Process for preparing non-hygroscopic sodium valproate composition

The invention is directed to non-hygroscopic oral pharmaceutical compositions of a salt of valproic acid, and processes for preparing the compositions. The non-hygroscopic pharmaceutical compositions are prepared by blending a hygroscopic salt of valproic acid, carbomer, and a non-hygroscopic additive.

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What is claimed is:

1. A process for preparing a pharmaceutical composition comprising as an active ingredient a hygroscopic salt of valproic acid, comprising the step of intimately mixing (i)said hygroscopic salt; (ii) a carbomer and (iii) a non-hygroscopic additive to form a homogeneous mixture; wherein the amount of said carbomer and said non-hygroscopic additive are sufficient relative to the amount of said hygroscopic salt to producesaid mixture having the following property: when compressed into tablets, said tablets do not absorb more than 5% water by weight when tested after being stored for 3 months at 75% relative humidity; wherein said pharmaceutical composition is free ofvalproic acid; and wherein the weight ratio of carbomer to the hygroscopic salt of valproic acid ranges from about 1:3 to about 1:100.

2. The process of claim 1, wherein said hygroscopic salt of valproic acid is sodium valproate.

3. The process of claim 1, wherein the weight ratio of carbomer to the hygroscopic salt of valproic acid ranges from about 1:3 to about 1:10.

4. The process of claim 1, wherein the weight ratio of non-hygroscopic additive to the hygroscopic salt of valproic acid ranges from about 1:6 to about 1:2.

5. The process of claim 1, further comprising a step of adding at least one excipient to the mixture of said hygroscopic salt, said carbomer and said non-hygroscopic additive.

6. The process of claim 1, further comprising a step of directly compressing said non-hygroscopic composition into a solid dosage form.

7. The process of claim 6, wherein said solid dosage form contains from about 50 to about 1200 mg of sodium valproate.

8. The process of claim 7, wherein said solid dosage form contains from about 6 mg to about 400 mg of carbomer.

9. The process of claim 8, wherein, said solid dosage form contains from about 90 mg to about 400 mg of non-hygroscopic additive.

10. The process of claim 1, wherein said non-hygroscopic additive is selected from the group consisting of dibasic calcium phosphate anhydrous, calcium silicate, microcrystalline cellulose and mixtures thereof.

11. The process of claim 1, wherein said non-hygroscopic additive is present in an amount such that the weight ratio of non-hygroscopic additive to the hygroscopic salt of valproic acid is in the range of from about 1:6 to 1:2.

12. The process of claim 5, wherein said excipient is selected from the group consisting of lubricants, disintegrators, glidants, adsorbents, and mixtures thereof.

13. The process of claim 12, wherein said lubricant is selected from the group consisting of stearic acid, a salt of stearic acid, talc, sodium lauryl sulfate, sodium stearyl fumarate and mixtures thereof.

14. The process of claim 13, wherein said lubricant is present in an amount of from about 0.25% to about 5% of the weight of the final composition.

15. The process of claim 12, wherein said disintegrator is selected from the group consisting of crosscarmelose sodium, sodium starch glycolate, starch, magnesium aluminum silicate, colloidal silicon dioxide, carboxymethyl cellulose,microcrystalline cellulose, and mixtures thereof.

16. The process of claim 15, wherein said disintegrator is present in an amount of from about 0.5% to about 25% of the weight of the final composition.

17. The process of claim 12, wherein said glidant is selected from the group consisting of colloidal silicon dioxide, talc and mixtures thereof.

18. The process of claim 17, wherein said glidant is present in an amount of from about 0.1% to about 10% of the weight of the final composition.

19. The process of claim 12, wherein said adsorbent is selected from the group consisting of colloidal silicon dioxide, microcrystalline cellulose, calcium silicate and mixtures thereof.

20. The process of claim 19, wherein said adsorbent is present in an amount of from about 0.05% to about 42% of the weight of the final composition.

21. The process of claim 6, wherein said solid dosage form is selected from the group consisting of a tablet, a caplet, a pellet, a capsule, a tablet which disintegrates into granules, and a pill.

22. The process of claim 21, wherein the tablet is an enteric coated tablet.

23. The process of claim 21, wherein the tablet is coated with an anti-moisture barrier.

24. The process of claim 1, wherein said mixing is carried out in conditions of relative humidity of greater than 30%.

25. A non-hygroscopic oral pharmaceutical composition comprising a pharmaceutically effective amount of a hygroscopic salt of valproic acid, a carbomer, and a non-hygroscopic additive, wherein the amount of said carbomer and said non-hygroscopicadditive are sufficient relative to the amount of said hygroscopic salt to produce said composition having the following property: not absorbing more than 5% by weight water when tested after being stored for 3 months at 75% relative humidity; whereinsaid pharmaceutical composition is free of valproic acid; and wherein the weight ratio of carbomer to the hygroscopic salt of valproic acid ranges from about 1:3 to about 1:100.

26. A non-hygroscopic oral pharmaceutical composition comprising a pharmaceutically effective amount of a hygroscopic salt of valproic acid, a carbomer, and a non-hygroscopic additive, wherein the amount of said carbomer and said non-hygroscopicadditive are sufficient relative to the amount of said hygroscopic salt to produce said composition having the following property: when compressed into tablets, said tablets do not absorb more than 5% by weight water when tested after being stored for 3months at 75% relative humidity; wherein said pharmaceutical composition is free of valproic acid; and wherein the weight ratio of carbomer to the hygroscopic salt of valproic acid ranges from about 1:3 to about 1:100.

27. The pharmaceutical composition of claim 26, wherein said hygroscopic salt of valproic acid is sodium valproate.

28. The pharmaceutical composition of claim 26, wherein the weight ratio of carbomer to the hygroscopic salt of valproic acid ranges from about 1:3 to about 1:10.

29. The pharmaceutical composition of claim 26, wherein the non-hygroscopic additive is present in an amount such that the weight ratio of non-hygroscopic additive to the hygroscopic salt of valproic acid is in the range of from about 1:6 toabout 1:2.

30. The pharmaceutical compostion of claim 29, wherein said non-hygroscopic additive is present in an amount such that the weight ratio of the non-hygroscopic additive to the carbomer is in the range of from about 2:1 to about 35:1.

31. The pharmaceutical composition of claim 26, further comprising at least one excipient.

32. The pharmaceutical composition of claim 26, wherein the composition contains from about 50 to about 1200 mg of sodium valproate.

33. The pharmaceutical composition of claim 32, wherein the composition contains from about 6 mg to about 400 mg of carbomer.

34. The pharmaceutical composition of claim 33, wherein the composition contains from about 90 mg to about 400 mg of non-hygroscopic additive.

35. The pharmaceutical composition of claim 26, wherein said non-hygroscopic additive is selected from the group consisting of dibasic calcium phosphate anhydrous, calcium silicate, microcrystalline cellulose and mixtures thereof.

36. The pharmaceutical composition of claim 26, further comprising an excipient selected from the group consisting of lubricants, disintegrators, glidants, adsorbents, and mixtures thereof.

37. The pharmaceutical composition of claim 36 wherein said lubricant is selected from the group consisting of stearic acid, a salt of stearic acid, talc, sodium lauryl sulfate, sodium stearyl fumarate and mixtures thereof.

38. The pharmaceutical composition of claim 37, wherein said lubricant is present in an amount of from out 0.25% to about 5% of the weight of the final composition.

39. The pharmaceutical composition of claim 36, wherein said disintegrator is selected from the group consisting of crosscarmelose sodium, sodium starch glycolate, starch, magnesium aluminum silicate, colloidal silicon dioxide, carboxymethylcellulose, microcrystalline cellulose, and mixtures thereof.

40. The pharmaceutical composition of claim 39, wherein said disintegrator is present in an amount of from about 0.5% to about 25% of the weight of the final composition.

41. The pharmaceutical composition of claim 36, wherein said glidant is selected from the group consisting of colloidal silicon dioxide, talc and mixtures thereof.

42. The pharmaceutical composition of claim 41, wherein said glidant is present in an amount of from about 0.1% to about 10% of the weight of the final composition.

43. The pharmaceutical composition of claim 36, wherein said adsorbent is selected from the group consisting of colloidal silicon dioxide, microcrystalline cellulose, calcium silicate and mixtures thereof.

44. The pharmaceutical composition of claim 43, wherein said adsorbent is present in an amount of from about 0.05% to about 42% of the weight of the final composition.

45. The pharmaceutical composition of claim 26, wherein the non-hygroscopic oral pharmaceutical composition is a tablet, a caplet, a pellet, a capsule, a tablet which disintegrates into granules, and a pill.

46. The pharmaceutical composition of claim 45, wherein the tablet is an enteric coated tablet.

47. The pharmaceutical composition of claim 46, wherein the tablet is coated with an anti-moisture barrier.

48. The pharmaceutical composition of claim 26, wherein the non-hygroscopic oral pharmaceutical composition is a sustained release tablet.

49. The pharmaceutical composition of claim 48, wherein the weight ratio of carbomer to the hygroscopic salt of valproic acid ranges from about 1:6 to about 1:20.

50. A method of treating a medical condition in a human patient, the method comprising the step of orally administering a non-hygroscopic pharmaceutical composition for release of a salt of valproic acid into the bloodstream at a physiologicallyeffective level, wherein said composition comprises a pharmaceutically effective amount of a hygroscopic salt of valproic acid, a carbomer, and a non-hygroscopic additive, and wherein the weight ratio of the carbomer to the hygroscopic salt of valproicacid is from about 1:3 to about 1:100 and the weight ratio of the non-hygroscopic additive to the hygroscopic salt of valproic acid is from about 1:6 to about 1:2; wherein said pharmaceutical composition is free of valproic acid; and wherein saidmedical condition is epilepsy.

51. A method of treating a medical condition in a human patient, the method comprising the step of orally administering a non-hygroscopic pharmaceutical composition for release of a salt of valproic acid into the bloodstream at a physiologicallyeffective level, wherein said composition comprises a pharmaceutically effective amount of a hygroscopic salt of valproic acid, a carbomer, and a non-hygroscopic additive, and wherein the weight ratio of the carbomer to the hygroscopic salt of valproicacid is from about 1:3 to about 1:100 and the weight ratio of the non-hygroscopic additive to the hygroscopic salt of valproic acid is from about 1:6 to about 1:2; wherein said pharmaceutical composition is free of valproic acid; and wherein saidmedical condition is a psychotic disorder.

52. A method of treating a medical condition in a human patient, the method comprising the step of orally administering a non-hygroscopic pharmaceutical composition for release of a salt of valproic acid into the bloodstream at a physiologicallyeffective level, wherein said composition comprises a pharmaceutically effective amount of a hygroscopic salt of valproic acid, a carbomer, and a non-hygroscopic additive, and wherein the weight ratio of the carbomer to the hygroscopic salt of valproicacid is from about 1:3 to about 1:100 and the weight ratio of the non-hygroscopic additive to the hygroscopic salt of valproic acid is from about 1:6 to about 1:2; wherein said medical condition is a migraine headache.

53. The method of claim 1 wherein the weight ratio of the carbomer to the hygroscopic salt of valproic acid ranges from about 1:3 to about 1:100, and the weight ratio of the non-hygroscopic additive to the hygroscopic salt of valproic acidranges from about 1:6 to about 1:2.

54. The method of claim 53 further comprising a step of directly compressing the composition into a solid dosage form.

55. The composition of claim 26, said composition having been formed into a solid dosage form by direct compression.