
It was unexpectedly found that the dissolution rate of a pharmacologically active substance from a slow release composition is materially extended when a balanced proportion of the pharmaco-logically active moiety in its free or base form is eombined with the salt form of the substance in the slow release matrix. Thi~
extension of the dissolution time for this eombination is not achiéved through a use of larger amounts of the drug substances. In 15~0S~
fact, essentially the same quantity of active drug i5 employed to obtain the extended effect through the use of the compositions of the present invention as is used for the earlier prior art prepara-tions. Moreover, the desired extension in dissolution time of a pharmacologically active moiety from a slow release preparation is not achieved through modification of either the carrier core, the retarding matrix or by altering any of the retardant coatings that may be used in the preparation. This effect is achieved through a preferential selective change in the inherent properties of the lo pharmacologically active substance of the composition to provide new dissolution characteristics in the physiologic fluid~ for the combination.
In order to obtain the desired extension in the dissolu- t tion time of a pharmacologically active moiety from a slow release preparation prepared with a salt of the pharmacologically active moiety, an amount of from 25% to 75% by weight of said salt is re-placed with the free, or non-salt base o~ said pharmacologically act-ive moiety. The combination of pharmacologically active salt and free base is then used as the active pharmacologic component in manufacture 20 of the particular slow release preparation in the same manner as is known in the art to prepare the earlier slow acting dosage form.
It was found that, by appropriate selection of the ratio of-base form to salt form of the active substance used as the active sub-stance to manufacture a slow relea$e preparation, different degrees of extension of the time for release of the active ingredient was -obtained .
53~
It was found in a test that when the dissolution time of a slow release preparation prepared with propranolol hydrochloride as the active ingredient was tested, 10~/~ of the active material was released within 6 hours. However, when 5~/O by weight of the amount of propranolol contained in the propranolol hydrochloride was replaced with propranolol base, then the dissolution time was extended to 7 hours. When the ratio of propranolol salt to propranolol base is 40 parts by weight of sàlt and 60 parts by weight of propranolol base, the dissolution time determined for the preparation was approximately lo 10 to 12 hours.
In still another test a slow release antiarrhythmic tablet comprising quinidine polygalacturonate was formulated to provide a dissolution time of about 10 hours by methods known in the axt. How-ever, the dissolution time was materially extended by utilizing a combination of quinidine polygalacturonate and quinidine base. Thus, i~
if the combination of active ingredient comprises 75% by weight of qulnidine polygalacturonate and 25% by weight of quinidine base (based on quinidine equivalent content), the dissolution time is extended to 15 hours. When 5~/O by weight of the quinidine poly- ll galacturonate is replaced with quinidine bas~, then the dissolution time for the preparation is extended to virtually 20 hours.
When a xanthine salt active ingredient, as for example, ', aminophylline or theophylline ethylenediamine, is used to prepare a slow release tablet in accord with the teachings of U.S. Patent 3,965,256, all of the active material is released over the period of up to 9 hours. However, when theophylline base is used to replace 25% of the aminophylline (based on theophylline content equivalency) the dissolution time is extended to 12 hours.
53~
The prior art teaches that absorption of an active drug across alimentary tract tissues is enhanced when the electrically uncharged form of the pharmacologically active substance is used rather than the electrically charged ionized form of the same sub-stance. An opposite condition was unexpectedly found to occur with the new salt-base formulated dosage'form since the presence o~ the electrically uncharged free base moiety caused a slowed dissolution time and extended biavailability rather than a more rapid absorption.
Thus we find that the use of the electrically uncharged and lipid favoring base material does not accelerate dissolu~'ion time or stimulate absorption, and therefore increase bioavailability as taught in the prior art, but rather slows absorption and extends dissolution time and hioavailability. Then phenomenon is contrary to the present teachings of the prior art.
Moreover, solubility, per se, is not found to be a con- ' trolling factor as is also taught in the art, w~nce the ~ame degree -- ' of extension in dissolution time and bioavailability was unexpectedly ,`
found when the combination salt-base active substance is used whether an insoluble salt or a soluble salt i8 combined with the appropriate base material. Thus we find that when the electrically uncharged codeine base is used to replace 5~/O of both the codeine content of - 1 codeine sulfate (solubility in water: 1:30) and codeine phosphate (solubility in water: 1:2), the bioavailability of both preparations -~ !
is extended by approximately 12 hours. If solubility was the con- ' trolling factor in affecting the extension in the dissolution time and/or bioavailability, different values should have been found for the tablet preparation made with the more soluble salt codeine' ~21)531~
phosphate than that prepared with the less soluble salt, codeine sulfate.
While the invention is not meant to be limited to any specific theorty as to why or how the extended release and increased bioavailability is obtained by using the combination of the salt form and free base form in the compositions of the invention, the follow-ing theory is given ln the hope that it will help others in the further investigation of this field~
It appears that a new mechanism controls this unexpected -lo phenomenon which involves the dynamic resonant interchange of ionizing salt moiety and electrically uncharged base moiety. When a salt i~ ¦
incorporated in a slow release carrier, the total number of particles released into the physiologic fluids comprise both dissociated and undissociated materials which give rise to a constant dissolution time for the formulation and which is correlatable to the bioavail-ability for the preparation. However, when the free base replaces a proportion of the salt, a shift in the ratio of the charged to un-charged particles in solution occurs and thus slows the avai1ability of active moiety at the absoxption site since there i~ now a.dispro- .
portionate composition of salt to base moietias in solution with greater competition for the electrically charged ions by the electric- .-ally neutral base particles, thereby altering the entire equilibrium of the system. This shift in equilibrium is reflected in the extended .
dissolution time and consequent ex.tended bioavailability to result in materially new and advantageous properties for the composition.
Slow release tablets and capsules utilizing the new com-bined salt-base active ingredient may be prepared with the matrix .
~Z~:)S381L
and other carriers used for this purpose which are known in the art.
Thus, tablet cores intended for special coatings a~ a means to retard the release of active ingredient may ~e prepared with the new salt-hase active incredient to result in a further extension of the bio-availability of the active ingredient used alone in the same vehicle.
Preferred slow release pharmaceutical compositions utilizing the new combined salt-base active ingredient may be prepared with the sus-tained release matrix comprising hydroxyalkylcellulose components and higher aliphatic alcohols as described in U.S. Patent 4,235,870.
10 By utilizing the appropriate proportions of from 25% to 7S% of base to salt, an extension of from 3 to 15 hours in the already delayed release of the active ingredient is ~btained. Such extended duration in dissolution ~ime enables optimal bioavailability of the active therapeutic agent oveF a sufficient duration to permit one-a-day medication. -Among the preferred pharmacologically active base`substance-~
which are suitable ~or the preparation of slow release tablets and -capsules utilizing the new combined salt-base mechanism are those listed in Table I. `
TABLE I
SOME PREFERRED BASE ACTIVE SUBSTANCES USEFUL IN ---THE PREPARATION OF SLCW RELEASE COMPOSITIONS
Amitryptaline - Morphine - L
Atropine Oxycodone Chlorpheniramine Papvarine - ' Chlorpromizine , Phenylpropanolamine Codeine Propranolol Dexbrompheniramine Quinidine Diphenylhydramine Scopolamine 30 Doxilamine Theophylline Ephedrine Thioridazine Hyoscyamine ~.
...... . ..
~053~
The substances described in Table I above are representative of pharmacologically active classes of compounds which are desirable for dispensing in the form of a slow release composition intended to provide an active pharmacologic effect over an extended period. When preparing slow release preparations with the base substances de~-cribed in Table I, these base substances are used to replace a pro- ]
portion of from 25% to 75% by weight o the amount of the pharma- -cologically active salt of said base which would be ordinarily used to prepare a slow release tablet or capsule preparation. .
In practice, the appropriate salt-base combina~ion used as the active ingredient is intimately mixed, with both the ~alt and the base being preferably of the same particle size. As a general rule a particle size of about 20 - 60 US Standard Mesh Screen size will be found to be an optimal particle size for this purpose. The pow-dered salt-base active ingredient is then utilized in the same manner as in the preparation of conventional slow release tablet or capsule preparations. Thus the active ingredient is added to the carrier materials at the indicated step in the process as are known to the art when the core tablet to be used for coating is manufactured.
When a slow release tablet matrix is used as a vehicle for - the salt-base active ingredient, then the combination powdered active ingredient is added to the composition at the appropriate step in the `
manufacturing process as though it consisted of the salt alone. How-ever, the unique properties of the salt-base ~ormulation enables modification in the teaching of the art in the manufacture of slow release tablets and capsules utilizing a matrix. Thus, in the manu- - ;
facture of an antiarrhythmic slow release tablet employing quinidine --10-- , polygalacturonate and quinidinc base in proportions of 60 parts by weight of salt to 40 parts by weight of base as the active ingredient, the following manufacturing method will be found to be satisfactory.
(%) Parts by Weight Quinidine Polygalacturonate 56.8 Quinidine Base 22.9 Hydroxyethylcellulose 6.4 Stearyl alcohol 12.8 Lubricants (Silicon dioxide) 1.1 1 ~0 . O
In this formula 6~/o of the quinidine content is represented by quinidine polygalacturonate and 4~/O by quinidine base. _ Step 1: Intimately mix the appropriate quantity of quinidine poly-galacturonate and quinidine base and pass through a ~o. 20 U.S.
Standard Mesh Screen and add the necessary quantity of hydroxy-ethylcellulose and blend to obtain a uniform composition.
Step 2: Hydrate the mixture of Step 1 with from 2 to 4 parts by ~r weight of water for each part by weight of cellulose component used in Step l with a preferred ratio being 3:1 parts by weight. Stir - , the granular paste until uniform.
Step 3: Dry the mass and pass through a ~o. 16 US Standard Mesh Screen.
SteP 4: In a separate vessel melt the stearyl alcohol and add the granules obtained as a result of Step 3 to the molten alcohol. ~~~
Step 5: Cool to room temperature and pass the granules of Step 4 through a No. 12 or No. 14 US standard Mesh Screen, Add appropriate lubricants and compress into tablets of suitable size and shape.
Final tablet weight ~ 360.0 mgm. ;~
Tablet Diameter 13/32 inch Hardness 8 kg stokes Quinidine content per tablet ~ 206.0 mgm.
~()53~
When capsules are desired as the slow release unit dosage form, then the composition obtained prior to the compression tableting Step 5, described above, is filled into capsules of appropriate size, shape and weight.
This manufacturing procedure may be used to prepare a 510w release preparation with propranolol hydrochloride/propranolol base;
codeine phosphate/codeine base; aminophylline/theophylline, as well as slow release tablets and capsules prepared with the base materials in Table I utilizing either the hydrochloride, sulfate or maleate lo salts of the respective base active substances listed in ~able I.
When preparing slow release unit dosage forms with the base substances described above (Table I), the active base materials may be used to replace from 25% to 75% by weight of the amount of the corresponding salt which is ordinarily used to prepare a slow release tablet or capsule preparation. When the new combined sal -base active ingredient is used, an extension of the dissolution time for the product normally obtained for the particular vehicle will be extended by a period of at least 3 hours, when from 25% to 75% by weight of the active ingredient salt is replaced wlth the particular 20 base. When from 6~/o to 75% by weight of the pharmacologically active '~
salt is replaced with the indicated base of the active salt ingredient, -t then an extension in the dissolution time of from 10 to 14 hour~ and i even longer periods, is observed. When a 50/50 mixture of the salt-base active ingredient is used, th~e usual extension dissolution time over that observed when the salt form is used, alone, is approximately 5 hours. Thus, by appropriate adjustment of the proportion of the amount of the salt form of the active ingredient being replaced with ~Z0~3~1 the respective base, a broad range in the extension of the observed dissolution time and correspondiny bioavailability for the active ingredient occurs to provide a flexibility to meet the required therapeutic needs of the particular base as well as to provide a means to achieve one-a-day therapy.
It was further unexpectedly found that when an organic salt is used to formulate the 510w release tablet, that the new combination salt-base active ingredient permitted the preparation of a tablet of smaller size with an improved tablet hardness. Thus lo when quinidine polygalacturonate is utilized to prepare a slow re-lease tablet in accord with the teaching of U.S. Patent 3,965,256, the resultant slow release tablet has a tablet hardness character-istic determined by the stokes Hardness Testor of 4 kg. This value is at the lower limit of acceptable hardness and inherently leads to increased tablet ~riability, but when the combined salt-base active 1l ingredient of the present invention is used in the appropriate pro- - ¦
portions, a tablet with a hardness value of 7 to 8 Xg. is obtained without altering the disintegration time of the tablet and without increasing tablet xize or the need for added binders. _ j Tablet hardness is the term used to describe the resistance of a tablet to chipping, erosion, abrasion and breakage under condi- !
tions of storage, transportation and handling. A tablet is considered to be of proper hardness when a clean break is achieved when snapped between the second and third fingers, using the thumb a,~ a fulcrum and further, if the tablet does not break when dropped from a height `
of at least 3 feet. If the tablet is tGo hard, it will not disinte-grate within the required time period to release the active ingredients. `
~ 0538~
If it is too soft, it will not witllstand the handling durations during packaging, as well as the mechanical stress of shipping and distribution.
The problem of~tablet hardness is frequently encountered when active ingredients comprising organic c~alts such as gluconates, polygalacturonates, tannates, maleates, high fatty acids as for example, the alkyl fatty acids having a carbon chain length of from 3 to 18 carbon atoms, or aromatic acids as for example, benzoates, salicylates and phtalates are used to prepare slow release tablets.
lo Although appropriate binders may be added to correct this problem, the tablet size increases proportionately to present new problems in swallowing the tablet. If the compression force is increased to produce a harder tablet, the disintegration time of the tablet,is adversely affected to result in unsatisfactory values. This problem of tablet hardness is expecially encountered in the preparation of the tablet core intended to be coated with a slow release coating, since the soft tablet core will not withstand the tumbling compres-sion encountered in the coating step. Consequen ly a high order of tablet rejection results even approaching 2~/o of the batch when the 20 core has a tablet hardness of about 5 kg. When a lipophilic/hydro-phobic tablet matrix is used to prepare a slow releac~e preparation, i~
the inherent nature of the wax materials often results in a soft tablet. Such tablets require special handling thereby increasing costs of manufacture and shipping.
It was unexpectedly found that when a proportion of the organic salt used as the active substance is replaced with the same active base moiety, the characteristic of tablet hardness was ~s~
advantageously improved withou~ affecting the disintegration time or tablet size. Thus for example, when quinidine polygalacturonate is used to prepare slow release pharmaceutical compositions comprising a hydrated hydroxyalkylcellulose and higher fatty alcohol in accord with the method of Examples 1 and 7 of U.S. Patent 3,965,256 (pat-ented June 22, 1976), the tablet hardness measured by the Stokes Hardness Testor is 4 kg. This tablet exhibits about 15% chipping and friable erosion during packaging, thus requiring costly special handling. When added tablet excipients and binders are utilized to lo increase tablet hardness to 6 kg. as measured by the Sto~es Tablet Hardness instrument, a tablet o extraordinary size results. However, when at least l~/o by weight of the amount of quinidine polygalacturo-nate present in the formulation is replaced with quinidine base, the tablet hardness is appreciably and favorably improved without mater-ially affecting the disintegration time of tablet size. When optimal proportions of base to salt, as for example the ratio of from 25% to 35% by weight of the quinidine base to from 65% to 75% of the salt is used, this results in a tablet hardness of about 7 to 10 kg. (Stokes).
Furthermore such slow release tabLet now has less than 0.01% chipping -~
20 and erosive friability during manufacture, handling and shipping. (~
Similar favorable results are obtained when a proportion of other ~ ~-organic salts which are used as the active ingredient is replaced with the base moiety. Il When it is desired to utilize the new slow release compo- I
sitions in therapy, the dosage form may be either a tablet or a cap-sule and the particular salt-base replacement proportions will depend on the preferred specific therapeutic needs. When it is desired to ~20S31~
utilize one-a-day therapy dosage schedules, then it will be found useful to replace 75~/0 of the pharmacologically active salt used as the therapeutic ingredient with the base moiety and in certain instances it may be desired to use even a higher base salt replace-ment ratio of up to 9~/~ of the amount of the salt used being replaced by the base. The exact proportion of active salt replaced by the base is dependent on the duration of bioavailability desired to be achieved with the particular dosage form. A particular advantage of the present slow release composition is obtained by adjusting the lo proportion of salt/base active ingredient in slow release pharmaceu-tical compositions to obtain the desired bioavailability for one-a-day administration schedules of a therapeutic dosage form, without materially modifying tablet size or increasing the amount of active ingredients.
The general method utilized in the production of the com-position of the present invention is set forth below:
To further extend the dissolution time of an active ingred-ient from a slow release tablet or capsule composition prepared with a pharmacologically active salt, from 25% to 75% of the amount of pharmacologically active salt used in the formula is replaced with the free active base moiety of said salt. When sèlecting the quan-tity of the pharmacologically active salt to be replaced with the base, the pharmacologically active portion of the salt enters into such determination. For example, if the active salt used is theophylline ethylenediamine, which is also known as aminophylline, and it is desired to replace from 25% to 75% of the active base moiety of the salt, then the calculations are based on the theophylline 1~0531!~, content of the quantity of ~minophylline used to prepare the slow release tablet intended to be extended, and the weight of the ethylenediamine portion is disregarded.
Thus all replacement steps described in accord with the present method to further extend the dissolution time of an active ingredient used in a slow release tablet is based on the quantity of pharmacologically active moiety of the product, not the overall weight of the active salt, per se. The new base salt combination is used as the single active ingredient when calculating the active ingredient lo weights in tablet or capsule dosage forms.
When utilizing the combination of pharmacologically active salt and active base, the materials are intimately mixed and preferably granulated through a No. 16 US Standard Mesh Screen. In practice, it will be found convenient to combine the mixing and granulating steps with other ingredients in the manufacture of slow release preparations.
When the salt base active ingredient is incorporated into the tablet core, it is preferably mixed with the indicated diluents in the same order and sequence as would be used in the manufacture of the tablet had the single salt active ingredient been used. The finished tab-let core is then coated with an appropriate release retarding coating.
When a balanced matrix comprising a hydrophilic cellulose ~' component and a hydrophobic alcohol wax component is used as the car-rier for the active ingredient of an uncoated slow release tablet, then the combination of the salt base active materials is preferably mixed with the hydrophilic components, including the other appro-priate diluents, before the mixture is granulated. While it is pre-ferred that the active salt base components be included with the 5~
hydrophilic ingredients, as for example, cellulose, lactose, staxch and povidone, it may be found useful in certain instances to incorp-orate the active salt base composition with the cydrophobic compo-nents as for example, the fatty alcohols and waxes which are used to prepare the slow release matrix.
The following method is useful to obtain an extension of the dissolution time of the active ingredients of a slow release tablet.
Step 1: Intimately mix the appropriate quantities of the pharma-lo cologically active salt and its free active baqe together with the cellulose component and other hydrophilic diluents, such as lactose, starch and povidone, as may be required.
Step 2: Hydrate the mixture of Step 1 with from 2 parts by weight to 4 parts by weight of water for each part by weight f cellulose component and stir to form a granular past~. If other hydrophylic polymers are present, then slightly less - !
water should be used as for example, 2-3 parts by weight of water.
SteP 3: Dry the mixture and gramllate through a No. 16 US Standard Mexh Screen.
SteP 4: Melt the hydrophobic components as for example, a fatty -~
alcohol of rom 10 to 18 carbon atoms in chain length, waxes, petroleum waxes and mixtures of these and add the melt to the granules obtained from Step 3 above. The mixture should be well stirred until uniform.
Step 5: Allow the coated granules to cool to room temperature and granulate through a No. 12 or No. 14 US standard Mesh Screen.
~2~
Step 6: Add the appropriate lubricants to the granules o Step 5 and compress into tablets of desired shape, size and weight.
The dissolution time determined for such slow release tablets will be significantly slowed to enable a wide range of therapeutic dosage flexibility, including one-a-day regimens.
Should it be desired to ut.ilize capsule dosage forms, then the mixtures obtained prior to tablet compression are filled into appropriate capsules and the whole coated with a retarding coat in the manner well known to the art.
When it is desirec to further retard the dissolution time of the active quinidine content from a quinidine polygalacturonate slow release tablet, then a slow release tablet of the following composition is prepared:
_ Tablet A _ _Parts by Weight (%) Quinidine Polygalacturonate 56.8 ~`
Quinidine Base 22.9 Hydroxyethylcellulose 6.4 Stearyl alcohol 12.8 Tablet Lubricants - 1.1 100. 0 In this formulation, 6~/o Of the active quinidine content for the tablet is contributed by the salt, quinidine polygalacturo-nate, and 4~/O of the quinidine content of the tablet is contributed by quinidine base.
The following method is used to manufacture the slow release tablets:
SteE~l: Intimately mix the quinidine polygalacturonate and quini- ;~
dine base and add the hydroxyethylcellulose; continue mixing until uniform.
~2053~L
Step 2: llydrate the ~xture of Step l with sufficient water to -form a granular paste. From 2-4 parts by weight of water for each part by weight of the cellulose material will be found to be sufficient.
Step 3: Dry the mixture and ~ranulate through a No. 16 US standard Mesh Screen.
Step 4: Melt the stearyl alcohol and coat the prepared granules with the melted fatty alcohol; mix well to obtain a uniform coating.
lo SteP 5: Allow the coated granules to cool and granul~te through a i No. 12 or No. 14 US standard Mesh Screen.
Step 6: Add the appropriate lubricants and compress into tablets of desired size, shape and weight, as follows: i Final tablet weight = 360.0 mgm~
Tablet diamèter = 13/32"
Hardness: 8 kg (Stokes) Quinidine content per tablet - 206.0 mgm.
The dissolution time determined for this slow release tablet estab-lishes that the release of 100/o of active quinidine content occurs 20 over 20 hours. ~
When a slow release tablet is prepared with the same car- .
rier but utilizing only the salt, quinidine polygalacturonate, as the active ingredient, as for example:
Tablet BParts bv Weiqht (%) Quinidine Polygalacturonate77.0 Hydroxyethylcellulose 7.0 Stearyl alcohol 14.0 Tablet Lubricants 2.0 1 00 . o '120S38~
Tablet ~ ession Data .
Final tablet weight = 442.6 Diameter of tablet = 14/32"
Hardness: 4 kg (Stokes) Quinidine content per tablet = 206.0 mgm.
and utilizing the same method of manufacture as described above, the dissolution time for 100% of the quinidine content to be released is 12 hours.
A comparison of the dissolution rates determined for both tablets is as follows:
Tablet A Tablet B
Quinidine Quinidine Polygalacturonate Polygalacturonate 0,uinidine Base (60:40) 100%
% Quinidine Content Released 1 hour in simulated gastric juice 26% 18%
EXTENDED ACTION CONTROLLED RE:LE~SE COMPOSITIONS
It is known in the pharmaceutical art to prepare a compo-sitions which provide for slow release of pharmacologically active substances contained in said compositions after oral administration to humans and animals in order to delay absorption of a medicament until it has reached certain portions of the alimentary tract and to further maintain à desired concentration of the medicament in the blood stream for a longer duration than would occur if conventional rapid release dosage forms are administered.
lo Some slow release formulations provide for related sequen-tial release of a single dose of an active compound at predetermined periods a~ter administration.
- It is the intent of all slow release preparations to pro- j vide a longer period of pharmacological response after the administra-tion of a drug than is ordinarily experienced after the administration of the rapid release dosage forms.
Another critical role for extended acting medications is in therapy of cardiovascular diseases whereby optimal peak blood levels of a medicament must be maintained at the steady state level to 20 achieve the desired therapeutic effect. -The prior art teaching of the preparation and use of compo-sitions providing the slow release of an active compound from a car-rier is basically concerned with the release of the active substance into the physiologic fluids of the alimentary tract. However, it is generally recognized that the mere presence of an active drug sub-stance in the gastrointestinal fluids does not, by itself, insure ~2~
bioavailability. Bioavailability is the availability of a drug sub-stance to the bloodstream and to the receptor site to achieve a desired pharmacologic action. Bioavailability~ in a more meaningful sense, is the degree (or amount) to which a drug substance is bsorbed to be available to a target tissue site after administration of a unit dosage form.
To be absorbed, an active drug substance must be in solu-tion. The time required for a given proportion of an active drug substance contained in unit dosage form to enter into solution in lo appropriate physiologic fluids, is known as the dissolution time. , The dissolution time of an active substance from a unit dosage form is determined as the proportion of the amount of active drug substance released from a unit dosage form over a specified time base by a test method conducted under standardized conditions. The physiologic fluids of the gastrointestinal tract are the media for determining dissolution time.
Although there are many diverse factors which influenee the dissolution of a drug substance from its carrier, the dissolution time determined for a pharmacologically active substance from the specific composition is relatively constant and reproducible. Among the different factors affecting the dissolution time are the surface area of the drug substance presented to the dissolution solvent medium, the pH of solution, the solubility of the substance in the specific solvent medium, and the driving forces of the saturation concentration of dissolved materials in the solvent medium. Thus, the dissolution concentration of an active drug substance is dynam-ically modified in its steady state as components are removed from ~z~
the dissolution medium through absorption across the tissue site.
Under physiologic conditions, the saturation level of the dissolved materials is replenished from the dosage form reserves to maintain a relatively uniform and constant dissolution concentration in the solvent medium providing for a steady state absorption.
The prior art teaches that the absorption of drugs is influenced by the degree of electrical charges borns by the drug at the absorption site. Drugs which are present in an electrically uncharged form more readily cross the tissue absorption barrier than lo drugs in a dissociated or electrically charged state. F~rthermore, the intrinsic oil-water partition coefficient for a substance which ' favors the oil phase is another characteristic leading to an in-creased rapid absorption of the drug substance across the alimentary tract and a slowed absorption of a drug substance is observed with an increased ionization strength o the substance. These relation- ,~
ships are well established in the art through findings that absorb- '-able materials must pass through a lipoid-like barrier when pene-trating membranes at the absorption site. - ~
Notwithstanding the diverse factors influencing both ,-dissolution and absorption of a drug substan~e, a strong correlation has been established between the in-vitro dissolution time determined -for a dosage form and in the in-vivo bioavailability. This correla~ ', tion is so firmly established in the art that dissolution time has become generally descriptive of bioavailability potential for the active component of the particular unit dosage composition. In view of this relationship it is clear that the dissolution time determined for a composition is one of the important undamental eharacteristics for consideration when evaluating slow release eompositions.
This invention relates to pharmaeeutical compositions with an extended and improved controlled rate of drug release providing for an extended bioavailability of the active materials incorporated therein. In particular, it provides for novel slow release composi-tions comprising a balanced combination of a salt of a pharmacolog-ically active substance and the free active base moiety of said pharmacologically active salt in specific proportion to eaeh other lo which, when incorporated into a slow release composition seleetively modified the period of release of said pharmacologically active eom-ponent from said slow release composition to materially affeet the bioavailability of said pharmaeologieally aetive substanee~
The present invention mainly comprises an ~xtended eon- S
trolled release pharmaceutical eomposition comprising a slow release matrix having dispersed therein both the pharmaeologieally active salt form of a medication and the free base form of the same medi- -eation in a proportion of 25-75 parts by weight of said salt form to-25-75 parts by weight of said free base form, ealeulated with respeet 20 to the pharmacologically active non salt moiety.
It was unexpectedly found that the dissolution rate of a pharmacologically active substance from a slow release composition is materially extended when a balanced proportion of the pharmaco-logically active moiety in its free or base form is eombined with the salt form of the substance in the slow release matrix. Thi~
extension of the dissolution time for this eombination is not achiéved through a use of larger amounts of the drug substances. In 15~0S~
fact, essentially the same quantity of active drug i5 employed to obtain the extended effect through the use of the compositions of the present invention as is used for the earlier prior art prepara-tions. Moreover, the desired extension in dissolution time of a pharmacologically active moiety from a slow release preparation is not achieved through modification of either the carrier core, the retarding matrix or by altering any of the retardant coatings that may be used in the preparation. This effect is achieved through a preferential selective change in the inherent properties of the lo pharmacologically active substance of the composition to provide new dissolution characteristics in the physiologic fluid~ for the combination.
In order to obtain the desired extension in the dissolu- t tion time of a pharmacologically active moiety from a slow release preparation prepared with a salt of the pharmacologically active moiety, an amount of from 25% to 75% by weight of said salt is re-placed with the free, or non-salt base o~ said pharmacologically act-ive moiety. The combination of pharmacologically active salt and free base is then used as the active pharmacologic component in manufacture 20 of the particular slow release preparation in the same manner as is known in the art to prepare the earlier slow acting dosage form.
It was found that, by appropriate selection of the ratio of-base form to salt form of the active substance used as the active sub-stance to manufacture a slow relea$e preparation, different degrees of extension of the time for release of the active ingredient was -obtained .
53~
It was found in a test that when the dissolution time of a slow release preparation prepared with propranolol hydrochloride as the active ingredient was tested, 10~/~ of the active material was released within 6 hours. However, when 5~/O by weight of the amount of propranolol contained in the propranolol hydrochloride was replaced with propranolol base, then the dissolution time was extended to 7 hours. When the ratio of propranolol salt to propranolol base is 40 parts by weight of sàlt and 60 parts by weight of propranolol base, the dissolution time determined for the preparation was approximately lo 10 to 12 hours.
In still another test a slow release antiarrhythmic tablet comprising quinidine polygalacturonate was formulated to provide a dissolution time of about 10 hours by methods known in the axt. How-ever, the dissolution time was materially extended by utilizing a combination of quinidine polygalacturonate and quinidine base. Thus, i~
if the combination of active ingredient comprises 75% by weight of qulnidine polygalacturonate and 25% by weight of quinidine base (based on quinidine equivalent content), the dissolution time is extended to 15 hours. When 5~/O by weight of the quinidine poly- ll galacturonate is replaced with quinidine bas~, then the dissolution time for the preparation is extended to virtually 20 hours.
When a xanthine salt active ingredient, as for example, ', aminophylline or theophylline ethylenediamine, is used to prepare a slow release tablet in accord with the teachings of U.S. Patent 3,965,256, all of the active material is released over the period of up to 9 hours. However, when theophylline base is used to replace 25% of the aminophylline (based on theophylline content equivalency) the dissolution time is extended to 12 hours.
53~
The prior art teaches that absorption of an active drug across alimentary tract tissues is enhanced when the electrically uncharged form of the pharmacologically active substance is used rather than the electrically charged ionized form of the same sub-stance. An opposite condition was unexpectedly found to occur with the new salt-base formulated dosage'form since the presence o~ the electrically uncharged free base moiety caused a slowed dissolution time and extended biavailability rather than a more rapid absorption.
Thus we find that the use of the electrically uncharged and lipid favoring base material does not accelerate dissolu~'ion time or stimulate absorption, and therefore increase bioavailability as taught in the prior art, but rather slows absorption and extends dissolution time and hioavailability. Then phenomenon is contrary to the present teachings of the prior art.
Moreover, solubility, per se, is not found to be a con- ' trolling factor as is also taught in the art, w~nce the ~ame degree -- ' of extension in dissolution time and bioavailability was unexpectedly ,`
found when the combination salt-base active substance is used whether an insoluble salt or a soluble salt i8 combined with the appropriate base material. Thus we find that when the electrically uncharged codeine base is used to replace 5~/O of both the codeine content of - 1 codeine sulfate (solubility in water: 1:30) and codeine phosphate (solubility in water: 1:2), the bioavailability of both preparations -~ !
is extended by approximately 12 hours. If solubility was the con- ' trolling factor in affecting the extension in the dissolution time and/or bioavailability, different values should have been found for the tablet preparation made with the more soluble salt codeine' ~21)531~
phosphate than that prepared with the less soluble salt, codeine sulfate.
While the invention is not meant to be limited to any specific theorty as to why or how the extended release and increased bioavailability is obtained by using the combination of the salt form and free base form in the compositions of the invention, the follow-ing theory is given ln the hope that it will help others in the further investigation of this field~
It appears that a new mechanism controls this unexpected -lo phenomenon which involves the dynamic resonant interchange of ionizing salt moiety and electrically uncharged base moiety. When a salt i~ ¦
incorporated in a slow release carrier, the total number of particles released into the physiologic fluids comprise both dissociated and undissociated materials which give rise to a constant dissolution time for the formulation and which is correlatable to the bioavail-ability for the preparation. However, when the free base replaces a proportion of the salt, a shift in the ratio of the charged to un-charged particles in solution occurs and thus slows the avai1ability of active moiety at the absoxption site since there i~ now a.dispro- .
portionate composition of salt to base moietias in solution with greater competition for the electrically charged ions by the electric- .-ally neutral base particles, thereby altering the entire equilibrium of the system. This shift in equilibrium is reflected in the extended .
dissolution time and consequent ex.tended bioavailability to result in materially new and advantageous properties for the composition.
Slow release tablets and capsules utilizing the new com-bined salt-base active ingredient may be prepared with the matrix .
~Z~:)S381L
and other carriers used for this purpose which are known in the art.
Thus, tablet cores intended for special coatings a~ a means to retard the release of active ingredient may ~e prepared with the new salt-hase active incredient to result in a further extension of the bio-availability of the active ingredient used alone in the same vehicle.
Preferred slow release pharmaceutical compositions utilizing the new combined salt-base active ingredient may be prepared with the sus-tained release matrix comprising hydroxyalkylcellulose components and higher aliphatic alcohols as described in U.S. Patent 4,235,870.
10 By utilizing the appropriate proportions of from 25% to 7S% of base to salt, an extension of from 3 to 15 hours in the already delayed release of the active ingredient is ~btained. Such extended duration in dissolution ~ime enables optimal bioavailability of the active therapeutic agent oveF a sufficient duration to permit one-a-day medication. -Among the preferred pharmacologically active base`substance-~
which are suitable ~or the preparation of slow release tablets and -capsules utilizing the new combined salt-base mechanism are those listed in Table I. `
TABLE I
SOME PREFERRED BASE ACTIVE SUBSTANCES USEFUL IN ---THE PREPARATION OF SLCW RELEASE COMPOSITIONS
Amitryptaline - Morphine - L
Atropine Oxycodone Chlorpheniramine Papvarine - ' Chlorpromizine , Phenylpropanolamine Codeine Propranolol Dexbrompheniramine Quinidine Diphenylhydramine Scopolamine 30 Doxilamine Theophylline Ephedrine Thioridazine Hyoscyamine ~.
...... . ..
~053~
The substances described in Table I above are representative of pharmacologically active classes of compounds which are desirable for dispensing in the form of a slow release composition intended to provide an active pharmacologic effect over an extended period. When preparing slow release preparations with the base substances de~-cribed in Table I, these base substances are used to replace a pro- ]
portion of from 25% to 75% by weight o the amount of the pharma- -cologically active salt of said base which would be ordinarily used to prepare a slow release tablet or capsule preparation. .
In practice, the appropriate salt-base combina~ion used as the active ingredient is intimately mixed, with both the ~alt and the base being preferably of the same particle size. As a general rule a particle size of about 20 - 60 US Standard Mesh Screen size will be found to be an optimal particle size for this purpose. The pow-dered salt-base active ingredient is then utilized in the same manner as in the preparation of conventional slow release tablet or capsule preparations. Thus the active ingredient is added to the carrier materials at the indicated step in the process as are known to the art when the core tablet to be used for coating is manufactured.
When a slow release tablet matrix is used as a vehicle for - the salt-base active ingredient, then the combination powdered active ingredient is added to the composition at the appropriate step in the `
manufacturing process as though it consisted of the salt alone. How-ever, the unique properties of the salt-base ~ormulation enables modification in the teaching of the art in the manufacture of slow release tablets and capsules utilizing a matrix. Thus, in the manu- - ;
facture of an antiarrhythmic slow release tablet employing quinidine --10-- , polygalacturonate and quinidinc base in proportions of 60 parts by weight of salt to 40 parts by weight of base as the active ingredient, the following manufacturing method will be found to be satisfactory.
(%) Parts by Weight Quinidine Polygalacturonate 56.8 Quinidine Base 22.9 Hydroxyethylcellulose 6.4 Stearyl alcohol 12.8 Lubricants (Silicon dioxide) 1.1 1 ~0 . O
In this formula 6~/o of the quinidine content is represented by quinidine polygalacturonate and 4~/O by quinidine base. _ Step 1: Intimately mix the appropriate quantity of quinidine poly-galacturonate and quinidine base and pass through a ~o. 20 U.S.
Standard Mesh Screen and add the necessary quantity of hydroxy-ethylcellulose and blend to obtain a uniform composition.
Step 2: Hydrate the mixture of Step 1 with from 2 to 4 parts by ~r weight of water for each part by weight of cellulose component used in Step l with a preferred ratio being 3:1 parts by weight. Stir - , the granular paste until uniform.
Step 3: Dry the mass and pass through a ~o. 16 US Standard Mesh Screen.
SteP 4: In a separate vessel melt the stearyl alcohol and add the granules obtained as a result of Step 3 to the molten alcohol. ~~~
Step 5: Cool to room temperature and pass the granules of Step 4 through a No. 12 or No. 14 US standard Mesh Screen, Add appropriate lubricants and compress into tablets of suitable size and shape.
Final tablet weight ~ 360.0 mgm. ;~
Tablet Diameter 13/32 inch Hardness 8 kg stokes Quinidine content per tablet ~ 206.0 mgm.
~()53~
When capsules are desired as the slow release unit dosage form, then the composition obtained prior to the compression tableting Step 5, described above, is filled into capsules of appropriate size, shape and weight.
This manufacturing procedure may be used to prepare a 510w release preparation with propranolol hydrochloride/propranolol base;
codeine phosphate/codeine base; aminophylline/theophylline, as well as slow release tablets and capsules prepared with the base materials in Table I utilizing either the hydrochloride, sulfate or maleate lo salts of the respective base active substances listed in ~able I.
When preparing slow release unit dosage forms with the base substances described above (Table I), the active base materials may be used to replace from 25% to 75% by weight of the amount of the corresponding salt which is ordinarily used to prepare a slow release tablet or capsule preparation. When the new combined sal -base active ingredient is used, an extension of the dissolution time for the product normally obtained for the particular vehicle will be extended by a period of at least 3 hours, when from 25% to 75% by weight of the active ingredient salt is replaced wlth the particular 20 base. When from 6~/o to 75% by weight of the pharmacologically active '~
salt is replaced with the indicated base of the active salt ingredient, -t then an extension in the dissolution time of from 10 to 14 hour~ and i even longer periods, is observed. When a 50/50 mixture of the salt-base active ingredient is used, th~e usual extension dissolution time over that observed when the salt form is used, alone, is approximately 5 hours. Thus, by appropriate adjustment of the proportion of the amount of the salt form of the active ingredient being replaced with ~Z0~3~1 the respective base, a broad range in the extension of the observed dissolution time and correspondiny bioavailability for the active ingredient occurs to provide a flexibility to meet the required therapeutic needs of the particular base as well as to provide a means to achieve one-a-day therapy.
It was further unexpectedly found that when an organic salt is used to formulate the 510w release tablet, that the new combination salt-base active ingredient permitted the preparation of a tablet of smaller size with an improved tablet hardness. Thus lo when quinidine polygalacturonate is utilized to prepare a slow re-lease tablet in accord with the teaching of U.S. Patent 3,965,256, the resultant slow release tablet has a tablet hardness character-istic determined by the stokes Hardness Testor of 4 kg. This value is at the lower limit of acceptable hardness and inherently leads to increased tablet ~riability, but when the combined salt-base active 1l ingredient of the present invention is used in the appropriate pro- - ¦
portions, a tablet with a hardness value of 7 to 8 Xg. is obtained without altering the disintegration time of the tablet and without increasing tablet xize or the need for added binders. _ j Tablet hardness is the term used to describe the resistance of a tablet to chipping, erosion, abrasion and breakage under condi- !
tions of storage, transportation and handling. A tablet is considered to be of proper hardness when a clean break is achieved when snapped between the second and third fingers, using the thumb a,~ a fulcrum and further, if the tablet does not break when dropped from a height `
of at least 3 feet. If the tablet is tGo hard, it will not disinte-grate within the required time period to release the active ingredients. `
~ 0538~
If it is too soft, it will not witllstand the handling durations during packaging, as well as the mechanical stress of shipping and distribution.
The problem of~tablet hardness is frequently encountered when active ingredients comprising organic c~alts such as gluconates, polygalacturonates, tannates, maleates, high fatty acids as for example, the alkyl fatty acids having a carbon chain length of from 3 to 18 carbon atoms, or aromatic acids as for example, benzoates, salicylates and phtalates are used to prepare slow release tablets.
lo Although appropriate binders may be added to correct this problem, the tablet size increases proportionately to present new problems in swallowing the tablet. If the compression force is increased to produce a harder tablet, the disintegration time of the tablet,is adversely affected to result in unsatisfactory values. This problem of tablet hardness is expecially encountered in the preparation of the tablet core intended to be coated with a slow release coating, since the soft tablet core will not withstand the tumbling compres-sion encountered in the coating step. Consequen ly a high order of tablet rejection results even approaching 2~/o of the batch when the 20 core has a tablet hardness of about 5 kg. When a lipophilic/hydro-phobic tablet matrix is used to prepare a slow releac~e preparation, i~
the inherent nature of the wax materials often results in a soft tablet. Such tablets require special handling thereby increasing costs of manufacture and shipping.
It was unexpectedly found that when a proportion of the organic salt used as the active substance is replaced with the same active base moiety, the characteristic of tablet hardness was ~s~
advantageously improved withou~ affecting the disintegration time or tablet size. Thus for example, when quinidine polygalacturonate is used to prepare slow release pharmaceutical compositions comprising a hydrated hydroxyalkylcellulose and higher fatty alcohol in accord with the method of Examples 1 and 7 of U.S. Patent 3,965,256 (pat-ented June 22, 1976), the tablet hardness measured by the Stokes Hardness Testor is 4 kg. This tablet exhibits about 15% chipping and friable erosion during packaging, thus requiring costly special handling. When added tablet excipients and binders are utilized to lo increase tablet hardness to 6 kg. as measured by the Sto~es Tablet Hardness instrument, a tablet o extraordinary size results. However, when at least l~/o by weight of the amount of quinidine polygalacturo-nate present in the formulation is replaced with quinidine base, the tablet hardness is appreciably and favorably improved without mater-ially affecting the disintegration time of tablet size. When optimal proportions of base to salt, as for example the ratio of from 25% to 35% by weight of the quinidine base to from 65% to 75% of the salt is used, this results in a tablet hardness of about 7 to 10 kg. (Stokes).
Furthermore such slow release tabLet now has less than 0.01% chipping -~
20 and erosive friability during manufacture, handling and shipping. (~
Similar favorable results are obtained when a proportion of other ~ ~-organic salts which are used as the active ingredient is replaced with the base moiety. Il When it is desired to utilize the new slow release compo- I
sitions in therapy, the dosage form may be either a tablet or a cap-sule and the particular salt-base replacement proportions will depend on the preferred specific therapeutic needs. When it is desired to ~20S31~
utilize one-a-day therapy dosage schedules, then it will be found useful to replace 75~/0 of the pharmacologically active salt used as the therapeutic ingredient with the base moiety and in certain instances it may be desired to use even a higher base salt replace-ment ratio of up to 9~/~ of the amount of the salt used being replaced by the base. The exact proportion of active salt replaced by the base is dependent on the duration of bioavailability desired to be achieved with the particular dosage form. A particular advantage of the present slow release composition is obtained by adjusting the lo proportion of salt/base active ingredient in slow release pharmaceu-tical compositions to obtain the desired bioavailability for one-a-day administration schedules of a therapeutic dosage form, without materially modifying tablet size or increasing the amount of active ingredients.
The general method utilized in the production of the com-position of the present invention is set forth below:
To further extend the dissolution time of an active ingred-ient from a slow release tablet or capsule composition prepared with a pharmacologically active salt, from 25% to 75% of the amount of pharmacologically active salt used in the formula is replaced with the free active base moiety of said salt. When sèlecting the quan-tity of the pharmacologically active salt to be replaced with the base, the pharmacologically active portion of the salt enters into such determination. For example, if the active salt used is theophylline ethylenediamine, which is also known as aminophylline, and it is desired to replace from 25% to 75% of the active base moiety of the salt, then the calculations are based on the theophylline 1~0531!~, content of the quantity of ~minophylline used to prepare the slow release tablet intended to be extended, and the weight of the ethylenediamine portion is disregarded.
Thus all replacement steps described in accord with the present method to further extend the dissolution time of an active ingredient used in a slow release tablet is based on the quantity of pharmacologically active moiety of the product, not the overall weight of the active salt, per se. The new base salt combination is used as the single active ingredient when calculating the active ingredient lo weights in tablet or capsule dosage forms.
When utilizing the combination of pharmacologically active salt and active base, the materials are intimately mixed and preferably granulated through a No. 16 US Standard Mesh Screen. In practice, it will be found convenient to combine the mixing and granulating steps with other ingredients in the manufacture of slow release preparations.
When the salt base active ingredient is incorporated into the tablet core, it is preferably mixed with the indicated diluents in the same order and sequence as would be used in the manufacture of the tablet had the single salt active ingredient been used. The finished tab-let core is then coated with an appropriate release retarding coating.
When a balanced matrix comprising a hydrophilic cellulose ~' component and a hydrophobic alcohol wax component is used as the car-rier for the active ingredient of an uncoated slow release tablet, then the combination of the salt base active materials is preferably mixed with the hydrophilic components, including the other appro-priate diluents, before the mixture is granulated. While it is pre-ferred that the active salt base components be included with the 5~
hydrophilic ingredients, as for example, cellulose, lactose, staxch and povidone, it may be found useful in certain instances to incorp-orate the active salt base composition with the cydrophobic compo-nents as for example, the fatty alcohols and waxes which are used to prepare the slow release matrix.
The following method is useful to obtain an extension of the dissolution time of the active ingredients of a slow release tablet.
Step 1: Intimately mix the appropriate quantities of the pharma-lo cologically active salt and its free active baqe together with the cellulose component and other hydrophilic diluents, such as lactose, starch and povidone, as may be required.
Step 2: Hydrate the mixture of Step 1 with from 2 parts by weight to 4 parts by weight of water for each part by weight f cellulose component and stir to form a granular past~. If other hydrophylic polymers are present, then slightly less - !
water should be used as for example, 2-3 parts by weight of water.
SteP 3: Dry the mixture and gramllate through a No. 16 US Standard Mexh Screen.
SteP 4: Melt the hydrophobic components as for example, a fatty -~
alcohol of rom 10 to 18 carbon atoms in chain length, waxes, petroleum waxes and mixtures of these and add the melt to the granules obtained from Step 3 above. The mixture should be well stirred until uniform.
Step 5: Allow the coated granules to cool to room temperature and granulate through a No. 12 or No. 14 US standard Mesh Screen.
~2~
Step 6: Add the appropriate lubricants to the granules o Step 5 and compress into tablets of desired shape, size and weight.
The dissolution time determined for such slow release tablets will be significantly slowed to enable a wide range of therapeutic dosage flexibility, including one-a-day regimens.
Should it be desired to ut.ilize capsule dosage forms, then the mixtures obtained prior to tablet compression are filled into appropriate capsules and the whole coated with a retarding coat in the manner well known to the art.
When it is desirec to further retard the dissolution time of the active quinidine content from a quinidine polygalacturonate slow release tablet, then a slow release tablet of the following composition is prepared:
_ Tablet A _ _Parts by Weight (%) Quinidine Polygalacturonate 56.8 ~`
Quinidine Base 22.9 Hydroxyethylcellulose 6.4 Stearyl alcohol 12.8 Tablet Lubricants - 1.1 100. 0 In this formulation, 6~/o Of the active quinidine content for the tablet is contributed by the salt, quinidine polygalacturo-nate, and 4~/O of the quinidine content of the tablet is contributed by quinidine base.
The following method is used to manufacture the slow release tablets:
SteE~l: Intimately mix the quinidine polygalacturonate and quini- ;~
dine base and add the hydroxyethylcellulose; continue mixing until uniform.
~2053~L
Step 2: llydrate the ~xture of Step l with sufficient water to -form a granular paste. From 2-4 parts by weight of water for each part by weight of the cellulose material will be found to be sufficient.
Step 3: Dry the mixture and ~ranulate through a No. 16 US standard Mesh Screen.
Step 4: Melt the stearyl alcohol and coat the prepared granules with the melted fatty alcohol; mix well to obtain a uniform coating.
lo SteP 5: Allow the coated granules to cool and granul~te through a i No. 12 or No. 14 US standard Mesh Screen.
Step 6: Add the appropriate lubricants and compress into tablets of desired size, shape and weight, as follows: i Final tablet weight = 360.0 mgm~
Tablet diamèter = 13/32"
Hardness: 8 kg (Stokes) Quinidine content per tablet - 206.0 mgm.
The dissolution time determined for this slow release tablet estab-lishes that the release of 100/o of active quinidine content occurs 20 over 20 hours. ~
When a slow release tablet is prepared with the same car- .
rier but utilizing only the salt, quinidine polygalacturonate, as the active ingredient, as for example:
Tablet BParts bv Weiqht (%) Quinidine Polygalacturonate77.0 Hydroxyethylcellulose 7.0 Stearyl alcohol 14.0 Tablet Lubricants 2.0 1 00 . o '120S38~
Tablet ~ ession Data .
Final tablet weight = 442.6 Diameter of tablet = 14/32"
Hardness: 4 kg (Stokes) Quinidine content per tablet = 206.0 mgm.
and utilizing the same method of manufacture as described above, the dissolution time for 100% of the quinidine content to be released is 12 hours.
A comparison of the dissolution rates determined for both tablets is as follows:
Tablet A Tablet B
Quinidine Quinidine Polygalacturonate Polygalacturonate 0,uinidine Base (60:40) 100%
% Quinidine Content Released 1 hour in simulated gastric juice 26% 18%
2 hours in simulated intestinal juice~ 31% 24%
3 hours in simulated intestinal juice36% 33%
4 hours in simulated intestinal juice40% 43%
6 hours in simulated intestinal juice51% 61%
9 hours in simulated intestinal juice69% 82%
12 hours in simulated intestinal juice 90% 100%
18 hours in simulated intestinal juice 93% --20 hours in simulated intestinal juice 100% ---It will be seen that the replacement of 40% of the amount of the quinidine present in the salt quinidine polygalacturonate, used to prepare the tablets of Formula B, with quinidine base (Formula A) results in an extension of the dissolution time by approximately 8 hours over that determined for the salt formulation (Formula B) to achieve the 100% release of active ingredient.
This order of extended dissolution time of 20 hours for the release of the active ingredient enables a one-a-day regimen for the administration of quinidine therapy to control an arrhythmic heart beat.
The tablet hardness of 4 kg (Stokes) obtained for the slow release tablet utilizing 100% of the organic salt, quinidine polygalacturonate, as the active ingredient (Formula H) is improved to ~05~1 provide a tablet hardness of 8 kg (Stokes) when the Formula A, wherein 4~/0 by weight of the amount of quinidine in the salt active ingredient replaced with quinidine base, is used. This improved tablet hardness overcomes problems of packaging and transport tablet friability.
To extend the dissolution time of a slow release tablet containing propranolol hydrochloride as the active ingredient, the following formula is used:
lo Formula A Part by.Wei~ht Propranolol HCl 22.0 Propranolol base 34.0 Lactose 4~8 Hydroxyethylcellulose 5.2 Paraffin Wax 28.2 Lubricants (Talc, Magnesium Stearate) 2.0 In above Formula A, about 4~/O of the propranolol content of the tablet is present as propranolol HC1 and about 6~/o as propranolol base. The method o manuacture for these tablets is as follows:
0 Step l: Mix the propranolol HCl, lactose and propranolol base together with the hydroxyethylcellulose utilizing a suit-able mixer.~
SteP 2: Hydrate the mixture of Step l with sufficient water to obtain a granular paste utilizing from 2 to 4 parts by weight of water for each part by weight of hydroxyethyl-cellulose.
Step 3: Dry the mixture and granulate through a ~o~ 16 US Standard Mesh Screen.
` 22-
6 hours in simulated intestinal juice51% 61%
9 hours in simulated intestinal juice69% 82%
12 hours in simulated intestinal juice 90% 100%
18 hours in simulated intestinal juice 93% --20 hours in simulated intestinal juice 100% ---It will be seen that the replacement of 40% of the amount of the quinidine present in the salt quinidine polygalacturonate, used to prepare the tablets of Formula B, with quinidine base (Formula A) results in an extension of the dissolution time by approximately 8 hours over that determined for the salt formulation (Formula B) to achieve the 100% release of active ingredient.
This order of extended dissolution time of 20 hours for the release of the active ingredient enables a one-a-day regimen for the administration of quinidine therapy to control an arrhythmic heart beat.
The tablet hardness of 4 kg (Stokes) obtained for the slow release tablet utilizing 100% of the organic salt, quinidine polygalacturonate, as the active ingredient (Formula H) is improved to ~05~1 provide a tablet hardness of 8 kg (Stokes) when the Formula A, wherein 4~/0 by weight of the amount of quinidine in the salt active ingredient replaced with quinidine base, is used. This improved tablet hardness overcomes problems of packaging and transport tablet friability.
To extend the dissolution time of a slow release tablet containing propranolol hydrochloride as the active ingredient, the following formula is used:
lo Formula A Part by.Wei~ht Propranolol HCl 22.0 Propranolol base 34.0 Lactose 4~8 Hydroxyethylcellulose 5.2 Paraffin Wax 28.2 Lubricants (Talc, Magnesium Stearate) 2.0 In above Formula A, about 4~/O of the propranolol content of the tablet is present as propranolol HC1 and about 6~/o as propranolol base. The method o manuacture for these tablets is as follows:
0 Step l: Mix the propranolol HCl, lactose and propranolol base together with the hydroxyethylcellulose utilizing a suit-able mixer.~
SteP 2: Hydrate the mixture of Step l with sufficient water to obtain a granular paste utilizing from 2 to 4 parts by weight of water for each part by weight of hydroxyethyl-cellulose.
Step 3: Dry the mixture and granulate through a ~o~ 16 US Standard Mesh Screen.
` 22-
5~
SteP 4: Melt the paraffin wax and add to the prepared granules of Step 3 to coat the granules.
SteP 5: Allow the coated granules to cool and granulate through a No. 12 or No. 14 US Standard Mesh Screen.
SteP 6: Add the appropriate tablet lubricants and compress into tablets of the following size, shape and weight:
Final tablet weight = 124.0 mg.
Tablet diameter = 9/32"
Propranolol content per tablet - 70 mgm.
In order to demonstrate the degree of extension of the dissolution time obtained when propranolol base is used to replace a proportion of the active ingredient salt, propranolol hydrochloride, slow release tablets utilizing the same matrix and the same method of manufacture, but only the salt, propranolol hydrochloride, a~ the active ingredient, were prepared as the following Formula B:
Formula B Parts bv Weiqht (%~ !~
Propranolol HCl 64.5 HydroxyethylcellulOse 5.2 Paraffin wax 28.3 Lubricants (Talc, Magnesium Stearate) 2.0 100. 0 Tablet_Compression Data ~-Final tablet weight = 124.0 mg.
Tablet diameter = 9/32"
Propranolol content per tablet - 70 mgm.
Side-by-side comparative dissolution time requirements for the respective tablets were determined with the following results:
~2~S31~1 Tablet A Tablet B
Propranolol HCl Propranolol HCl Propranolol Base _10~ 6~0,~ ( lOOD/o) After: % ProPranolol Released 1 hour in simulated gastric juice 3&/o 35%
2 hours in simulated intestinal juice 55% sp/~
3 hours in simulated intestinal juice 63% 6~/o 4 hours in simulated intestinal juice 6~/~ 83%
lo 5 hours in simulated intestinal juice 73% 93%
SteP 4: Melt the paraffin wax and add to the prepared granules of Step 3 to coat the granules.
SteP 5: Allow the coated granules to cool and granulate through a No. 12 or No. 14 US Standard Mesh Screen.
SteP 6: Add the appropriate tablet lubricants and compress into tablets of the following size, shape and weight:
Final tablet weight = 124.0 mg.
Tablet diameter = 9/32"
Propranolol content per tablet - 70 mgm.
In order to demonstrate the degree of extension of the dissolution time obtained when propranolol base is used to replace a proportion of the active ingredient salt, propranolol hydrochloride, slow release tablets utilizing the same matrix and the same method of manufacture, but only the salt, propranolol hydrochloride, a~ the active ingredient, were prepared as the following Formula B:
Formula B Parts bv Weiqht (%~ !~
Propranolol HCl 64.5 HydroxyethylcellulOse 5.2 Paraffin wax 28.3 Lubricants (Talc, Magnesium Stearate) 2.0 100. 0 Tablet_Compression Data ~-Final tablet weight = 124.0 mg.
Tablet diameter = 9/32"
Propranolol content per tablet - 70 mgm.
Side-by-side comparative dissolution time requirements for the respective tablets were determined with the following results:
~2~S31~1 Tablet A Tablet B
Propranolol HCl Propranolol HCl Propranolol Base _10~ 6~0,~ ( lOOD/o) After: % ProPranolol Released 1 hour in simulated gastric juice 3&/o 35%
2 hours in simulated intestinal juice 55% sp/~
3 hours in simulated intestinal juice 63% 6~/o 4 hours in simulated intestinal juice 6~/~ 83%
lo 5 hours in simulated intestinal juice 73% 93%
6 hours in simulated intestinal juice 76% 10~/o 9 hours in simulated intestinal juice 10~/o ----The salt base combination active ingredient extends the dissolution time for propranolol in the slow release tablet, from 6 hours when 10~/o of the active ingredient is in the salt form, to 9 hours when 6~/o of the salt has been replaced by the base.
When it is desired to prepare an extended ~low release tab-let with a xanthine active ingredient, as for example, theophylline, to accomplish a one-a-day dosage regimen, then the following procedure i preferred.
Aminophylline is a well known water soluble salt of theo-phylline which is commonly used to prepare theophylline-containing slow release preparations. In such a formula 3~/O by weight of the theophylline content of the extended slow release tablet is contri-buted by aminophylline and the remaining 7~/O by weight of the theo-phylline content of the tablet is in the form of theophylline base, so that the total amount of theophylline per tablet is 280 mg. The - formula and method of manufacture for such extended release tablets are as follows:
Formula A Parts by Weiqht ~%) Aminophylline 24.0 Theophylline 45.6 Hydroxyethylcellulose 6.2 Polyvinylpyrrolidone 1.0 Cetostearyl alcohol 20.6 Lubricants (Talc, Magnesium Stearate) 2.6 100.0 -2~-~s~
Step 1: Mix the appropriate quantity of aminophylline with the hydroxyethylcellulose.
Step 2: Dissolve the indicated ~uantity of polyvinyl pyrrolidone in a sufficient quantity of water equivalent ro from 2.4 parts by weight of water for each part by weight hydroxyethyl-cellulose, used in Step 1, above, and add the solution to the solid mixture obtained from Step 1, mixing well until a granular paste forms.
steP 3: Dry the mixture and granulate through a No. 16 US Standard lo Mesh Screen.
SteP 4: Melt the cetostearyl alcohol and coat granules prepared with the melted fatty alcohol.
Step 5: Allow the coated granules to cool and granulate through No. 12 or No. 14 US Standard Mesh Screen.
Step 6: Add the appropriate lubricants and press into tablets of desired shape, size and weight, as follows: -Final tablet weight = 430.9 mg.
Final tablet diameter = 14/32"
Theophylline content per tablet - 280 mg.
Tablet hardness: 12 kg The dissolution time determined for Formula A consisting of (30:70 salt:base) is 24 hours. When aminophylline is the sole active ingredient (10~/~ salt) the dissolution time is determined to be approximately 9 hours. When 25% of the theophylline content of the salt, aminophylline, is replaced with theo phylline base, then the dissolution time is extended to approximately 12 hours. Side-by-side - ~5 -53~
dissolution time values for the separate aminophylline salt/theophylline base slow release tablets are as follows:
Xanthine Slow Release Tablets Aminophylline Salt 75% Salt 30%
(100% Salt) Base 25% Base 70%
% Theophylline Released After:
1 hour in simulated gastric juice 15.5 10.0 9.2 2 hours in simulated intestinal juice30.1 20.2 18.0 3 hours in simulated intestinal juice42.7 29.6 25.8 4 hours in simulatedlintestinal juice51.7 39.1 31.6 6 hours in simulated intestinal juice61.3 54.2 42.0 9 hours in simulated intestinal juice100.0 79.1 55.1 2 hours in simulated intestinal juice ----- 100.0 67.0 5 hours in simulated intestinal juice ----- ----- 76.1 8 hours in simulated intestinal juice ----- ----- 86.0 1 hours in simulated intestinal juice~ - ----- 95.2 4 hours in simulated intestinal juice ----- ----- 100.0 Thus it will be seen that a new degree of therapeutic flexibility results with the new method for-xanthine dosage preparations as for example, theophylline compositions since by appropriate salt to base ratio of the xanthine content of a particular slow release product, a wide range in therapeutic effects as demonstrated by dissolution time will be achieved, to meet the individual patients needs including one-a-day administration.
-To further extend dissolution time of codeine from a slow release codeine phosphate tablet, containing a codeine content equivalent to 60 mg.
codeine per tablet, the following formula is used:
Formula A Parts by Weight (%)_ Codeine Phosphate 29.6 - Codeine Base . 22.3 Hydroxyethylcellulose - 6.0 Cetrostearyl Alcohol 23.8 Lactose 16.3 Lubricants (Talc, Magnesium Stearate) 2.0 100.O
In this formulation the codeine content is equally contri-buted by equal parts of codeine phosphate, (the salt,) and codeine base (50:50 base/salt). The improved extended dissolution time slow release tablets are manufactured as follows:
SteP 1: Mix indicated quantities of codeine phosphate and codeine base with the lactose.
SteP 2: Add the appropriate quantity of hydroxyethylcellulose to the mixture obtained from Step 1, and hydrate with from 2 parts by weight to 4 parts by weight of water for each part lo by weight of hydroxyethylcellulose until a granular paste is obtained.
SteP 3: Dry the hydrated mixture and granulate through a No. 16 US
Standard Mesh Screen.
Step 4: Melt the cetostearyl alcohol and add to the granules ob-tained from Step 3 until a uni~orm distribution is obtained, and set aside to cool to room temperature. -_teP 5: Granulate the mixture of Step 4 through a No. 12 or No. 14 US Standard Mesh Screen~
SteP 6: Add appropriate lubricants and compress into tablets of the following size, shape and weight:
- Tablet weight = 134.5 mgm.
Codeine Content per tablet - 60 mg.
Tablet diameter = 9/32"
The dissolution time for the codeine phosphate/codeine base (50:50 ratio) is 7 hours for 100~/~ of the codeine content of the tab-let to be released. This value represents an extension of twice the dissolution time obtained when 100/o salt is used as the active 538~L
ingredient, as for exampl~ codeine phosphate, in the same tablet matrix, for which formula the dissolution time to release 100% of the codeine content is 3.5 hours. This is demonstrated when side-by-side dissolution time testing is conducted.
A slow release tablet was prepared with codeine phosphate as the sole active ingredient, in an amount sufficient to provide 60 mg. of codeine content per tablet utilizing essentially the same matrix formula as Formula A, above:
Formula B Parts b~ Weiqht (%) lo codeine Phosphate 59.5 Hydroxyethylcellulose 6.
Lactose 8.8 Cetostearyl alcohol 23.7 Lubricants (Talc, Magnesium Stearate) 2.0 100.0 The tablets were manufactured in essentially the same steps as that described above. The slow release tablets were compressed to the following description-`
Tablet weight = 134.5 mg.
Codeine content per tablet - 60 mg.
Tablet diameter - 9/32" -The side-by-side dissolution time was determined for both tablets using the U.S.P. paddle method, to yield the following results:
Table~ ATablet B
Codeine Phosphate/ Codeine Codeine Base Phosphate ~ (50:50) (lO~h) A~ter: /O Codeine Released _ 30 1 hour in simulated gastric juice 46% 5~/o 2 hours in simulated intestinal juice 6P/o 82%
3 hours in simulated intestinal juice 79~/o 96%
3.5 hours in simulated intestinal juice 88~/o lO~/o 5 hours in simulated intestinal juice 92%
6 hours in simulated intestinal juice 95%
When it is desired to prepare an extended ~low release tab-let with a xanthine active ingredient, as for example, theophylline, to accomplish a one-a-day dosage regimen, then the following procedure i preferred.
Aminophylline is a well known water soluble salt of theo-phylline which is commonly used to prepare theophylline-containing slow release preparations. In such a formula 3~/O by weight of the theophylline content of the extended slow release tablet is contri-buted by aminophylline and the remaining 7~/O by weight of the theo-phylline content of the tablet is in the form of theophylline base, so that the total amount of theophylline per tablet is 280 mg. The - formula and method of manufacture for such extended release tablets are as follows:
Formula A Parts by Weiqht ~%) Aminophylline 24.0 Theophylline 45.6 Hydroxyethylcellulose 6.2 Polyvinylpyrrolidone 1.0 Cetostearyl alcohol 20.6 Lubricants (Talc, Magnesium Stearate) 2.6 100.0 -2~-~s~
Step 1: Mix the appropriate quantity of aminophylline with the hydroxyethylcellulose.
Step 2: Dissolve the indicated ~uantity of polyvinyl pyrrolidone in a sufficient quantity of water equivalent ro from 2.4 parts by weight of water for each part by weight hydroxyethyl-cellulose, used in Step 1, above, and add the solution to the solid mixture obtained from Step 1, mixing well until a granular paste forms.
steP 3: Dry the mixture and granulate through a No. 16 US Standard lo Mesh Screen.
SteP 4: Melt the cetostearyl alcohol and coat granules prepared with the melted fatty alcohol.
Step 5: Allow the coated granules to cool and granulate through No. 12 or No. 14 US Standard Mesh Screen.
Step 6: Add the appropriate lubricants and press into tablets of desired shape, size and weight, as follows: -Final tablet weight = 430.9 mg.
Final tablet diameter = 14/32"
Theophylline content per tablet - 280 mg.
Tablet hardness: 12 kg The dissolution time determined for Formula A consisting of (30:70 salt:base) is 24 hours. When aminophylline is the sole active ingredient (10~/~ salt) the dissolution time is determined to be approximately 9 hours. When 25% of the theophylline content of the salt, aminophylline, is replaced with theo phylline base, then the dissolution time is extended to approximately 12 hours. Side-by-side - ~5 -53~
dissolution time values for the separate aminophylline salt/theophylline base slow release tablets are as follows:
Xanthine Slow Release Tablets Aminophylline Salt 75% Salt 30%
(100% Salt) Base 25% Base 70%
% Theophylline Released After:
1 hour in simulated gastric juice 15.5 10.0 9.2 2 hours in simulated intestinal juice30.1 20.2 18.0 3 hours in simulated intestinal juice42.7 29.6 25.8 4 hours in simulatedlintestinal juice51.7 39.1 31.6 6 hours in simulated intestinal juice61.3 54.2 42.0 9 hours in simulated intestinal juice100.0 79.1 55.1 2 hours in simulated intestinal juice ----- 100.0 67.0 5 hours in simulated intestinal juice ----- ----- 76.1 8 hours in simulated intestinal juice ----- ----- 86.0 1 hours in simulated intestinal juice~ - ----- 95.2 4 hours in simulated intestinal juice ----- ----- 100.0 Thus it will be seen that a new degree of therapeutic flexibility results with the new method for-xanthine dosage preparations as for example, theophylline compositions since by appropriate salt to base ratio of the xanthine content of a particular slow release product, a wide range in therapeutic effects as demonstrated by dissolution time will be achieved, to meet the individual patients needs including one-a-day administration.
-To further extend dissolution time of codeine from a slow release codeine phosphate tablet, containing a codeine content equivalent to 60 mg.
codeine per tablet, the following formula is used:
Formula A Parts by Weight (%)_ Codeine Phosphate 29.6 - Codeine Base . 22.3 Hydroxyethylcellulose - 6.0 Cetrostearyl Alcohol 23.8 Lactose 16.3 Lubricants (Talc, Magnesium Stearate) 2.0 100.O
In this formulation the codeine content is equally contri-buted by equal parts of codeine phosphate, (the salt,) and codeine base (50:50 base/salt). The improved extended dissolution time slow release tablets are manufactured as follows:
SteP 1: Mix indicated quantities of codeine phosphate and codeine base with the lactose.
SteP 2: Add the appropriate quantity of hydroxyethylcellulose to the mixture obtained from Step 1, and hydrate with from 2 parts by weight to 4 parts by weight of water for each part lo by weight of hydroxyethylcellulose until a granular paste is obtained.
SteP 3: Dry the hydrated mixture and granulate through a No. 16 US
Standard Mesh Screen.
Step 4: Melt the cetostearyl alcohol and add to the granules ob-tained from Step 3 until a uni~orm distribution is obtained, and set aside to cool to room temperature. -_teP 5: Granulate the mixture of Step 4 through a No. 12 or No. 14 US Standard Mesh Screen~
SteP 6: Add appropriate lubricants and compress into tablets of the following size, shape and weight:
- Tablet weight = 134.5 mgm.
Codeine Content per tablet - 60 mg.
Tablet diameter = 9/32"
The dissolution time for the codeine phosphate/codeine base (50:50 ratio) is 7 hours for 100~/~ of the codeine content of the tab-let to be released. This value represents an extension of twice the dissolution time obtained when 100/o salt is used as the active 538~L
ingredient, as for exampl~ codeine phosphate, in the same tablet matrix, for which formula the dissolution time to release 100% of the codeine content is 3.5 hours. This is demonstrated when side-by-side dissolution time testing is conducted.
A slow release tablet was prepared with codeine phosphate as the sole active ingredient, in an amount sufficient to provide 60 mg. of codeine content per tablet utilizing essentially the same matrix formula as Formula A, above:
Formula B Parts b~ Weiqht (%) lo codeine Phosphate 59.5 Hydroxyethylcellulose 6.
Lactose 8.8 Cetostearyl alcohol 23.7 Lubricants (Talc, Magnesium Stearate) 2.0 100.0 The tablets were manufactured in essentially the same steps as that described above. The slow release tablets were compressed to the following description-`
Tablet weight = 134.5 mg.
Codeine content per tablet - 60 mg.
Tablet diameter - 9/32" -The side-by-side dissolution time was determined for both tablets using the U.S.P. paddle method, to yield the following results:
Table~ ATablet B
Codeine Phosphate/ Codeine Codeine Base Phosphate ~ (50:50) (lO~h) A~ter: /O Codeine Released _ 30 1 hour in simulated gastric juice 46% 5~/o 2 hours in simulated intestinal juice 6P/o 82%
3 hours in simulated intestinal juice 79~/o 96%
3.5 hours in simulated intestinal juice 88~/o lO~/o 5 hours in simulated intestinal juice 92%
6 hours in simulated intestinal juice 95%
7 hours in simulated intestinal juice 100% _ -- 28 ~
~2~5;311~
The salt-base active inyredient extended the dissolution time of codeine from the slow release tablet of the same compositions by 10~/o without requiring increasing amounts of matrix components or other formula changes.
The bioavailability study of Tablet A comprising codeine phosphate/codeine base (50:50) demonstrated that satisfactory blood levels were maintained over a period of 7 hours thus confirming that extended bioavailability follows dissolution time.
! ExAMpLE 5 lo In place of the hydroxyethylcellulose as used above, there may be substituted in equal amounts, hydroxymethylcellulose, hydroxy-propylcellulose and mixtures of these.
In place of the fatty alcohol used as described above, there may be substituted in equivalent amounts any one of the higher aliphatic alcohols having from 10 to 18 carbon atoms in chain length and mixtures of these. Such aliphatic alcohols such as cetostearyl alcohol may be substituted in equal quantities for the cetyl alcohol as described above.
Lauryl alcohol, myristyl alcohol and stearyl alcohol are preferred alternate alcohols to the cetyl alcohol used as described above. In each and every instance wherein a fatty alcohol is used, an equivalent amount of paraffin wax may be substituted.
When these alternate hydrophilic and hydrophobic components are utulized in a slow release formulation, the manufacturing pro-cedures described for the particular tablet remains the same and the resulting tablet will behave in essentially the same manner as described above.
53~3~
The present method providing for the use of a pharmaco-lo~ically active combination of a salt and base as an active ingred-ient to extend the dissolution time of slow release tablets provide~
a wide degree of flexibility in the therapeutic regimen for patients requiring extended bioavailability of a therapeutic agent. Thus, improved blood levels for extended periods of time results when the tablet compositions described in Examples 1-5 above are administered to a human or animal form 1 to 4 times daily after appropriate selection of the desired ratio of active base moiety to active pharmacologic salt as the active ingredient.
When the ratio of active base to salt is up to equal parts of each, the dissolution time extension is of a lesser magnitude than that obtained when the proportion of salt to base is greater than 50:50. The exact ratio to use to obtain a particular extension in dissolution time depends upon the particular active ingredient as well , as the patients therapeutic needs.
~2~5;311~
The salt-base active inyredient extended the dissolution time of codeine from the slow release tablet of the same compositions by 10~/o without requiring increasing amounts of matrix components or other formula changes.
The bioavailability study of Tablet A comprising codeine phosphate/codeine base (50:50) demonstrated that satisfactory blood levels were maintained over a period of 7 hours thus confirming that extended bioavailability follows dissolution time.
! ExAMpLE 5 lo In place of the hydroxyethylcellulose as used above, there may be substituted in equal amounts, hydroxymethylcellulose, hydroxy-propylcellulose and mixtures of these.
In place of the fatty alcohol used as described above, there may be substituted in equivalent amounts any one of the higher aliphatic alcohols having from 10 to 18 carbon atoms in chain length and mixtures of these. Such aliphatic alcohols such as cetostearyl alcohol may be substituted in equal quantities for the cetyl alcohol as described above.
Lauryl alcohol, myristyl alcohol and stearyl alcohol are preferred alternate alcohols to the cetyl alcohol used as described above. In each and every instance wherein a fatty alcohol is used, an equivalent amount of paraffin wax may be substituted.
When these alternate hydrophilic and hydrophobic components are utulized in a slow release formulation, the manufacturing pro-cedures described for the particular tablet remains the same and the resulting tablet will behave in essentially the same manner as described above.
53~3~
The present method providing for the use of a pharmaco-lo~ically active combination of a salt and base as an active ingred-ient to extend the dissolution time of slow release tablets provide~
a wide degree of flexibility in the therapeutic regimen for patients requiring extended bioavailability of a therapeutic agent. Thus, improved blood levels for extended periods of time results when the tablet compositions described in Examples 1-5 above are administered to a human or animal form 1 to 4 times daily after appropriate selection of the desired ratio of active base moiety to active pharmacologic salt as the active ingredient.
When the ratio of active base to salt is up to equal parts of each, the dissolution time extension is of a lesser magnitude than that obtained when the proportion of salt to base is greater than 50:50. The exact ratio to use to obtain a particular extension in dissolution time depends upon the particular active ingredient as well , as the patients therapeutic needs.
Claims (7)
CLAIMED ARE DEFINED AS FOLLOWS:
1. Extended action controlled release pharmaceutical com-position, comprising a pharmaceutically acceptable controlled release core or matrix for pharmaceutically active agents having distributed therethrough a pharmaceutically effective amount of a pharmacolog-ically active substance, said pharmaceutically effective amount com-prising between about 75% and 25% by weight of the salt form of said pharmacologically active substance and between about 25% and 75% by weight of the free base form of said pharmacologically active sub-stance, the amounts being based on the pharmacologically active moiety of said pharmacologically active substance.
2. Extended action controlled release composition according to claim 1 wherein said composition is in tablet form.
3. Extended action controlled release pharmaceutical composition according to claim 1 wherein said composition is in capsule form.
4. Extended action controlled release pharmaceutical composition according to any one of claims 1 - 3, wherein the pharma-cologically active substance is amitryptaline, atropine, chlorphenir-amine, chlorpromizine, codeine, dexbrompheniramine, diphenylhydra-mine, doxilamine, ephedrine, hyoscyamine, morphine, oxycodone, papa-varine, phenylpropanolamine, propranolol, quinidine, scopolamine, theophylline or thioridazine.
5. Composition according to claim 1 wherein the pharma-ceutically effective amount of said pharmacologically active sub-stance comprises between about 60% and 40% by weight of the salt form and about 40% - 60% by weight of the free base form.
6. Method of producing extended action controlled release pharmaceutical compositions which comprises mixing a pharmaceutically effective amount of a pharmacologically active substance comprising between about 75% and 25% by weight of the salt form of the pharma-cologically active substance and between about 25% and 75% by weight of the free base form of the pharmacologically active substance with hydroxyethylcellulose to form a uniform mixture, hydrating the mixture with water to form a paste thereof, drying the forms paste, to obtain granules of the mixture, adding the granules to a molten higher alcohol, cooling to form granules thereof, and forming the resulting granules into tablets or capsules.
7. Method according to claim 6 wherein the higher alcohol is stearyl alcohol.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/390,540 US4443428A (en) | 1982-06-21 | 1982-06-21 | Extended action controlled release compositions |
| US390,540 | 1982-06-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1205381A true CA1205381A (en) | 1986-06-03 |
Family
ID=23542881
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000430797A Expired CA1205381A (en) | 1982-06-21 | 1983-06-20 | Extended action controlled release compositions |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US4443428A (en) |
| EP (1) | EP0097523B1 (en) |
| JP (1) | JPS5925316A (en) |
| AR (1) | AR230783A1 (en) |
| AT (1) | ATE31874T1 (en) |
| AU (1) | AU556588B2 (en) |
| CA (1) | CA1205381A (en) |
| DE (1) | DE3375283D1 (en) |
| ES (1) | ES523427A0 (en) |
| IE (1) | IE55190B1 (en) |
| IL (1) | IL68887A (en) |
| MX (1) | MX156495A (en) |
| NZ (1) | NZ204438A (en) |
| PT (1) | PT76873B (en) |
| SE (1) | SE8303531D0 (en) |
| ZA (1) | ZA834424B (en) |
Families Citing this family (103)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0729927B2 (en) * | 1983-04-09 | 1995-04-05 | 日研化学株式会社 | Theophylline sustained release formulation |
| GB8514665D0 (en) * | 1985-06-11 | 1985-07-10 | Eroceltique Sa | Oral pharmaceutical composition |
| US4826688A (en) * | 1985-11-13 | 1989-05-02 | 501 Elan Corporation PLC. | Controlled absorption pharmaceutical formulation |
| GB2186485B (en) * | 1986-02-13 | 1988-09-07 | Ethical Pharma Ltd | Slow release formulation |
| US4861598A (en) * | 1986-07-18 | 1989-08-29 | Euroceltique, S.A. | Controlled release bases for pharmaceuticals |
| GB8626098D0 (en) * | 1986-10-31 | 1986-12-03 | Euro Celtique Sa | Controlled release hydromorphone composition |
| US4789549A (en) * | 1987-03-09 | 1988-12-06 | Warner-Lambert Company | Sustained release dosage forms |
| ATE73333T1 (en) * | 1987-07-29 | 1992-03-15 | Upjohn Co | CONTROLLED RELEASE OF ANTIBIOTIC SALTS FROM AN IMPLANT. |
| GB8813064D0 (en) | 1988-06-02 | 1988-07-06 | Euro Celtique Sa | Controlled release dosage forms having defined water content |
| JPH04504103A (en) * | 1988-07-01 | 1992-07-23 | ファルマシア・アンド・アップジョン・カンパニー | Controlled release of antibiotic salts from implanted tablets |
| US5612059A (en) * | 1988-08-30 | 1997-03-18 | Pfizer Inc. | Use of asymmetric membranes in delivery devices |
| JPH0794379B2 (en) * | 1990-08-07 | 1995-10-11 | ファイザー・インコーポレーテッド | Methods of using interfacial polymerized membranes in release formulations |
| JP2538134B2 (en) * | 1991-04-08 | 1996-09-25 | 田辺製薬株式会社 | Sustained release preparation and method for producing the same |
| US5266331A (en) * | 1991-11-27 | 1993-11-30 | Euroceltique, S.A. | Controlled release oxycodone compositions |
| US5968551A (en) | 1991-12-24 | 1999-10-19 | Purdue Pharma L.P. | Orally administrable opioid formulations having extended duration of effect |
| US5958459A (en) * | 1991-12-24 | 1999-09-28 | Purdue Pharma L.P. | Opioid formulations having extended controlled released |
| US5478577A (en) * | 1993-11-23 | 1995-12-26 | Euroceltique, S.A. | Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level |
| SE9202250D0 (en) * | 1992-07-29 | 1992-07-29 | Gacell Lab Ab | CONTROLLED RELEASE MORPHINE PREPARATION |
| US20080075781A1 (en) * | 1992-11-25 | 2008-03-27 | Purdue Pharma Lp | Controlled release oxycodone compositions |
| SE9301057L (en) * | 1993-03-30 | 1994-10-01 | Pharmacia Ab | Controlled release preparation |
| US5656291A (en) * | 1994-03-16 | 1997-08-12 | Pharmacia & Upjohn Aktiebolag | Controlled release preparation |
| IL119660A (en) | 1993-05-10 | 2002-09-12 | Euro Celtique Sa | Controlled release formulation comprising tramadol |
| AU6552699A (en) * | 1993-05-10 | 2000-03-02 | Euro-Celtique S.A. | Controlled release formulation |
| US20070275062A1 (en) * | 1993-06-18 | 2007-11-29 | Benjamin Oshlack | Controlled release oxycodone compositions |
| IL109944A (en) * | 1993-07-01 | 1998-12-06 | Euro Celtique Sa | Sustained release dosage unit forms containing morphine and a method of preparing these sustained release dosage unit forms |
| US7740881B1 (en) | 1993-07-01 | 2010-06-22 | Purdue Pharma Lp | Method of treating humans with opioid formulations having extended controlled release |
| IL110014A (en) * | 1993-07-01 | 1999-11-30 | Euro Celtique Sa | Solid controlled-release oral dosage forms of opioid analgesics |
| US5879705A (en) * | 1993-07-27 | 1999-03-09 | Euro-Celtique S.A. | Sustained release compositions of morphine and a method of preparing pharmaceutical compositions |
| EP1442745A1 (en) * | 1993-10-07 | 2004-08-04 | Euro-Celtique | Orally administrable opioid formulations having extended duration of effect |
| US5891471A (en) * | 1993-11-23 | 1999-04-06 | Euro-Celtique, S.A. | Pharmaceutical multiparticulates |
| KR100354702B1 (en) * | 1993-11-23 | 2002-12-28 | 유로-셀티크 소시에떼 아노뉨 | Manufacturing method and sustained release composition of pharmaceutical composition |
| US5843480A (en) * | 1994-03-14 | 1998-12-01 | Euro-Celtique, S.A. | Controlled release diamorphine formulation |
| AUPM814994A0 (en) * | 1994-09-14 | 1994-10-06 | Sterling Winthrop Inc. | Codeine-containing formulations |
| GB9422154D0 (en) | 1994-11-03 | 1994-12-21 | Euro Celtique Sa | Pharmaceutical compositions and method of producing the same |
| US5965161A (en) | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
| US20020006438A1 (en) * | 1998-09-25 | 2002-01-17 | Benjamin Oshlack | Sustained release hydromorphone formulations exhibiting bimodal characteristics |
| GB9519363D0 (en) * | 1995-09-22 | 1995-11-22 | Euro Celtique Sa | Pharmaceutical formulation |
| US5811126A (en) * | 1995-10-02 | 1998-09-22 | Euro-Celtique, S.A. | Controlled release matrix for pharmaceuticals |
| US5851555A (en) * | 1997-08-15 | 1998-12-22 | Fuisz Technologies Ltd. | Controlled release dosage forms containing water soluble drugs |
| CN1204890C (en) * | 1997-12-22 | 2005-06-08 | 欧罗赛铁克股份有限公司 | Method for preventing abuse of opioid dosage forms |
| RU2241458C2 (en) | 1997-12-22 | 2004-12-10 | Эро-Селтик, С.А. | Combinations of agonist/antagonist for opioid |
| US20030091629A1 (en) * | 1998-03-27 | 2003-05-15 | Cima Labs Inc. | Sublingual buccal effervescent |
| US20030118645A1 (en) * | 1998-04-29 | 2003-06-26 | Pather S. Indiran | Pharmaceutical compositions for rectal and vaginal administration |
| US6974590B2 (en) | 1998-03-27 | 2005-12-13 | Cima Labs Inc. | Sublingual buccal effervescent |
| US20010038855A1 (en) * | 1998-06-05 | 2001-11-08 | Desjardin Michael A. | Dosage form for administering prescribed dose |
| US6806294B2 (en) | 1998-10-15 | 2004-10-19 | Euro-Celtique S.A. | Opioid analgesic |
| DE19918325A1 (en) | 1999-04-22 | 2000-10-26 | Euro Celtique Sa | Extruded drug dosage form, e.g. granulate for tableting, comprising an active agent in a polysaccharide-containing matrix, giving a release profile which is controllable by extrusion conditions and/or the inclusion of additives |
| US10179130B2 (en) | 1999-10-29 | 2019-01-15 | Purdue Pharma L.P. | Controlled release hydrocodone formulations |
| EP2295043A1 (en) | 1999-10-29 | 2011-03-16 | Euro-Celtique S.A. | Controlled release hydrocodone formulations |
| JP2003522144A (en) | 2000-02-08 | 2003-07-22 | ユーロ−セルティーク，エス．エイ． | Controlled release compositions comprising opioid agonists and antagonists |
| DE10029201A1 (en) | 2000-06-19 | 2001-12-20 | Basf Ag | Retarded release oral dosage form, obtained by granulating mixture containing active agent and polyvinyl acetate-polyvinyl pyrrolidone mixture below the melting temperature |
| DE10031043A1 (en) * | 2000-06-26 | 2002-02-14 | Bayer Ag | Retarded preparations of quinolone antibiotics and process for their preparation |
| CN101317825A (en) | 2000-10-30 | 2008-12-10 | 欧罗赛铁克股份有限公司 | Controlled release hydrocodone formulations |
| UA81224C2 (en) * | 2001-05-02 | 2007-12-25 | Euro Celtic S A | Dosage form of oxycodone and use thereof |
| US20110104214A1 (en) | 2004-04-15 | 2011-05-05 | Purdue Pharma L.P. | Once-a-day oxycodone formulations |
| CN1525851A (en) | 2001-05-11 | 2004-09-01 | ������ҩ������˾ | Abuse-resistant controlled-release opioid dosage form |
| US7052706B2 (en) * | 2001-06-08 | 2006-05-30 | Nostrum Pharmaceuticals, Inc. | Control release formulation containing a hydrophobic material as the sustained release agent |
| US20030068356A1 (en) * | 2001-07-10 | 2003-04-10 | Pather S. Indiran | Sequential drug delivery systems |
| SI1416842T1 (en) * | 2001-07-18 | 2009-06-30 | Euro Celtique Sa | Pharmaceutical combinations of oxycodone and naloxone |
| US20030157168A1 (en) | 2001-08-06 | 2003-08-21 | Christopher Breder | Sequestered antagonist formulations |
| US20030044458A1 (en) | 2001-08-06 | 2003-03-06 | Curtis Wright | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
| ES2326794T3 (en) | 2001-08-06 | 2009-10-20 | Euro-Celtique S.A. | FORMULATIONS OF OPIOID AGONISTS WITH LIBERABLE AND SEQUESTED ANTAGONISTS. |
| US20030068375A1 (en) | 2001-08-06 | 2003-04-10 | Curtis Wright | Pharmaceutical formulation containing gelling agent |
| US20030060422A1 (en) | 2001-08-31 | 2003-03-27 | Balaji Venkataraman | Tannate compositions and methods of treatment |
| PE20030527A1 (en) * | 2001-10-24 | 2003-07-26 | Gruenenthal Chemie | DELAYED-RELEASE PHARMACEUTICAL FORMULATION CONTAINING 3- (3-DIMETHYLAMINO-1-ETHYL-2-METHYL-PROPYL) PHENOL OR A PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME AND ORAL TABLETS CONTAINING IT |
| US7022342B2 (en) | 2002-03-28 | 2006-04-04 | Andrx Corporation, Inc. | Controlled release oral dosage form of beta-adrenergic blocking agents |
| ES2546010T3 (en) | 2002-04-05 | 2015-09-17 | Euro-Celtique S.A. | Pharmaceutical preparation containing oxycodone and naloxone |
| PT1551372T (en) * | 2002-09-20 | 2018-07-23 | Alpharma Pharmaceuticals Llc | Sequestering subunit and related compositions and metohds |
| US20040202717A1 (en) | 2003-04-08 | 2004-10-14 | Mehta Atul M. | Abuse-resistant oral dosage forms and method of use thereof |
| MY135852A (en) * | 2003-04-21 | 2008-07-31 | Euro Celtique Sa | Pharmaceutical products |
| ITMI20032399A1 (en) * | 2003-12-09 | 2005-06-10 | Zambon Spa | PHARMACEUTICAL COMPOSITION CONTAINING GABAPENTIN. |
| EA010826B1 (en) * | 2003-12-31 | 2008-12-30 | Сайма Лэбс Инк. | Fentanyl dosage form for oral administration, methods of making thereof and methods of treatment |
| WO2005065317A2 (en) * | 2003-12-31 | 2005-07-21 | Cima Labs Inc. | Effervescent oral fentanyl dosage form |
| CA2549642C (en) * | 2003-12-31 | 2012-10-30 | Cima Labs Inc. | Effervescent oral opiate dosage forms and methods of administering opiates |
| US20050226929A1 (en) * | 2004-04-12 | 2005-10-13 | Jianbo Xie | Controlled release opioid analgesic formulation |
| MXPA06013397A (en) * | 2004-05-21 | 2007-01-23 | Alza Corp | Dosage form for delivery of multiple drug forms. |
| EP1604666A1 (en) * | 2004-06-08 | 2005-12-14 | Euro-Celtique S.A. | Opioids for the treatment of the Chronic Obstructive Pulmonary Disease (COPD) |
| HUE037643T2 (en) | 2004-06-12 | 2018-09-28 | Collegium Pharmaceutical Inc | Abuse-deterrent drug formulations |
| US9308164B2 (en) * | 2004-06-30 | 2016-04-12 | Sovereign Pharmaceuticals, Llc | Hyoscyamine dosage form |
| US20060110439A1 (en) * | 2004-10-22 | 2006-05-25 | Dynamis Therapeutics, Inc. | Dermal delivery of n-methyl-glucamine and n-methyl-glucamine compounds |
| EP1702558A1 (en) * | 2005-02-28 | 2006-09-20 | Euro-Celtique S.A. | Method and device for the assessment of bowel function |
| US20060275367A1 (en) * | 2005-04-25 | 2006-12-07 | Shubha Chungi | Extended release formulations |
| US20070160641A1 (en) * | 2006-01-12 | 2007-07-12 | Eun-Hyun Jang | Coated medical devices and methods of making the same |
| PL2526932T3 (en) * | 2006-06-19 | 2017-12-29 | Alpharma Pharmaceuticals Llc | Pharmaceutical composition |
| WO2008011596A2 (en) * | 2006-07-21 | 2008-01-24 | Lab International Srl | Hydrophilic abuse deterrent delivery system |
| US8623418B2 (en) * | 2007-12-17 | 2014-01-07 | Alpharma Pharmaceuticals Llc | Pharmaceutical composition |
| AU2008346870A1 (en) * | 2007-12-17 | 2009-07-16 | Alpharma Pharmaceuticals, Llc | Pharmaceutical composition |
| US20100151014A1 (en) * | 2008-12-16 | 2010-06-17 | Alpharma Pharmaceuticals, Llc | Pharmaceutical composition |
| ES2635733T3 (en) * | 2008-07-07 | 2017-10-04 | Euro-Celtique S.A. | Use of opioid antagonists to treat urinary retention |
| SG174286A1 (en) | 2009-03-10 | 2011-10-28 | Euro Celtique Sa | Immediate release pharmaceutical compositions comprising oxycodone and naloxone |
| US10668060B2 (en) | 2009-12-10 | 2020-06-02 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
| CA2690488C (en) * | 2010-01-19 | 2013-06-11 | Accucaps Industries Limited | Pharmaceutical formulations of naproxen for soft gel encapsulation and combinations thereof |
| ES2643291T3 (en) | 2010-12-22 | 2017-11-22 | Purdue Pharma L.P. | Controlled release dosage forms with inviolable closure coated |
| CA2822769C (en) | 2010-12-23 | 2016-10-04 | Purdue Pharma L.P. | Tamper resistant solid oral dosage forms |
| CN110101702A (en) | 2012-04-17 | 2019-08-09 | 普渡制药公司 | System and method for treating bad pharmacodynamics response caused by opioid |
| KR101840526B1 (en) | 2013-02-05 | 2018-03-20 | 퍼듀 퍼머 엘피 | Tamper resistant pharmaceutical formulations |
| US10751287B2 (en) | 2013-03-15 | 2020-08-25 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
| NZ716267A (en) | 2013-07-23 | 2017-05-26 | Euro Celtique Sa | A combination of oxycodone and naloxone for use in treating pain in patients suffering from pain and a disease resulting in intestinal dysbiosis and/or increasing the risk for intestinal bacterial translocation |
| US9849124B2 (en) | 2014-10-17 | 2017-12-26 | Purdue Pharma L.P. | Systems and methods for treating an opioid-induced adverse pharmacodynamic response |
| GB201420311D0 (en) * | 2014-11-14 | 2014-12-31 | Bio Images Drug Delivery Ltd | Pharmaceutical processing |
| GB201420306D0 (en) | 2014-11-14 | 2014-12-31 | Bio Images Drug Delivery Ltd | Compositions |
| GB201420300D0 (en) | 2014-11-14 | 2014-12-31 | Bio Images Drug Delivery Ltd | Tablet |
| WO2017222575A1 (en) | 2016-06-23 | 2017-12-28 | Collegium Pharmaceutical, Inc. | Process of making more stable abuse-deterrent oral formulations |
Family Cites Families (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE856039C (en) * | 1944-04-22 | 1952-11-17 | Boehringer & Soehne Gmbh | Process for the preparation of durable preparations from acylsalicylic acids and minor alkaloids of cinchona bark |
| US3400197A (en) * | 1965-01-26 | 1968-09-03 | Robins Co Inc A H | Compressible sustained release pharmaceutical tablet lipid-colloidal silica gel matrix fragment granules |
| FR5581M (en) * | 1965-06-09 | 1967-12-04 | ||
| IT1050353B (en) * | 1966-01-06 | 1981-03-10 | Ceskoslovenska Akademie Ved | SUPPORTS FOR BIOLOGICALLY ACTIVE SUBSTANCES |
| GB1182179A (en) * | 1966-06-22 | 1970-02-25 | Nippon Kayaku Kk | Anti-Peptic Ulcer Composition. |
| GB1184110A (en) * | 1966-11-16 | 1970-03-11 | Geigy Ag J R | Compositions for Treating Mental Disorders |
| NL148500B (en) * | 1967-10-07 | 1976-02-16 | Scherer Gmbh R P | DEPOTED MEDICINAL PRODUCTS IN CAPSULE FORM. |
| US3525790A (en) * | 1968-08-21 | 1970-08-25 | Mortimer D Sackler | Dihydroquinidine polygalacturonate and dihydroquinidine galacturonate compositions |
| US3608063A (en) * | 1969-08-15 | 1971-09-21 | Gilbert S Banker | Molecular drug entrapment process and compositions |
| GB1405088A (en) * | 1971-06-03 | 1975-09-03 | Mundipharma Ag | Slow release formulation |
| US3965256A (en) * | 1972-05-16 | 1976-06-22 | Synergistics | Slow release pharmaceutical compositions |
| US4179497A (en) * | 1973-12-17 | 1979-12-18 | Merck & Co., Inc. | Solid state ophthalmic medication |
| FR2255890B1 (en) * | 1973-12-28 | 1978-01-13 | Centre Etd Ind Pharma | |
| US4002756A (en) * | 1974-04-22 | 1977-01-11 | Interx Research Corporation | Useful pro-drug forms of theophylline |
| US4049791A (en) * | 1974-06-21 | 1977-09-20 | Delco Chemical Company, Inc. | Prolonged acting appetite suppressant and anti-obesity compositions containing amphetamine adipate, dextroamphetamine adipate, amphetamine sulfate and dextroamphetamine sulfate as the active agents |
| DE2517434A1 (en) * | 1975-04-19 | 1976-10-28 | Artesan Gmbh Fabrik Chemisch P | Compsns. contg. papaverine and beta-pyridyl carbinol - having synergistic cerebral vasodilating activity |
| SE418247B (en) * | 1975-11-17 | 1981-05-18 | Haessle Ab | SET TO MAKE BODIES WITH REGULATED RELEASE OF AN ACTIVE COMPONENT |
| US4077407A (en) * | 1975-11-24 | 1978-03-07 | Alza Corporation | Osmotic devices having composite walls |
| US4014334A (en) * | 1976-02-02 | 1977-03-29 | Alza Corporation | Laminated osmotic system for dispensing beneficial agent |
| US4160452A (en) * | 1977-04-07 | 1979-07-10 | Alza Corporation | Osmotic system having laminated wall comprising semipermeable lamina and microporous lamina |
| DE2717062C2 (en) * | 1977-04-18 | 1982-11-25 | Karl O. Helm Ag, 2000 Hamburg | Medicines with an antitussive effect |
| GB1561204A (en) * | 1977-06-01 | 1980-02-13 | Ici Ltd | Sustained release pharmaceutical composition |
| AU537741B2 (en) * | 1979-03-21 | 1984-07-12 | British Technology Group Limited | Controlled release compositions |
| US4248858A (en) * | 1979-08-09 | 1981-02-03 | American Home Products Corporation | Sustained release pharmaceutical compositions |
| US4304765A (en) * | 1980-10-14 | 1981-12-08 | Alza Corporation | Ocular insert housing steroid in two different therapeutic forms |
-
1982
- 1982-06-21 US US06/390,540 patent/US4443428A/en not_active Expired - Lifetime
-
1983
- 1983-06-01 NZ NZ204438A patent/NZ204438A/en unknown
- 1983-06-03 IL IL68887A patent/IL68887A/en not_active IP Right Cessation
- 1983-06-10 AU AU15708/83A patent/AU556588B2/en not_active Expired
- 1983-06-13 MX MX197634A patent/MX156495A/en unknown
- 1983-06-15 PT PT76873A patent/PT76873B/en unknown
- 1983-06-16 ZA ZA834424A patent/ZA834424B/en unknown
- 1983-06-20 CA CA000430797A patent/CA1205381A/en not_active Expired
- 1983-06-20 SE SE8303531A patent/SE8303531D0/en unknown
- 1983-06-20 ES ES523427A patent/ES523427A0/en active Granted
- 1983-06-20 IE IE1448/83A patent/IE55190B1/en not_active IP Right Cessation
- 1983-06-21 EP EP83303560A patent/EP0097523B1/en not_active Expired
- 1983-06-21 AT AT83303560T patent/ATE31874T1/en not_active IP Right Cessation
- 1983-06-21 AR AR293388A patent/AR230783A1/en active
- 1983-06-21 JP JP58111759A patent/JPS5925316A/en active Granted
- 1983-06-21 DE DE8383303560T patent/DE3375283D1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| EP0097523A3 (en) | 1984-12-12 |
| SE8303531D0 (en) | 1983-06-20 |
| IE831448L (en) | 1983-12-21 |
| AR230783A1 (en) | 1984-07-31 |
| ZA834424B (en) | 1984-03-28 |
| IL68887A0 (en) | 1983-10-31 |
| MX156495A (en) | 1988-08-30 |
| AU556588B2 (en) | 1986-11-13 |
| AU1570883A (en) | 1984-01-05 |
| PT76873A (en) | 1983-07-01 |
| PT76873B (en) | 1986-01-27 |
| EP0097523A2 (en) | 1984-01-04 |
| ES8500739A1 (en) | 1984-11-01 |
| ES523427A0 (en) | 1984-11-01 |
| US4443428A (en) | 1984-04-17 |
| JPH0521886B2 (en) | 1993-03-25 |
| ATE31874T1 (en) | 1988-01-15 |
| EP0097523B1 (en) | 1988-01-13 |
| JPS5925316A (en) | 1984-02-09 |
| NZ204438A (en) | 1985-05-31 |
| DE3375283D1 (en) | 1988-02-18 |
| IE55190B1 (en) | 1990-06-20 |
| IL68887A (en) | 1987-07-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1205381A (en) | Extended action controlled release compositions | |
| US4421736A (en) | Sustained release diethylpropion compositions | |
| US8506998B2 (en) | Pharmaceutical formulation | |
| EP0142561B1 (en) | Long-acting nifedipine preparation | |
| US5266331A (en) | Controlled release oxycodone compositions | |
| AU593038B2 (en) | New drug preparation with controlled release of the active compound, a method for the manufacture thereof and the use of the new preparation | |
| US5980942A (en) | Zero-order sustained release matrix tablet formulations of carbamazepine | |
| EP0218148B1 (en) | Slow-release pharmaceutical composition | |
| US5240712A (en) | Therapeutic agents | |
| NZ201008A (en) | Oral preparations containing dipyridamole and at least 5 molar equivalents of orally acceptable acidic excipient | |
| GB2196852A (en) | Sustained release composition | |
| CA1336069C (en) | Chewable medicament tablet containing means for taste masking | |
| US6579536B1 (en) | Sustained-release pharmaceutical preparation containing tilidine mesylate as active ingredient | |
| WO2010128525A2 (en) | A formulation of ivabradine for treating the cardiovascular disease | |
| CA2295469A1 (en) | Analgesic with controlled active substance release | |
| WO2002049608A1 (en) | Cabergoline pharmaceutical compositions and methods of use thereof | |
| JPH03500288A (en) | Extended release nifedipine formulation | |
| PT98758B (en) | Process for the preparation of a composition in the form of a compressed or dragee containing an active ingredient of preference A derivative of light-moisture-containing aminoguanidine having a monoclinic crystalline streak | |
| EP0299668B1 (en) | Pharmaceutical composition containing ibuprofen | |
| KR20050009983A (en) | Sustained release formulation of tramadol | |
| HU204998B (en) | Process for producing peroral pharmaceuticdal compositions comprising buspirone and its salts | |
| JPS61183225A (en) | Medicinal composition containing 9,10- dihydroergot alkaloid | |
| JP6106359B2 (en) | Solid formulation containing loxoprofen sodium and vitamin B1 | |
| JP3653747B2 (en) | Codeine-containing capsules | |
| JPS61152629A (en) | Slow acting theophylline drug and manufacture |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |