Oral capsule formulation with increased physical stability

• US 20030124182A1
• Filed: 12/20/2002
• Published: 07/03/2003
• Est. Priority Date: 12/21/2001
• Status: Active Grant

• Current Assignee: Supernus Pharmaceuticals Incorporated
• Original Assignee: Supernus Pharmaceuticals Incorporated
• Inventors: Burnside, Beth A., Ibrahim, Scott A., Shojaei, Amir H.
• Granted Patent: US 7,011,846 B2
• Time in Patent Office: Days
• US Class Current: 424/451
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds

Abstract

A formulation for a stabilized capsule for oral administration of a hydrophobic pharmaceutically active agent; comprising a non-aqueous solubilizer selected from 2-pyrrolidone, N-alkylpyrrolidones and combinations thereof; and a capsule stabilizing agent selected from mono-,di-and triglycerides, mono-and di-fatty esters of polyethylene glycol, fatty acids and combinations thereof wherein capsule integrity is maintained for at least 24 hours is disclosed.

Claims

1. - A formulation for a stabilized capsule for oral administration of a hydrophobic pharmaceutically active agent;

comprising a non-aqueous solubilizer selected from 2-pyrrolidone, N-alkylpyrrolidones and combinations thereof; and

a capsule stabilizing agent selected from mono-,di-and triglycerides, mono-and di-fatty esters of polyethylene glycol, fatty acids and combinations thereof.

2. - A formulation according to claim 1 wherein the solubilizer is 2-pyrrolidone, N-Methyl-2-Pyrrolidone, N-Ethyl-2-pyrrolidone, N-Propyl-2-pyrrolidone, N-Isopropyl-2-pyrrolidone, N-Butyl-2-pyrrolidone, N-(2-Hydroxyethyl)-2-pyrrolidone and mixtures thereof.

3. - A formulation according to claim 2 wherein the solubilizer is N-Methyl-2-Pyrrolidone or 2-pyrrolidone.

4. - A formulation according to claim 1 wherein the stabilizing agent is C_6-18 fatty ester of glycerol, C_6-18 fatty ester of polyethylene glycol, C_6-18 fatty ester of propylene glycol, C_6-18 fatty acid, Labrasol(R), Capmul MCM(R), Captex 200 (R), Captex 300 (R) Miglyol (R) or mixtures thereof.

5. - A formulation according to claim 4 wherein the stabilizing agent is C_8-10 fatty acid, Labrasol(R), Capmul MCM(R), Captex 200 (R), Captex 300 (R) Miglyol (R) or combinations thereof.

6. - A formulation according to any of claims 1 to 5 wherein the capsule stabilizing agent is present in sufficient amounts to maintain capsule wall integrity for at least 24 hours.

7. - A formulation according to claim 6 wherein the capsule stabilizing agent is present in amounts of from about 5% to about 200% by weight with respect to the non-aqueous solubilizer.

8. - A formulation according to claim 7 wherein the capsule stabilizing agent is present in amounts of from about 10% to about 150% by weight with respect to the non-aqueous solubilizer.

9. - A formulation according to claim 8 wherein the capsule stabilizing agent is present in amounts of from about 20% to about 100% by weight with respect to the non-aqueous solubilizer.

10. - A formulation according to claim 1 wherein the non-aqueous solubilizer is present in sufficient amounts to maintain the hydrophobic pharmaceutically active agent in solution or suspension.

11. - A formulation according to claim 1 wherein the non-aqueous solubilizer is a complexing agent.

12. - A pharmaceutical dosage unit form comprising hydrophobic pharmaceutically active agent, a non-aqueous solubilizer selected from 2-pyrrolidone, N—

C₁₄ alkylpyrrolidones or mixtures thereof and a capsule stabilizing agent selected from fatty esters of glycerol, fatty esters of polyethylene glycol, fatty esters of propylene glycol, fatty acids or mixtures thereof.

13. - A pharmaceutical dosage unit form comprising hydrophobic pharmaceutically active agent solubilized in N-methyl-2-pyrrolidone in combination with at least one stabilizing agent selected from C_8-10 fatty acids, Labrasol(R), Capmul MCM(R), Captex 200 (R), Captex 300 (R) Miglyol (R) and combinations thereof.

14. - A method for producing a stabilized capsule for oral administration of a pharmaceutical agent comprising:

mixing a non-aqueous solubilizer selected from 2-pyrrolidone, N—

C_1-4 alkylpyrrolidones or mixtures thereof and a hydrophobic pharmaceutically active agent;

incorporating a capsule stabilizing agent selected from C_8-10 fatty acids, Labrasol(R), Capmul MCM(R), Captex 200 (R), Captex 300 (R) Miglyol (R) and combinations thereof to the result of the first step; and

incorporating the result of the second step in a capsule;

wherein the capsule stabilizing agent is present in sufficient amounts to maintain capsule wall integrity for at least 24 hours.