ENTERIC VALPROIC ACID

• US 20070098786A1
• Filed: 10/11/2006
• Published: 05/03/2007
• Est. Priority Date: 10/11/2005
• Status: Abandoned Application

• Current Assignee: Patheon Softgels, Inc. (Thermo Fisher Scientific Incorporated)
• Original Assignee: Banner Pharmacaps Incorporated (Thermo Fisher Scientific Incorporated)
• Inventors: Fatmi, Aqeel, Chidambaram, Nachiappan
• Application Number:
  US11/548,607
• Publication Number:
  US 20070098786A1
• Time in Patent Office: Days
• US Class Current: 424/456
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 9/4816 Wall or shell material
• CPC Class Codes: A61K 9/4833 Encapsulating processes; Filling of capsules mechanical aspects A61J3/07
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds

Abstract

An enteric valproic acid soft gelatin capsule, in which the enteric polymer is a component of the capsule shell rather than a coating, has been developed. The fill material comprises valproic acid or divalproex sodium and, optionally, one or more pharmaceutically acceptable excipients such as corn oil. The capsule shell is prepared from a mass comprising a film-forming polymer, an acid insoluble polymer, an aqueous solvent, and optionally a plasticizer. Suitable film-forming polymers include gelatin. Suitable acid-insoluble polymers include acrylic-acid/methacrylic acid copolymers. The acid-insoluble polymer is present in an amount from about 8% to about 20% by weight of the wet gel mass. The weight ratio of acid-insoluble polymer to film-forming polymer is from about 25% to about 50%. The aqueous solvent is water or an aqueous solution of alkalis such as ammonia or diethylene amine or hydroalcoholic solutions of the same. Suitable plasticizers include glycerin and triethylcitrate. The enteric soft gelatin capsule does not require an enteric coating and thus is not susceptible to the processing problems associated with enteric coated dosage forms. Enteric valproic acid soft gelatin capsules may be smaller in size and thus easier to swallow than currently available enteric coated tablets due to the presence of fewer ingredients, as well as smaller amounts of ingredients in the capsule shell.

Claims

1. An enteric valproic acid soft gelatin capsule comprising:

(a) a fill material comprising valproic acid or divalproex sodium; and

(b) a capsule shell comprising a gelatin mass, film-forming water soluble polymer, an acid-insoluble polymer, and an aqueous solvent.

2. The capsule of claim 1, wherein valproic acid is present in an amount from about 25% to about 100% by weight of the fill.

3. The capsule of claim 1, wherein the concentration of divalproex sodium is from about 25% to about 100% by weight of the fill, preferably 40%.

4. The capsule of claim 1 wherein the capsule contains a dosage of valproic acid, divalproex sodium, or mixture thereof selected from the group consisting of 125 mg, 250 mg, and 500 mg.

5. The capsule of claim 1 wherein the shell comprises additional components selected from the group consisting of plasticizers, coloring agents, opacifiers, humectants, preservatives, flavorings, and buffering salts and acids.

6. The capsule of claim 1, wherein the fill material further comprises one or more pharmaceutically acceptable excipients.

7. The capsule of claim 6, wherein the one or more excipients is selected from the group consisting of crystallization inhibitors, wetting agents, bulk filling agents, solubilizers, bioavailability enhancers, solvents, pH-adjusting agents, dyes, preservatives, solvents, surfactants, and combinations thereof.

8. The capsule of claim 6 wherein the excipient is a solubilizer selected from the group consisting of soybean oil, rapeseed oil, safflower oil, corn oil, olive oil, castor oil, oleic acid, medium chain triglycerides, mono- and diglycerides, medium chain triglyceride esters, medium chain partial triglycerides, sorbitan monooleate, polysorbates, ethoxylated castor oil, bees wax, hydrogenated soybean oil, partially hydrogenated soybean oil, and acetylated triglycerides.

9. The capsule of claim 8 wherein the solubilizer is corn oil.

10. The capsule of claim 1 wherein the film-forming polymer is of natural origin.

11. The capsule of claim 10 wherein the film forming polymer is a natural film forming material selected from the group consisting of gelatin, shellac, alginates, pectin, and zeins.

12. The capsule of claim 11 wherein the natural film-forming polymer is gelatin.

13. The capsule of claim 1 wherein the film forming polymer is of synthetic origin.

14. The capsule of claim 13 wherein the film-forming polymer is selected from the group consisting of hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, and cellulose acetate phthalate.

15. The capsule of claim 1 wherein the acid-insoluble polymer is selected from the group consisting of cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, alginic acid salts such as sodium or potassium alginate, shellac, acrylic acid-methylacrylic acid copolymers.

16. The capsule of claim 15 wherein the acid-insoluble polymer is an acrylic acid-methacrylic acid copolymer.

17. The capsule of claim 1 wherein the acid-insoluble polymer is present in an amount from about 8 to about 20% by weight of the wet gelatin mass.

18. The capsule of claim 17 wherein the acid-insoluble polymer is present in an amount of about 12% by weight of the wet gelatin mass.

19. The capsule of claim 1 wherein the weight ratio of acid-insoluble polymer to film-forming polymer is from about 15% to about 50%.

20. The capsule of claim 1 wherein the aqueous solvent is water

21. The capsule of claim 1 wherein the aqueous solvent an aqueous solution of an alkali selected from the group consisting of ammonia, sodium hydroxide, potassium hydroxide, hydroxyl amine, triethanol amine, and ethylene diamine.

22. The capsule of claim 21 wherein the aqueous solvent is present in an amount sufficient to give a final pH of the gelatin mass of less than or equal to 9.0.

23. The capsule of claim 21 wherein the aqueous solvent is present in an amount sufficient to give a final pH of the gelatin mass of less than or equal to 8.5.

24. The capsule of claim 20 wherein the aqueous solvent is present in an amount sufficient to give a final pH of the gelatin mass of less than or equal to 8.0.

25. The capsule of claim 1 wherein the plasticizer to polymer ratio is from about 10% to about 50% of the polymer weight.

26. The capsule of claim 1 wherein the final moisture content of the capsule is from about 2% to about 10% by weight of the capsule.

27. The capsule of claim 26 wherein the final moisture content of the capsule is from about 4% to about 8% by weight of the capsule.

28. A capsule comprising valproic acid, wherein the valproic acid is released following oral administration to a fasting individual to produce a C_max between approximately 37.6 and 72.5 mg valproic acid/ml blood with a T_max of between 1 and 4 hours.

29. The capsule of claim 28 wherein the valproic acid is released following oral administration to a non-fasting individual to produce a C_max between 27.2 and 58.64 mg valproic acid/ml blood with a T_max of between 3 and 9 hours.

30. The capsule of claim 28 wherein the C_max is between 42.3 and 67.5 mg valproic acid/ml blood with a T_max of between 1.35 and 3 hours in a fasting individual.

31. The capsule of claim 29 wherein the C_max is between 31 and 53.8 mg valproic acid/ml blood with a T_max of between 3 and 9 hours.