US3632778A - Tablets containing l-dopa - Google Patents

Tablets containing l-dopa Download PDF

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US3632778A
US3632778A US45244A US3632778DA US3632778A US 3632778 A US3632778 A US 3632778A US 45244 A US45244 A US 45244A US 3632778D A US3632778D A US 3632778DA US 3632778 A US3632778 A US 3632778A
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tablets
weight
dopa
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ldopa
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Prabhakar Ranchhordas Sheth
Gilbert Katz
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F Hoffmann La Roche AG
Hoffmann La Roche Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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

Definitions

  • LDOPA L-3,4-dihydroxyphenylalamine
  • the patients in most instances, must consume inordinately large quantities of the drug, i.e. on the average of from 3 to 8 grams daily.
  • the quantities of LDOPA which must be consumed remain large even when other compounds, such as decarboxylase inhibitors are utilized to potentiate its action. It is therefore readily apparent that it is advantageous to incorporate large quantities of LDOPA into small convenient dosage forms so that the expense and inconvenience of administering many tablets or capsules each day is avoided. Due to the low bulk density and other physical characteristics of LDOPA, No.
  • tablets of suitable size containing large amounts of L- DOPA could be formulated in accordance with the present invention by the wet granulation method utilizing as a binder a combination of amylopectin and polyvinylpyrrolidone.
  • pharmaceutically excellent tablets containing large quantities of LDOPA e.g., 500 mg. or more are prepared by the wet granulation method utilizing a formulation comprising LDOPA and no more than 10% of the total tablet weight of a binder composed of amylopectin and polyvinylpyrrolidone.
  • tablets containing LDOPA are prepared by the conventioal wet granulation method utilizing a binder material comprising amylopectin and polyvinylpyrrolidone.
  • the LDOPA tablets of the present invention contain from 1% to 10% of the total tablet weight of binders and not more than 35% by weight inert ingredients.
  • the tablets contain from about 1% to about 2% by weight binders based on the total tablet weight and between about 20% and 25% by Weight of a tablet disintegrant, between from about 1% to about 2% lubricants and the remainder other inert ingredients, such as dyes, and the like.
  • LDOPA tablets of the present invention may contain up to 750 mg. It is preferred, however, to produce tablets according to the invention which contain either 250 mg. of 500 mg. of L- DOPA. In any event, LDOPA constitutes from about 60 to about and preferably from about 70% to about 73% by weight of the tablets of the present invention.
  • the binder component of the novel LDOPA tablets of the present invention is composed of amylopectin, polyvinylpyrrolidone or mixtures thereof. Although either of these two substances will form an acceptable tablet without the other, it is preferred to have both components present. In the preferred composition the ratio of the two components may vary from 1:9 to 9:1. It is, however, especially preferred to use equal quantities of each.
  • the amylopectin utilized in the practice of the present invention is a soluble fraction derived from commercial starches. It has a molecular weight of from one million to about ten million with a preferred mean molecular weight of one million.
  • amylopectin is a White powder, water dispersible and of sufficiently low viscosity that a 20% weight to volume dispersion in water is pourable at room temperature.
  • the polyvinylpyrrolidone utilized in the practice of the present invention meets the specifications of the National Formulary.
  • a suitable commercial product is Plasdone K by the GAP Corporation.
  • the tablets of the present invention contain from 0.5 to 3.0% by weight preferably from 1% to 2% by weight of a tabletting lubricant conventional in the art.
  • the lubricant is comprised of talc and a substance such as stearic acid, calcium stearate, magnesium stearate or a commercial product consisting of diand tri-glycerides of certain fatty acids such as stearic and palmitic acid, e.g. Sterotex, by Capital City Products, Inc. Of these, magnesium stearate is preferred. While the two lubricant components may generally be used in a ratio of from 1:9 to 9:1 it is preferred to utilize equal quantities of each.
  • the function of the talc lubricant component is to promote the fiow of the granulation while at the same time preventing picking when the tablets are removed from the molds.
  • the second lubricant component functions to improve the overall flow properties and mold release of the granulation.
  • the L-DOPA tablets of the present invention contain a tablet disintegrant.
  • This class of substance includes, for example, cellulosic products such as methyl cellulose, hydroxy ethyl cellulose and the like, certain commercially available chemically modified starch fractions such as Sta-Rx 1500 by A. E. Staley and Company, and the like. It is preferred to utilize a disintegrant which possesses some tabletting properties.
  • a preferred example of such a substance is microcrystalline cellulose such as that commercially available under the trademark Avicel by the American Viscose Corporation.
  • the tablets of the present invention contain from about 1% to about 40% by weight of the disintegrating agent, preferably from about 20% to about 25% by weight.
  • the process of tablet making by wet granulation is well known in the pharmaceutical arts. It involves basically the intimate blending of the active ingredient and some or all of the inert ingredients with a suitable solvent, such as water, alcohol, methylene chloride, and the like. The granulation thus formed is then dried, such as, by placing it in shallow lined pans in an oven. The resulting dry mixture, which may be intimately mixed with other tabletting ingredients, is then compressed into tablets.
  • a suitable solvent such as water, alcohol, methylene chloride, and the like.
  • the granulation thus formed is then dried, such as, by placing it in shallow lined pans in an oven.
  • the resulting dry mixture which may be intimately mixed with other tabletting ingredients, is then compressed into tablets.
  • tablets containing L-DOPA can be prepared, utilizing the ingredients set forth herein, that are stable, pharmaceutically elegant, and approximately twenty percent smaller than tablets prepared by other tabletting methods known in the art.
  • the small tablet is important in the treatment of Parkinsonism as the disease strikes many elderly individuals who ordinarily have some difficulty in swallowing a large tablet.
  • the tablets prepared according to the present invention are free from problems such as capping and poor compressibility inherent in other methods of preparation and methods utilizing other binder materials.
  • the tablets of the present invention have been found to possess a dissolution rate in the body not only far superior to tablets made by other methods and containing other binders as described herein, but superior to standard gelatin capsules.
  • the relative dissolution of the tablet or capsule is critical as it is theorized that high initial blood levels of L-DOPA are required for the drug to be effective. This theory is based on the fact that the drug is metabolized by enzymes in the blood and the drug must be intact to 4 pass the blood brain barrier where its therapeutic action is exerted. Therefore, the L-DOPA tablets of the present invention, due to their rapid dissolution are superior to L-DOPA tablets and capsules made by other methods and with other inert ingredients.
  • EXAMPLE 1 One thousand tablets containing 250 mg. L-DOPA were produced as follows. Using a 1% excess in accordance with standard pharmaceutical practices 252.5 grams of L-DOPA were passed through a suitable comminuting mill and admixed with a certified coloring agent. The resulting powder was granulated with an aqueous suspension prepared by suspending 2.5 grams amylopectin and 2.5 grams polyvinylpyrrolidone in 12.5 ml. distilled water. The resulting wet granulation was dried on lined trays at 120 F. The dry powder was milled on a suitable milling machine utilizing a No. 12 screen and medium speed. The granulation was then blended with 84.7 grams microcrystalline cellulose and some additional coloring material.
  • a preblended lubricant comprising 2.5 grams talc and 2.5 grams magnesium stearate was intimately admixed with the granulation and tablets having a diameter of 9.6 mm., a thickness of approximately 3.8 mm., and a weight of approximately 348 mg. were produced therefrom on suitable conventional tabletting machinery,
  • EXAMPLE 2 One thousand tablets containing 500 mg. L-DOPA were produced as follows. .Using a 1% excess in accordance with standard pharmaceutical practices 505.0 grams of L-DOPA were passed through a suitable comminuting mill and admixed with a certified coloring agent. The resulting powder was granulated with an aqueous suspension prepared by suspending 5.0 grams amylopectin and 5.0 grams polyvinylpyrrolidone in 25.0 ml. distilled water. The resulting wet granulation was dried on lined trays at 120 F. The dry powder was milled on a suitable milling machine utilizing a No. 12 screen and medium speed. The granulation was then blended with 169.5 grams microcrystalline cellulose and some additional coloring material.
  • a preblended lubricant comprising 5.0 grams talc and 5 .0 grams magnesium stearate was intimately admixed with the granulation and tablets having a diameter of 18 mm., a thickness of approximately 6 mm., and a weight of approximately 695 mg. were produced therefrom on suitable conventional tabletting machinery.
  • a method of producing a stable tablet containing L-DOPA which comprises wet granulating drying and compressing into tablets a formulation comprising:
  • binder comprises from about 10% to about by weight amylopectin and from about 90% to about 10% by weight polyvinylpyrrolidone.
  • said binder comprises equal quantities of amylopectin and polyvinylpyrrolidone.
  • a pharmaceutical tablet compresed from a direct wet granulation comprising.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
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Abstract

IMPROVED TABLETS CONTAINING L-DOPA AND A BINDER COMPRISING AMYLOPECTIN ADMIXED WITH, POLYVINYLPYRROLIDONE, A LUBRICANT AND A TABLET DISINTEGRANT ARE DESCRIBED.

Description

Int. Cl. A6117 3/10 U.S. Cl. 424-319 11 Claims ABSTRACT OF THE DISCLOSURE Improved tablets containing LDOPA and a binder comprising amylopectin admixed with, polyvinylpyrrolidone, a lubricant and a tablet disintegrant are described.
BACKGROUND OF THE INVENTION L-3,4-dihydroxyphenylalamine, hereinafter referred to as LDOPA, is an important tool in the therapeutic treatment of Parkinsonism. In the therapeutic treatment of Parkinsonism utilizing LDOPA, the patients, in most instances, must consume inordinately large quantities of the drug, i.e. on the average of from 3 to 8 grams daily. The quantities of LDOPA which must be consumed remain large even when other compounds, such as decarboxylase inhibitors are utilized to potentiate its action. It is therefore readily apparent that it is advantageous to incorporate large quantities of LDOPA into small convenient dosage forms so that the expense and inconvenience of administering many tablets or capsules each day is avoided. Due to the low bulk density and other physical characteristics of LDOPA, No. and larger gelatin capsules are required for dosages of 500 mg. and above per capsule. Additionally, pregranulating LDOPA to increase its bulk density prior to encapsulation, although allowing larger amounts to be encapsulated, is an ineflicient, expensive process and not satisfactory for commercial purposes.
Attempts to formulate LDOPA into pharmaceutically elegant tablets of acceptable size prior to this invention encountered problems which resulted in unsatisfactory tablets. Direct compression techniques as recognized in the art of pharmaceutical compounding, usually produce a smaller tablet. LDOPA tablets produced using direct compression excipients commonly recognized in the art, however, 'were unsatisfactory as an unusually high percentage of excipient material was required and the tablets had a tendency to pick, i.e. break oif pieces which cling to the tabletting molds, and cap, i.e. split a small longitudinal section of the tablet in normal handling. Among the direct compression excipients which were unsatisfactory were direct compression grade lactose, microcrystalline cellulose, monocalcium phosphate and Sta-Rx, a commercially available fine grade of starch.
Other methods of tabletting LDOPA such as the conventional tabletting technique known as slugging and the technique of forming a melt of LDOPA and a substance such as, for example, stearic acid were unsatisfactory mainly due to inferior compressibility of the tablets and poor flow characteristics of the bulk mixtures. Another method which was unsatisfactory for forming LDOPA tablets due to inferior compressibility of the tablets and capping was the technique known in the art as placebo granulation. In this method a granulation is formed from such conventional tabletting materials as mannitol, dicalcium phosphate and the like. This granulation is then mixed in at least equal proportions with the drug and compressed into tablets. In addition to the other disadvantages mentioned, the tablets found by these methods also were disadvantageous since they were too large.
Still another method of tabletting LDOPA, the conventional tabletting practice of wet granulation, utilizing United States Patent 0 Patented Jan. 4, 1972 gelatin, acacia, pre-gelatinized starches and the like was unsatisfactory due to poor compressibility and capping.
It is therefore quite unexpected and surprising that tablets of suitable size containing large amounts of L- DOPA could be formulated in accordance with the present invention by the wet granulation method utilizing as a binder a combination of amylopectin and polyvinylpyrrolidone.
BRIEF SUMMARY OF THE INVENTION In accordance with the present invention, pharmaceutically excellent tablets containing large quantities of LDOPA, e.g., 500 mg. or more are prepared by the wet granulation method utilizing a formulation comprising LDOPA and no more than 10% of the total tablet weight of a binder composed of amylopectin and polyvinylpyrrolidone.
DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, tablets containing LDOPA are prepared by the conventioal wet granulation method utilizing a binder material comprising amylopectin and polyvinylpyrrolidone.
More particularly the LDOPA tablets of the present invention contain from 1% to 10% of the total tablet weight of binders and not more than 35% by weight inert ingredients. Preferably, the tablets contain from about 1% to about 2% by weight binders based on the total tablet weight and between about 20% and 25% by Weight of a tablet disintegrant, between from about 1% to about 2% lubricants and the remainder other inert ingredients, such as dyes, and the like.
It is contemplated that the LDOPA tablets of the present invention may contain up to 750 mg. It is preferred, however, to produce tablets according to the invention which contain either 250 mg. of 500 mg. of L- DOPA. In any event, LDOPA constitutes from about 60 to about and preferably from about 70% to about 73% by weight of the tablets of the present invention.
The binder component of the novel LDOPA tablets of the present invention is composed of amylopectin, polyvinylpyrrolidone or mixtures thereof. Although either of these two substances will form an acceptable tablet without the other, it is preferred to have both components present. In the preferred composition the ratio of the two components may vary from 1:9 to 9:1. It is, however, especially preferred to use equal quantities of each. The amylopectin utilized in the practice of the present invention is a soluble fraction derived from commercial starches. It has a molecular weight of from one million to about ten million with a preferred mean molecular weight of one million. The preferred amylopectin is a White powder, water dispersible and of sufficiently low viscosity that a 20% weight to volume dispersion in water is pourable at room temperature. The polyvinylpyrrolidone utilized in the practice of the present invention meets the specifications of the National Formulary. A suitable commercial product is Plasdone K by the GAP Corporation.
In addition to the binder component, the tablets of the present invention contain from 0.5 to 3.0% by weight preferably from 1% to 2% by weight of a tabletting lubricant conventional in the art. The lubricant is comprised of talc and a substance such as stearic acid, calcium stearate, magnesium stearate or a commercial product consisting of diand tri-glycerides of certain fatty acids such as stearic and palmitic acid, e.g. Sterotex, by Capital City Products, Inc. Of these, magnesium stearate is preferred. While the two lubricant components may generally be used in a ratio of from 1:9 to 9:1 it is preferred to utilize equal quantities of each. The function of the talc lubricant component is to promote the fiow of the granulation while at the same time preventing picking when the tablets are removed from the molds. The second lubricant component functions to improve the overall flow properties and mold release of the granulation.
In addition to the binder and lubricants set forth above, the L-DOPA tablets of the present invention contain a tablet disintegrant. This class of substance includes, for example, cellulosic products such as methyl cellulose, hydroxy ethyl cellulose and the like, certain commercially available chemically modified starch fractions such as Sta-Rx 1500 by A. E. Staley and Company, and the like. It is preferred to utilize a disintegrant which possesses some tabletting properties. A preferred example of such a substance is microcrystalline cellulose such as that commercially available under the trademark Avicel by the American Viscose Corporation. The tablets of the present invention contain from about 1% to about 40% by weight of the disintegrating agent, preferably from about 20% to about 25% by weight.
The process of tablet making by wet granulation is well known in the pharmaceutical arts. It involves basically the intimate blending of the active ingredient and some or all of the inert ingredients with a suitable solvent, such as water, alcohol, methylene chloride, and the like. The granulation thus formed is then dried, such as, by placing it in shallow lined pans in an oven. The resulting dry mixture, which may be intimately mixed with other tabletting ingredients, is then compressed into tablets.
It is further within the purview of the present invention to include in the tablets other therapeutically active ingredients such as compounds which potentiate the action of L-DOPA. It is further within the purview of the present invention to combine into the tablets negligible amounts of standard ingredients, such as FDA certified colors.
In accordance with the present invention it has been found that tablets containing L-DOPA can be prepared, utilizing the ingredients set forth herein, that are stable, pharmaceutically elegant, and approximately twenty percent smaller than tablets prepared by other tabletting methods known in the art. The small tablet is important in the treatment of Parkinsonism as the disease strikes many elderly individuals who ordinarily have some difficulty in swallowing a large tablet. In addition, the tablets prepared according to the present invention are free from problems such as capping and poor compressibility inherent in other methods of preparation and methods utilizing other binder materials. Finally, and most surprising, the tablets of the present invention have been found to possess a dissolution rate in the body not only far superior to tablets made by other methods and containing other binders as described herein, but superior to standard gelatin capsules. This property was demon strated in simulated gastric fluid utilizing tablets prepared in accordance with the present invention containing 500 mg. L-DOPA. Such tablets were found to be 47% dissolved in 2 minutes after exposure to the simulated gastric fluid and 90% dissolved after four minutes. In contrast, a group of tablets prepared by direct compression and film coated had 21% dissolved in 2 minutes and 90% dissolved only after 60 minutes had elapsed. Gelatin capsules containing the same amout of L-DOPA and talc were 1% dissolved after 2 minutes and 90% after 8 minutes. Similar capsules filled with a combination of talc and corn starch and LDOPA in the unmilled state had 27% dissolution in 2 minutes and 90% in 10 minutes. Milling the L-DOPA before filling the capsules produced rates of 55% in 2 minutes but took 9 minutes for 90% dissolution.
The relative dissolution of the tablet or capsule is critical as it is theorized that high initial blood levels of L-DOPA are required for the drug to be effective. This theory is based on the fact that the drug is metabolized by enzymes in the blood and the drug must be intact to 4 pass the blood brain barrier where its therapeutic action is exerted. Therefore, the L-DOPA tablets of the present invention, due to their rapid dissolution are superior to L-DOPA tablets and capsules made by other methods and with other inert ingredients.
The following examples are illustrative of the in vention.
EXAMPLE 1 One thousand tablets containing 250 mg. L-DOPA were produced as follows. Using a 1% excess in accordance with standard pharmaceutical practices 252.5 grams of L-DOPA were passed through a suitable comminuting mill and admixed with a certified coloring agent. The resulting powder was granulated with an aqueous suspension prepared by suspending 2.5 grams amylopectin and 2.5 grams polyvinylpyrrolidone in 12.5 ml. distilled water. The resulting wet granulation was dried on lined trays at 120 F. The dry powder was milled on a suitable milling machine utilizing a No. 12 screen and medium speed. The granulation was then blended with 84.7 grams microcrystalline cellulose and some additional coloring material. A preblended lubricant comprising 2.5 grams talc and 2.5 grams magnesium stearate was intimately admixed with the granulation and tablets having a diameter of 9.6 mm., a thickness of approximately 3.8 mm., and a weight of approximately 348 mg. were produced therefrom on suitable conventional tabletting machinery,
EXAMPLE 2 One thousand tablets containing 500 mg. L-DOPA were produced as follows. .Using a 1% excess in accordance with standard pharmaceutical practices 505.0 grams of L-DOPA were passed through a suitable comminuting mill and admixed with a certified coloring agent. The resulting powder was granulated with an aqueous suspension prepared by suspending 5.0 grams amylopectin and 5.0 grams polyvinylpyrrolidone in 25.0 ml. distilled water. The resulting wet granulation was dried on lined trays at 120 F. The dry powder was milled on a suitable milling machine utilizing a No. 12 screen and medium speed. The granulation was then blended with 169.5 grams microcrystalline cellulose and some additional coloring material. A preblended lubricant comprising 5.0 grams talc and 5 .0 grams magnesium stearate was intimately admixed with the granulation and tablets having a diameter of 18 mm., a thickness of approximately 6 mm., and a weight of approximately 695 mg. were produced therefrom on suitable conventional tabletting machinery.
We claim: 1. A method of producing a stable tablet containing L-DOPA which comprises wet granulating drying and compressing into tablets a formulation comprising:
(a) from about 60.0% to about 80.0% by weight LDOPA;
(b) from about 1.0% to about 10.0% by weight of a binder comprising amylopectin admixed with, polyvinylpyrrolidone;
(c) from about 1.0% to about 40.0% by weight of a tablet disintegrant; and
(d) from about 0.5% to about 3.0% by weight of a tabletting lubricant.
2. The method in accordance with claim 1 wherein said ingredient (a) is present in from about 70.0% to about 73.0% by weight, said ingredient (b) is present in from about 1.0% to about 2.0% by weight, said ingredient (c) is present in from about 20.0% to about 25.0% by weight and said ingredient (d) is present in from about 1.0% to about 2.0% by weight.
3. The method in accordance with claim 1 wherein said tablet disintegrant is microcrystalline cellulose and said lubricant is a mixture of equal parts of talc and magnesium stearate.
4. The method in accordance with claim 1 wherein said binder comprises from about 10% to about by weight amylopectin and from about 90% to about 10% by weight polyvinylpyrrolidone.
5. The method in accordance with claim 1 wherein said binder comprises equal quantities of amylopectin and polyvinylpyrrolidone.
6. The method in accordance with claim 1 wherein L-DOPA is present in a quantity of about 250 mg.
7. The method in accordance with claim 1 wherein L-DOPA is present in a quantity of about 500 mg.
8. A pharmaceutical tablet compresed from a direct wet granulation comprising.
(a) from about 60% to about 80% by weight L-DOPA;
(b) from about 1.0% to about 10.0% by weight of a binder comprising amylopectin admixed with, polyvinylpyrrolidone;
(c) from about 1% to about 40% by weight of a tablet disintegrant; and
(d) from about 0.5% to about 3.0% by weight of a tabletting lubricant.
9. A tablet in accordance with claim 8 wherein said ingredient (a) is present in from about 70.0% to about 73.0% by weight, said ingredient (b) is present in from about 1.0% to about 2.0% by weight, said ingredient (c) 6 is present in from about 20.0% to about 25.0% by weight and said ingredient (d) is present in from about 1.0% to References Cited UNITED STATES PATENTS 1/1969 Nurnberg 424319 X 1/1971 Bartholini 424-319 OTHER REFERENCES Lehrman, G. P. et 211.: Drug Standards, 26: -175 (1958), A Comparative Study of Polyvinylpyrrolidone and Other Binding Agents in Tablet Formulations.
SHEP K. ROSE, Primary Examiner US. Cl. X.R.
Po-wso UNITED sTATEs PA ENT OFFiCE 69 CERTIFICATE OF CORRECTION Patent No. 5,652,778 Dated Jemuarv 4. 1972 Inventor) Sheth and Katz It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
a- Column 6, line 1 of claim 11 "10 should be 8 Column 4, line 52 of claim 1,
a comma should be added after "granulating" Column 4, line 57 of claim 1 delete comma after "with" Column 5, line 10 of claim 8 compresed from a direct" should be compressed from a dried Column 5, line 15 of claim 8 delete comma after wi-th" I Signed and sealed this 20th day of June 1972.
(SEAL) Attest:
L EDWARD M.FLETCEER,JE. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents
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US3885026A (en) * 1972-09-20 1975-05-20 Boehringer Mannheim Gmbh Preparation of porous tablets
US4017636A (en) * 1973-10-23 1977-04-12 Abbott Laboratories Esters of γ-glutamyl amide of dopamine
US4021555A (en) * 1975-03-29 1977-05-03 Merck Patent Gesellschaft Mit Beschrankter Haftung Pharmaceutical preparation and method for treatment of parkinsonism
US4097606A (en) * 1975-10-08 1978-06-27 Bristol-Myers Company APAP Tablet containing an alkali metal carboxymethylated starch and processes for manufacturing same
US4143129A (en) * 1975-10-11 1979-03-06 Lilly Industries Limited Cephalexin tablets
US4151274A (en) * 1975-11-15 1979-04-24 Karl-Werner Schlueter G.m.b.H. Process and composition for the production of suppositories
US4159346A (en) * 1976-09-07 1979-06-26 Fmc Corporation Tablet compositions
US4195078A (en) * 1979-03-09 1980-03-25 Eli Lilly And Company Nabilone granulation
US4209513A (en) * 1974-02-14 1980-06-24 Burroughs Wellcome Co. Tablet formulation
US4254099A (en) * 1978-10-18 1981-03-03 Beiersdorf Aktiengesellschaft Pharmaceutical tablet composition
US4264573A (en) * 1979-05-21 1981-04-28 Rowell Laboratories, Inc. Pharmaceutical formulation for slow release via controlled surface erosion
US4327080A (en) * 1981-07-13 1982-04-27 E. R. Squibb & Sons, Inc. Novel Bendroflumethiazide formulations and method
DE3232873A1 (en) * 1981-09-14 1983-03-31 F. Hoffmann-La Roche & Co AG, 4002 Basel PHARMACEUTICAL PREPARATION
US4454108A (en) * 1981-09-04 1984-06-12 Chugai Seiyaku Kabushiki Kaisha Prolonged-action multiple-layer tablets
US4465660A (en) * 1981-04-01 1984-08-14 Mead Johnson & Company Sustained release tablet containing at least 95 percent theophylline
US4547358A (en) * 1980-05-06 1985-10-15 Mead Johnson & Company Sustained release tablet containing at least 95 percent theophylline
US4736527A (en) * 1982-12-13 1988-04-12 Konishiroku Photo Industry Co., Ltd. Apparatus for the heat treatment of powdery material
US5240662A (en) * 1991-01-30 1993-08-31 Egis Gyogyszergyar Process for the preparation of solid pharmaceutical compositions
US20170112834A1 (en) * 2014-05-29 2017-04-27 Novartis Ag Ceritinib formulation

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EP0275468B1 (en) * 1986-12-20 1991-02-06 Roche Diagnostics GmbH Pharmaceutical compositions containing clodronate, and process for their preparation

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US3133863A (en) * 1961-03-10 1964-05-19 Strong Cobb Arner Inc Sustained release therapeutic tablet compositions comprising organic solvent-gelled gums
US3458622A (en) * 1967-04-07 1969-07-29 Squibb & Sons Inc Controlled release tablet
US3557292A (en) * 1968-08-16 1971-01-19 Hoffmann La Roche Compositions and methods for treating parkinson's disease with combinations of l-3,4-dihydroxyphenylalanine and a hydrazine

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3885026A (en) * 1972-09-20 1975-05-20 Boehringer Mannheim Gmbh Preparation of porous tablets
US4017636A (en) * 1973-10-23 1977-04-12 Abbott Laboratories Esters of γ-glutamyl amide of dopamine
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US11000523B2 (en) * 2014-05-29 2021-05-11 Novartis Ag Ceritinib formulation

Also Published As

Publication number Publication date
FR2100742A1 (en) 1972-03-24
DK126236B (en) 1973-06-25
GB1296505A (en) 1972-11-15
FR2100742B1 (en) 1974-09-06
DE2128461A1 (en) 1971-12-16
ES392066A1 (en) 1974-10-16
BE768269A (en) 1971-12-09
NL7107643A (en) 1971-12-14

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