Production of solid pharmaceutical depot forms

• US 5,490,990 A
• Filed: 06/21/1993
• Issued: 02/13/1996
• Est. Priority Date: 06/25/1992
• Status: Expired due to Term

• Current Assignee: BASF AG (BASF SE)
• Original Assignee: BASF AG (BASF SE)
• Inventors: Kah-Helbig, Astrid, Sanner, Axel, Grabowski, Sven, Wendel, Kurt
• Primary Examiner(s): Kulkosky, Peter F.
• Application Number:
  US08/078,824
• Time in Patent Office: 967 Days
• Field of Search: 424/486, 424/465, 514/772.5, 514/772.6, 514/781, 523/342
• US Class Current: 424/486
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Abstract

A process for the production of solid pharmaceutical depot forms by application of a reconstituted aqueous dispersion of a pharmaceutically acceptable binder to a core which contains active substance or by wet granulation of the pharmaceutical active substance with such a binder dispersion or by direct tableting of an active substance with the redispersible binder powder, wherein the binder has been obtained by emulsion polymerization and subsequent spray drying of the resulting aqueous dispersion with a water-soluble pharmaceutically acceptable spraying aid with a glass transition temperature of at least 60° C. and with or without a pharmaceutically acceptable antiblocking agent.

Claims

1. A process for the production of solid pharmaceutical depot forms by application of an aqueous dispersion, reconstituted by the addition of water to a pharmaceutically acceptable binder, to a core which contains active substance, wherein the binder is prepared by emulsion polymerization of an ethylenically unsaturated compound selected from the group consisting of C_1-18 alkyl(meth)acrylates, hydroxyalkyl(meth)acrylates, vinyl esters, vinyl lactams, mono- or dicarboxylic acids, monoesters or monoamides of these acids, N-vinylimidazole, N-vinylimidazoline, N-vinylimidazolidine, N-vinylpyridine, monoalkyl- or dialkylaminoalkyl esters or monoalkyl- or dialkylaminoalkylamides of polymerizable carboxylic acids, acrylamidoalkylsulfonic acids, trimethylammonioethyl methacrylate chloride and methylol(meth)acrylamides, which produces a water insoluble polymer, and subsequent spray drying of the resulting aqueous polymer dispersion with 5-50% by weight of a water-soluble pharmaceutically acceptable spraying aid selected from the group consisting of cellulose derivatives, polyvinylpyrrolidones, copolymers of N-vinylpyrrolidone and vinylacetate, starch derivatives and polyvinylalcohols with a glass transition temperature of at least 60°

C. and 0-50% by weight, based on the amount of binder, of a pharmaceutically acceptable antiblocking agent, the solid pharmaceutical depot forms exhibiting undiminished release properties of the active substance of the core.

4. The process of claim 1, wherein from 5-50% by weight of antiblocking agent selected from the group consisting of colloidal silicon dioxide, talc, calcium, magnesium or sodium carbonate, tricalcium orthophosphate, magnesium orthophosphate, microcrystalline cellulose and magnesium stearate is present.

7. A process for the production of solid pharmaceutical depot forms as claimed in claim 1, wherein the emulsion polymer employed as binder is comprised of vinyl acetate.

10. A process for the production of solid pharmaceutical depot forms as claimed in claim 1, wherein the emulsion polymer employed as binder is comprised of ethyl acrylate and methyl methacrylate in the ratio 2:

1 by weight.

13. A process for the production of solid pharmaceutical depot forms as claimed in claim 1, wherein the spray-dried emulsion polymer employed as binder contains a water-soluble N-vinylpyrrolidone polymer which contains 0-50% by weight of vinyl acetate as copolymerized units.

16. A process for the production of solid pharmaceutical depot forms as claimed in claim 1, wherein a water-soluble polysaccharide is employed as spraying aid.

2. A process for the production of solid pharmaceutical depot forms by wet granulation of a pharmaceutically active substance, with a aqueous binder dispersion, which has been reconstituted by the addition of water to a binder, wherein the binder is prepared by emulsion polymerization of an ethylenically unsaturated compound selected from the group consisting of C_1-18 alkyl(meth)acrylates, hydroxyalkyl(meth) acrylates, vinyl esters, vinyl lactams, mono- or dicarboxylic acids, monoesters or monoamides of these acids, N-vinylimidazole, N-vinylimidazoline, N-vinylimidazolidine, N-vinylpyridine, monoalkyl- or dialkylaminoalkyl esters or monoalkyl- or dialkylaminoalkylamides of polymerizable carboxylic acids, acrylamidoalkylsulfonic acids, trimethylammonioethyl methacrylate chloride and methylol(meth)acrylamides, which produces a water insoluble polymer, and subsequent spray drying of the resulting aqueous polymer dispersion with 5-50% by weight of a water-soluble pharmaceutically acceptable spraying aid selected from the group consisting of cellulose derivatives, polyvinylpyrrolidones, copolymers of N-vinylpyrrolidone and vinylacetate, starch derivatives and polyvinylalcohols with a glass transition temperature of at least 60°

C. and 0-50% by weight, based on the amount of binder, of a pharmaceutically acceptable antiblocking agent, the solid pharmaceutical depot forms exhibiting undiminished release properties of the active substance.

5. The process of claim 2, wherein from 5-50% by weight of antiblocking agent selected from the group consisting of colloidal silicon dioxide, talc, calcium, magnesium or sodium carbonate, tricalcium orthophosphate, magnesium orthophosphate, microcrystalline cellulose and magnesium stearate is present.

8. A process for the production of solid pharmaceutical depot forms as claimed in claim 2, wherein the emulsion polymer employed as binder is comprised of vinyl acetate.

11. A process for the production of solid pharmaceutical depot forms as claimed in claim 2, wherein the emulsion polymer employed as binder is comprised of ethyl acrylate and methyl methacrylate in the ratio 2:

1 by weight.

14. A process for the production of solid pharmaceutical depot forms as claimed in claim 2, wherein the spray-dried emulsion polymer employed as binder contains a water-soluble N-vinylpyrrolidone polymer which contains 0-50% by weight of vinyl acetate as copolymerized units.

17. A process for the production of solid pharmaceutical depot forms as claimed in claim 2, wherein a water-soluble polysaccharide is employed as spraying aid.

3. A process for the production of drug tablets by direct tabletting of an active substance and 5-99.9% by weight of a conventional pharmaceutical aid, wherein 5-95% by weight, based on the tablet, of a binder powder is prepared by emulsion polymerization of an ethylenically unsaturated compound selected from the group consisting of C_1-18 alkyl(meth)acrylates, hydroxyalkyl(meth)acrylates, vinyl esters, vinyl lactams, mono- or dicarboxylic acids, monoesters or monoamides of these acids, N-vinylimidazole, N-vinylimidazoline, N-vinylimidazolidine, N-vinylpyridine, monoalkyl- or dialkylaminoalkyl esters or monoalkyl- or dialkylaminoalkylamides of polymerizable carboxylic acids, acrylamidoalkylsulfonic acids, trimethylammonioethyl methacrylate chloride and methylol(meth)acrylamides, which produces a water insoluble polymer, and subsequent spray drying of the resulting aqueous polymer dispersion with 5-50% by weight of a water-soluble pharmaceutically acceptable spraying aid selected from the group consisting of cellulose derivatives, polyvinylpyrrolidones, copolymers of N-vinylpyrrolidone and vinylacetate, starch derivatives and polyvinylalcohols with a glass transition temperature of at least 60°

C. and 0-50% by weight, based on the amount of binder, of a pharmaceutically acceptable antiblocking agent, the solid tablets exhibiting undiminished release properties of the active substance.

6. The process of claim 3, wherein from 5-50% by weight of antiblocking agent selected from the group consisting of colloidal silicon dioxide, talc, calcium, magnesium or sodium carbonate, tricalcium orthophosphate, magnesium orthophosphate, microcrystalline cellulose and magnesium stearate is present.

9. A process for the production of solid pharmaceutical depot forms as claimed in claim 3, wherein the emulsion polymer employed as binder is comprised of vinyl acetate.

12. A process for the production of solid pharmaceutical depot forms as claimed in claim 3, wherein the emulsion polymer employed as binder is comprised of ethyl acrylate and methyl methacrylate in the ratio 2:

1 by weight.

15. A process for the production of solid pharmaceutical depot forms as claimed in claim 3, wherein the spray-dried emulsion polymer employed as binder contains a water-soluble N-vinylpyrrolidone polymer which contains 0-50% by weight of vinyl acetate as copolymerized units.

18. A process for the production of solid pharmaceutical depot forms as claimed in claim 3, wherein a water-soluble polysaccharide is employed as spraying aid.