CA1336070C - Controlled release dosage form comprising different cellulose ethers - Google Patents
Controlled release dosage form comprising different cellulose ethersInfo
- Publication number
- CA1336070C CA1336070C CA000609648A CA609648A CA1336070C CA 1336070 C CA1336070 C CA 1336070C CA 000609648 A CA000609648 A CA 000609648A CA 609648 A CA609648 A CA 609648A CA 1336070 C CA1336070 C CA 1336070C
- Authority
- CA
- Canada
- Prior art keywords
- dosage form
- molecular weight
- average molecular
- number average
- hydroxypropylmethylcellulose
- 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 - Fee Related
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Classifications
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- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
Abstract
A dosage form is disclosed comprising a low number average molecular weight hydroxypropylmethylcellulose, a high number average molecular weight hydroxypropylmethylcellulose, and a beneficial drug.
Description
, . . . .
This invention concerns a controlled release dosage form.
11 More specifically, the invention relates to a dosage form comprising 12 at least two different cellulose ethers and at lease one beneficial 13 drug for administering the drug to a fluid environment of use. The 14 dosage form comprises at least thirty weight percent (wt %) of the cellulose ethers.
Tablets comprising a cellulose ether are known to the pharmaceu-21 tica1 drug delivery art. For example, tablets containing the cellu-22 lose ether hydroxypropylmethylcellulose are known in United States 23 Patents Nos. 3,870,790; 4,140,755; 4,167,588; 4,226,849; 4,259,314;
24 4,357,469; 4,369,172; 4,389,3g3 and 4,540,566.
The tablets known to the prior art using the hydroxypropyl-26 methylcellulose ether often have certain disadvantages associated with 27 their structure and with their use. For example, the mechanical 28 integrity of some prior art tablets frequently is insufficient to ~ 1 336070 ARC 1480 1 provide both a sustained and a rate controlled release of a drug over 2 a prolonged period of time in a moving fluid environment of use. The 3 prior art tablets often exhibit insufficient mechanical integrity, 4 that is the cohesive ability to stay together in a moving fluid envi-ronment such as the gastrointestinal tract, without prematurely 6 breaking-up and without prematurely releasing all of its drug content.
7 The above-mentioned desirable properties are not readily apparent in 8 the prior art tablets, which appear to undergo substantial disintegra-9 tion in a short time span, usually less than eight hours in a fluid environment of use.
11 Another disadvantage associated with the prior art tablets is 12 that they exhibit an unwanted, variable, and difficult to reproduce a 13 rate of release pattern. For example, prior art tablets comprising a 14 small amount of a cellulose ether exhibit this behavior, such as bytablets consisting of less than five weight percent of a hydroxy-16 propylmethylcellulose having a number average molecular weight greater 17 than 50,000. The presence of the small amount of this high molecular 18 weight polymeric ether in the tablet masks the release characteristic 19 of other polymeric ethers in the tablets resulting in an erratic release pattern which is difficult to reproduce from batch to batch 21 and from tablet to tablet.
22 Still other unacceptable disadvantages associated with the prior 23 art tablets are that the tablets during their shelf-life can exhibit 24 an unpredictable change in their release-rate characteristics; the prior art tablet when tested in an in vitro test that substantially 26 reproduces the in vivo environment of the gastrointestinal tract often 27 releases the drug at a greater rate of release in vivo than in vitro, 28 which difference can be attributed to a premature disintegration of 1 3 3 6 0 7 0 67696-l45 the prior art tablet; and the prior art tablet in a high fluid shear environment releases its drug too quickly, usually in less than six hours and these tablets therefore are not adapted to prolonged release.
Thus, in the light of the above presentation it will be appreciated by those versed in the dispensing art, that if a novel dosage form is made available to the medical and the pharmaceutical arts for dispensing a difficult to deliver drug free of the tribulation known to the prior art, such a dosage form would be a definite use and would also be a valuable contribution to the dispensing art. It will be further appreciated by those versed in the dispensing art that if a dosage form can be provided that (a) possesses a desirable rate of release and mechanical properties for dispensing a drug over a prolonged period of time, and which dosage form (b) can be manufactured at an economical cost, such a dosage form would have a positive and a practical value and it would also represent an advancement in the dispensing arts.
ASPECTS OF THE INVENTION
Accordingly, this invention seeks to provide a novel dosage form for the rate controlled delivery of a beneficial drug to a biological fluid environment of use, and which unique dosage form represents an improvement and an advancement in the drug delivery arts.
This invention also seeks to provide both a novel and a useful dosage form that substantially overcomes the difficulties associated with the tablets of the prior art.
The invention also seeks to provide a dosage form comprising at least thirty weight percent of a nontoxic cellulosic ether formulation.
The invention seeks to provide a dosage form comprising at least two cellulose ethers that function together for enhancing the pharmaco-release kinetics of the dosage form.
The invention also seeks to provide a novel dosage form that comprises a cellulose ether formulation, which cellulose ether formulation comprises a low number average molecular weight hydroxypropylmethylcellulose ether and a high number average molecular weight hydroxypropylmethyl~ellulose ether, which cellulose ether formulation operate as a unit in a moving fluid for ~ontrolling the rate of release of a benefi~ial drug from the dosage form.
This invention also seeks to provide a dosage form comprising means for delivering a beneficial drug formulation that is difficult to deliver at meaningful rates and now can be delivered by the dosage form of this invention in a high shear fluid environment of use at therapeutically useful rates over a prolonged period of time.
The present invention also seeks to provide a dosage form comprising a beneficial drug formulation that can be from insoluble to very soluble in an aqueous fluid, and which drug formulation can be delivered by the dosage form of this invention comprising two different cellulose ethers at an in vitro rate of release that is substantially paralleled by the in vivo rate of drug release.
A
1 3 3 6 0 7 ~ 67696-145 This invention also seeks to provide a dosage form that can administer to a warm-blooded host a complete pharmaceutical regimen comprising very soluble or poorly soluble drugs, at a rate controlled by the dosage form and at a continuous rate for a particular time period, the use of which dosage form requires intervention only for initiation of the drug delivery regimen.
The present invention also seeks to provide a dosage form for delivering a drug in the gastrointestinal tract that substantially avoids a premature disintegration and delivers a drug at a rate of dosage form release that corresponds to the rate of change of the integrity of the dosage form over a prolonged period of at least eight hours.
The invention further seeks to provide a dosage form ~omprising a high loading up to 70 wt % of an aqueous soluble drug, which can be delivered at a controlled rate by the dosage form and which high loading of the insoluble drug could not be delivered by prior art and osmotic tablets.
The invention also seeks to provide a dosage form comprising a low number molecular weight hydroxypropylmethyl-cellulose ether, a high number molecular weight hydroxypropyl~methylcellulose ether and an optional hydroxypropylcellulose ether for delivering a beneficial drug to the gastrointestinal tract of an animal.
Other features, aspects and advantages of the inven~ion will be more apparent to those versed in the dispensing art from the following detailed specification taken in conjunction with the drawing figures and the accompanying claims.
The invention provides a dosage form for delivering a beneficial drug to an environment of use, whi~h dosage form comprisesS a matrix adapted for entrance into the environment of use, said matrix comprising from 30% to 99.9% of a cellulosic ether formulation, which formulation comprises from 10% to ~9% of at least one hydroxypropylmethylcellulose comprising a high number average molecular weight of from 30,000 to 350,000; from 5% to 80%
of at least one hydroxypropylmethylcellulose comprising a low number average molecular weight of from 9,000 to 30,000; from 2%
to 30% of a hydroxypropylcellulose comprising a hydroxypropoxy content of 7% to 16%, and a dosage amount of the beneficial drug.
In a preferred embodiment 5% to 90% of a hydroxypropyl-methylcellulose comprising a different number average molecular weight of from 30,000 to 350,000 replaces the hydroxypropyl-cellulose in the dosage form.
The invention also relates to the use of such dosage forms and commercial packages comprising such dosage forms together with instru~tions for use thereof to deliver beneficial drugs to the gastrointestinal tract of a warm-blooded mammal, especially the stomach of a human.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings, which are not drawn to scale but are set forth to illustrate various embodiments that can be provided by the invention, the drawing figures are as follows:
Figure 1 is a side, elevational view of a dosage form provided by the invention, designed and adapted for orally 5a ~ 1 336070 administering a beneficial drug to the gastrointestinal tract of an animal;
Figure 2 is a cross-section through 2-2 of Figure 1 for illustrating the internal structure of the dosage form;
5b A
1 Figures 3, 4, 5 and 6 are graphs that depict release rate 2 patterns for dosage forms provided by the invention.
3 In the drawings and in the specifications like parts in related 4 figures are identified by like numbers. The terms appearing earlier in the specification and in the drawings, as well as embodiments 6 thereof, are further described elsewhere in this specification.
9 Turning now to the drawing figures in detail, which drawing figures are an example of the dosage forms provided by the invention, 11 and which example is not to be construed as limiting, one example of 12 the dosage form is illustrated in Figure 1 and in Figure 2 designated 13 by the numeral 10. In Figure 1, dosage form 10 comprises a body or 14 matrix 11, which can be ~anufactured into various sizes and shapes adapted for oral admittance into the gastrointestinal tract of a warm-16 blooded animal. That is, dosage form 10 can be any convenient shape, 17 such as ellipsoid, bean-shaped, circular shaped, rectangular-shaped, 18 caplet-shaped, and the like.
19 In Figure 2, dosage form 10 is seen in cross-section through 2-2 of Figure 1. In Figure 2, dosage form 10 comprises a body 11 comprising 21 a cellulosic ether formulation. The cellulosic ether formulation 22 comprised in one presently preferred embodiment a low number average 23 molecular weight hydroxypropylmethylcellulose ether 12, represented by 24 dashes, and a high number average molecular weight hydroxypropyl-methylcellulose ether 13, represented by wavy lines. In another 26 preferred embodiment, dosage form 10 comprises a low number average 27 molecular weight hydroxypropylmethylcellulose ether 12, a high number 28 average molecular weight hydroxypropylmethylcellulose ether 13, and a ~ 1 336070 ARC 1480 1 hydroxypropylcellulose 15, represented by vertical lines.
2 The expression low number average molecular weight as used for 3 the purposes of this invention comprise a cellulosic polymer compri-4 sing a low number average molecular weight of from about 9,000 to 30,000. Representative of hydroxypropylmethylcellulose polymers ex-6 hibiting a low number average molecular weight of about 9,000 to 7 30,000 are as follows: (a) a hydroxypropylmethylcellulose having a 8 viscosity of 3, a degree of polymerization (DP) of 48 and a low number 9 average molecular weight (MWn) of 9,200; (b) a hydroxypropylmethyl-cellulose having a viscosity of 3, a degree of polymerization of 48 11 and a low number average molecular weight of 9,600; (c) a hydroxy-12 propylmethylcellulose having a viscosity of 5, a degree of polymeriza-13 tion of 56, and a low number average molecular weight of 11,300; (d) 14 a hydroxypropylmethylcellulose having a viscosity of 15, a degree of polymérization of 79, and a number average molecular weight of 15,900;
16 (e) a hydroxypropylmethylcellulose having a viscosity of 35, a degree 17 of polymerization of 102, and a number average molecular weight of 18 19,600; (f) a hydroxypropylmethylcellulose having a viscosity of 50, 19 a degree of polymerization of 116, and a number average molecular weight of 22,600; (9) a hydroxypropylmethylcellulose having a visco-21 sity of 50, a degree of polymerization of 116, and a number average 22 molecular weight of 23,300; (h) a hydroxypropylmethylcellulose having 23 a viscosity of 100, a degree of polymerization of 145, and a number 24 average molecular weight of 27,800; (i) a hydroxypropylmethylcellulose having a viscosity of 106, a degree of polymerization of 156 and a low 26 number average molecular weight of about 30,000.
27 The expression "high numbér average molecular weight" as used for 28 the purpose of this invention comprises a high number average molecular ~ 1 336~7~ ARC 1480 1 weight of greater than 30,000 to 350,000. Representation of hydroxy-2 propylmethylcellulose ethers exhibiting a high number average molecular 3 weight of from 30,000 to 350,000 are as follows: (a) a hydroxypropyl-4 methylcellulose comprising a viscosity of 1,500, a degree of polymeri-zation of 335 and a number average molecular weight of 65,300; (b) a 6 hydroxypropylmethylcellulose ether comprising a viscosity of 4,000, a 7 degree of polymerization of 460 and a high number average molecular 8 weight of 88,300; (c) a hydroxypropylmethylcellulose comprising a 9 viscosity of 4,000, a degree of polymerization of 460 and a number average molecular weight of 92,500; (d) a hydroxypropylmethylcellulose 11 ether comprising a viscosity of 15,000, a degree of polymerization of 12 690 and a number average molecular weight of 132,500; (e) a hydroxy-13 propylmethylcellulose ether comprising a viscosity of 30,000, a degree 14 of polymerization of 860 and a number average molecular weight of 165,100; (f) a hydroxypropylmethylcellulose comprising a viscosity of 16 100,000, a degree of polymerization of 1,260 and a number average 17 molecular weight of 241,900; (9) a hydroxypropylmethylcellulose 18 comprising a viscosity of 220,000, a degree of polymerization of 1,600 19 and a number average molecular weight of 307,200. Viscosity is related to number average molecular weight and is determined from 21 measurements on aqueous solutions of the cellulosic polymer.
22 The expression "hydroxypropylcellulose" as used for the purpose 23 of this invention comprises a low substituted hydroxypropylcellulose 24 15 having a hydroxypropyl content of 7 to 16%. More specific hydroxy-propylcellulose ethers comprise a hydroxypropyl content of 7 to 10%, a 26 hydroxypropyl content of 10 to 13%, and a hydroxypropyl content of 13 27 to 16%.
28 In one presently preferred embodiment dosage form 10 provided by ~ ~ 33607~ ARC 1480 1 this invention comprises from 30% to 99.9% of a cellulose ether compo-2 sition. This cellulose ether composition comprises from 5 to 80% of a 3 low number average molecular weight cellulose ether and from 15 to 90%
4 of a high number average molecular weight hydroxypropylmethylcellulose ether. Dosage form 10 in another embodiment comprises from 30 to 6 99.9% of a cellulosic ether composition which composition comprises 7 from 5 to 80% of a low number average molecular weight hydroxypropyl-8 methylcellulose, from 10 to 90% of a high number average molecular 9 weight hydroxypropylmethylcellulose ether and 2 to 30% of a low sub-stituted hydroxypropylcellulose. Dosage form 10 comprises from 0.1 to 11 70% of drug 14, and other optional dosage form 10 forming ingredients, 12 with all the ingredients in dosage form 10 equal to 100%.
13 Dosage form 10 comprises beneficial drug 14. In the present 14 specificatio~ the term "drug" includes any physiologically or pharma-cologically active substance that produces a local or systemic effect 16 in animals, including warm-blooded mammals, humans and primates;
17 avians; household, sport and farm animals; laboratory animals;
18 fishes, reptiles and zoo animals. The term "physiologically", as used 19 herein, denotes the administration of a drug to produce generallynormal levels and functions in a warm-blooded animal. The term 21 "pharmacologically" generally denotes variations in response to the 22 amount of drug administered to the host. See Stedman's Medical 23 Dictionary, 1966, published by Williams and Wilkins, Baltimore, MD.
24 The active drug that can be delivered includes inorganic and organic compounds without limitation, including drugs that act on the 26 peripheral nerves, adrenergic receptors, cholinergic receptors, 27 nervous system, skeletal muscles, cardiovascular system, smooth muscles, 28 blood circulatory system, synaptic sites, neuroeffector junctional l ~ ~ 6 0 7 0 ARC 1480 1 sites, endocrine system, hormone systems, immunological system, organ 2 systems, reproductive system, skeletal system, autacoid systems, 3 alimentary and excretory systems, inhibitory or autocoids and 4 histamine systems. The active drug that can be delivered for acting on these recipients include anticonvulsants, analgesics, anti-parkinsons, 6 anti-inflammatories, anesthetics, antimicrobials, antimalarials, anti-7 parasitic, anti-hypertensives, angiotensin converting enzyme inhibitor, 8 antihistamines, antipyretics, alpha-adrenergic agnoist, alpha-blockers,9 biocides, bactericides, bronchial dilators, beta-adrenergic stimulators, beta-adrenergic blocking drugs, contraceptives, cardiovascular drugs, 11 calcium channel inhibitors, depressants, diagnostics, diuretics, elec-12 trolytes, hypnotics, hormonals, hyperglycemics, muscle contractants, 13 muscle relaxants, opthalmics, psychic energizers, parasympathomimetics,14 sedatives, sympathomimetics, tranquilizers, urinary tract drugs, vaginal drugs, vitamins, and the like.
16 Exemplary drugs that are very soluble in water can be delivered 17 by dosage form 10 of this invention include prochlorperazine edisylate,18 ferrous sulfate, aminocaproic acid, potassium chloride, mecamylamine 19 hydrochloride, procainamide hydrochloride, amphetamine sulfate, benzphetamine hydrochloride, isoproteronol sulfate, methamphetamine 21 hydrochloride, phenmetrazine hydrochloride, bethanechol chloride, 22 methacholine chloride, pilocarpine hydrochloride, atropine sulfate, 23 scopolamine bromide, isopropamide iodide, tridihexethyl chloride, 24 phenformin hydrochloride, methylphenidate hydrochloride, cimetidine hydrochloride, theophylline cholinate, cephalexin hydrochloride, and 26 the like.
27 Exemplary drugs that are poorly soluble in water and that can be 28 delivered by dosage form 10 of this invention include diphenidol, ~ 1 336070 ARC 1480 1 meclizine hydrochloride, prochlorperazine maleate, phenoxybenzamine, 2 thiethylperazine maleate, anisindone, diphenadione erythrityl tetra-3 nitrate, digoxin, isoflurophate, acetazolamide, methazolamide, 4 bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin, methotrexate, 6 acetyl sulfisoxazole, erythromycin, progestins, esterogenic, progesta-7 tional, corticosteroids, hydrocortisone, hydrocorticosterone acetate, 8 cortisone acetate, triamcinolone, methyltesterone, 17-beta-estradiol, 9 ethinyl estradiol, prazosin hydrochloride, ethinyl estradiol 3-methyl ether, pednisolone, 17-alpha-hydroxyprogesterone acetate, 19-nor-11 progesterone, norgestrel, norethindrone, norethindrone, norethindrone, 12 progesterone, norgesterone, norethynodrel, and the like.
13 Examples of other drugs that can be delivered by dosage form 10 14 inciude aspirin, indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin, propranolol, timolol, atenolol, alprenolol, 16 cimetidine, clonidine, imipramine, levodopa, chloropromazine, methyl-17 dopa, dihydroxyphenylalanine, pivaloyloxyethyl ester of alpha-methyldopa, 18 theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin,19 erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine, diazepam, captopril, phenoxybenzamine, nifedipine, diltiazem, 21 milrinone, madol, quanbenz, hydrochlorothiazide, and the like. The 22 beneficial drugs are know to the art in Pharmaceutical Sciences, 14th 23 Ed., edited by Remington, (1979) published by Mack Publishing Co., 24 Easton, PA; The Drug, The Nurse, The Patient, Including Current Drug Handbook, by Falconer et al., (1974-1976) published by Sunder Co., 26 Philadelphia, PA; Medicinal Chemistry, 3rd Ed., Vol. 1 and 2, by 27 Burger, published by Wiley-Interscience, New York and in Physicians' 28 Desk Reference, 38 Ed., (1984) published by Medical Economics Co., 1 Oradell, NJ.
2 The drug in dosage form 10 can be in various forms, such as 3 uncharged molecules, molecular complexes, pharmacologically acceptable 4 salts such as hydrochloride, hydrobromide, sulfate, laurate, palmitate, phosphate, nitrite, borate, acetate, maleate, tartrate, oleate and 6 salicylate. For acidic drugs, salts of metals, amines or organic 7 cations, for example, quaternary ammonium can be used. Derivatives of 8 drugs such as ester, ethers and amides can be used. Also, a drug that 9 is water insoluble can be used in a form that is a water soluble derivative thereof to serve as a solute, and on its release from the 11 device is converted by enzymes, hydrolyzed by body pH or other 12 metabolic processes to the original biologically active form.
13 Drug 14 can be present in dosage form 10 neat or, as in a 14 presently preferred optional embodiment, with a binder, dispersant, wetting agent, lubricant, or dye. Representative of these include 16 acacia, agar, calcium carrageenan, alginic acid, algin, agarose powder, 17 colloidal magnesium silicate, pectin, gelatin, and the like; binders 18 like polyvinyl pyrrolidone; lubricants such as magnesium stearate;
19 wetting agent such as fatty amines, fatty quaternary ammonium salts;
esters of sorbitol, and the like. The phrase drug formulation 21 indicates the drug is present in dosage form 10 neat or accompanied by 22 a binder, and the like. The amount of beneficial drug in dosage form 23 10 generally is from about 0.05 ng to 5 g or more, with individual 24 dosage form 10 comprising for example, 25 ng, 1 mg, 5 mg, 10 mg, 25 mg, 250 mg, 750 mg, 1.0 g, 1.2 g, 1.5 g, and the like. The dosage 26 form can be administered once, twice or three times a day.
27 Dosage form 10 is manufactured from a well-mixed composition of 28 dosage-forming members. For example, a particular dosage form is made -~ 1 336070 ARC 1480 1 as follows: first, each of the ingredients comprising a dosage form2 are independently screened and then blended together, except for the 3 lubricant. Then, the homogeneous blend is wet granulated by adding a 4 solvent such as anhydrous ethanol, and the wet ingredients mixed until a uniform blend is obtained by said process. Next, the wet blend is 6 passed through a screen and dried to evaporate the solvent. The 7 resulting granules are passed again through a sieve. Next, a small 8 amount of a finely divided lubricant is added to the dry granules and 9 the lubricant and granules blended to provide a uniform blend. Then, the dosage forming composition is fed to the hopper of a compression 11 machine, and the composition pressed into a dosage form. Typically,12 about two tons of pressure are applied to yield the final dosage form.
13 The dosage form can be made also by a dry granulation process of 14 manufacture. The dry process co~prises first mixing all the dosage forming ingredients, except for the lubricant, passing the mixed 16 ingredients through a grinding mill to a small mesh size, and then 17 transferring the sized powder to a dry compactor. The compactor 18 densifies the powder, which dense powder is then passed through a 19 sizing mill to regrind the composition. The composition is ground to a small size, typically 20 mesh or smaller. Finally, a dry lubricant 21 is added and the ingredients blended to produce the final dosage 22 forming composition. Then, the composition is fed to a compaction 23 press and compressed into the dosage form 10.
24 Other standard manufacturing procedures can be used to form the dosage form. For example, the various ingredients can be mixed with a 26 solvent by ballmilling, calendering, stirring or rollmilling, and then 27 pressed into a preselected sized and shaped dosage form 10.
28 Exemplary solvents suitable for manufacturing the dosage form 1 33607~
1 include inorganic and organic solvents that do not adversely harm the 2 dosage form. The solvents broadly include a member selected from the 3 group consisting of alcohols, ketones, esters, ethers, aliphatic 4 hydrocarbons, halogenated solvents, cycloaliphatic solvents, aromatic, heterocyclic solvents, and mixtures thereof. Typical solvents include 6 acetone, diacetone, methanol, ethanol, isopropyl alcohol, butyl 7 alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-8 butylacetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, 9 n-heptane, methylene dichloride, ethylene dichloride, propylene dichloride, ethyl ether, mixtures such as acetone and ethanol, acetone 11 and methanol, methylene dichloride and methanol, ethylene dichloride 12 and methanol, and the like.
13 The following examples illustrate means and methods for carrying 14 out the present invention. The examples are merely illustrative and they should not be considered as limiting the scope of the invention, 16 as these examples and other equivalents thereof will become more 17 apparent to those versed in the pharmaceutical dispensing art in the 18 light of the present disclosure, the drawings and the accompanying 19 claims.
21 A dosage form 10 comprising 29.5% isosorbide dinitrate (5,900 9);
22 29.5% lactose (5,900 9); 20% hydroxypropylmethylcellulose ether 23 (4,000 9) exhibiting a low 27,800 number average molecular weight and 24 20% hydroxypropylmethylcellulose ether (4,000 9) exhibiting a high 88,300 number average molecular weight, were presieved through a 26 40 mesh screen. The presieved ingredients were mixed in a twin shell 27 blender for 15 minutes and then transferred to a Hobart~ mixer. Next, 28 anhydrous methyl alcohol was added slowly with mixing to form a 1 uniform dough. The dough was passed through a 20 mesh screen and then 2 air dried for 2 hours at room temperature. The resulting granules 3 were repassed through the 20 mesh screen and dried at ambient 4 conditions overnight. Then, magnesium stearate, 1~, (200 9), was passed through an 80 mesh per inch screen and then was blended into 6 the mixture in a twin shell mixer for 3 minutes. The resulting 7 granulation was compressed on a D3B Manesty~ Press at 2 tons pressure 8 using a 13/32 inch, (1.0 mm) round standard concave punch. The dosage 9 form 10 provided by the manufacture weight 271 mg, comprising 54.2 mg of the hydroxypropylmethylcellulose ether having the low number 11 average molecular weight of 27,800; 54.2 mg of the hydroxypropyl-12 methylcellulose having the high molecular number average molecular 13 weight of 88,300; and 80 mg of isosorbide dinitrate. The dosage forms 14 were placed in artificial gastric fluid and the release of drug measured from the dosage form. The results of the test indicated 78%
16 of the drug was delivered in a 24 hour period at an average delivery 17 rate of isosorbide dinitrate of 2.5 mg per hour. Accompanying Figure 18 3 depicts the release rate pattern for the dosage form and 19 accompanying Figure 4 depicts the cumulative amount released over a prolonged period of 24 hours.
22 A dosage form 10 comprising 15% of the enzyme inhibitor captopril,23 5% of a low 9,200 number average molecular weight hydroxypropylmethyl-24 cellulose, 78% of a high 88,300 molecular weight hydroxypropylmethyl-cellulose and 2% of stearic acid was prepared as follows: first, 26 1,500 9 of the enzyme inhibitor, 500 9 of the low number average 27 molecular weight hydroxypropylmethylcellulose, and 7,800 9 of the high 28 molecular weight hydroxypropylmethylcellulose are presieved through a 1 40 mesh screen and mixed for 15 minutes in a twin shell blender, and 2 the resulting mixture transferred to a Hobart~ blender. Then, anhydrous 3 ethanol was added slowly with mixing to form a damp mass. The ethanol 4 alcohol damp mass was passed through a 20 mesh screen and air dried overnight. The dry product was repassed through a 20 mesh screen.
6 The resulting granules were lubricated with 200 9 of stearic acid by 7 passing the stearic acid through an 80 mesh screen over the granules 8 and mixing the granules in a twin shell blender for 3 minutes. Next, 9 the resulting granulation was compressed into dosage forms using a Manesty press fitted with a standard concave round die of 3/8 inch ll (0.95 mm) diameter under a compression head of 2 tons. The dosage 12 forms weighed 334 mg and contained 50 mg of captopril.
14 A dosage form 10 was prepared by following the procedure of Example 2. The dosage form of this example comprises 53% ibuprofen;
16 20% of a hydroxypropylmethylcellulose having a number average molecular 17 weight of 9,200; 20% of a hydroxypropylmethylcellulose having a 18 number average molecular weight of 241,900; 5% hydroxypropylmethyl-19 cellulose, and 2% magnesium stearate. The drug release rate pattern for this dosage form is seen in Figure 5 and the cumulative amount 21 released over a prolonged period of time is seen in Figure 6.
23 The procedures described above are followed for manufacturing 24 dosage forms comprising the following drugs and the cellulosic ethers:
(a) 120 mg of propanolol hydrochloride and 40 wt % of a cellulosic 26 ether formulation comprising 20 wt % hydroxypropylmethylcellulose 27 having a number average molecular weight of 241,900 and 20 wt % of a 28 hydroxypropylmethylcellulose having a number average molecular weight 1 of 9,200; (b) a dosage form comprising 50 mg of hydrochlorothiazide 2 and 60 wt % of a cellulosic ether formulation comprising 20 wt %
3 hydroxypropylmethylcellulose having a molecular weight of 132,500 and 4 40 wt % of a hydroxypropylmethylcellulose having a molecular weight of 9,200; (c) a dosage form comprising 75 mg of dipyridamole and 60 wt %
6 of a cellulosic ether composition comprising 20 wt % of a hydroxy-7 propylmethylcellulose having a number average molecular weight of 8 88,300 and 40 wt % of a hydroxypropylmethylcellulose having a number 9 average molecular weight of 27,800; (d) a dosage form comprising 100 mg of verapamil hydrochloride and 50 wt % of a hydroxypropylmethyl-11 cellulose having a number average molecular weight of 307,200 and 15 12 wt % of a hydroxypropylmethylcellulose having a number average molecular 13 weight of 19,600; (e) a dosage form comprising 50 mg of codeine 14 phosphate, 60 wt % of a hydroxypropy~methylcellulose having a number average molecular weight of 241,900 and 15 wt % of a hydroxypropyl-16 methylcellulose having a number average molecular weight of 9,200;
17 (f) a dosage form comprising 200 mg of nitrofurantoin, 15 wt % of a 18 hydroxypropylmethylcellulose having a number average molecular weight 19 of 241,900 and 45 wt % of a hydroxypropylmethylcellulose having a 2~ number average molecular weight of 19,600.
22 The procedures described above are followed for manufacturing 23 dosage forms comprising the following drugs and cellulosic ether 24 formulation: (g) 250 mg of tetracycline; 5 wt % of hydroxypropyl-methylcellulose having a number average molecular weight of 132,500, 26 and, 10 wt % of hydroxypropylmethylcellulose comprising a number 27 average molecular weight of 241,900; and 40 wt % of a hydroxypropyl-28 methylcellulose comprising a number average molecular weight of 9,200;
1 336~7~1 (h) 300 mg of cimetidine; 5 wt % of hydroxypropylmethylcellulose having a number average molecular weight of 88,300; 25 wt % of hydroxypropylmethylcellulose comprising a number average molecular weight of 241,900; and, 10 wt % of a hydroxypropylmethylcellulose comprising a number average molecular weight of 9,200; (i) 160 mg of nadolol; 20 wt % of hydroxypropylmethylcellulose having a number average molecular weight of 88,300; 5 wt % of hydroxypropylmethyl-cellulose comprising a number average molecular weight of 307,200;
and, 40 wt % of a hydroxypropylmethylcellulose comprising a number average molecular weight of 9,200; (j) 300 mg of quinidine gluconate;
11 20 wt % of hydroxypropylmethylcellulose having a number average 12 molecular weight of 241,900; 20 wt % of hydroxypropylmethylcellulose 13 comprising a number average molecular weight of 307,200; and, 20 wt %
14 of a hydroxypropylmethylcellulose comprising a number average molecular weight of 9,200, (k) 30 mg of morphine suifate; 60 wt % of hydroxy-16 propylmethylcellulose having a number average molecular weight of17 132,500; 20 wt % of hydroxypropylmethylcellulose comprising a number 18 average molecular weight of 307,200; and, 10 wt % of a hydroxypropyl-methylcellulose comprising a number average molecular weight of 9,200;
and, (1) 20 mg of nifedipine; 5 wt % of hydroxypropylmethylcellulose 21 having a number average molecular weight of 132,500; 10 wt ~ of 22 hydroxypropylmethylcellulose comprising a number average molecular 23 weight of 241,900; and, 75 wt % of a hydroxypropylmethylcellulose24 comprising a number average molecular weight of 9,200.
26 The procedures described above are followed for manufacturing dosage forms comprising the following drugs and cellulosic ether 28 formulation: (m) 250 mg of erthromycin stearate; 15 wt % of 1 hydroxypropylmethylcellulose having a number average molecular weight 2 Of 241,900; 15 wt % of hydroxypropylmethylcellulose comprising a 3 number average molecular weight of 9,200; and, S wt % of a hydroxy-4 propylcellulose comprising a hydroxypropoxy content of 7 to 10%; (n) 12 mg of chlorpheniramine maleate; 70 wt % of hydroxypropyl-6 methylcellulose having a number average molecular weight of 241,900;
7 20 wt % of hydroxypropylmethylcellulose comprising a number average 8 molecular weight of 9,600; and, 5 wt % of a hydroxypropylcellulose 9 comprising a hydroxypropoxy content of 10 to 16%; (o) 8 mg of brompheniramine maleate; 70 wt % of hydroxypropylmethylcellulose 11 having a number average molecular weight of 241,900; 20 wt % of 12 hydroxypropylmethylcellulose comprising a number average molecular 13 weight of 19,600; and, 5 wt % of a hydroxypropylcellulose consisting 14 of a hydroxypropoxy content of 13 to 16%; (p) a dosage form comprising 8 mg of chlorpheniramine maleate; 120 mg of pseudoephedrine 16 sulfate; 25 wt % of hydroxypropylmethylcellulose consisting of a 17 number average molecular weight of 241,900; 25 wt % of hydroxypropyl-18 methylcellulose consisting of a number average molecular weight of 19 27,800; and, 10 wt % hydroxypropylcellulose consisting of 10 to 13%
hydroxypropoxy; and (q) 150 mg of ranitidine hydrochloride; 35 Wt %
21 of hydroxypropoxymethylcellulose having a number average molecular 22 weight of 241,900; 15 wt % of hydroxypropoxymethylcellulose consisting 23 essentially of a low number average molecular weight of 19,600; and, 24 15 wt % hydroxypropylcellulose consisting of 13 to 16 hydroxypropoxy content.
26 Dosage form 10 provided by the invention makes available a drug 27 delivery matrix suitable for retention in the stomach for gastric 28 retention over the drug releasing life time of the dosage system.
1 Also, when all the drug is released, the system bfoerodes into 2 innocuous particles and dissolved polymers that pass from the 3 gastrointestinal tract. The dosage form of the invention comprising 4 higher concentrations of cellulosic ether formulations exhibit better mechanical integrity and they better withstand the abrasive fluidic 6 action of the gastrointestinal tract. The dosage form of the 7 invention provides a broader range of erosion rates including 8 decreased and increased erosion rates in its use of low and high 9 numbe~ average molecular weight blends of cellulosic ethers. Another advantage provided by dosage form 10 resulting from its use of high 11 number average molecular weight cellulose ethers is that it provides 12 more physical stability, improved resistance to thermal shock and it 13 helps lessen the incidence of matrix cracking over storage time, when 14 stored in fluctuating ambient temperature conditions. Also, the dosage forms use of the high number average molecular weight cellulosic 16 ethers exhibit decreased tackiness in high humidity thereby preventing 17 sticking of one to another. The use of high number average molecular 18 weight cellulose ethers provides more rate control of the drug admini-19 stration over time. The use of the cellulose ethers, especially the high number average molecular wt cellulose ethers which swell 21 extensively when hydrated, lessens direct drug contact with mucosal 22 tissues and thereby lessens the incidence of tissue irritation for 23 irritating drugs.
24 The novel dosage form of this invention comprises means for the obtainment of precise release rates in the environment of use while 26 simultaneously providing beneficial therapy to a recipient. While 27 there has been described and pointed out features of the invention as 28 applied to presently preferred embodiments, those skilled in the 1 dispensing art will appreciate that various modifications, changes, 2 additions and omissions in the dosage form illustrated and described 3 can be made without departing from the spirit of this invention.
17.
This invention concerns a controlled release dosage form.
11 More specifically, the invention relates to a dosage form comprising 12 at least two different cellulose ethers and at lease one beneficial 13 drug for administering the drug to a fluid environment of use. The 14 dosage form comprises at least thirty weight percent (wt %) of the cellulose ethers.
Tablets comprising a cellulose ether are known to the pharmaceu-21 tica1 drug delivery art. For example, tablets containing the cellu-22 lose ether hydroxypropylmethylcellulose are known in United States 23 Patents Nos. 3,870,790; 4,140,755; 4,167,588; 4,226,849; 4,259,314;
24 4,357,469; 4,369,172; 4,389,3g3 and 4,540,566.
The tablets known to the prior art using the hydroxypropyl-26 methylcellulose ether often have certain disadvantages associated with 27 their structure and with their use. For example, the mechanical 28 integrity of some prior art tablets frequently is insufficient to ~ 1 336070 ARC 1480 1 provide both a sustained and a rate controlled release of a drug over 2 a prolonged period of time in a moving fluid environment of use. The 3 prior art tablets often exhibit insufficient mechanical integrity, 4 that is the cohesive ability to stay together in a moving fluid envi-ronment such as the gastrointestinal tract, without prematurely 6 breaking-up and without prematurely releasing all of its drug content.
7 The above-mentioned desirable properties are not readily apparent in 8 the prior art tablets, which appear to undergo substantial disintegra-9 tion in a short time span, usually less than eight hours in a fluid environment of use.
11 Another disadvantage associated with the prior art tablets is 12 that they exhibit an unwanted, variable, and difficult to reproduce a 13 rate of release pattern. For example, prior art tablets comprising a 14 small amount of a cellulose ether exhibit this behavior, such as bytablets consisting of less than five weight percent of a hydroxy-16 propylmethylcellulose having a number average molecular weight greater 17 than 50,000. The presence of the small amount of this high molecular 18 weight polymeric ether in the tablet masks the release characteristic 19 of other polymeric ethers in the tablets resulting in an erratic release pattern which is difficult to reproduce from batch to batch 21 and from tablet to tablet.
22 Still other unacceptable disadvantages associated with the prior 23 art tablets are that the tablets during their shelf-life can exhibit 24 an unpredictable change in their release-rate characteristics; the prior art tablet when tested in an in vitro test that substantially 26 reproduces the in vivo environment of the gastrointestinal tract often 27 releases the drug at a greater rate of release in vivo than in vitro, 28 which difference can be attributed to a premature disintegration of 1 3 3 6 0 7 0 67696-l45 the prior art tablet; and the prior art tablet in a high fluid shear environment releases its drug too quickly, usually in less than six hours and these tablets therefore are not adapted to prolonged release.
Thus, in the light of the above presentation it will be appreciated by those versed in the dispensing art, that if a novel dosage form is made available to the medical and the pharmaceutical arts for dispensing a difficult to deliver drug free of the tribulation known to the prior art, such a dosage form would be a definite use and would also be a valuable contribution to the dispensing art. It will be further appreciated by those versed in the dispensing art that if a dosage form can be provided that (a) possesses a desirable rate of release and mechanical properties for dispensing a drug over a prolonged period of time, and which dosage form (b) can be manufactured at an economical cost, such a dosage form would have a positive and a practical value and it would also represent an advancement in the dispensing arts.
ASPECTS OF THE INVENTION
Accordingly, this invention seeks to provide a novel dosage form for the rate controlled delivery of a beneficial drug to a biological fluid environment of use, and which unique dosage form represents an improvement and an advancement in the drug delivery arts.
This invention also seeks to provide both a novel and a useful dosage form that substantially overcomes the difficulties associated with the tablets of the prior art.
The invention also seeks to provide a dosage form comprising at least thirty weight percent of a nontoxic cellulosic ether formulation.
The invention seeks to provide a dosage form comprising at least two cellulose ethers that function together for enhancing the pharmaco-release kinetics of the dosage form.
The invention also seeks to provide a novel dosage form that comprises a cellulose ether formulation, which cellulose ether formulation comprises a low number average molecular weight hydroxypropylmethylcellulose ether and a high number average molecular weight hydroxypropylmethyl~ellulose ether, which cellulose ether formulation operate as a unit in a moving fluid for ~ontrolling the rate of release of a benefi~ial drug from the dosage form.
This invention also seeks to provide a dosage form comprising means for delivering a beneficial drug formulation that is difficult to deliver at meaningful rates and now can be delivered by the dosage form of this invention in a high shear fluid environment of use at therapeutically useful rates over a prolonged period of time.
The present invention also seeks to provide a dosage form comprising a beneficial drug formulation that can be from insoluble to very soluble in an aqueous fluid, and which drug formulation can be delivered by the dosage form of this invention comprising two different cellulose ethers at an in vitro rate of release that is substantially paralleled by the in vivo rate of drug release.
A
1 3 3 6 0 7 ~ 67696-145 This invention also seeks to provide a dosage form that can administer to a warm-blooded host a complete pharmaceutical regimen comprising very soluble or poorly soluble drugs, at a rate controlled by the dosage form and at a continuous rate for a particular time period, the use of which dosage form requires intervention only for initiation of the drug delivery regimen.
The present invention also seeks to provide a dosage form for delivering a drug in the gastrointestinal tract that substantially avoids a premature disintegration and delivers a drug at a rate of dosage form release that corresponds to the rate of change of the integrity of the dosage form over a prolonged period of at least eight hours.
The invention further seeks to provide a dosage form ~omprising a high loading up to 70 wt % of an aqueous soluble drug, which can be delivered at a controlled rate by the dosage form and which high loading of the insoluble drug could not be delivered by prior art and osmotic tablets.
The invention also seeks to provide a dosage form comprising a low number molecular weight hydroxypropylmethyl-cellulose ether, a high number molecular weight hydroxypropyl~methylcellulose ether and an optional hydroxypropylcellulose ether for delivering a beneficial drug to the gastrointestinal tract of an animal.
Other features, aspects and advantages of the inven~ion will be more apparent to those versed in the dispensing art from the following detailed specification taken in conjunction with the drawing figures and the accompanying claims.
The invention provides a dosage form for delivering a beneficial drug to an environment of use, whi~h dosage form comprisesS a matrix adapted for entrance into the environment of use, said matrix comprising from 30% to 99.9% of a cellulosic ether formulation, which formulation comprises from 10% to ~9% of at least one hydroxypropylmethylcellulose comprising a high number average molecular weight of from 30,000 to 350,000; from 5% to 80%
of at least one hydroxypropylmethylcellulose comprising a low number average molecular weight of from 9,000 to 30,000; from 2%
to 30% of a hydroxypropylcellulose comprising a hydroxypropoxy content of 7% to 16%, and a dosage amount of the beneficial drug.
In a preferred embodiment 5% to 90% of a hydroxypropyl-methylcellulose comprising a different number average molecular weight of from 30,000 to 350,000 replaces the hydroxypropyl-cellulose in the dosage form.
The invention also relates to the use of such dosage forms and commercial packages comprising such dosage forms together with instru~tions for use thereof to deliver beneficial drugs to the gastrointestinal tract of a warm-blooded mammal, especially the stomach of a human.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings, which are not drawn to scale but are set forth to illustrate various embodiments that can be provided by the invention, the drawing figures are as follows:
Figure 1 is a side, elevational view of a dosage form provided by the invention, designed and adapted for orally 5a ~ 1 336070 administering a beneficial drug to the gastrointestinal tract of an animal;
Figure 2 is a cross-section through 2-2 of Figure 1 for illustrating the internal structure of the dosage form;
5b A
1 Figures 3, 4, 5 and 6 are graphs that depict release rate 2 patterns for dosage forms provided by the invention.
3 In the drawings and in the specifications like parts in related 4 figures are identified by like numbers. The terms appearing earlier in the specification and in the drawings, as well as embodiments 6 thereof, are further described elsewhere in this specification.
9 Turning now to the drawing figures in detail, which drawing figures are an example of the dosage forms provided by the invention, 11 and which example is not to be construed as limiting, one example of 12 the dosage form is illustrated in Figure 1 and in Figure 2 designated 13 by the numeral 10. In Figure 1, dosage form 10 comprises a body or 14 matrix 11, which can be ~anufactured into various sizes and shapes adapted for oral admittance into the gastrointestinal tract of a warm-16 blooded animal. That is, dosage form 10 can be any convenient shape, 17 such as ellipsoid, bean-shaped, circular shaped, rectangular-shaped, 18 caplet-shaped, and the like.
19 In Figure 2, dosage form 10 is seen in cross-section through 2-2 of Figure 1. In Figure 2, dosage form 10 comprises a body 11 comprising 21 a cellulosic ether formulation. The cellulosic ether formulation 22 comprised in one presently preferred embodiment a low number average 23 molecular weight hydroxypropylmethylcellulose ether 12, represented by 24 dashes, and a high number average molecular weight hydroxypropyl-methylcellulose ether 13, represented by wavy lines. In another 26 preferred embodiment, dosage form 10 comprises a low number average 27 molecular weight hydroxypropylmethylcellulose ether 12, a high number 28 average molecular weight hydroxypropylmethylcellulose ether 13, and a ~ 1 336070 ARC 1480 1 hydroxypropylcellulose 15, represented by vertical lines.
2 The expression low number average molecular weight as used for 3 the purposes of this invention comprise a cellulosic polymer compri-4 sing a low number average molecular weight of from about 9,000 to 30,000. Representative of hydroxypropylmethylcellulose polymers ex-6 hibiting a low number average molecular weight of about 9,000 to 7 30,000 are as follows: (a) a hydroxypropylmethylcellulose having a 8 viscosity of 3, a degree of polymerization (DP) of 48 and a low number 9 average molecular weight (MWn) of 9,200; (b) a hydroxypropylmethyl-cellulose having a viscosity of 3, a degree of polymerization of 48 11 and a low number average molecular weight of 9,600; (c) a hydroxy-12 propylmethylcellulose having a viscosity of 5, a degree of polymeriza-13 tion of 56, and a low number average molecular weight of 11,300; (d) 14 a hydroxypropylmethylcellulose having a viscosity of 15, a degree of polymérization of 79, and a number average molecular weight of 15,900;
16 (e) a hydroxypropylmethylcellulose having a viscosity of 35, a degree 17 of polymerization of 102, and a number average molecular weight of 18 19,600; (f) a hydroxypropylmethylcellulose having a viscosity of 50, 19 a degree of polymerization of 116, and a number average molecular weight of 22,600; (9) a hydroxypropylmethylcellulose having a visco-21 sity of 50, a degree of polymerization of 116, and a number average 22 molecular weight of 23,300; (h) a hydroxypropylmethylcellulose having 23 a viscosity of 100, a degree of polymerization of 145, and a number 24 average molecular weight of 27,800; (i) a hydroxypropylmethylcellulose having a viscosity of 106, a degree of polymerization of 156 and a low 26 number average molecular weight of about 30,000.
27 The expression "high numbér average molecular weight" as used for 28 the purpose of this invention comprises a high number average molecular ~ 1 336~7~ ARC 1480 1 weight of greater than 30,000 to 350,000. Representation of hydroxy-2 propylmethylcellulose ethers exhibiting a high number average molecular 3 weight of from 30,000 to 350,000 are as follows: (a) a hydroxypropyl-4 methylcellulose comprising a viscosity of 1,500, a degree of polymeri-zation of 335 and a number average molecular weight of 65,300; (b) a 6 hydroxypropylmethylcellulose ether comprising a viscosity of 4,000, a 7 degree of polymerization of 460 and a high number average molecular 8 weight of 88,300; (c) a hydroxypropylmethylcellulose comprising a 9 viscosity of 4,000, a degree of polymerization of 460 and a number average molecular weight of 92,500; (d) a hydroxypropylmethylcellulose 11 ether comprising a viscosity of 15,000, a degree of polymerization of 12 690 and a number average molecular weight of 132,500; (e) a hydroxy-13 propylmethylcellulose ether comprising a viscosity of 30,000, a degree 14 of polymerization of 860 and a number average molecular weight of 165,100; (f) a hydroxypropylmethylcellulose comprising a viscosity of 16 100,000, a degree of polymerization of 1,260 and a number average 17 molecular weight of 241,900; (9) a hydroxypropylmethylcellulose 18 comprising a viscosity of 220,000, a degree of polymerization of 1,600 19 and a number average molecular weight of 307,200. Viscosity is related to number average molecular weight and is determined from 21 measurements on aqueous solutions of the cellulosic polymer.
22 The expression "hydroxypropylcellulose" as used for the purpose 23 of this invention comprises a low substituted hydroxypropylcellulose 24 15 having a hydroxypropyl content of 7 to 16%. More specific hydroxy-propylcellulose ethers comprise a hydroxypropyl content of 7 to 10%, a 26 hydroxypropyl content of 10 to 13%, and a hydroxypropyl content of 13 27 to 16%.
28 In one presently preferred embodiment dosage form 10 provided by ~ ~ 33607~ ARC 1480 1 this invention comprises from 30% to 99.9% of a cellulose ether compo-2 sition. This cellulose ether composition comprises from 5 to 80% of a 3 low number average molecular weight cellulose ether and from 15 to 90%
4 of a high number average molecular weight hydroxypropylmethylcellulose ether. Dosage form 10 in another embodiment comprises from 30 to 6 99.9% of a cellulosic ether composition which composition comprises 7 from 5 to 80% of a low number average molecular weight hydroxypropyl-8 methylcellulose, from 10 to 90% of a high number average molecular 9 weight hydroxypropylmethylcellulose ether and 2 to 30% of a low sub-stituted hydroxypropylcellulose. Dosage form 10 comprises from 0.1 to 11 70% of drug 14, and other optional dosage form 10 forming ingredients, 12 with all the ingredients in dosage form 10 equal to 100%.
13 Dosage form 10 comprises beneficial drug 14. In the present 14 specificatio~ the term "drug" includes any physiologically or pharma-cologically active substance that produces a local or systemic effect 16 in animals, including warm-blooded mammals, humans and primates;
17 avians; household, sport and farm animals; laboratory animals;
18 fishes, reptiles and zoo animals. The term "physiologically", as used 19 herein, denotes the administration of a drug to produce generallynormal levels and functions in a warm-blooded animal. The term 21 "pharmacologically" generally denotes variations in response to the 22 amount of drug administered to the host. See Stedman's Medical 23 Dictionary, 1966, published by Williams and Wilkins, Baltimore, MD.
24 The active drug that can be delivered includes inorganic and organic compounds without limitation, including drugs that act on the 26 peripheral nerves, adrenergic receptors, cholinergic receptors, 27 nervous system, skeletal muscles, cardiovascular system, smooth muscles, 28 blood circulatory system, synaptic sites, neuroeffector junctional l ~ ~ 6 0 7 0 ARC 1480 1 sites, endocrine system, hormone systems, immunological system, organ 2 systems, reproductive system, skeletal system, autacoid systems, 3 alimentary and excretory systems, inhibitory or autocoids and 4 histamine systems. The active drug that can be delivered for acting on these recipients include anticonvulsants, analgesics, anti-parkinsons, 6 anti-inflammatories, anesthetics, antimicrobials, antimalarials, anti-7 parasitic, anti-hypertensives, angiotensin converting enzyme inhibitor, 8 antihistamines, antipyretics, alpha-adrenergic agnoist, alpha-blockers,9 biocides, bactericides, bronchial dilators, beta-adrenergic stimulators, beta-adrenergic blocking drugs, contraceptives, cardiovascular drugs, 11 calcium channel inhibitors, depressants, diagnostics, diuretics, elec-12 trolytes, hypnotics, hormonals, hyperglycemics, muscle contractants, 13 muscle relaxants, opthalmics, psychic energizers, parasympathomimetics,14 sedatives, sympathomimetics, tranquilizers, urinary tract drugs, vaginal drugs, vitamins, and the like.
16 Exemplary drugs that are very soluble in water can be delivered 17 by dosage form 10 of this invention include prochlorperazine edisylate,18 ferrous sulfate, aminocaproic acid, potassium chloride, mecamylamine 19 hydrochloride, procainamide hydrochloride, amphetamine sulfate, benzphetamine hydrochloride, isoproteronol sulfate, methamphetamine 21 hydrochloride, phenmetrazine hydrochloride, bethanechol chloride, 22 methacholine chloride, pilocarpine hydrochloride, atropine sulfate, 23 scopolamine bromide, isopropamide iodide, tridihexethyl chloride, 24 phenformin hydrochloride, methylphenidate hydrochloride, cimetidine hydrochloride, theophylline cholinate, cephalexin hydrochloride, and 26 the like.
27 Exemplary drugs that are poorly soluble in water and that can be 28 delivered by dosage form 10 of this invention include diphenidol, ~ 1 336070 ARC 1480 1 meclizine hydrochloride, prochlorperazine maleate, phenoxybenzamine, 2 thiethylperazine maleate, anisindone, diphenadione erythrityl tetra-3 nitrate, digoxin, isoflurophate, acetazolamide, methazolamide, 4 bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin, methotrexate, 6 acetyl sulfisoxazole, erythromycin, progestins, esterogenic, progesta-7 tional, corticosteroids, hydrocortisone, hydrocorticosterone acetate, 8 cortisone acetate, triamcinolone, methyltesterone, 17-beta-estradiol, 9 ethinyl estradiol, prazosin hydrochloride, ethinyl estradiol 3-methyl ether, pednisolone, 17-alpha-hydroxyprogesterone acetate, 19-nor-11 progesterone, norgestrel, norethindrone, norethindrone, norethindrone, 12 progesterone, norgesterone, norethynodrel, and the like.
13 Examples of other drugs that can be delivered by dosage form 10 14 inciude aspirin, indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin, propranolol, timolol, atenolol, alprenolol, 16 cimetidine, clonidine, imipramine, levodopa, chloropromazine, methyl-17 dopa, dihydroxyphenylalanine, pivaloyloxyethyl ester of alpha-methyldopa, 18 theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin,19 erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine, diazepam, captopril, phenoxybenzamine, nifedipine, diltiazem, 21 milrinone, madol, quanbenz, hydrochlorothiazide, and the like. The 22 beneficial drugs are know to the art in Pharmaceutical Sciences, 14th 23 Ed., edited by Remington, (1979) published by Mack Publishing Co., 24 Easton, PA; The Drug, The Nurse, The Patient, Including Current Drug Handbook, by Falconer et al., (1974-1976) published by Sunder Co., 26 Philadelphia, PA; Medicinal Chemistry, 3rd Ed., Vol. 1 and 2, by 27 Burger, published by Wiley-Interscience, New York and in Physicians' 28 Desk Reference, 38 Ed., (1984) published by Medical Economics Co., 1 Oradell, NJ.
2 The drug in dosage form 10 can be in various forms, such as 3 uncharged molecules, molecular complexes, pharmacologically acceptable 4 salts such as hydrochloride, hydrobromide, sulfate, laurate, palmitate, phosphate, nitrite, borate, acetate, maleate, tartrate, oleate and 6 salicylate. For acidic drugs, salts of metals, amines or organic 7 cations, for example, quaternary ammonium can be used. Derivatives of 8 drugs such as ester, ethers and amides can be used. Also, a drug that 9 is water insoluble can be used in a form that is a water soluble derivative thereof to serve as a solute, and on its release from the 11 device is converted by enzymes, hydrolyzed by body pH or other 12 metabolic processes to the original biologically active form.
13 Drug 14 can be present in dosage form 10 neat or, as in a 14 presently preferred optional embodiment, with a binder, dispersant, wetting agent, lubricant, or dye. Representative of these include 16 acacia, agar, calcium carrageenan, alginic acid, algin, agarose powder, 17 colloidal magnesium silicate, pectin, gelatin, and the like; binders 18 like polyvinyl pyrrolidone; lubricants such as magnesium stearate;
19 wetting agent such as fatty amines, fatty quaternary ammonium salts;
esters of sorbitol, and the like. The phrase drug formulation 21 indicates the drug is present in dosage form 10 neat or accompanied by 22 a binder, and the like. The amount of beneficial drug in dosage form 23 10 generally is from about 0.05 ng to 5 g or more, with individual 24 dosage form 10 comprising for example, 25 ng, 1 mg, 5 mg, 10 mg, 25 mg, 250 mg, 750 mg, 1.0 g, 1.2 g, 1.5 g, and the like. The dosage 26 form can be administered once, twice or three times a day.
27 Dosage form 10 is manufactured from a well-mixed composition of 28 dosage-forming members. For example, a particular dosage form is made -~ 1 336070 ARC 1480 1 as follows: first, each of the ingredients comprising a dosage form2 are independently screened and then blended together, except for the 3 lubricant. Then, the homogeneous blend is wet granulated by adding a 4 solvent such as anhydrous ethanol, and the wet ingredients mixed until a uniform blend is obtained by said process. Next, the wet blend is 6 passed through a screen and dried to evaporate the solvent. The 7 resulting granules are passed again through a sieve. Next, a small 8 amount of a finely divided lubricant is added to the dry granules and 9 the lubricant and granules blended to provide a uniform blend. Then, the dosage forming composition is fed to the hopper of a compression 11 machine, and the composition pressed into a dosage form. Typically,12 about two tons of pressure are applied to yield the final dosage form.
13 The dosage form can be made also by a dry granulation process of 14 manufacture. The dry process co~prises first mixing all the dosage forming ingredients, except for the lubricant, passing the mixed 16 ingredients through a grinding mill to a small mesh size, and then 17 transferring the sized powder to a dry compactor. The compactor 18 densifies the powder, which dense powder is then passed through a 19 sizing mill to regrind the composition. The composition is ground to a small size, typically 20 mesh or smaller. Finally, a dry lubricant 21 is added and the ingredients blended to produce the final dosage 22 forming composition. Then, the composition is fed to a compaction 23 press and compressed into the dosage form 10.
24 Other standard manufacturing procedures can be used to form the dosage form. For example, the various ingredients can be mixed with a 26 solvent by ballmilling, calendering, stirring or rollmilling, and then 27 pressed into a preselected sized and shaped dosage form 10.
28 Exemplary solvents suitable for manufacturing the dosage form 1 33607~
1 include inorganic and organic solvents that do not adversely harm the 2 dosage form. The solvents broadly include a member selected from the 3 group consisting of alcohols, ketones, esters, ethers, aliphatic 4 hydrocarbons, halogenated solvents, cycloaliphatic solvents, aromatic, heterocyclic solvents, and mixtures thereof. Typical solvents include 6 acetone, diacetone, methanol, ethanol, isopropyl alcohol, butyl 7 alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-8 butylacetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, 9 n-heptane, methylene dichloride, ethylene dichloride, propylene dichloride, ethyl ether, mixtures such as acetone and ethanol, acetone 11 and methanol, methylene dichloride and methanol, ethylene dichloride 12 and methanol, and the like.
13 The following examples illustrate means and methods for carrying 14 out the present invention. The examples are merely illustrative and they should not be considered as limiting the scope of the invention, 16 as these examples and other equivalents thereof will become more 17 apparent to those versed in the pharmaceutical dispensing art in the 18 light of the present disclosure, the drawings and the accompanying 19 claims.
21 A dosage form 10 comprising 29.5% isosorbide dinitrate (5,900 9);
22 29.5% lactose (5,900 9); 20% hydroxypropylmethylcellulose ether 23 (4,000 9) exhibiting a low 27,800 number average molecular weight and 24 20% hydroxypropylmethylcellulose ether (4,000 9) exhibiting a high 88,300 number average molecular weight, were presieved through a 26 40 mesh screen. The presieved ingredients were mixed in a twin shell 27 blender for 15 minutes and then transferred to a Hobart~ mixer. Next, 28 anhydrous methyl alcohol was added slowly with mixing to form a 1 uniform dough. The dough was passed through a 20 mesh screen and then 2 air dried for 2 hours at room temperature. The resulting granules 3 were repassed through the 20 mesh screen and dried at ambient 4 conditions overnight. Then, magnesium stearate, 1~, (200 9), was passed through an 80 mesh per inch screen and then was blended into 6 the mixture in a twin shell mixer for 3 minutes. The resulting 7 granulation was compressed on a D3B Manesty~ Press at 2 tons pressure 8 using a 13/32 inch, (1.0 mm) round standard concave punch. The dosage 9 form 10 provided by the manufacture weight 271 mg, comprising 54.2 mg of the hydroxypropylmethylcellulose ether having the low number 11 average molecular weight of 27,800; 54.2 mg of the hydroxypropyl-12 methylcellulose having the high molecular number average molecular 13 weight of 88,300; and 80 mg of isosorbide dinitrate. The dosage forms 14 were placed in artificial gastric fluid and the release of drug measured from the dosage form. The results of the test indicated 78%
16 of the drug was delivered in a 24 hour period at an average delivery 17 rate of isosorbide dinitrate of 2.5 mg per hour. Accompanying Figure 18 3 depicts the release rate pattern for the dosage form and 19 accompanying Figure 4 depicts the cumulative amount released over a prolonged period of 24 hours.
22 A dosage form 10 comprising 15% of the enzyme inhibitor captopril,23 5% of a low 9,200 number average molecular weight hydroxypropylmethyl-24 cellulose, 78% of a high 88,300 molecular weight hydroxypropylmethyl-cellulose and 2% of stearic acid was prepared as follows: first, 26 1,500 9 of the enzyme inhibitor, 500 9 of the low number average 27 molecular weight hydroxypropylmethylcellulose, and 7,800 9 of the high 28 molecular weight hydroxypropylmethylcellulose are presieved through a 1 40 mesh screen and mixed for 15 minutes in a twin shell blender, and 2 the resulting mixture transferred to a Hobart~ blender. Then, anhydrous 3 ethanol was added slowly with mixing to form a damp mass. The ethanol 4 alcohol damp mass was passed through a 20 mesh screen and air dried overnight. The dry product was repassed through a 20 mesh screen.
6 The resulting granules were lubricated with 200 9 of stearic acid by 7 passing the stearic acid through an 80 mesh screen over the granules 8 and mixing the granules in a twin shell blender for 3 minutes. Next, 9 the resulting granulation was compressed into dosage forms using a Manesty press fitted with a standard concave round die of 3/8 inch ll (0.95 mm) diameter under a compression head of 2 tons. The dosage 12 forms weighed 334 mg and contained 50 mg of captopril.
14 A dosage form 10 was prepared by following the procedure of Example 2. The dosage form of this example comprises 53% ibuprofen;
16 20% of a hydroxypropylmethylcellulose having a number average molecular 17 weight of 9,200; 20% of a hydroxypropylmethylcellulose having a 18 number average molecular weight of 241,900; 5% hydroxypropylmethyl-19 cellulose, and 2% magnesium stearate. The drug release rate pattern for this dosage form is seen in Figure 5 and the cumulative amount 21 released over a prolonged period of time is seen in Figure 6.
23 The procedures described above are followed for manufacturing 24 dosage forms comprising the following drugs and the cellulosic ethers:
(a) 120 mg of propanolol hydrochloride and 40 wt % of a cellulosic 26 ether formulation comprising 20 wt % hydroxypropylmethylcellulose 27 having a number average molecular weight of 241,900 and 20 wt % of a 28 hydroxypropylmethylcellulose having a number average molecular weight 1 of 9,200; (b) a dosage form comprising 50 mg of hydrochlorothiazide 2 and 60 wt % of a cellulosic ether formulation comprising 20 wt %
3 hydroxypropylmethylcellulose having a molecular weight of 132,500 and 4 40 wt % of a hydroxypropylmethylcellulose having a molecular weight of 9,200; (c) a dosage form comprising 75 mg of dipyridamole and 60 wt %
6 of a cellulosic ether composition comprising 20 wt % of a hydroxy-7 propylmethylcellulose having a number average molecular weight of 8 88,300 and 40 wt % of a hydroxypropylmethylcellulose having a number 9 average molecular weight of 27,800; (d) a dosage form comprising 100 mg of verapamil hydrochloride and 50 wt % of a hydroxypropylmethyl-11 cellulose having a number average molecular weight of 307,200 and 15 12 wt % of a hydroxypropylmethylcellulose having a number average molecular 13 weight of 19,600; (e) a dosage form comprising 50 mg of codeine 14 phosphate, 60 wt % of a hydroxypropy~methylcellulose having a number average molecular weight of 241,900 and 15 wt % of a hydroxypropyl-16 methylcellulose having a number average molecular weight of 9,200;
17 (f) a dosage form comprising 200 mg of nitrofurantoin, 15 wt % of a 18 hydroxypropylmethylcellulose having a number average molecular weight 19 of 241,900 and 45 wt % of a hydroxypropylmethylcellulose having a 2~ number average molecular weight of 19,600.
22 The procedures described above are followed for manufacturing 23 dosage forms comprising the following drugs and cellulosic ether 24 formulation: (g) 250 mg of tetracycline; 5 wt % of hydroxypropyl-methylcellulose having a number average molecular weight of 132,500, 26 and, 10 wt % of hydroxypropylmethylcellulose comprising a number 27 average molecular weight of 241,900; and 40 wt % of a hydroxypropyl-28 methylcellulose comprising a number average molecular weight of 9,200;
1 336~7~1 (h) 300 mg of cimetidine; 5 wt % of hydroxypropylmethylcellulose having a number average molecular weight of 88,300; 25 wt % of hydroxypropylmethylcellulose comprising a number average molecular weight of 241,900; and, 10 wt % of a hydroxypropylmethylcellulose comprising a number average molecular weight of 9,200; (i) 160 mg of nadolol; 20 wt % of hydroxypropylmethylcellulose having a number average molecular weight of 88,300; 5 wt % of hydroxypropylmethyl-cellulose comprising a number average molecular weight of 307,200;
and, 40 wt % of a hydroxypropylmethylcellulose comprising a number average molecular weight of 9,200; (j) 300 mg of quinidine gluconate;
11 20 wt % of hydroxypropylmethylcellulose having a number average 12 molecular weight of 241,900; 20 wt % of hydroxypropylmethylcellulose 13 comprising a number average molecular weight of 307,200; and, 20 wt %
14 of a hydroxypropylmethylcellulose comprising a number average molecular weight of 9,200, (k) 30 mg of morphine suifate; 60 wt % of hydroxy-16 propylmethylcellulose having a number average molecular weight of17 132,500; 20 wt % of hydroxypropylmethylcellulose comprising a number 18 average molecular weight of 307,200; and, 10 wt % of a hydroxypropyl-methylcellulose comprising a number average molecular weight of 9,200;
and, (1) 20 mg of nifedipine; 5 wt % of hydroxypropylmethylcellulose 21 having a number average molecular weight of 132,500; 10 wt ~ of 22 hydroxypropylmethylcellulose comprising a number average molecular 23 weight of 241,900; and, 75 wt % of a hydroxypropylmethylcellulose24 comprising a number average molecular weight of 9,200.
26 The procedures described above are followed for manufacturing dosage forms comprising the following drugs and cellulosic ether 28 formulation: (m) 250 mg of erthromycin stearate; 15 wt % of 1 hydroxypropylmethylcellulose having a number average molecular weight 2 Of 241,900; 15 wt % of hydroxypropylmethylcellulose comprising a 3 number average molecular weight of 9,200; and, S wt % of a hydroxy-4 propylcellulose comprising a hydroxypropoxy content of 7 to 10%; (n) 12 mg of chlorpheniramine maleate; 70 wt % of hydroxypropyl-6 methylcellulose having a number average molecular weight of 241,900;
7 20 wt % of hydroxypropylmethylcellulose comprising a number average 8 molecular weight of 9,600; and, 5 wt % of a hydroxypropylcellulose 9 comprising a hydroxypropoxy content of 10 to 16%; (o) 8 mg of brompheniramine maleate; 70 wt % of hydroxypropylmethylcellulose 11 having a number average molecular weight of 241,900; 20 wt % of 12 hydroxypropylmethylcellulose comprising a number average molecular 13 weight of 19,600; and, 5 wt % of a hydroxypropylcellulose consisting 14 of a hydroxypropoxy content of 13 to 16%; (p) a dosage form comprising 8 mg of chlorpheniramine maleate; 120 mg of pseudoephedrine 16 sulfate; 25 wt % of hydroxypropylmethylcellulose consisting of a 17 number average molecular weight of 241,900; 25 wt % of hydroxypropyl-18 methylcellulose consisting of a number average molecular weight of 19 27,800; and, 10 wt % hydroxypropylcellulose consisting of 10 to 13%
hydroxypropoxy; and (q) 150 mg of ranitidine hydrochloride; 35 Wt %
21 of hydroxypropoxymethylcellulose having a number average molecular 22 weight of 241,900; 15 wt % of hydroxypropoxymethylcellulose consisting 23 essentially of a low number average molecular weight of 19,600; and, 24 15 wt % hydroxypropylcellulose consisting of 13 to 16 hydroxypropoxy content.
26 Dosage form 10 provided by the invention makes available a drug 27 delivery matrix suitable for retention in the stomach for gastric 28 retention over the drug releasing life time of the dosage system.
1 Also, when all the drug is released, the system bfoerodes into 2 innocuous particles and dissolved polymers that pass from the 3 gastrointestinal tract. The dosage form of the invention comprising 4 higher concentrations of cellulosic ether formulations exhibit better mechanical integrity and they better withstand the abrasive fluidic 6 action of the gastrointestinal tract. The dosage form of the 7 invention provides a broader range of erosion rates including 8 decreased and increased erosion rates in its use of low and high 9 numbe~ average molecular weight blends of cellulosic ethers. Another advantage provided by dosage form 10 resulting from its use of high 11 number average molecular weight cellulose ethers is that it provides 12 more physical stability, improved resistance to thermal shock and it 13 helps lessen the incidence of matrix cracking over storage time, when 14 stored in fluctuating ambient temperature conditions. Also, the dosage forms use of the high number average molecular weight cellulosic 16 ethers exhibit decreased tackiness in high humidity thereby preventing 17 sticking of one to another. The use of high number average molecular 18 weight cellulose ethers provides more rate control of the drug admini-19 stration over time. The use of the cellulose ethers, especially the high number average molecular wt cellulose ethers which swell 21 extensively when hydrated, lessens direct drug contact with mucosal 22 tissues and thereby lessens the incidence of tissue irritation for 23 irritating drugs.
24 The novel dosage form of this invention comprises means for the obtainment of precise release rates in the environment of use while 26 simultaneously providing beneficial therapy to a recipient. While 27 there has been described and pointed out features of the invention as 28 applied to presently preferred embodiments, those skilled in the 1 dispensing art will appreciate that various modifications, changes, 2 additions and omissions in the dosage form illustrated and described 3 can be made without departing from the spirit of this invention.
17.
Claims (6)
1. A dosage form for delivering a beneficial drug to an environment of use, which dosage form comprises: a matrix adapted for entrance into the environment of use, said matrix comprising from 30% to 99.9% of a cellulosic ether formulation, which formulation comprises from 10% to 99% of at least one hydroxypropylmethylcellulose comprising a high number average molecular weight of from 30,000 to 350,000; from 5% to 80% of at least one hydroxypropylmethylcellulose comprising a low number average molecular weight of from 9,000 to 30,000; from 2% to 30%
of a hydroxypropylcellulose comprising a hydroxypropoxy content of 7% to 16%, and a dosage amount of the beneficial drug.
of a hydroxypropylcellulose comprising a hydroxypropoxy content of 7% to 16%, and a dosage amount of the beneficial drug.
2. The dosage form for delivering the beneficial drug to the environment of use according to claim 1, wherein from 5% to 90% of a hydroxypropylmethylcellulose comprising a different number average molecular weight of from 30,000 to 350,000 replaces the hydroxypropylcellulose in the dosage form.
3. Use of a dosage form according to claim 1 or claim 2 to deliver a beneficial drug to the gastrointestinal tract of a warm-blooded animal.
4. Use of a dosage form according to claim 1 or claim 2 to deliver a beneficial drug to the stomach of a human.
5. A commercial package comprising a dosage form according to claim 1 or claim 2 together with instructions for use thereof to deliver a beneficial drug to the gastrointestinal tract of a warm-blooded animal.
6. A commercial package comprising a dosage form according to claim 1 or claim 2 together with instructions for use thereof to deliver a beneficial drug to the stomach of a human.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000609648A CA1336070C (en) | 1987-04-06 | 1989-08-29 | Controlled release dosage form comprising different cellulose ethers |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/034,971 US4786503A (en) | 1987-04-06 | 1987-04-06 | Dosage form comprising parallel lamine |
| US07/039,405 US4871548A (en) | 1987-04-06 | 1987-04-17 | Controlled release dosage form comprising different cellulose ethers |
| US07/239,231 US4946685A (en) | 1987-04-06 | 1988-09-01 | Cellulosic dosage form |
| CA000609648A CA1336070C (en) | 1987-04-06 | 1989-08-29 | Controlled release dosage form comprising different cellulose ethers |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1336070C true CA1336070C (en) | 1995-06-27 |
Family
ID=39154985
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000609648A Expired - Fee Related CA1336070C (en) | 1987-04-06 | 1989-08-29 | Controlled release dosage form comprising different cellulose ethers |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1336070C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8911778B2 (en) | 1997-07-30 | 2014-12-16 | Dr. Falk Pharma Gmbh | Pellet formulation for the treatment of the intestinal tract |
-
1989
- 1989-08-29 CA CA000609648A patent/CA1336070C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8911778B2 (en) | 1997-07-30 | 2014-12-16 | Dr. Falk Pharma Gmbh | Pellet formulation for the treatment of the intestinal tract |
| US8940328B2 (en) | 1997-07-30 | 2015-01-27 | Dr. Falk Pharma Gmbh | Pellet formulation for the treatment of the intestinal tract |
| US8956647B2 (en) | 1997-07-30 | 2015-02-17 | Dr. Falk Pharma Gmbh | Pellet formulation for the treatment of the intestinal tract |
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