Claims for Patent: 6,514,531

Summary for Patent: 6,514,531

Title:	Controlled-release dosage forms comprising zolpidem or a salt thereof
Abstract:	The present invention relates to controlled-release dosage forms of zolpidem or salts thereof adapted to release zolpidem over a predetermined time period, according to a biphasic profile of dissolution, where the first phase is an immediate release phase and the second phase is a prolonged release phase and particular embodiments thereof intended to avoid abuse.
Inventor(s):	Alaux; Gerard (Beynes, FR), Lewis; Gareth (Dourdan, FR), Andre; Frederic (Antony, FR)
Assignee:	Sanofi-Synthelabo (Paris, FR)
Application Number:	09/857,154
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,514,531
Patent Claims:	1. A pharmaceutical controlled-release dosage form adapted to release zolpidem or a salt thereof over a predetermined time period, according to a biphasic in vitro profile of dissolution when measured in a type II dissolution apparatus according to the U.S. Pharmacopoeia in 0.01M hydrochloric acid buffer at 37.degree. C., where the first phase is an immediate release phase having a maximum duration of 30 minutes and the second phase is a prolonged release phase, and wherein 40 to 70% of the total amount of zolpidem is released during the immediate release phase and the time for release of 90% of the total amount of zolpiderm is between 2 and 6 hours. 2. A pharmaceutical controlled-release dosage form according to claim 1 wherein the second phase has a profile of zero order release. 3. A pharmaceutical controlled-release dosage form according to claim 1 wherein the second phase has a profile where the release is proportional to the square root of the time. 4. A pharmaceutical controlled-release dosage form according to claim 1 wherein the second phase has a profile of first order release. 5. A pharmaceutical controlled-release dosage form according to claim 1 wherein the second phase has a sigmoidal release profile. 6. A pharmaceutical composition comprising zolpidem or a salt thereof in the form of a controlled-release dosage form according to claim 1 wherein said composition comprises an immediate release entity and a prolonged release entity. 7. A pharmaceutical composition according to claim 6 in a dosage form selected from capsules, tablets, multilayer tablets and multicoated tablets. 8. A pharmaceutical composition according to claim 7 in the form of a capsule comprising one or more immediate release tablets and one or more prolonged release tablets. 9. A pharmaceutical composition according to claim 7 in the form of a capsule comprising a mixture of prolonged release pellets and immediate release pellets. 10. A pharmaceutical composition according to claim 7 in the form of a tablet comprising a number of prolonged release coated pellets comprising the drug imbedded in a matrix also comprising the drug. 11. A pharmaceutical composition according to claim 7 in the form of a multilayer tablet comprising: (i) one or two prolonged release layers, comprising the drug and a hydrophilic polymer, and (ii) one or more immediate release layers comprising the drug. 12. A pharmaceutical composition according to claim 7 in the form of a multicoated tablet comprising: (i) a core comprising the drug, (ii) a polymer coating layer giving slow release of the drug from this core, (iii) a coating layer comprising the drug which is released rapidly or immediately on contact of the dosage form with fluid. 13. A pharmaceutical composition according to claim 6 wherein the immediate release entity and the prolonged release entity are administered simultaneously but separately. 14. A pharmaceutical controlled-release dosage form according to claim 1 containing a pharmaceutically acceptable organic acid selected from tartaric, malic, fumaric, lactic, citric, adipic and succinic acids or their acid salts. 15. A pharmaceutical controlled-release dosage form according to claim 1 capable of generating visual change if it is introduced into a drink, whether or not containing alcohol. 16. A pharmaceutical controlled-release dosage form according to claim 15 wherein the visual change consists of release of coloring excipients, or floating of the dosage form at the surface of the drink, or formation of insoluble particles on the surface of the drink, on the brim of the glass, in the drink and/or on the bottom of the glass or a combination thereof. 17. A pharmaceutical controlled-release dosage form according to claim 16 containing an effervescence generator, a hydrophilic excipient and optionnally a lipophilic excipient and a colouring excipient, in the form of a tablet, a multilayer tablet or a capsule containing controlled release pellets and immediate release pellets or granulates. 18. A pharmaceutical controlled-release dosage form according to claim 1 wherein zolpidem is present as zolpidem hemitartrate. 19. A pharmaceutical controlled-release dosage form according to claim 1 wherein the release rate profile of the second phase is zero order, first order, sigmoidal, proportional to the square root of the time or is intermediate between said profiles. 20. A pharmaceutical composition according to claim 11 wherein the hydrophilic polymer in the one or two prolonged release layers is a cellulose derivative. 21. A pharmaceutical composition according to claim 11 additionally comprising a layer containing hydrophilic polymers but not drug. 22. A pharmaceutical composition according to claim 12 wherein the core contains a pharmaceutically acceptable organic acid. 23. A pharmaceutical composition according to claim 6 wherein the prolonged release entity comprises a pharmaceutically acceptable organic acid selected among tartaric, malic, fumaric, lactic, citric, adipic and succinic acids or their acid salts. 24. A pharmaceutical composition according to claim 22 wherein the prolonged release entity comprises a pharmaceutically acceptable organic acid selected from tartaric, malic, fumaric, lactic, citric, adipic, and succinic acids or their acid salts. 25. A pharmaceutical composition according to claim 6 capable of generating visual change if it is introduced into a drink whether or not containing alcohol. 26. A pharmaceutical composition according to claim 25 wherein the visual change consists of release of included coloring excipients, or floating of the composition at the surface of the drink, a formation of insoluble particles on the surface of the drink, on the brim of the glass, in the drink and/or on the bottom of the glass or a combination thereof. 27. A pharmaceutical composition according to claim 26 containing an effervescence generator, a hydrophilic excipient and optionally a lipophilic excipient and a coloring excipient, in the form of a table, a multilayer tablet or a capsule containing controlled-release pellets and immediate-release pellets or granulates. 28. A pharmaceutical composition according to claim 6 wherein zolpidem is present as zolpidem hemitartrate. 29. A pharmaceutical composition according to claim 28 containing 12.5 mg of zolpidem hemitartrate. 30. A pharmaceutical controlled-release dosage form according to claim 1 containing 4 to 16 mg of zolpidem as zolpidem base. 31. A pharmaceutical composition according to claim 6 containing 4 to 16 mg of zolpidem as zolpidem base. 32. A pharmaceutical composition according to claim 7 in the form of a multilayer tablet comprising an immediate release layer and a prolonged release layer. 33. A pharmaceutical composition according to claim 32 wherein the multilayer tablet is a bi-layer tablet. 34. A pharmaceutical controlled-release dosage form according to claim 18 containing 12.5 mg of zolpidem hemitartrate. 35. A pharmaceutical controlled-release dosage form according to claim 1 wherein the in vitro profile of dissolution is measured in a type II dissolution apparatus according to the U.S. Pharmacopoeia in 0.01M hydrochloric acid buffer at 37.degree. C. stirred at a rate of about 50-75 rpm. 36. A pharmaceutical controlled-release dosage form according to claim 35 containing a pharmaceutically acceptable organic acid selected from tartaric, malic, fumaric, lactic, citric, adipic, and succinic acids or their acid salts. 37. A pharmaceutical controlled-release dosage form according to claim 35 containing 4 to 16 mg of zolpidem as zolpidem base. 38. A pharmaceutical controlled-release dosage form according to claim 35 wherein zolpidem is present as zolpidem hemitartrate. 39. A pharmaceutical controlled-release dosage form according to claim 38 containing 12.5 mg of zolpidem hemitartrate. 40. A pharmaceutical composition comprising zolpidem or a salt thereof in the form of a controlled-release dosage form according to claim 35 wherein said composition comprises an immediate release entity and a prolonged release entity. 41. A pharmaceutical composition according to claim 40 wherein the prolonged release entity comprises a pharmaceutically acceptable organic acid selected from tartaric, malic, fumaric, lactic, citric, adipic, and succinic acids or their acid salts. 42. A pharmaceutical composition according to claim 40 containing 4 to 16 mg of zolpidem as zolpidem base. 43. A pharmaceutical composition according to claim 40 wherein zolpidem is present as zolpidem hemitartrate. 44. A pharmaceutical composition according to claim 43 containing 12.5 mg of zolpidem hemitartrate. 45. A pharmaceutical controlled-release dosage form according to claim 35 wherein the release rate profile of the second phase is zero order, first order, sigmoidal, proportional to the square root of the time or is intermediate between said profiles. 46. A pharmaceutical composition according to claim 40 in the form of a multilayer tablet comprising an immediate release layer and a prolonged release layer. 47. A pharmaceutical composition according to claim 46 wherein the multilayer tablet is a bi-layer tablet.