Process for preparing non-hygroscopic sodium valproate composition

Abstract

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.

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 produce said mixture having the following property: when compressed into tablets, said tablets do not absorb more than 5% water by weight after being stored for 3 months at 75% relative humidity.  
     
     
         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 1:100.  
     
     
         4 . 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.  
     
     
         5 . 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.  
     
     
         6 . 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.  
     
     
         7 . The process of  claim 1 , further comprising a step of compressing said non-hygroscopic composition into a solid dosage form.  
     
     
         8 . The process of  claim 7 , wherein said solid dosage form contains from about 50 to about 1200 mg of sodium valproate.  
     
     
         9 . The process of  claim 8 , wherein said solid dosage form contains from about 6 mg to about 400 mg of carbomer.  
     
     
         10 . The process of  claim 9 , wherein, said solid dosage form contains from about 90 mg to about 400 mg of non-hygroscopic additive.  
     
     
         11 . The process of  claim 3 , wherein said non-hygroscopic additive is selected from the group consisting of dibasic calcium phosphate anhydrous, calcium silicate, microcrystalline cellulose and mixtures thereof.  
     
     
         12 . The process of  claim 3 , 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.  
     
     
         13 . The process of  claim 6 , wherein said excipient is selected from the group consisting of lubricants, disintegrators, glidants, adsorbents, and mixtures thereof.  
     
     
         14 . The process of  claim 13 , 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.  
     
     
         15 . The process of  claim 14 , wherein said lubricant is present in an amount of from about 0.25% to about 5% of the weight of the final composition.  
     
     
         16 . The process of  claim 13 , 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.  
     
     
         17 . The process of  claim 16 , wherein said disintegrator is present in an amount of from about 0.5% to about 25% of the weight of the final composition.  
     
     
         18 . The process of  claim 12 , wherein said glidant is selected from the group consisting of colloidal silicon dioxide, talc and mixtures thereof.  
     
     
         19 . The process of  claim 18 , wherein said glidant is present in an amount of from about 0.1% to about 10% of the weight of the final composition.  
     
     
         20 . The process of  claim 13 , wherein said adsorbent is selected from the group consisting of colloidal silicon dioxide, microcrystalline cellulose, calcium silicate and mixtures thereof.  
     
     
         21 . The process of  claim 20 , wherein said adsorbent is present in an amount of from about 0.05% to about 42% of the weight of the final composition.  
     
     
         22 . The process of  claim 7 , 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.  
     
     
         23 . The process of  claim 21 , wherein the tablet is an enteric coated tablet.  
     
     
         24 . The process of  claim 21 , wherein the tablet is coated wi th an anti-moisture barrier.  
     
     
         25 . The process of  claim 1 , wherein said mixing is carried out in conditions of relative humidity of greater than 30%.  
     
     
         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-hygroscopic additive 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 after being stored for 3 months at 75% relative humidity.  
     
     
         27 . 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-hygroscopic additive 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 after being stored for 3 months at 75% relative humidity.  
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein said hygroscopic salt of valproic acid is sodium valproate.  
     
     
         29 . The pharmaceutical composition of  claim 27 , wherein the weight ratio of carbomer to the hygroscopic salt of valproic acid ranges from about 1:3 to about 1:100.  
     
     
         30 . The pharmaceutical composition of  claim 27 , wherein the weight ratio of carbomer to the hygroscopic salt of valproic acid ranges from about 1:3 to about 1:10.  
     
     
         31 . The pharmaceutical composition of  claim 29 , 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 to about 1:2.  
     
     
         32 . The pharmaceutical compostion of  claim 31 , 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.  
     
     
         33 . The pharmaceutical composition of  claim 27 , further comprising at least one excipient.  
     
     
         34 . The pharmaceutical composition of  claim 27 , wherein the composition contains from about 50 to about 1200 mg of sodium valproate.  
     
     
         35 . The pharmaceutical composition of  claim 34 , wherein the composition contains from about 6 mg to about 400 mg of carbomer.  
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein the composition contains from about 90 mg to about 400 mg of non-hygroscopic additive.  
     
     
         37 . The pharmaceutical composition of  claim 27 , wherein said non-hygroscopic additive is selected from the group consisting of dibasic calcium phosphate anhydrous, calcium silicate, microcrystalline cellulose and mixtures thereof.  
     
     
         38 . The pharmaceutical composition of  claim 27 , further comprising an excipient selected from the group consisting of lubricants, disintegrators, glidants, adsorbents, and mixtures thereof.  
     
     
         39 . The pharmaceutical composition of  claim 38  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.  
     
     
         40 . The pharmaceutical composition of  claim 39 , wherein said lubricant is present in an amount of from out 0.25% to about 5% of the weight of the final composition.  
     
     
         41 . The pharmaceutical composition of  claim 38 , 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.  
     
     
         42 . The pharmaceutical composition of  claim 41 , wherein said disintegrator is present in an amount of from about 0.5% to about 25% of the weight of the final composition.  
     
     
         43 . The pharmaceutical composition of  claim 38 , wherein said glidant is selected from the group consisting of colloidal silicon dioxide, talc and mixtures thereof.  
     
     
         44 . The pharmaceutical composition of  claim 43 , wherein said glidant is present in an amount of from about 0.1% to about 10% of the weight of the final composition.  
     
     
         45 . The pharmaceutical composition of  claim 38 , wherein said adsorbent is selected from the group consisting of colloidal silicon dioxide, microcrystalline cellulose, calcium silicate and mixtures thereof.  
     
     
         46 . The pharmaceutical composition of  claim 45 , wherein said adsorbent is present in an amount of from about 0.05% to about 42% of the weight of the final composition.  
     
     
         47 . The pharmaceutical composition of  claim 27 , 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.  
     
     
         48 . The pharmaceutical composition of  claim 47 , wherein the tablet is an enteric coated tablet.  
     
     
         49 . The pharmaceutical composition of  claim 48 , wherein the tablet is coated with an anti-moisture barrier.  
     
     
         50 . The pharmaceutical composition of  claim 27 , wherein the non-hygroscopic oral pharmaceutical composition is a sustained release tablet wherein the weight ratio of carbomer to the hygroscopic salt of valproic acid ranges from about 1:6 to about 1:20.  
     
     
         51 . The pharmaceutical composition of  claim 50 , wherein the non-hygroscopic oral pharmaceutical composition is a sustained release tablet.  
     
     
         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 physiologically effective level, wherein said composition comprises a pharmaceutically effective amount of a hygroscopic salt of valproic acid, a carrier, and a non-hygroscopic additive, and wherein the weight ratio of the carbomer to the hygroscopic salt of valproic acid 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.  
     
     
         53 . The method of  claim 52 , wherein said medical condition is epilepsy.  
     
     
         54 . The method of  claim 52 , wherein said medical condition is a psychotic disorder.  
     
     
         55 . The method of  claim 52 , wherein said medical condition is a migraine headache.