US3374146A - Sustained release encapsulation - Google Patents

Sustained release encapsulation Download PDF

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US3374146A
US3374146A US543041A US54304166A US3374146A US 3374146 A US3374146 A US 3374146A US 543041 A US543041 A US 543041A US 54304166 A US54304166 A US 54304166A US 3374146 A US3374146 A US 3374146A
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sustained release
glyceryl
medicament
release
alcohol
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US543041A
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Blicharz Mitchell Stanley
Jackson Gerald James
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Wyeth Holdings LLC
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American Cyanamid Co
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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • This invention relates to an improved sustained release med'cament composition and a method ofproduoing it.
  • Many medicaments are required to be in sustained release form to make it possible to take fewer doses during a day and to space out the release of the medicament.
  • the medicament is to be released gradually in the stomach, and in other cases part or all of the medicament may be released not in the stomach but in the intestines by using so-called enteric coatings.
  • sustained release medicaments have usually been made by coating granular or finely divided medicament with a coating which dissolves slowly. The individual particles are then compressed into a tablet or filled. into a capsule or otherwise incorporated in the final dosage form.
  • Typical of such agents with which the medicament particles are coated are solutions of waxy compounds, such as glyceryl monostearate, in an ordinary coating pan. It has been quite possible to produce sustained release compositions inthe manner described above, but they have certain drawbacks. First of all, it is necessary to granulate accurately to predetermined and uniform size or size range, and secondly, in the caseofa number of products, the amount of additional waxy material is quite large, which adds to the cost of the medicament composition.
  • Another method which has been proposed is to suspend or dissolve medicament in.molten material, such as waxy material, allowto solidify by cooling in sheets I or cakes, and then milling to form granules. It has also been proposed to follow this procedure and then to ini- :tially coat the granules with other sustained release coatings.
  • This method sufiers from the same drawbacks as the first method described above, for it is practically imf'hpossible to duplicate granulations of exactly the same particle size distribution and if thegranules are additionally coated with fairly waxy material, the amount required in the coating is quite large, As in the first method, the result is not" uniform and the cost is increased.
  • the medicament is melted, if stable at its melting temperature, or suspended in a molten material, such as waxy 3,374,146 Patented Mar. 19, 1968 "ice than some other shapes which are not so well streaming a constant shape andeven in one of its modifications choosing the 'exact' shape desired.
  • a molten material such as waxy 3,374,146 Patented Mar. 19, 1968
  • Typical illustrative materials are fatty acid esters, saturated fatty acids, low melting solid alcohols, monoand polyethers of saturated fatty alcohols, saturated solid aliphatic ketones, and pharmacologically acceptable stearols.
  • Specific members are stearic acid, stearyl alcohol, myristic acid, and myristic alcohol, glyceryl monostea rate, glyceryl tristearate, glyceryl distearate, acetylated glycerides, carnauba wax, hydrogenated tallow, hydrogenated lard, soybean oil, and similar hydrogenated glycerides, beeswax, cetyl alcohol, and the like.
  • the size of the molded or cast dosage units is not sharply critical. Obviously, of course, the size must not be so minute that the surface to volume ratio is so high that rapid digestion or solution takes place, because of course this defeats the purpose of sustained release. Also, it is obvious that the upper limit on size is determined by the dosage unit or by the size which is readily swallowed by a man or animal for. whom the product is intended. As a typical practical lower limit, cast dosage units of 5 mm. in cross section are useful.
  • compositions of the present invention can be prepared after one or more constituents of the composition have been melted. If the composition is to be administered in hard shelled gelatin capsules, the capsules may be used themselves as the molds, always of course provided that the melted constituent melts at a low enough temperature so that the gelatin is not excessively softened or melted. It is also possible, and in many cases advantageous, to use metal or other molds to produce the cast product.
  • the present invention can be used to achieve this effect very simply by having a portion of the medicament in the cast or molded unit associated with a material which dissolves rapidly in the gastric juice, such as for example water soluble or dispersible waxes.
  • the present invention therefore, includes not only dosage units which are all of the sustained release type but also those which release a portion of their medicament more rapidly.
  • Example 1 Meprobamate was melted and then poured into hard shell gelatin capsules. No. 2 hard shell capsules were used and each contained 408 mg. of meprobamate. Release time was tested in this as in other examples unless differently specified by using artificial simulated gastric juice for the first two hours followed by simulated intestinal juice. The results are as follows:
  • Example 2 Molten meprobamate at a temperature of 100105 C. was mixed with glyceryl monostearate in two different proportions and filled into No. 2 hard shell capsules, the weights varying between 400 and 410 mg.
  • the release results are as follows:
  • Example 3 A mixture of molten meprobamate and various proportions of glyceryl monostearate (temperatures 105 to 110 C.), were mixed with powdered d-amphetamine sulfate and filled into gelatin capsules, producing doses from 400 to 416 mg. of meprobamate and 15-16 mg. of d-amphetamine.
  • the release results are as follows:
  • Example 4 A combined initial and sustained release medicament was prepared by pouring a portion of molten meprobamate into capsules and another portion of a mixture of meprobamate with soluble wax, polyethylene glycol. The mixture with the soluble material gives a rapid initial release and the solidified meprobamate is released more slowly, as is brought out in Example 1.
  • Example 5 A molten mixture, (5558 C.), of glyceryl monostearate and polyethylene glycol with an average molecular weight of about 4000 was prepared. Finely divided solid d-amphetamine sulfate was suspended in the mixture of waxes and cast in molds. Products were obtained which showed sustained release, the release weight being varied by varying the relative proportions of glyceryl monostearate and polyethylene glycol.
  • Example 6 Glyceryl monos'tearate was melted at the temperature given in Example 5 and polyethylene glycol and propyl thiouracil were dissolved in the melt. This was then poured into molds, and produced sustained release capsules.
  • Example 7 40 grams of glyceryl monostearate was heated to 65 C. and when completely melted, 8.4 grams of Pathilon ethochloride powder stirred in. The mixture was heated and stirred until the Pathilon was completely dissolved, the temperature rising to C., and was then poured into No. 1 hard shell gelatin capsules and allowed to harden. There were 79 mg. of Pathilon per capsule and sustained release first in artificial gastric juices and then in artificial intestinal fluid was tested. The results were as follows:
  • a cast pharmaceutical hard shell gelatin capsule product having a cross section of at least 5 mm. but below a size at which swallowing is diflicult and filled with a sustained release pharmaceutical composition containing up to about 2% of an adjuvant selected from the group consisting of stearic acid, stearyl alcohol, myristic acid, myristic alcohol, glyceryl monostearate, glyceryl tristearate, glyceryl distearate, acetylated glycerides, carnauba wax, hydrogenated tallow, hydrogenated lard, soybean oil, beeswax, cetyl alcohol, polyethylene glycol having an average molecular weight of about 4,000, and mixtures thereof, together with a medicament not damaged by heating to the melting point of said adjuvant.
  • an adjuvant selected from the group consisting of stearic acid, stearyl alcohol, myristic acid, myristic alcohol, glyceryl monostearate, glyceryl tristearate

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Description

United States Patent This invention relates to an improved sustained release med'cament composition and a method ofproduoing it. Many medicaments are required to be in sustained release form to make it possible to take fewer doses during a day and to space out the release of the medicament. Sometimes the medicament is to be released gradually in the stomach, and in other cases part or all of the medicament may be released not in the stomach but in the intestines by using so-called enteric coatings. In the past, sustained release medicaments have usually been made by coating granular or finely divided medicament with a coating which dissolves slowly. The individual particles are then compressed into a tablet or filled. into a capsule or otherwise incorporated in the final dosage form. Typical of such agents with which the medicament particles are coated are solutions of waxy compounds, such as glyceryl monostearate, in an ordinary coating pan. It has been quite possible to produce sustained release compositions inthe manner described above, but they have certain drawbacks. First of all, it is necessary to granulate accurately to predetermined and uniform size or size range, and secondly, in the caseofa number of products, the amount of additional waxy material is quite large, which adds to the cost of the medicament composition.
Another method which has been proposed is to suspend or dissolve medicament in.molten material, such as waxy material, allowto solidify by cooling in sheets I or cakes, and then milling to form granules. It has also been proposed to follow this procedure and then to ini- :tially coat the granules with other sustained release coatings. This method sufiers from the same drawbacks as the first method described above, for it is practically imf'hpossible to duplicate granulations of exactly the same particle size distribution and if thegranules are additionally coated with fairly waxy material, the amount required in the coating is quite large, As in the first method, the result is not" uniform and the cost is increased. i
According to the present invention it is found that if the medicament is melted, if stable at its melting temperature, or suspended in a molten material, such as waxy 3,374,146 Patented Mar. 19, 1968 "ice than some other shapes which are not so well streaming a constant shape andeven in one of its modifications choosing the 'exact' shape desired. -It is, of course, possible to, have dosage units put up in two or more different sizes so that a portion are released more rapidly than the larger sizes] However, this refinement is rarely needed, and presents the problem that the user has to select numbers of units to obtain this desired additional effect, Also, as will be described below, it is possible to obtain a rapid release of a portion of the medicament and a sustained release of further portion in a single dosage unit, which presents advantages of uniform production and more simple use.
Surprisingly, a sustained release effect is obtained even if the medicament or one of the medicaments is melted and cast in suitable molds. However, often the presence of additional waxy material is desirable, but in such case a very much smaller amount can be used than was formerly needed when'medicament particles were granulated to produce the usual sustained release granules as described above. When a sustained release is prolonged by the addition of waxy materials, which are sometimes referred to as adjuvants, it is an advantage of the invention that it is in no sense critical what particular adjuvant is used or what particular combination or adjuvants are used. Typical illustrative materials are fatty acid esters, saturated fatty acids, low melting solid alcohols, monoand polyethers of saturated fatty alcohols, saturated solid aliphatic ketones, and pharmacologically acceptable stearols. Specific members are stearic acid, stearyl alcohol, myristic acid, and myristic alcohol, glyceryl monostea rate, glyceryl tristearate, glyceryl distearate, acetylated glycerides, carnauba wax, hydrogenated tallow, hydrogenated lard, soybean oil, and similar hydrogenated glycerides, beeswax, cetyl alcohol, and the like. These typical adjuvants may be used alone or in mixture with material, and molded into suitable dosage forms, either perfectly uniform, which was not practical with coated granules or granules obtained by milling cakes or sheets of suspended medicaments. In general, with similar compositionsof medicaments the larger the size of molded or cast dosage units, the longer the disintegration time in the gastro-intestinal tract and hence the greater the degree of sustained release. The upper limito'f course is set by the size of molded or cast dosage unit which can be comfortably swallowed. This depends both on unit size and on shape. For exampldspheres or' short cylinders with rounded ends can-be swallowed in -larger sizes each other or also in admixture with water soluble waxes, such as polyethylene glycols.
It has been pointed out above that it is not necessary that all of the components of the composition be heated to their individual melting points. It is sufiicient if one or more are stable when melted, and the other components can be present in 'the form of finely divided solids suspended in the molten constituent. Obviously, of course, the medicamentsv must not be injured by the melting temperature of the component or components which are melted prior to casting or molding. Apart from this requirement, the present invention is applicable to any solid medicament and is not intended tobe limited to particular medicaments which will be described in typical examples.
It is an advantage of the present invention that the size of the molded or cast dosage units is not sharply critical. Obviously, of course, the size must not be so minute that the surface to volume ratio is so high that rapid digestion or solution takes place, because of course this defeats the purpose of sustained release. Also, it is obvious that the upper limit on size is determined by the dosage unit or by the size which is readily swallowed by a man or animal for. whom the product is intended. As a typical practical lower limit, cast dosage units of 5 mm. in cross section are useful.
There are various ways in which the compositions of the present invention can be prepared after one or more constituents of the composition have been melted. If the composition is to be administered in hard shelled gelatin capsules, the capsules may be used themselves as the molds, always of course provided that the melted constituent melts at a low enough temperature so that the gelatin is not excessively softened or melted. It is also possible, and in many cases advantageous, to use metal or other molds to produce the cast product.
Sometimes it is desirable to have a dosage unit which will release a portion of the medicament quite rapidly and the balance more slowly. It is an advantage that the present invention can be used to achieve this effect very simply by having a portion of the medicament in the cast or molded unit associated with a material which dissolves rapidly in the gastric juice, such as for example water soluble or dispersible waxes. The present invention, therefore, includes not only dosage units which are all of the sustained release type but also those which release a portion of their medicament more rapidly.
When waxy adjuvants are used, an example of the saving is the reduction of the amount of adjuvant required to as little as 2%, a very large saving, which of course is reflected in a reduced cost.
The invention will be described in greater detail in conjunction with the following specific examples, in which the parts are by weight unless otherwise specified.
Example 1 Meprobamate was melted and then poured into hard shell gelatin capsules. No. 2 hard shell capsules were used and each contained 408 mg. of meprobamate. Release time was tested in this as in other examples unless differently specified by using artificial simulated gastric juice for the first two hours followed by simulated intestinal juice. The results are as follows:
Time, hrs. Percent released /2 12.8
This example is not necessarily the ideal formulation. It shows, however, that even without added adjuvants a substantial degree of sustained release is obtained.
Example 2 Molten meprobamate at a temperature of 100105 C. was mixed with glyceryl monostearate in two different proportions and filled into No. 2 hard shell capsules, the weights varying between 400 and 410 mg. The release results are as follows:
1 Glyceryl Mono- 2% Glyccryl Monostearate, percent stearate, percent It will be noted that with 1% adjuvant the release times were not greatly different from me-probamate castings without any adjuvants but a marked increase in release time resulted with 2% of adjuvant.
Example 3 A mixture of molten meprobamate and various proportions of glyceryl monostearate (temperatures 105 to 110 C.), were mixed with powdered d-amphetamine sulfate and filled into gelatin capsules, producing doses from 400 to 416 mg. of meprobamate and 15-16 mg. of d-amphetamine. The release results are as follows:
2% Glyceryl Monostearate,
4% Glyccryl Monostearate percent Released It will be noted that the release time of the highly soluble amphetamine salt was well controlled by the meprobamate.
Example 4 A combined initial and sustained release medicament was prepared by pouring a portion of molten meprobamate into capsules and another portion of a mixture of meprobamate with soluble wax, polyethylene glycol. The mixture with the soluble material gives a rapid initial release and the solidified meprobamate is released more slowly, as is brought out in Example 1.
Example 5 A molten mixture, (5558 C.), of glyceryl monostearate and polyethylene glycol with an average molecular weight of about 4000 was prepared. Finely divided solid d-amphetamine sulfate was suspended in the mixture of waxes and cast in molds. Products were obtained which showed sustained release, the release weight being varied by varying the relative proportions of glyceryl monostearate and polyethylene glycol.
Example 6 Glyceryl monos'tearate was melted at the temperature given in Example 5 and polyethylene glycol and propyl thiouracil were dissolved in the melt. This was then poured into molds, and produced sustained release capsules.
Example 7 40 grams of glyceryl monostearate was heated to 65 C. and when completely melted, 8.4 grams of Pathilon ethochloride powder stirred in. The mixture was heated and stirred until the Pathilon was completely dissolved, the temperature rising to C., and was then poured into No. 1 hard shell gelatin capsules and allowed to harden. There were 79 mg. of Pathilon per capsule and sustained release first in artificial gastric juices and then in artificial intestinal fluid was tested. The results were as follows:
Release rate, hr.:
Artificial gastric fluid.
7 n 753 7 Artificial intestinal fluid- We claim:
1. A cast pharmaceutical hard shell gelatin capsule product having a cross section of at least 5 mm. but below a size at which swallowing is diflicult and filled with a sustained release pharmaceutical composition containing up to about 2% of an adjuvant selected from the group consisting of stearic acid, stearyl alcohol, myristic acid, myristic alcohol, glyceryl monostearate, glyceryl tristearate, glyceryl distearate, acetylated glycerides, carnauba wax, hydrogenated tallow, hydrogenated lard, soybean oil, beeswax, cetyl alcohol, polyethylene glycol having an average molecular weight of about 4,000, and mixtures thereof, together with a medicament not damaged by heating to the melting point of said adjuvant.
2. A product according to claim 1 in which the cast product contains meprobamate which has been melted and hardened.
. 3. A product according to claim 1 in which a d-amphetamine powder is dispersed in the meprobamate after melting and before it has been hardened.
References Cited UNITED STATES PATENTS 1,366,941 2/1921 Rhodehamel l67--64 3,061,510 10/1962 Numerof et al. 16783 XR 3,139,383 6/1964 Neville 167-83 3,197,3. 69 7/1965 Widmann et al. 167-64 3,297,804 1/ 1967 Iwamoto et al. 167-83 XR LEWIS GOTTS, Primary Examiner. S. K. ROSE, Assistant Examiner.

Claims (1)

1. A CAST PHARMACEUTICAL HARD SHELL GELATIN CAPSULE PRODUCT HAVING A CROSS SECTION OF AT LEAST 5 MM. BUT BELOW A SIZE AT WHICH SWALLOWING IS DIFFICULT AND FILLED WITH A SUSTAINED RELEASE PHARMACEUTICAL COMPOSITION CONTAINING UP TO ABOUT 2% OF AN ADJUVANT SELECTED FROM THE GROUP CONSISTING OF STEARIC ACID, STEARYL ALCOHOL, MYRISTIC ACID, MYRISTIC ALCOHOL, GLYCERYL MONOSTARATE, GLYCERYL TRISTEARATE, GLYCERYL DISTEARATE, ACETYLATED GLYCERIDES, CARNAUBA WAX, HYDROGENATED TALLOW, HYDROGENATED LARD, SOYBEAN OIL, BEESWAX, CETYL ALCOHOL, POLYETHYLENE GLYCOL HAVING AN AVERAGE MOLECULAR WEIGHT OF ABOUT 4,000, AND MIXTURES THEREOF, TOGETHER WITH A MEDICAMENT NOT DAMAGED BY HEATING TO THE MELTING POINT OF SAID ADJUVANT.
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Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3670065A (en) * 1968-06-19 1972-06-13 Karl Gunnar Eriksson Process for producing dosage units of a type resembling tablets
US3696189A (en) * 1970-05-18 1972-10-03 Frank M Snyder Stabilized antibiotic and method
US3857933A (en) * 1969-10-17 1974-12-31 Hoechst Ag Process for the manufacture of a drug dosage form permitting controlled release of active ingredient
US3864469A (en) * 1967-12-16 1975-02-04 Hoechst Ag Xanthines in pharmaceutical preparations and for stabilization of vitamins
US3883648A (en) * 1972-10-31 1975-05-13 Hoechst Ag Method of making stable granules of N-4-{8 2-(5-chloro-2-methoxybenzamido)-ethyl{9 -phenylsulfonyl-N{40 -cyclohexyl urea and its salts and process for preparing same
US4151273A (en) * 1974-10-31 1979-04-24 The Regents Of The University Of California Increasing the absorption rate of insoluble drugs
US4251506A (en) * 1977-05-25 1981-02-17 Commonwealth Scientific And Industrial Research Organization Controlled-release compositions for administration of therapeutic agents to ruminants
US4343789A (en) * 1979-07-05 1982-08-10 Yamanouchi Pharmaceutical Co., Ltd. Sustained release pharmaceutical composition of solid medical material
EP0068450A2 (en) * 1981-06-25 1983-01-05 Dr. Rentschler Arzneimittel GmbH & Co. Pharmaceutical forms for oral administration
EP0095123A2 (en) * 1982-05-20 1983-11-30 Merrell Dow Pharmaceuticals Inc. Sustained release diethylpropion compositions
US4483847A (en) * 1980-06-28 1984-11-20 Warner-Lambert Company Process for the manufacture of a pharmaceutical composition with a retarded liberation of active material
EP0190255A1 (en) * 1984-07-23 1986-08-13 Zetachron Inc Erodible matrix for sustained release bioactive composition.
US4663149A (en) * 1984-03-21 1987-05-05 Alza Corporation Dispenser comprising inner and outer walls functioning as cooperative unit
US4663148A (en) * 1984-03-21 1987-05-05 Alza Corporation Dispenser comprising telescopically engaging members
US4690822A (en) * 1985-03-26 1987-09-01 Fujisawa Pharmaceutical Co., Ltd. Novel drug carrier and pharmaceutical preparation comprising the same
US4692326A (en) * 1984-03-21 1987-09-08 Alza Corporation Dispenser comprising inner positioned soft or hard capsule
US4713245A (en) * 1984-06-04 1987-12-15 Mitsui Toatsu Chemicals, Incorporated Granule containing physiologically-active substance, method for preparing same and use thereof
US4716031A (en) * 1984-03-21 1987-12-29 Alza Corporation Drug dispenser comprising a multiplicity of members acting together for successfully dispensing drug
DK151931B (en) * 1977-11-03 1988-01-18 Hoechst Ag PROCEDURE FOR THE PREPARATION OF A PHARMACENTAL PREPARATION UNIT
US4777048A (en) * 1983-07-07 1988-10-11 American Home Products Corporation Pharmaceutical composition containing a liquid lubricant
US4832952A (en) * 1983-07-07 1989-05-23 American Home Products Corporation Pharmaceutical composition containing a liquid lubricant
US4894235A (en) * 1984-10-23 1990-01-16 Dr. Rentschler, Arzneimmittel Gmbh & Co. Nifedipine-containing form of administration and method for its production
US5082655A (en) * 1984-07-23 1992-01-21 Zetachron, Inc. Pharmaceutical composition for drugs subject to supercooling
WO1993000891A1 (en) * 1991-07-01 1993-01-21 The Upjohn Company Enzyme-sensitive enteric preparation for oral administration
US5281420A (en) * 1992-05-19 1994-01-25 The Procter & Gamble Company Solid dispersion compositions of tebufelone
US5455045A (en) * 1993-05-13 1995-10-03 Syntex (U.S.A.) Inc. High dose formulations
AT401727B (en) * 1989-02-23 1996-11-25 Glaxo Canada GELATINE CAPSULES CONTAINING RANITIDINE (SALT)
US5891456A (en) * 1997-06-30 1999-04-06 Medical University Of South Carolina Glyceryl monosterate based biodegradable implants for site-specific delivery of drugs
US6171615B1 (en) 1998-07-06 2001-01-09 Gattefoss{acute over (e)} Sustained release theophylline formulations, excipient systems and methods of production
US20160015651A1 (en) * 2013-03-07 2016-01-21 Capsugel Belgium Nv Hard capsule formulation
WO2016020901A1 (en) 2014-08-07 2016-02-11 Acerta Pharma B.V. Methods of treating cancers, immune and autoimmune diseases, and inflammatory diseases based on btk occupancy and btk resynthesis rate

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US1366941A (en) * 1916-01-13 1921-02-01 Lilly Co Eli Suppository
US3061510A (en) * 1958-08-01 1962-10-30 Olin Mathieson Radioactive iodinated (i131) fatty material admixed with wax-like material in capsule
US3139383A (en) * 1961-06-26 1964-06-30 Norton Co Encapsulated time release pellets and method for encapsulating the same
US3197369A (en) * 1962-02-15 1965-07-27 Scherer Gmbh R P Coated gelatin capsules
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US1366941A (en) * 1916-01-13 1921-02-01 Lilly Co Eli Suppository
US3061510A (en) * 1958-08-01 1962-10-30 Olin Mathieson Radioactive iodinated (i131) fatty material admixed with wax-like material in capsule
US3139383A (en) * 1961-06-26 1964-06-30 Norton Co Encapsulated time release pellets and method for encapsulating the same
US3197369A (en) * 1962-02-15 1965-07-27 Scherer Gmbh R P Coated gelatin capsules
US3297804A (en) * 1964-05-19 1967-01-10 Ono Pharmaceutical Co Method of filling hard capsules with granules by the open-mouth-down punching method

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3864469A (en) * 1967-12-16 1975-02-04 Hoechst Ag Xanthines in pharmaceutical preparations and for stabilization of vitamins
US3670065A (en) * 1968-06-19 1972-06-13 Karl Gunnar Eriksson Process for producing dosage units of a type resembling tablets
US3857933A (en) * 1969-10-17 1974-12-31 Hoechst Ag Process for the manufacture of a drug dosage form permitting controlled release of active ingredient
US3696189A (en) * 1970-05-18 1972-10-03 Frank M Snyder Stabilized antibiotic and method
US3883648A (en) * 1972-10-31 1975-05-13 Hoechst Ag Method of making stable granules of N-4-{8 2-(5-chloro-2-methoxybenzamido)-ethyl{9 -phenylsulfonyl-N{40 -cyclohexyl urea and its salts and process for preparing same
US4151273A (en) * 1974-10-31 1979-04-24 The Regents Of The University Of California Increasing the absorption rate of insoluble drugs
US4251506A (en) * 1977-05-25 1981-02-17 Commonwealth Scientific And Industrial Research Organization Controlled-release compositions for administration of therapeutic agents to ruminants
DK151931B (en) * 1977-11-03 1988-01-18 Hoechst Ag PROCEDURE FOR THE PREPARATION OF A PHARMACENTAL PREPARATION UNIT
US4343789A (en) * 1979-07-05 1982-08-10 Yamanouchi Pharmaceutical Co., Ltd. Sustained release pharmaceutical composition of solid medical material
US4483847A (en) * 1980-06-28 1984-11-20 Warner-Lambert Company Process for the manufacture of a pharmaceutical composition with a retarded liberation of active material
EP0068450A2 (en) * 1981-06-25 1983-01-05 Dr. Rentschler Arzneimittel GmbH & Co. Pharmaceutical forms for oral administration
EP0068450A3 (en) * 1981-06-25 1985-04-17 Meditest Institut Fur Medizinisch-Pharmazeutische Untersuchungen Gmbh & Co. Kg Pharmaceutical forms for oral administration
US4421736A (en) * 1982-05-20 1983-12-20 Merrel Dow Pharmaceuticals Inc. Sustained release diethylpropion compositions
EP0095123A3 (en) * 1982-05-20 1984-12-12 Merrell Dow Pharmaceuticals Inc. Sustained release diethylpropion compositions
EP0095123A2 (en) * 1982-05-20 1983-11-30 Merrell Dow Pharmaceuticals Inc. Sustained release diethylpropion compositions
US4832952A (en) * 1983-07-07 1989-05-23 American Home Products Corporation Pharmaceutical composition containing a liquid lubricant
US4777048A (en) * 1983-07-07 1988-10-11 American Home Products Corporation Pharmaceutical composition containing a liquid lubricant
US4692326A (en) * 1984-03-21 1987-09-08 Alza Corporation Dispenser comprising inner positioned soft or hard capsule
US4716031A (en) * 1984-03-21 1987-12-29 Alza Corporation Drug dispenser comprising a multiplicity of members acting together for successfully dispensing drug
US4663148A (en) * 1984-03-21 1987-05-05 Alza Corporation Dispenser comprising telescopically engaging members
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