Patent EA-002695-B1 (EA)
Title: Pharmaceutical compositions containing calcium valproate with delayed active substance release and method for the production of said composition
Inventor: GOBEL DAGMAR
IPC: A61K9/20
Filed: 1999-09-03
Abstract: 1. A pharmaceutical composition with delayed active substance release, characterized in that comprises calcium valproate, at least one acryl polymer and at least one sugar ester. 2. The pharmaceutical composition according to claim 1, characterized in that the acryl polymer is selected from the group comprising Eudragit<(RTM)> NE, Eudragit<(RTM)> L, Eudragit<(RTM)> S, Eudragit<(RTM)> RS and mixtures thereof. 3. The pharmaceutical composition according to claim 1 or 2, characterized in that a part of acryl polymer is substituted with shellac. 4. The pharmaceutical composition according to any of claims 1 to 3, characterized in that the sugar ester has a HLB balance greater than 10, preferably from 14 to 16, especially preferable from 15 to 16, solubility in water at 37 degree C not more than 1 portion of the sugar ester per 100 portions of water and solubility in water at 60-80 degree C of at least 1 portion of sugar ester per 10 portions of water, each time counting on the weight. 5. The pharmaceutical composition according to any of claims 1 to 4, characterized in that the sugar ester is sucrose palmitate or stearate. 6. The pharmaceutical composition according to any of claims 1 to 5, characterized in that the sugar ester sucrose palmitate is sucrose monopalmitate by about 70 %wt based to the sucrose palmitate. 7. The pharmaceutical composition according to any of claims 1 to 6, characterized in that comprises from 150 to 1000 mg of calcium valproate, from 1 to 5 wt%, preferably from 2 to 3 %wt, especially preferable about 2%wt, from 1 to 3 %wt of the Eudragit<(RTM)> NE, from 1 to 3 %wt, preferably from 2 to 3 %wt, especially preferable about 2.5%wt of the Eudragit<(RTM)> L and from 0.9 to 10%wt, preferably from 4 to 6%wt, especially preferable about 5%wt of the sucrose palmitate, each time the weight % is counted on the calcium valproate. 8. The pharmaceutical composition according to any of claims 1 to 7, characterized in that the composition is in the form of a breakable tablet. 9. The pharmaceutical composition according to claim 8, characterized in that the tablet or a part thereof provides in vitro at pH 6.8 a delayed active substance release maximum by 70% after 4 hours and a full active substance release after 12-6 hours, each time counting on the active substance content. 10. A method for producing a pharmaceutical composition with a delayed active substance release comprising calcium valproate according to any of claims 1 to 9, characterized by steps of introducing in the calcium valproate an aqueous dispersion, comprising Eudragit<(RTM)> NE or Eudragit<(RTM)> RS or a mixture thereof, an aqueous dispersion, comprising Eudragit<(RTM)> L or Eudragit<(RTM)> S or shellac or a mixture thereof, and an aqueous solution of sugar ester, if necessary, by adding suitable auxiliary substances such as talc, microcrystalline cellulose and magnesium stearate and, if necessary, by one or several drying steps to prepare a mixture for tabletting which is then pressed into tablets. 11. The method according to claim 8, characterized in that additions to the calcium valproate are effected in the following sequence: 1). Eudragit<(RTM)> NE or Eudragit<(RTM)> RS or a mixture thereof, 2). Eudragit<(RTM)> L or Eudragit<(RTM)> S or shellac or a mixture thereof, 3). sugar ester, each time with a subsequent drying. 12. The method according to claim 10 or 11, characterized in that the aqueous dispersion comprising Eudragit<(RTM)> L or Eudragit<(RTM)> S or shellac or a mixture thereof further comprises talc. 13. The method according to any of claims 1 to 12, characterized in that the sugar ester has a HLB balance greater than 10, preferably from 14 to 16, especially preferable from 15 to 16, solubility in water at 37 degree C not more than 1 portion of the sugar ester per 100 portions of water and solubility in water at 60-80 degree C of at least 1 portion of sugar ester per 10 portions of water, each time counting on the weight. 14. A pharmaceutical composition with a delayed active substance release, characterized in that said composition is produced by the method according to any of claims 1 to 13. 15. Use of the pharmaceutical composition according to one of claims 1 to 9 and 14 for treating epilepsy in humans and other mammals. 16. Use according to claim 15, characterized in that epilepsy is treated by administering said composition orally once or twice a day. 17. Use of the pharmaceutical composition according to one of claims 1 to 9 and 14 for treating migraine in humans or other mammals. 18. Use of the pharmaceutical composition according to one of claims 1 to 9 and 14 for treating manic-depressive diseases in humans or other mammals.