Sustained release capsule or tablet formulation comprising a pharmaceutically acceptable dihydropyridine

• US 5,015,479 A
• Filed: 09/30/1988
• Issued: 05/14/1991
• Est. Priority Date: 02/02/1987
• Status: Expired due to Term

• Current Assignee: Elan Pharma International Limited (Perrigo Company PLC)
• Original Assignee: Elan Corporation PLC (Perrigo Company PLC)
• Inventors: Mulligan, Seamus, Sparks, Randall T.
• Primary Examiner(s): GRIFFIN, RONALD
• Application Number:
  US07/253,357
• Time in Patent Office: 956 Days
• Field of Search: 424/80, 424/457, 424/462, 424/463, 424/464, 424/465, 424/468, 424/469, 514/356, 514/965
• US Class Current: 424/457
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 9/146 with organic macromolecular 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 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• 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
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds

Abstract

A sustained release capsule or tablet formulation suitable for once-daily administration comprises an adsorbate of a mixture of a pharmaceutically useful dihydropyridine and a polyvinylpyrrolidone having an average-molecular weight greater than 55,000 adsorbed on a cross-linked polyvinylpyrrolidone and blended with a polymer or mixture of polymers which gel in the presence of water, the amount of said polymer or polymers being effective to produce the desired sustained release effect.

Claims

1. A sustained release capsule or tablet formulation suitable for once daily administration comprising an adsorbate of a mixture of 1 part by weight of a pharmaceutically acceptable substantially amorphous dihydropyridine and from 0.1 to 10 parts by weight of a polyvinylpyrrolidone having an average molecular weight of at least 55,000 and having a viscosity which serves to sustain the release of active ingredients, the mixture being adsorbed on a cross-linked polyvinylpyrrolidone in a ratio of 1 part by weight of said mixture to 0.5 to 20 parts by weight of cross-linked polyvinylpyrrolidone, blended with a polymeric material which gels in the presence of water, wherein said polymeric material is selected from the group consisting of a pharmaceutically acceptable water-soluble polymer, a pharmaceutically acceptable water-insoluble polymer or mixtures of said polymers, the amount and ratio of said water-soluble polymer to said water-insoluble polymer being effective in combination with the viscosity of the polyvinylpyrrolidone to produce the desired sustained release effect.

2. A formulation according to claim 1, wherein said gel forming polymer is present in an effective amount between 3 to 50% by weight of the formulation.

3. A formulation according to claim 1, wherein the dihydropyridine falls within the formula (I) ##STR2## wherein R₁ is aryl or heteroaryl each of which is unsubstituted or substituted and R₂, R₃, R₄ and R₅, which may be the same or different, each represents an unsubstituted or substituted alkyl group.

4. A sustained release formulation according to claim 3, wherein in the dihydropyridine of the formula I, R₁ is aryl or heteroaryl each of which is unsubstituted or substituted by a halogen atom or a nitro group and R₂, R₃, R₄ and R₅, which may be the same or different, each represents an alkyl group unsubstituted or substituted by a halogen atom or by an alkoxy, amino, alkylamino or aralkylamino group.

5. A sustained release formulation according to claim 4, wherein the dihydropyridine is selected from the group consisting of felodipine, nicardipine, nifedipine, nitrendipine, nimodipine, nisoldipine and 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydro-3-isopropyloxycarbonyl- pyridine-5-carboxylic acid methyl ester.

6. A sustained release formulation according to claim 1, wherein the polyvinylpyrrolidone is present in the adsorbate in an amount of 0.25-2 parts by weight relative to 1 part by weight of the dihydropyridine.

7. A sustained release formulation according to claim 1, which contains 1 part by weight of adsorbate relative to 1-10 parts by weight of cross-linked polyvinylpyrrolidone.

8. A sustained release formulation according to claim 1, wherein the polyvinylpyrrolidone has an average molecular weight in the range 55,000 to 75,000.

9. A sustained release formulation according to claim 1, wherein the polymer which gels in the presence of water is selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, alkylcelluloses, copolymers of acrylic and methacrylic acid esters, polyethylene glycol, sodium alginate, galactomannone and carboxypolymethylene or mixtures thereof.

10. A sustained release formulation according to claim 9, wherein the polymer is hydroxypropylmethylcellulose.

11. A process for preparing a sustained release formulation according to claim 1, which comprises dissolving the dihydropyridine and the polyvinylpyrrolidone in a common solvent, mixing the solution thereby obtained with a given quantity of the cross-linked polyvinylpyrrolidone so as to permit adsorption of said dihydropyridine and said polyvinylpyrrolidone to said cross-linked polyvinylpyrrolidone, removing the solvent, and blending the resulting product with said polymer or mixture of polymers which gel in the presence of water and encapsulating or tabletting the resulting blend.

12. A process according to claim 11, wherein the solvent used is any pharmaceutically acceptable co-solvent for the dihydropyridine and the polyvinylpyrrolidone.

13. A process according to claim 12, wherein the, solvent is selected from the group consisting of water, hexane, heptane, alcohols, ketones, halogenated aliphatic compounds, halogenated aromatic hydrocarbon compounds, aromatic hydrocarbon compounds and cyclic ethers or a mixture thereof.

14. A process according to claim 13, wherein the solvent is selected from the group consisting of water, hexane, heptane, methanol, ethanol, isopropyl alcohol, acetone, methylethyl ketone, methylisobutyl ketone, methylene chloride, chloroform, carbon tetrachloride, toluene, xylene and tetrahydrofuran.