US3853988A - Sustained released pharmaceutical compositions - Google Patents
Sustained released pharmaceutical compositions Download PDFInfo
- Publication number
- US3853988A US3853988A US00184634A US18463471A US3853988A US 3853988 A US3853988 A US 3853988A US 00184634 A US00184634 A US 00184634A US 18463471 A US18463471 A US 18463471A US 3853988 A US3853988 A US 3853988A
- Authority
- US
- United States
- Prior art keywords
- matrix
- solvent
- acetylsalicylic acid
- cellulose
- polysiloxane
- 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 - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K31/60—Salicylic acid; Derivatives thereof
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
-
- 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
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- 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
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
Definitions
- a sustained release pharmaceutical composition comprising a solid matrix of acetylsalicylic acid or its pharmaceutically acceptable salts or complexes; a polysiloxane; and a water insoluble cellulose ether or ester.
- sustained release compositions In the practice of medicine, it is often desirable to administer various orally resorbable drugs in the form of sustained release compositions so that the drug is released only gradually upon passage of the composition through the digestive system, thereby achieving a more prolonged duration of action.
- sustained release compositions which have previously been proposed include compositions wherein the drug is incorporated in a water-insoluble matrix derived from certain water insoluble inorganic salts or synthetic resins such as polyvinyl chloride, polyacrylates, polystyrene, polythene, ion exchange resins, etc., the matrix providing the sustained release effect for the drug material.
- ASA sustained release pharmaceutical compositions containing as active ingredient acetylsalicylic acid, hereinafter called ASA, which expression includes pharmaceutically acceptable salts and complexes thereof, with, for example sodium, calcium, glycine and urea.
- sustained release pharmaceutical compositions comprising a matrix formed from ASA (as herein defined), a polysiloxane and a water-insoluble cellulose ether or ester.
- ASA as herein defined
- polysiloxane a polysiloxane
- a water-insoluble cellulose ether or ester we provide sustained release pharmaceutical compositions comprising a matrix formed from ASA (as herein defined), a polysiloxane and a water-insoluble cellulose ether or ester.
- a valuable advantage of our new sustained release compositions is that the weight ratio of matrix material to ASA in such compositions can, if desired, be of a low order, e. g. as low as 1:9 or lower. It is therefore possible to provide practical unit doses of the compositions containing high concentrations of ASA which provide on administration a long-lasting effect.
- compositions according to the invention may if desired be formulated to provide a prompt release of some ASA for immediate effect and a subsequent gradual release of further ASA, e.g. over a period 6-8 hours.
- Compositions of this type are in principle prepared by forming our new ASA matrix composition and then mixing the resultant ASA matrix composition with further ASA in free form.
- the rate of release of ASA in the compositions according to the invention will in general depend upon the release proportion of the ASA in the composition according to the invention and also upon the nature of the matrix itself, the latter being dependent upon the amounts and nature of the cellulose ether or ester and the polysiloxane used to form the matrix. It has been found that the rate of release of the drug is also dependent to some extent on the nature of the liquid medium in which the matrix is prepared, e.g. upon the solvent medium in which the polysiloxane is combined with water-insoluble cellulose ether or ester.
- the rate of release of ASA following administration of the pharmaceutical compositions according to the invention can thus be adjusted to provide substantially constant blood levels of the drug, adjustments being possible, e.g. by varying the composition of the matrix to avoid too high levels (which might give rise to undesired side effects) or too low levels (which would not give the desired pharmacological effect).
- the correct selection of parameters in the process for preparing the matrix composition as hereinafter described to provide the desired result can be readily determined by preliminary experiment.
- the polysiloxane component of the matrix is advantageously a dialkylpolysiloxane, preferably a dimethyl polysiloxane.
- Dimethyl polysiloxanes having a viscosity of from 20,000 to 150,000 cps, preferably about 60,000 cps (as determined by the Ubbelohole Tube method, according to A.S.T.M. D 448) are particularly preferred.
- the water-insoluble cellulose ether or ester employed in the preparation of the matrix is generally a water-insoluble cellulose ether or ester of low viscosity, for example a low viscosity ethyl cellulose or cellulose acetobutyrate, the former being generally preferred.
- a particularly preferred ethyl cellulose for the new composition is one having a viscosity of 18 to 22 cps for a 5% by weight solution thereof in a /20 toluene/ethanol mixture at 25C; an example of such an ethyl cellulose is sold under the trade-name Ethocel by Dow Chemical Company.
- the polysiloxane and cellulose ether or ester are preferably employed in the preparation of the matrix in a weight ratio ranging from 10:1 to 1:1, the preferred ratio being about 2.511 when ethyl cellulose and di methyl-polysiloxane are employed.
- the proportion of ASA combined within the abovedefined matrix may also be varied widely dependent upon the drug and upon the effects, e.g. blood levels desired. Such proportions may be as low as 10 percent by weight but are in general conveniently between 80 and 98 percent by weight based upon the whole matrix compositions generally, preferred proportions being from 88 to 94 percent by weight.
- a process for preparing sustained release pharmaceutical compositions which comprises combining ASA, a polysiloxane and a water-insoluble cellulose ether or ester in a liquid medium and removing the liquid medium to obtain a solid matrix comprising ASA, the polysiloxane and the water-insoluble ether or ester.
- the ASA, cellulose ether or ester and polysiloxane may be admixed in a solvent medium and the solvent medium subsequently removed to obtain a solid matrix incorporating the drug.
- solutions of the cellulose ether or ester and of the polysiloxane in appropriate solvents are first prepared, the two solutions then being admixed in the presence of the ASA in solid form.
- the choice of the solvent or solvents for the matrix components is important since it has been found that, in general, the nature of the solvent or solvents may determine the release rate of the therapeutic material in the final composition.
- the solvents employed will be non-aqueous solvents for the polysiloxane and cellulose derivatives respectively, the solvent being so chosen that the two resulting solutions are miscible. It is further preferred that the solvent or solvents used should be solvents in which the ASA itself is insoluble.
- solvents from which solvents for the cellulose ether'or ester and the polysiloxane may be selected include aliphatic solvents such as halohydrocarbons (e.g. methylene chloride, chloroform, carbon tetrachloride etc) and aromatic solvents such as aromatic hydrocarbons (e.g. benzene, toluene etc), and mixtures of such solvents.
- aliphatic solvents such as halohydrocarbons (e.g. methylene chloride, chloroform, carbon tetrachloride etc) and aromatic solvents such as aromatic hydrocarbons (e.g. benzene, toluene etc), and mixtures of such solvents.
- halohydrocarbons e.g. methylene chloride, chloroform, carbon tetrachloride etc
- aromatic solvents such as aromatic hydrocarbons (e.g. benzene, toluene etc)
- mixtures of such solvents e.g.
- the solvent may be removed, e.g. by evaporation or distillation, to leave a residue which generally comprises a pasty mass. This residue can be subsequently dried and/or processed to prepare pharmaceutical compositions in conventional manner.
- the above mentioned pasty mass obtained as described above can be granulated e.g. by extrusion from an extruder wherein the extrusion orifices are preferably about 0.5 mm to 2.5 mm, particularly 0.8 to 1.4 mm in diameter; the extruded material may then be cut into lengths of the desired sizes, preferably at the 'to, form pellets.
- the resultant granules or pellets may, if desired, then be hardened, e.g. by drying in air and then under a vacuum.
- the pellets or granules may then be formulated in suitable form for administration.
- the new compositions may be formulated in conventional manner using one or more pharmaceutical excipients and carriers to provide compositions of the desired nature, such excipients and carriers including flavouring agents, sweetening agents, lubricants etc.
- the new compositions may, for example, be formulated as dosage unit forms, e.g. as capsules, tablets, coated tablets, dragees or sachets, or as powders or granulates e.g. for the preparation of gels and suspensrons.
- the final composition may as noted above also include the ASA in uncombined form, where, for example, it is desired to obtain both a rapid as well as a prolonged action. This may for example be achieved by including free ASA, for example ASA in granulated form in a tablet containing the ASA matrix or by preparing a capsule containing ASA matrix and free ASA. ln
- compositions containing the ASA matrix composition according to the invention the proportion of free ASA in the total composition is preferably within the range of from -60% by weight.
- Unit dose compositions in accordance with the invention advantageously contain 0.1 to lg, preferably 0.325 to 0.750 g. of ASA per dosage unit combined in point of extrusion. If desired, the thus obtained granules may be centrifuged while still in a plastic condition the matrix, composition being preferably from 88 to 94% by weight. However, if it is desired to provide an increased dosage of ASA during, for example, the first hour after administration, further amounts of ASA in uncombined form e.g. can be included in the compositions in addition to that incorporated in the matrix.
- the following Examples illustrate the invention.
- EXAMPLE 1 1000 g of powdered acetylsalicylic acid mesh) are slowly added, with stirring, to a solution obtained by dissolving 70 g of Ethocel 20 (available from Dow Chemical Company being an ethoxyl ethylcellulose having a viscosity of 9-11 centipoises and an ethoxyl content of 12%) in 300 ml of 1:1 (v/v) mixture of to]- uene-methylenechloride. A solution of 30 g of 60,000 cps dimethylpolysiloxane in ml of toluene is then added.
- the solvent is evaporated off until a pasty mass is obtained, which is granulated through a 12 mesh sieve or extruded by means of a screw feed device having 1 mm orifices.
- the extruded strand is cut to a length of 1 mm.
- the granular product obtained, spread out on trays, is hardenedwith the aid of dry air and subsequently dried under vacuum until the solvent is completely removed.
- the extruded granules, before evaporating the solvent and drying under vacuum, can be centrifuged so that pellets are obtained.
- Each tablet contains: Acetylsalicylic acid granules or pellets (obtained as described in Example 1) 0.715 g Starch 0.040 g Glyceryl palmito-stearate 0.030 g Talc 0.005 g Microcrystalline cellulose 0.010 g EXAMPLE 3
- Pediatric gel g of acetylsalicylic acid granules or pellets (obtained as described in Example 1) are added to 820 g of sugar, 50 g of sodium carboxymethylcellulose and 20 g of powdered flavouring and the resulting mixture placed into small sachets, each containing 1 g of the mixture. After damping with little water a pediatric gel ready for use can be obtained.
- EXAMPLE 4 Sustained release tablets also containing free ASA Acetylsalicylic acid granules or pellets (obtained as described in Example 1) 495 g. Acetylsalicylic acid granulated in conventional manner 235 g Glyceryl palmito-stearate 35 g Starch 20 g. Microcrystalline cellulose 10 g. Tale 5 g.
- a matrix suitable for formulating a sustained release pharmaceutical composition consisting essentially of from about 80% 98% by weight of acetylsalicylic acid or a pharmaceutically acceptable salt or complex thereof, dimethyl polysiloxane having a viscosity of 20,000 to 150,000cps and a cellulose derivative selected from the group consisting of a waterinsoluble low viscosity cellulose ether or ester, the weight ratio of said cellulose derivative to said polysiloxane being within the range of from :1 to 1:1.
- a matrix according to claim 1 suitable for formulation into sustained release pharmaceutical compositions containing 0.1 to 1.0g of acetylsalicylic acid per dosage unit, said matrix being in the form of pellets or granules for filling into dosage units of hard gelatine capsules or pediatric gel sachets having sugar and flavoring, for use with water, or formed into tablet dosage units with starch, glyceryl palmito-stearate, talc and microcrystalline cellulose tableting excipients, said pellet or granule matrix being conveniently 80-98% by weight of acetylsalicylic acid, said matrix being in the form of a.
- pellets suitable for filling hard gelatine capsules or pediatric gel sachets, having sugar and flavoring, for use with water, said pellets having been obtained by being centrifuged before evaporating solvent and drying under vacuum from extruded granules, cut to 1mm length from strands formed by extrusion from an extruder wherein the extrusion orifices are about 0.5mm to 2.5mm in diameter of a pasty mass obtained by evaporating off solvent after thorough mixing of powdered 80 mesh acetylsalicylic acid, a solution of dimethylpolysiloxane, 20,000 to 150,000cps, in a nonaqueous solvent therefore, in which solvent the acetylsalicylic acid itself is insoluble, said solvent being selected from the group consisting of methylene chloride, chloroform, carbon tetrachloride, benzene, toluene and mixtures thereof and a solution in said nonaqueous solvent of ethoxyl ethy
- a matrix according to claim 1 wherein the amount of acetylsalicylic acid in said matrix is 88-94% by thereof in free form.
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB4816770A GB1357737A (en) | 1970-10-09 | 1970-10-09 | Sustained release pharmaceutical compositions |
Publications (1)
Publication Number | Publication Date |
---|---|
US3853988A true US3853988A (en) | 1974-12-10 |
Family
ID=10447626
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US00184634A Expired - Lifetime US3853988A (en) | 1970-10-09 | 1971-09-28 | Sustained released pharmaceutical compositions |
Country Status (8)
Country | Link |
---|---|
US (1) | US3853988A (de) |
CA (1) | CA974883A (de) |
DE (1) | DE2149699A1 (de) |
DK (1) | DK129434B (de) |
ES (1) | ES395533A1 (de) |
FR (1) | FR2110314B1 (de) |
GB (1) | GB1357737A (de) |
SE (1) | SE382560B (de) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4675175A (en) * | 1981-10-08 | 1987-06-23 | A.E.C. Societe De Chimie Organique Et Biologique | Coated methionine granules for ruminants |
US4880791A (en) * | 1984-07-21 | 1989-11-14 | Hoechst Aktiengesellschaft | Combination product composed of xanthine derivatives and O-acetylsalicylic acid or its pharmacologically tolerated salts, and its use |
US6706281B2 (en) * | 1994-11-04 | 2004-03-16 | Euro-Celtique, S.A. | Melt-extrusion multiparticulates |
US20110039807A1 (en) * | 2009-08-13 | 2011-02-17 | Kim Hyoung-Chun | Anti-parkinsonian compound acetylsalicylic acid maltol ester |
KR20150031300A (ko) * | 2012-07-17 | 2015-03-23 | 다우 글로벌 테크놀로지스 엘엘씨 | 유기 액체 희석제 및 매우 낮은 점도의 셀룰로즈 에테르를 포함하는 조성물 |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS51123814A (en) * | 1975-04-22 | 1976-10-28 | Shin Etsu Chem Co Ltd | A process for preparing gradually releasable solid medicines |
US4167558A (en) | 1976-02-13 | 1979-09-11 | Hoffmann-La Roche Inc. | Novel sustained release tablet formulations |
DE2902414A1 (de) * | 1979-01-23 | 1980-08-07 | Hoechst Ag | Depotkoerper auf basis silicon- kautschuk sowie verfahren zu seiner herstellung |
FR2653338B1 (fr) * | 1989-10-23 | 1994-06-10 | Dow Corning Sa | Formulation pour des pansements a liberation prolongee de medicament et son utilisation. |
NZ282804A (en) * | 1994-03-18 | 2000-12-22 | Hans Jurgen Upmeyer | Use of dimethylpolysiloxane (dimeticone) for treating helicobacter pylori infections |
DE4409357C2 (de) * | 1994-03-18 | 1996-10-17 | Upmeyer Hans Juergen | Verwendung von Dimeticon zur Eradikation von Heliobacter pylori |
AU6403196A (en) * | 1995-06-30 | 1997-02-05 | Baylor University | Polyester/carboxylic acid composite materials |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2805977A (en) * | 1955-01-04 | 1957-09-10 | Smith Kline French Lab | Sustained release pharmaceutical preparation |
US3094464A (en) * | 1960-04-01 | 1963-06-18 | Rech S Et Propagande Scient | Aspirin-antacid polysiloxane tablet |
US3133863A (en) * | 1961-03-10 | 1964-05-19 | Strong Cobb Arner Inc | Sustained release therapeutic tablet compositions comprising organic solvent-gelled gums |
US3382150A (en) * | 1962-05-01 | 1968-05-07 | Smith Kline French Lab | Spray-dried coated organopolysiloxane oral pharmaceutical or veterinary composition |
US3501571A (en) * | 1965-12-06 | 1970-03-17 | Smithkline Corp | Novel silicone compositions and method of preparing same |
US3518344A (en) * | 1967-10-02 | 1970-06-30 | Miles Lab | Tableting lubricant |
-
1970
- 1970-10-09 GB GB4816770A patent/GB1357737A/en not_active Expired
-
1971
- 1971-09-28 US US00184634A patent/US3853988A/en not_active Expired - Lifetime
- 1971-09-28 CA CA123,851A patent/CA974883A/en not_active Expired
- 1971-09-29 ES ES395533A patent/ES395533A1/es not_active Expired
- 1971-10-04 FR FR7135618A patent/FR2110314B1/fr not_active Expired
- 1971-10-05 DE DE19712149699 patent/DE2149699A1/de active Pending
- 1971-10-07 DK DK487571AA patent/DK129434B/da unknown
- 1971-10-08 SE SE7112796A patent/SE382560B/xx unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2805977A (en) * | 1955-01-04 | 1957-09-10 | Smith Kline French Lab | Sustained release pharmaceutical preparation |
US3094464A (en) * | 1960-04-01 | 1963-06-18 | Rech S Et Propagande Scient | Aspirin-antacid polysiloxane tablet |
US3133863A (en) * | 1961-03-10 | 1964-05-19 | Strong Cobb Arner Inc | Sustained release therapeutic tablet compositions comprising organic solvent-gelled gums |
US3382150A (en) * | 1962-05-01 | 1968-05-07 | Smith Kline French Lab | Spray-dried coated organopolysiloxane oral pharmaceutical or veterinary composition |
US3501571A (en) * | 1965-12-06 | 1970-03-17 | Smithkline Corp | Novel silicone compositions and method of preparing same |
US3518344A (en) * | 1967-10-02 | 1970-06-30 | Miles Lab | Tableting lubricant |
Non-Patent Citations (1)
Title |
---|
S. Africa, 67 04 097, 3/68, as abstracted in Chem. Abst., 70, No. 50482Z (1969). * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4675175A (en) * | 1981-10-08 | 1987-06-23 | A.E.C. Societe De Chimie Organique Et Biologique | Coated methionine granules for ruminants |
US4880791A (en) * | 1984-07-21 | 1989-11-14 | Hoechst Aktiengesellschaft | Combination product composed of xanthine derivatives and O-acetylsalicylic acid or its pharmacologically tolerated salts, and its use |
US6706281B2 (en) * | 1994-11-04 | 2004-03-16 | Euro-Celtique, S.A. | Melt-extrusion multiparticulates |
US20040081694A1 (en) * | 1994-11-04 | 2004-04-29 | Euro-Celtique, S.A. | Melt-extruded orally administrable opioid formulations |
US7510727B2 (en) | 1994-11-04 | 2009-03-31 | Purdue Pharma L.P. | Melt-extrusion multiparticulates |
US20110039807A1 (en) * | 2009-08-13 | 2011-02-17 | Kim Hyoung-Chun | Anti-parkinsonian compound acetylsalicylic acid maltol ester |
KR20150031300A (ko) * | 2012-07-17 | 2015-03-23 | 다우 글로벌 테크놀로지스 엘엘씨 | 유기 액체 희석제 및 매우 낮은 점도의 셀룰로즈 에테르를 포함하는 조성물 |
US20170028069A1 (en) * | 2012-07-17 | 2017-02-02 | Dow Global Technologies Llc | Composition comprising an organic liquid diluent and a cellulose ether of very low viscosity |
US10272156B2 (en) * | 2012-07-17 | 2019-04-30 | Dow Global Technologies Llc | Composition comprising an organic liquid diluent and a cellulose ether of very low viscosity |
US11000594B2 (en) | 2012-07-17 | 2021-05-11 | Dow Global Technologies Llc | Composition comprising an organic liquid diluent and a cellulose ether of very low viscosity |
Also Published As
Publication number | Publication date |
---|---|
DE2149699A1 (de) | 1972-04-13 |
FR2110314B1 (de) | 1975-06-06 |
DK129434C (de) | 1975-03-10 |
GB1357737A (en) | 1974-06-26 |
CA974883A (en) | 1975-09-23 |
SE382560B (sv) | 1976-02-09 |
DK129434B (da) | 1974-10-14 |
FR2110314A1 (de) | 1972-06-02 |
ES395533A1 (es) | 1974-10-16 |
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