Claims for Patent: 9,533,046

Summary for Patent: 9,533,046

Title:	Controlled release formulations of levodopa and uses thereof
Abstract:	The current invention provides a controlled release oral solid formulation of levodopa comprising levodopa, a decarboxylase inhibitor, and a carboxylic acid. Also provided by this invention is multiparticulate, controlled release oral solid formulations of levodopa comprising: i) a controlled release component comprising a mixture of levodopa, a decarboxylase inhibitor and a rate controlling excipient; ii) a carboxylic acid component; and iii) an immediate release component comprising a mixture of levodopa and a decarboxylase inhibitor.
Inventor(s):	Hsu; Ann (Los Altos Hills, CA), Kou; Jim (San Jose, CA), Alani; Laman (Fort Worth, TX)
Assignee:	Impax Laboratories, Inc. (Hayward, CA)
Application Number:	14/958,975
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,533,046
Patent Claims:	1. A method for treating Parkinson's disease comprising orally administering to a human patient in need of such treatment a multiparticulate formulation comprising about 10 mg to about 300 mg of carbidopa and about 25 mg to about 1200 mg of levodopa wherein the multiparticulate formulation comprises: a. an immediate release component comprising a mixture of carbidopa and levodopa in a ratio of about 1 to about 4; and b. a controlled release component comprising more than one bead, pellet or granule and at least one controlled release excipient that provides for the controlled release of carbidopa, levodopa and a carboxylic acid that is not carbidopa or levodopa from the bead, pellet or granule, wherein the molar ratio of carboxylic acid to levodopa is greater than 1:4 and less than 4:1, and following oral administration of the multiparticulate formulation the carbidopa, levodopa and carboxylic acid are released over a period of time of about 6 hours, and wherein following a single dose administration of the multiparticulate formulation the patient's levodopa plasma concentration profile comprises: (i) a time of administration; (ii) a first concentration that occurs at a first time and within one hour of the time of administration; (iii) a second concentration that occurs at a second time after said first time; and (iv) a third concentration that occurs after said second concentration and at a third time that is at least four hours after said second concentration, and the second concentration is the maximum concentration of levodopa in the profile; the first concentration is greater than or equal to about fifty percent of the second concentration; the peak-to-trough ratio of the second concentration to the third concentration is about 1.5 to about 2.5 and the levodopa plasma concentration decreases after the third concentration, wherein following a single dose administration of the multiparticulate formulation the levodopa blood plasma levels do not fluctuate more than 40% between 0.5 hours and six hours after administration, and wherein the administration of the multiparticulate formulation is effective in alleviating at least one symptom of Parkinson's disease. 2. The method of claim 1 wherein the disease is secondary Parkinsonism. 3. The method of claim 1 wherein the first concentration is about fifty percent of the second concentration. 4. The method of claim 1 wherein the third concentration occurs about four hours after the second concentration. 5. The method of claim 1 wherein the third concentration occurs about six hours after the time of administration. 6. The method of claim 1 wherein the second concentration occurs about one hour after the first concentration. 7. The method of claim 1 wherein the first, second and third concentrations are mean plasma concentrations. 8. The method of claim 1 wherein the first, second and third concentrations are median plasma concentrations. 9. The method of claim 1 wherein the multiparticulate formulation is administered three times a day. 10. The method of claim 9 wherein the multiparticulate formulation is administered every six hours. 11. The method of claim 1 wherein the carboxylic acid is selected from the group consisting of tartaric acid, adipic acid, succinic acid, citric acid, benzoic acid, acetic acid, ascorbic acid, edetic acid, fumaric acid, lactic acid, malic acid, oleic acid, sorbic acid, stearic acid, palmitic acid, boric acid and mixtures thereof. 12. The method of claim 11 wherein the carboxylic acid is tartaric acid. 13. The method of claim 1 wherein the carbidopa, levodopa and the carboxylic acid are in the same controlled release bead, pellet or granule. 14. The method of claim 1 wherein the carbidopa and levodopa are in different controlled release bead, pellet or granule from the carboxylic acid. 15. The method of claim 1 wherein the carboxylic acid and levodopa are present in the formulation in a carboxylic acid to levodopa molar ratio of greater than 1:4 and less than 3:2. 16. The method of claim 1 wherein the carboxylic acid and levodopa are present in the formulation in a carboxylic acid to levodopa molar ratio of greater than 1:2 and less than 4:3. 17. The method of claim 1 wherein the immediate release component and controlled release component are in a capsule. 18. The method of claim 1 wherein the controlled release component comprises at least two different populations of controlled release beads, pellets or granules wherein the first population of controlled release beads, pellets or granules exhibits a slower in vitro dissolution profile of levodopa compared to the second population of controlled release beads, pellets or granules. 19. The method of claim 1 wherein the molar ratio of carboxylic acid to levodopa is greater than 2:3 and less than 5:4. 20. A method for treating Parkinson's disease comprising orally administering to a human patient in need of such treatment a multiparticulate formulation comprising about 10 mg to about 300 mg of carbidopa and about 25 mg to about 1200 mg of levodopa wherein the multiparticulate formulation comprises: a. an immediate release component comprising a mixture of carbidopa and levodopa in a ratio of about 1 to about 4; and b. a controlled release component comprising at least two different populations of controlled release beads, pellets or granules comprising carbidopa and levodopa and a controlled release excipient, wherein a first population of controlled release beads, pellets or granules exhibits a slower in vitro dissolution profile of levodopa compared to a second population of controlled release beads, pellets or granules, and following oral administration of the multiparticulate formulation the carbidopa and levodopa are released from the controlled release component over a period of time of about 6 hours, wherein following a single dose administration of the multiparticulate formulation the patient's levodopa plasma concentration profile comprises: (i) a time of administration; (ii) a first concentration that occurs at a first time and within one hour of the time of administration; (iii) a second concentration that occurs at a second time after said first time; and (iv) a third concentration that occurs after said second concentration and at a third time that is about six hours after the time of administration, and the second concentration is the maximum concentration of levodopa in the profile; the first concentration is greater than or equal to about fifty percent of the second concentration; the peak-to-trough ratio of the second concentration to the third concentration is about 1.5 to about 2.5 and the levodopa plasma concentration decreases after the third concentration, wherein following a single dose administration of the multiparticulate formulation the levodopa blood plasma levels do not fluctuate more than 40% between 0.5 hours and six hours after administration, and wherein the administration of the multiparticulate formulation is effective in alleviating at least one symptom of Parkinson's disease. 21. The method of claim 20 wherein the first population of controlled release beads, pellets or granules releases less than 20% of the levodopa after 120 minutes, less than 40% of levodopa after 150 minutes, less than 80% after 210 minutes, and 100% after 260 minutes of testing using a USP basket dissolution apparatus at 75 rpms with simulated gastric fluid medium for the first 120 minutes and simulated intestinal fluid thereafter. 22. The method of claim 20 wherein the second population of controlled release beads, pellets or granules comprise a core comprising carbidopa and levodopa and an enteric coating applied to the core. 23. A method for treating Parkinson's disease comprising orally administering to a human patient in need of such treatment a multiparticulate formulation comprising about 10 mg to about 300 mg of carbidopa and about 25 mg to about 1200 mg of levodopa wherein the multiparticulate formulation comprises: a. an immediate release component comprising a mixture of carbidopa and levodopa in a ratio of about 1 to about 4; and b. a controlled release component comprising more than one bead, pellet or granule and at least one controlled release excipient that provides for the controlled release of carbidopa, levodopa and tartaric acid from the bead, pellet or granule wherein the molar ratio of tartaric acid to levodopa is greater than 1:4 and less than 4:1 and wherein following a single dose administration of the multiparticulate formulation the patient's levodopa plasma concentration profile comprises: (i) a time of administration; (ii) a first concentration that occurs at a first time and within one hour of the time of administration; (iii) a second concentration that occurs at a second time after said first time; and (iv) a third concentration that occurs after said second concentration and at a third time that is at least four hours after said second concentration, and the second concentration is the maximum concentration of levodopa in the profile; the first concentration is greater than or equal to about fifty percent of the second concentration; the peak-to-trough ratio of the second concentration to the third concentration is about 1.5 to about 2.5 and the levodopa plasma concentration decreases after the third concentration, wherein following a single dose administration of the multiparticulate formulation the levodopa blood plasma levels do not fluctuate more than 40% between 0.5 hours and six hours after administration, and wherein the administration of the multiparticulate formulation is effective in alleviating at least one symptom of Parkinson's disease. 24. The method of claim 1 wherein the controlled release excipient comprises a coating that comprises an enteric polymer. 25. The method of claim 20 wherein the controlled release excipient comprises a coating that comprises an enteric polymer. 26. The method of claim 23 wherein the controlled release excipient comprises a coating that comprises an enteric polymer. 27. The method of claim 20 wherein the immediate release component and the controlled release component are in a capsule. 28. The method of claim 23 wherein the immediate release component and the controlled release component are in a capsule. 29. The method of claim 1 wherein the immediate release component and the controlled release component are sprinkled onto food or liquids for administration. 30. The method of claim 20 wherein the immediate release component and the controlled release component are sprinkled onto food or liquids for administration. 31. The method of claim 23 wherein the immediate release component and the controlled release component are sprinkled onto food or liquids for administration.