|Publication number||US3577514 A|
|Publication date||May 4, 1971|
|Filing date||Jun 10, 1968|
|Priority date||Jun 10, 1968|
|Also published as||DE1927130A1|
|Publication number||US 3577514 A, US 3577514A, US-A-3577514, US3577514 A, US3577514A|
|Inventors||Robinson Ira C|
|Export Citation||BiBTeX, EndNote, RefMan|
|Referenced by (29), Classifications (5)|
|External Links: USPTO, USPTO Assignment, Espacenet|
United States Patent O M Int. Cl. Afilk 27/12 US. Cl. 424-22 4 Claims ABSTRACT OF THE DISCLOSURE A sustained release pharmaceutical tablet characterized by a substantially constant rate of drug release comprising: (a) a medicament; (b) a hydrophobic dissolution retardant; (c) an acid-insoluble release agent; and (b) a water-soluble or dispersible binder.
BACKGROUND OF THE INVENTION This invention relates to novel orally administrable dosage forms. In particular, it relates to the preparation of sustained release tablets capable of disintegrating at a constant and uniform rate.
Although many of the newer drugs now being prescribed are extremely effective, in many instances serious side-effects are encountered with conventional dosage forms, even at low dosage levels. As a consequence, it is advantageous to carefully control the rate of release of medicaments of this type. One means of overcoming this problem is to employ dosage forms that are capable of slowly releasing the medicament at a reasonably uniform and constant rate.
In addition, such dosage forms enable the physician to more carefully regulate the level of drug administration to the patient. A further advantage of sustained release dosage forms to the patient is the fact that a lesser number of them need be taken during the course of treatment.
Where oral administration is desired, one means for obtaining the above objective is to employ capsules or tablets which release the drug at a uniform rate during the capsules passage through the gastro-intestinal tract.
In the past this object has been achieved by admixing one or more inert ingredients with the drug in such a manner that these inactive materials interfere with the disintegration of the tablet or the dissolution of the drug. An obvious form of such a tablet is one wherein a core containing the active ingredient is surrounded by a layer of inert materials. For example, the tablet may be coated with an enteric substance, in which case the tablet passes unchanged through the stomach and disintegrates in the intestinal tract. Alternatively, tablets can be composed of several alternate layers of medicament and inert material. In this manner, as each alternate protective layer disintegrates the patient receives a further dose of medicament. However, tablets of this type suffer from the disadvantage of not providing a uniform and constant drug release. Furthermore, such tablets are difficult to prepare with precision so that in many instances the desired dosage level cannot be assured.
The present invention describes sustained release dosage forms which will provide a uniform and constant liberation of medicament,
SUMMARY OF THE INVENTION This invention comprises a sustained release pharmaceutical tablet comprising: (a) a medicament; (b) a hydrophobic dissolution retardant; (c) an acid insoluble release agent; and (d) a water soluble or dispersible binder. The product of this invention is characterized by having a substantially constant erosion rate in gastro-in- 3,577,514 Patented May 4, 1971 testinal fluid wherein the medicament is released at a constant and uniform rate.
This invention further comprises a sustained release pharmaceutical tablet containing up to 70% by weight of a medicament, 15-50% by Weight of a hydrophobic dissolution retardant, 0.l5.0% by weight of an acid-insoluble release agent and 5-15 by weight of a water soluble or dispersible binder.
DETAILED DESCRIPTION OF THE INVENTION I have now discovered a dosage pharmaceutical formulation that will provide a sustained release of medicament. The formulation comprises an intimate uniform blend of a water soluble or insoluble medicament, a hydrophobic dissolution retardant, an acid-insoluble release agent, and a water soluble or dispersible binder. Other customary tablet ingredients such as fillers, colorants, lubricants, stabilizers and excipients can also be included in the formulation as required. Tabletting of this blend provides a pharmaceutical tablet wherein the aforesaid constituents are uniformly dispersed throughout the tablet matrix. Alternatively, the blend can be formulated into a capsular form as well.
The range of the basic ingredients can be varied over a considerable latitude and yet will provide an orally administrable dosage form having a constant and uniform rate of disintegration, Thus, the following ranges have been found to be effective (the percentages are by weight): up to 70% of medicament; 15-50% of hydrophobic dissolution retardant; 0.l5% of acid insoluble release agent; and 5-15 of a water soluble binder.
A preferred formulation would comprise about 5-25% of medicament; 2030% of hydrophobic dissolution retardant; 05-10% of acid-insoluble release agent; and -11% of water-soluble binder.
An outstanding advantage of the present invention is the fact that a mixture of Water soluble and insoluble medicaments can be incorporated into the blend and after tableting each individual medicament will he released from the tablet at a uniform and constant rate. Thus we have prepared a sustained release dosage form containing theophylline, ephedrine sulfate and hydroxyzine hydrochloride, wherein each pharmaceutical has been found to be released in simulated intestinal fluid at a reasonably constant and uniform rate.
Various types of medicaments can be used in the instant invention, such as antihistamines, hypoglycemics, antidepressants, coronary vasodilators, bronchodilators, sedatives, decongestants, antispasmodics, vitamins, and the antibiotics.
The hydrophobic dissolution retardants, by virtue of their water insolubility, function by retarding the dissolution and diffusion of the drug from the tablet or granulates into the gastro-intestinal fluid, Among the hydrophobic dissolution retardants that we have found effective are the natural and synthetic waxes, resins and plastics. Of these we prefer carnauba wax, beeswax, spermaceti, and the commercial product Sterotex K-lOO, which is a hydrogenated cottonseed oil available from Capital City Products, Columbus, Ohio.
Enteric substances, insoluble in the acidic stomach juices, are the preferred acid-insoluble release agents. Of these we prefer cellulose acetate phthalate and the other acetate phthalates; the esters of the carbohydrate polymers; and the phthalic acid derivatives of polyacrylic acid.
The effect of the water-soluble or dispersible binder is to insure a uniform release of the drug. Although the binders of choice are the polyvinyl pyrrolidones, acacia and other water-soluble or dispersible binders well known to those skilled in the art, may be used.
As previously stated, besides the above essential ingredients other conventional tableting ingredients may also be included in the blend. Thus, antioxidants, e.g., ascorbic acid, sodium metabisulfite; lubricants, e.g., talc, magnesium stearate and sodium lauryl sulfate; fillers e.g., calcium diphosphate; and colorants are generally added to further improve the product. Nevertheless, it should be understood that the inclusion of the hydrophobic dissolution retardant, the acid-insoluble release agent, and the water-soluble or dispersible binder, in amounts constituting an effective ratio, within the ranges previously indicated, constitute the critical features of the present invention.
The tablets can be prepared from the blended ingredients in the usual manner, e.g., dry blending followed by compression into tablets, or dry slugging and granulating the blended ingredients prior to compressing them into tablets, etc. The tablets may also be prepared by first wet granulating the blend with a suitable solvent or binder solution or dispersion, such as alcohol or polyvinyl pyrrolidone colloidal solution.
The tablet erosion studies are conducted with the tablet distintegration apparatus described in U.S.P. XVII. Simulated gastro-intestina] fluids, the preparation of which are described in U.S.P. XVII, are used in the test. The tablets are placed in the apparatus and initially contacted with simulated gastric juices for one hour. The weight loss of the tablets is then determined. The gastric juice is then removed, simulated intestinal fluid is added to the apparatus, and the course of the disintegration of the tablets is followed over the course of the next few hours by periodically determining the weight loss of the tablets. The drug dissolution rate is also determined in this test by periodically assaying the amount of drug that dissolves in these fluids over the course of several hours. The drug dissolution rate ran also be determined by the in vitro test for timed-release capsules and tablets outlined in the second supplement of N. F. XII.
The following examples are provided to further illustrate the scope of the present invention; however, they should not be considered as limiting the scope thereof.
EXAMPLE I The ingredients listed below are dry blended and directly compressed into tablets on a rotary or single punch tableting machine:
Total Weight, ca s40 l Representing 30% active potency. 17.5% oi total blend. 2 Anhydrous particulate silica available from Cabot Corporation, 125 High Street, Boston, Massachusetts.
I Available from the Cabot Corp.
144 tablets are tested in the disintegration test described in U.S.P. XVII. For the first hour the tablets are contacted with gastric juice and for the remaining time with intestinal juice. At the end of each hours testing, the apparatus containing the tablets is placed in a beaker containing fresh gastro-intestinal fluid. The fluid containing the dissolved drug is filtered and an aliquot is taken and quantitatively assayed by a suitable method. The quantity of drug determined to have dissolved in the total amount of gastro-intestinal fluid is converted to percent of total drug contained in the aggregate of tablets by dividing with the total amount of drug represented by the aggregate of tablets, and multiplying by 100%.
The pertinent results are given in the table below.
DRUG DISSOLUTION RATE Cumulative Amount of amount 01 metamine metarnine released] released, hour,
Time/hours percent percent I First hour in gastric juice; thereafter in intestinal fluid.
EXAMPLE II All of the ingredients below, except the lubricant magnesium stearate are dry-blended for 15 minutes.
The particles are passed through a 40 mesh screen using a Fitzmill, hammers leading at medium speed. The mixture is reblended for 30 minutes and moistened with 50 g. of methanol in a Hobart blender. The moist mixture is passed through a 40 mesh screen (Fitzmill, hammers leading at medium speed). The final mixture is air dried without heat for 3045 minutes. The magnesium stearate is then added and the mixture is blended for 5 to 10 minutes. The tablets are prepared by compressing on a rotary tablet press using in. standard round concave punches and dies, to a thickness of 014110.005 in. thick and a hardness of 7 kg. (Pfizer tester).
The rate of drug dissolution is determined in the same manner as detailed above.
DRUG DISSOLUTION RATE Amount 0! Cumulative 1 First hour in gastric juice; thereafter in intestinal fluid.
EXAMPLE III With the exception of magnesium stearate, the ingredients listed below are dry-blended for 15 minutes and passed through a 40 mesh screen:
Metamine and dicaleium phosphate 1 183. 50 35. 70 (5. 5%) Butabarbltal 247. 40. 57 (2t. 8%) Dlcalciurn phosphate 150. 64 30. 12B FDdzC Blue No. 1, Lake (11%). 0. 50 0.10 Cab-O-Sil 10. 00 2. 0 Magnesium stearate 5. 00 1. 00 Carnauba Wax, 60 Mesh 285. 00 57. 00 (28. 5%) Polyvinylpyrrolidone type C 100.0 20.00 (10%) Cellulose acetate phthalate l7. 3. 50 (1. 76%) Total weight, ca l, 000 200 1 Representing 30% active potcncyl8.3% oi total blend.
The ingredients are reblended for 30 minutes and moistened with 75 g. of 2B ethanol. The mixture is stirred in a Hobart mixer until nearly dry and passed through a 40 mesh screen and reblended. The mixture is then air dried until the odor of the solvent is no longer detectable, and the lubricant is added. The mixture is briefly blended and compressed into tablets under the following conditions: the dry powder granulates are placed in the hopper without further processing and compacted into tablets using in. standard round concave punches and dies on a rotary tablet press to a hardness of 7 kg. (Pfizer tester).
EXAMPLE V With the exception of magnesium stearate, the ingredients listed below are blended together for 30 minutes in a suitable blender, after passage through a 40 mesh screen 5 on a Fitzmill comminator. A portion of the magnesium th The "E qif g fi lgdetmumd ldenucany to stearate (1.5%) is added, and the mixture is briefly blende Prevlous Y 6 met 0 ed and slugged with /2 in. standard round flat punches D RUG DISSOLUTION RATES and dies to a hardness of 8 kg. and 400 mg. weight. The Amount slugs are granulated through an 18 mesh screen on an Cumulattive Amr mnt oi (lumulat ive g1 bma 10 oscillating granulator. The remainder of the magnesium 3,1 3,233.3 i fig gggg g fg g, stearate is blended into the resultant granulation. The Ti r a d. h u r e blend is compressed on a suitable tablet press, to a weight perm percent pmen perm of 512.5 mg. for a hardness of 10 kg. (Pfizer tester).
a; as as 1 a? 2a Milligrams 8 :3 :2: Z13? tablets tablet 80.0 9.
Theophylline 400 200 (39 J 5 5 4 m Ephedrine sulfate 100 50 9. @9 3 I First hour in gastric juice; thereafter in intestinal fluid. giggg y g gi ggggggg fi f ffi g 87%) Oab'O-SiI III 10 5 EXAMPLE IV Sterotex K-IOO 260 130 (25. 4%) The ingredients tabulated below are blended together ggl gfgg figff g g gg-a 8 g -2233 under the following conditions: All except the metamln Talc 40 20 and the lubricant are preblended, passed through a 40 Magnesium steam" i mesh screen in a Fitzmill, hammers leading at high speed. 25 Totalweight, ca 1,025 512.5 The mixture is reblended, half the lubricant is added, and the blend is briefly mixed again prior to slugging. The RATE TEGRAIION slugs are granulated on a stokes or other suitable oscrllatcumulative ing granulator. Fines 60 mesh) are separated and 0 53: Pfiggent thoroughly blended with the metamlne. This mixture con- 3 Time/hours 1035 g; taining the active drug is blended with the remainder, the 229 22 9 dry granulation. The remaining half of magnesium stearate is added to the total blend of granules, followed by 1 15.8 13.1 brief reblending. Tablets are prepared by compressing on 15:9 arrgcsgrgzblet press in accordance with previously defined mm hour in gastric juice; thereafter In intestinal fluid. p DRUG DISSOLUTION RATE Gram] Cumulative Amount oi 10,000 Milligrams] amount oi theophyl- Cumulative Amount of tablets tablet 4o theophylline amount of ephedrine line released! ephedrine released] Metamine and dicalcium phosphate blend 428.85 42. 89 (3.14%) relemed, hour, released, hour, Butabarbital 495. 72 49. 57 (23.6%) Time/hours pH percent percent percent percent Dicalciurn phosphate 343. 93 34. 39 FD2O Blue No. 1, Lake (11%) 2.00 0.20 14. 3 32. 7 Cab-O-Sil 21. 00 2. 1o 22. 7 22. 7 45. 3 45. 3 Magnesium stearate 31. 3. 15 37. 9 16. 2 62. 4 17. 1 Sterotex K-loo 1 315.00 31.5 (1 50.1 12.2 74.7 12.3 Polyvinyl pyrrolidone, type C- 315. 00 31. 6 (1 62. 8 12. 7 87. 3 12. 6 Dextrose 52. 50 5. 25 75. 4 12. 6 96. 1 8. 8 Cellulose acetate phthalate 63.00 6.30 (3 c 31.50 3.15 Flrst hour in gastric juice; thereafter in intestinal fluid.
Total ca 100 Cumulattlv? hAdrpounii of I Representing 307 active otency 20.4'7 0i total blend. 50 811101111 0 1' MW I16 2 Hydrogenated cottonseed oil available irom Capital City Products Y W- dihydmchloridfl (30., Columbus, Ohio. iiiigiah relegsggll RATE OF DISINTEGRA'IION Time/hours pH percent percent Percegz Plercerllt 1.3 215. 1 we our y l. 3 36. 4 Time/hours oss change 2.5 50.9 1 2.: 6.8 53.1 7.8 .25 67.0 8.3 7. 5 76. 2 9. 2
I First hour in gastric juice; thereafter in intestinal fluid.
EXAMPLE VI I First hour in gastric juice; thereafter in intestinal fiuid. The rate of drug dissolution is as follows:
DRUG DISSOLUTION RATES 1 First hour in gastric juice; thereafter in intestinal fluid.
The ingredients listed below are blended and tableted according to the procedure in Example V.
The rate of disintegration and rate of drug dissolution of these tablets are found to be constant and uniform when determined according to the tests described in the preceding examples.
EXAMPLE VII The ingredients listed below are blended and tableted according to the procedure of Example V.
Grams/ Milligrams] tablets tablet Theophylllne 350 175 235%) Ephedrine sul to 70 35 77) Hydroxyzine dlhydrochlorlde-.- an (3 Sterotex 200 100 (207) Cellulose acetate hthalate. 50 25 (573) Polyvinylpyrroll one Type C 150 75 (15%) Dicalcium phosphate 50 25 Cab-O-Sll 5 Tale 50 25 Magnesium stearate 40 20 Total weight, ca 1, 000 500 The rate of disintegration and rate of drug dissolution of these tablets are found to be constant and uniform when determined according to the tests described in the preceding examples.
EXAMPLE VIII The ingredients listed below are blended and tableted according to the procedure of Example V.
The rate of disintegration and rate of drug dissolution of these tablets are found to be constant and uniform when determined according to the tests described in the preceding examples.
EXAMPLE IX The procedure of Examples VI-VIII is repeated with substantially the same results, replacing the Sterotex K- 100 with the following ingredients:
Carnauba wax Spermaceti Hydrogenated castor oil Shellac EXAMPLE X The procedures of Examples VI to IX are repeated with substantially the same results replacing the cellulose acetate phthalate with starch acetate phthalate.
EXAMPLE XI The ingredients below are blended and tableted in the manner described in the previous examples.
Grams/ 10.000 Milligraml tablets tablet 1 Metarnlne and dlcalclum phosphate 1 367. 60 36. 76 (4. 8%) Dicalclum phosphate 801. 60 89. 16 Light brown dye 1. 3 0. 13 Cab-O-Sll 21 2. 1 Magnesium stearate. 42 4. 2 Sterotex K100 462 46. 2 (20.08%) Polyvlnylpyrrolldone Type 210 21. 0 (0.13%) Cellulose acetate phthaiate. 63 6. 30 (2. 74%) 31. 5 3. 15 Dextrose 21 2. 10 Dried corn starch 189 1B. 90
Total Weight, ca 2, 300 230 1 Representing 30% active potency. 16% of total blend.
Tests A, B, and C below are conducted with the disintegration aparatus described in USP XVII. In Tests A and B, the tablets are contacted with gastric juice to 1 hour and then with intestinal fluid to 4 hours. At the end of the 4 hour period the tablets are contacted with fresh intestinal fluid to 7 hours. In Test C the tablets are contacted with gastric juice for the first hour and thereafter 'with intestinal fluid, with hourly change to fresh fluid.
Test A.144 tablets Amount of metamine Time/ hours: released/ time interval 1 33.3 4 16.3 7 20.4
Test B.48 tablets Amount of metamine Time/hours: released/time interval 1 34.2 4 12.5 7 19.2
Test C.l44 tablets Amount of metamine Time/hours: released/ time interval 1 30.4
Test D This test is conducted according to the procedure in N.F. XII, using 12 tablets per screw cap bottle.
Metamine dissolution rate Metamlne dissolution rate l. A sustained released pharmaceutical tablet essentially containing, uniformly dispersed throughout the tablet matrix, about 5 up to 70% by weight of a medicament, 550% by weight of a hydrophobic dissolution retardant selected from the group consisting of hydrogenated cottonseed oil, hydrogenated castor oil, carnauba wax, beeswax, spermaceti, and shellac, ill-5.0% by Weight of an enteric acid-insoluble release agent selected from the group consisting of cellulose acetate phthalate, starch acetate phthalate and a phthalic acid derivative of polyacrylic acid, and 5-15% by weight of a water-soluble or dispersible binder, eifective to insure a uniform release of the medicament, selected from the group consisting of polyvinyl pyrrolidone and acacia.
2. A sustained release pharmaceutical tablet according to claim 1 comprising: (a) 56% by weight of triethanolamine trinitrate biphosphate; (b) 22-25% by weight of carnauba wax; (c) 0.80-1.20% by weight of cellulose acetate phthalate; and (d) 812% by weight of polyvinyl pyrrolidone.
3. A sustained release pharmaceutical tablet according to claim 1 comprising: (a) 57% by weight of triethan0l amine trinitrate biphosphate; (b) 2225% by weight of butabarbital; (c) 13-17% by weight of hydrogenated cottonseed oil; (cl) 24% by weight of cellulose acetate phthalate; and (e) 13-18% by weight of polyvinylpyrrolidone.
4. A sustained release pharmaceutical tablet according to claim 1 comprising: (a) 37-41% by weight of theophylline; (b) 8-1l% by weight of ephedrine sulfate; (c) 4-6% by weight of hydroxyzine dihydrochloride; (d) 23- 10 26% by weight of cottonseed oil; (e) (LS-1.2% by weight of cellulose acetate phthalate; and (f) 812% by weight of polyvinylpyrrolidone.
References Cited UNITED STATES PATENTS 3,062,720 11/ 1962 Costello 42422 3,136,695 6/1964 Tansey 424-22 3,328,256 6/1967 Gaunt 42419 3,400,197 9/ 1968 Lippmann 42422X 3,402,240 9/ 1968 Cain et a1 424 22 3,449,489 6/1969 Gaunt 4243l SHEP K. ROSE, Primary Examiner US. Cl. X.R. 42419
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US3909444 *||Aug 5, 1971||Sep 30, 1975||Ncr Co||Microcapsule|
|US4189469 *||May 6, 1976||Feb 19, 1980||Hoechst Aktiengesellschaft||Pharmaceutical compositions|
|US4244941 *||Oct 23, 1975||Jan 13, 1981||Gist-Brocades N.V.||Controlled release composition and process for preparing same|
|US4264573 *||May 21, 1979||Apr 28, 1981||Rowell Laboratories, Inc.||Pharmaceutical formulation for slow release via controlled surface erosion|
|US4308251 *||Oct 17, 1980||Dec 29, 1981||Boots Pharmaceuticals, Inc.||Controlled release formulations of orally-active medicaments|
|US4461759 *||Jan 3, 1983||Jul 24, 1984||Verex Laboratories, Inc.||Constant release rate solid oral dosage formulations of veropamil|
|US4521401 *||Feb 16, 1984||Jun 4, 1985||Verex Laboratories, Inc.||Constant release rate solid oral dosage formulations of quinidine|
|US4522804 *||Feb 16, 1984||Jun 11, 1985||Verex Laboratories, Inc.||Constant release rate solid oral dosage formulations of propranolol|
|US4540602 *||Sep 20, 1982||Sep 10, 1985||Freund Industry Company, Limited||Process for the preparation of activated pharmaceutical compositions|
|US4590062 *||Jul 6, 1984||May 20, 1986||Tech Trade Corp.||Dry direct compression compositions for controlled release dosage forms|
|US4608248 *||Feb 24, 1986||Aug 26, 1986||Warner-Lambert Company||Process for time-controlled release of active ingredients|
|US4704284 *||Aug 12, 1982||Nov 3, 1987||Pfizer Inc.||Long-acting matrix tablet formulations|
|US4726952 *||Mar 21, 1986||Feb 23, 1988||Mission Pharmacal||Slow-release sodium fluoride tablet, method of making, and method of treatment of osteoporosis|
|US4820523 *||Apr 15, 1986||Apr 11, 1989||Warner-Lambert Company||Pharmaceutical composition|
|US4837032 *||Feb 4, 1986||Jun 6, 1989||Farval Ag||Theophylline sustained release tablet|
|US4882167 *||Nov 24, 1987||Nov 21, 1989||Jang Choong Gook||Dry direct compression compositions for controlled release dosage forms|
|US4904478 *||Oct 22, 1987||Feb 27, 1990||Mission Pharmacal Company||Slow-release sodium fluoride tablet and method for treatment of osteoporosis|
|US4960814 *||Jun 13, 1988||Oct 2, 1990||Eastman Kodak Company||Water-dispersible polymeric compositions|
|US5025004 *||Jun 4, 1990||Jun 18, 1991||Eastman Kodak Company||Water-dispersible polymeric compositions|
|US8309104 *||Feb 28, 2007||Nov 13, 2012||Watson Pharmaceuticals, Inc.||Oral controlled release formulation for sedative and hypnotic agents|
|US20060147526 *||Dec 1, 2003||Jul 6, 2006||Cipla Limted||Pharmaceutical formulations comprising ß-2 adrenoreceptor agonists and xanthines|
|US20070042041 *||Aug 17, 2005||Feb 22, 2007||Board Of Trustees Of The University Of Arkansas||Drug-surfactant complexes for sustained release|
|US20070207203 *||Feb 28, 2007||Sep 6, 2007||Xiu Xiu Cheng And Dacheng Tian||Oral controlled release formulation for sedative and hypotnic agents|
|US20090123535 *||Dec 4, 2008||May 14, 2009||Xiu Xiu Cheng||Oral Controlled Release Formulation for Sedatives and Hypnotic Agents|
|US20100105637 *||Oct 22, 2009||Apr 29, 2010||Kim Cherng-Ju||Drug-surfactant complexes for sustained release|
|DE3100191A1 *||Jan 7, 1981||Dec 10, 1981||Boots Co Ltd||Pharmazeutische zubereitung und verfahren zu ihrer herstellung|
|EP0103387A2 *||Aug 3, 1983||Mar 21, 1984||Pfizer Inc.||Long-acting matrix tablet formulations|
|EP0103387A3 *||Aug 3, 1983||Dec 12, 1984||Pfizer Inc.||Long-acting matrix tablet formulations|
|WO1984004674A1 *||May 29, 1984||Dec 6, 1984||Jang Choong Gook||Dry direct compression compositions for controlled release dosage forms|
|International Classification||A61K9/22, A61K9/20|