Claims for Patent: 12,263,149

Summary for Patent: 12,263,149

Title:	Levodopa dosing regimen
Abstract:	The invention is a method for treating patients with Parkinson's disease, primary parkinsonism/idiopathic parkinsonism, post-encephalitic parkinsonism, parkinsonism that may follow carbon monoxide intoxication, or parkinsonism that may follow manganese intoxication and provides an improvement of a patient's total post-dose “Off” time compared to post-dose of treatment regimens with oral immediate release levodopa tablets.
Inventor(s):	Richard D′Souza, Hester Visser, Suneel Gupta
Assignee:	Amneal Pharmaceuticals LLC
Application Number:	US18/817,743
Patent Claims:	1. A method for reducing “Off” time in a Parkinson's disease patient comprising: i) selecting a patient experiencing an average of at least 2.5 hours per day of “Off” time and being treated with oral immediate release levodopa tablets, administered three, four, five or more times a day for a total daily levodopa dose of greater than 500 mg; ii) determining the most frequent immediate release levodopa dose from each administration of immediate release tablets of step (i); iii) discontinuing the administration of the immediate release levodopa tablets to the patient of step (i); and iv) orally administering one or more multiparticulate controlled release levodopa dosage forms 2, 3 or 4 times a day to the patient, wherein the amount of levodopa administered with each administration of the multiparticulate controlled release levodopa dosage form is 2.8 times the amount of levodopa the patient was receiving with each administration of the most frequent immediate release levodopa dose of step (ii); wherein the patient after receiving treatment with the multiparticulate controlled release levodopa dosage form exhibits a decrease of at least 20 minutes of the patient's total post dose “Off” time as compared to post dose of the oral immediate release levodopa tablets, wherein the multiparticulate controlled release dosage form comprises: (a) a plurality of controlled release components comprising a core comprising levodopa, a controlled release material, and a coating comprising an enteric polymer surrounding the levodopa and controlled release material wherein the controlled release components pass through a 12 mesh screen; and (b) an immediate release component comprising levodopa and carbidopa wherein the plurality of controlled release components are free of carbidopa; and wherein the controlled release dosage form when tested using a USP Type I apparatus at 37° C.±0.5° C. with a rotational speed of 75 rpm and about 900 ml of simulated gastric fluid for 2 hours and pH 6.8 phosphate buffer thereafter, about 75% to about 100% of CD is released within 30 minutes; about 15% to about 45% of LD is released within 30 minutes and not less than 85% of the LD is released after 7 hours; wherein the simulated gastric fluid has a pH of from about 1 to about 4.0. 2. The method of claim 1, wherein the administration of the multiparticulate controlled release dosage form provides a total “Off” time during a 24 hour period of less than 5 hours. 3. The method of claim 1 wherein the multiparticulate controlled release dosage form is a capsule comprising: 140 mg of levodopa and 35 mg of carbidopa; 210 mg of levodopa and 52.5 mg of carbidopa; 280 mg of levodopa and 70 mg of carbidopa; or 350 mg of levodopa and 87.5 mg of carbidopa; and the dose of levodopa administered in step (iv) is provided by administering one or a combination of the foregoing capsules per dosing time. 4. The method of claim 1 wherein after administration of the multiparticulate controlled release dosage form the patient exhibits a levodopa plasma level of from about 200 ng/ml to about 2000 ng/ml within 0.25 to 1 hour after administration. 5. The method of claim 1, wherein the administration of the multiparticulate controlled release dosage form provides a levodopa fluctuation index of about 1.7±0.5 hours. 6. The method of claim 1, wherein in step (i) the patient is being treated with a stable dosing regimen of oral immediate release levodopa tablets, wherein the dosing regimen is stable for at least 5 days prior to step (iii). 7. The method of claim 6, wherein the stable dosing regimen includes no change in dose or dosing frequency. 8. The method of claim 1, wherein the most-frequent single dose of the immediate release levodopa tablets is the highest dose of immediate release levodopa tablets the patient is receiving prior to step (iii). 9. The method of claim 1, wherein the Parkinson disease is selected from the group consisting of primary parkinsonism/idiopathic parkinsonism, post-encephalitic parkinsonism, parkinsonism following carbon monoxide intoxication, and parkinsonism following manganese intoxication. 10. The method of claim 1 wherein the patient is not being treated with a catechol-O-methyl transferase inhibitor. 11. A method for reducing “Off” time in a Parkinson's disease patient comprising: i) selecting a patient experiencing an average of at least 2.5 hours per day of “Off” time and being treated with oral immediate release levodopa tablets for a total daily levodopa dose of less than 500 mg; ii) determining the most frequent immediate release levodopa dose from each administration of immediate release tablets of step (i); iii) discontinuing the administration of the immediate release levodopa tablets to the patient of step (i); and iv) orally administering one or more multiparticulate controlled release levodopa dosage forms 2 or 3 times a day to the patient, wherein the amount of levodopa administered with each administration of the multiparticulate controlled release levodopa dosage form is 2.8 times the amount of levodopa the patient was receiving with each administration of the most frequent immediate release levodopa dose of step (ii); wherein the patient after receiving treatment with the multiparticulate controlled release levodopa dosage form exhibits a decrease of at least 20 minutes of the patient's total post dose “Off” time as compared to post dose of the oral immediate release levodopa tablets, wherein the multiparticulate controlled release dosage form comprises: (a) a plurality of controlled release components comprising a core comprising levodopa, a controlled release material, and a coating comprising an enteric polymer surrounding the levodopa and controlled release material wherein the controlled release components pass through a 12 mesh screen; and (b) an immediate release component comprising levodopa and carbidopa wherein the plurality of controlled release components are free of carbidopa; and wherein the controlled release dosage form when tested using a USP Type I apparatus at 37° C.±0.5° C. with a rotational speed of 75 rpm and about 900 ml of simulated gastric fluid for 2 hours and pH 6.8 phosphate buffer thereafter, about 75% to about 100% of CD is released within 30 minutes; about 15% to about 45% of LD is released within 30 minutes and not less than 85% of the LD is released after 7 hours; wherein the simulated gastric fluid has a pH of from about 1 to about 4.0. 12. The method of claim 11, wherein the Parkinson disease is selected from the group consisting of primary parkinsonism/idiopathic parkinsonism, post-encephalitic parkinsonism, parkinsonism following carbon monoxide intoxication, and parkinsonism following manganese intoxication. 13. The method of claim 11, wherein the administration of the multiparticulate controlled release dosage form provides a total “Off” time during a 24 hour period of less than 5 hours. 14. The method of claim 11 wherein the patient is not being treated with a catechol-O-methyl transferase inhibitor and the patient has not been previously treated with levodopa. 15. The method of claim 11 wherein the multiparticulate controlled release dosage form is a capsule comprising: 140 mg of levodopa and 35 mg of carbidopa; 210 mg of levodopa and 52.5 mg of carbidopa; 280 mg of levodopa and 70 mg of carbidopa; or 350 mg of levodopa and 87.5 mg of carbidopa; and the dose of levodopa administered in step (iv) is provided by administering one or a combination of the foregoing capsules per dosing time. 16. The method of claim 11 wherein the multiparticulate controlled release dosage form is a tablet comprising: 140 mg of levodopa and 35 mg of carbidopa; 210 mg of levodopa and 52.5 mg of carbidopa; 280 mg of levodopa and 70 mg of carbidopa; or 350 mg of levodopa and 87.5 mg of carbidopa; and the dose of levodopa administered in step (iv) is provided by administering one or a combination of the foregoing tablets per dosing time. 17. The method of claim 11 wherein the plurality of controlled release components comprise beads with a spheronized core comprising levodopa. 18. The method of claim 17 wherein the beads pass through a 14 mesh screen but are retained on 24 mesh screen. 19. The method of claim 1 wherein the multiparticulate controlled release dosage form is a tablet comprising: 140 mg of levodopa and 35 mg of carbidopa; 210 mg of levodopa and 52.5 mg of carbidopa; 280 mg of levodopa and 70 mg of carbidopa; or 350 mg of levodopa and 87.5 mg of carbidopa; and the dose of levodopa administered in step (iv) is provided by administering one or a combination of the foregoing tablets per dosing time. 20. The method of claim 1 wherein the plurality of controlled release components comprise beads with a spheronized core comprising levodopa. 21. The method of claim 20 wherein the beads pass through a 14 mesh screen but are retained on 24 mesh screen.