Claims for Patent: 12,251,365

Summary for Patent: 12,251,365

Title:	Pharmaceutical formulations for subcutaneous administration
Abstract:	The present disclosure relates to compositions of levodopa 4′-monophosphate and carbidopa 4′-monophosphate having a weight by weight ratio of about 20:1 and methods of treating Parkinson's disease and associated conditions by subcutaneous administration of such compositions.
Inventor(s):	Ehab Moussa, Matthew Rosebraugh, Feroz Jameel, Nancy Sever, Maurizio F. Facheris, Weining Z Robieson, Charles S. Locke, Sven Stodtmann
Assignee:	AbbVie Inc
Application Number:	US16/684,874
Patent Claims:	1. A method of treating Parkinson's disease in a subject, comprising continuously subcutaneously administering a therapeutically effective amount of an aqueous pharmaceutical composition comprising: about 240 mg/mL of a compound of formula: and about 12 mg/mL of a compound of formula: wherein the weight to weight ratio of compound (A-1) to compound (B-1) is about 20:1; and wherein said therapeutically effective amount is an amount which, when continuously subcutaneously administered to a population of Parkinson's disease patients, achieves a mean plasma concentration of levodopa having a degree of fluctuation of about 0.3 or less over a time period of 2-16 hours following administration, wherein the degree of fluctuation is defined as the ([Cmax−Cmin/Cave]) for the given time period, and wherein said Parkinson's disease is treated. 2. The method of claim 1, wherein the pharmaceutical composition has a pH of between about 6.5 and about 9.2. 3. The method of claim 2, wherein the pharmaceutical composition has a pH of about 7.4. 4. The method of claim 3, wherein the pharmaceutical composition does not comprise an antioxidant. 5. The method of claim 3, wherein the mean plasma concentration of levodopa has a degree of fluctuation of about 0.40 over 2-72 hours following administration. 6. The method of claim 3, wherein the subject is treated for at least 10 days with no incidence of developing skin nodules. 7. The method of claim 3, wherein said therapeutically effective amount is an amount which, when continuously subcutaneously administered to the population of Parkinson's disease patients, provides a mean plasma exposure ratio of levodopa to carbidopa between 6.57 and 8.03 levodopa to about 1 carbidopa as measured by AUC(0-t) to AUC(0-t). 8. The method of claim 1, wherein said method improves a Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score in the subject, wherein the subject has a baseline MDS-UPDRS score, and said method reduces the baseline MDS-UPDRS total score by at least 9 units; thereby improving the (MDS-UPDRS) total score. 9. The method of claim 8, wherein the pharmaceutical composition has a pH of between about 6.5 and about 9.2. 10. The method of claim 9, wherein the pharmaceutical composition has a pH of about 7.4. 11. The method of claim 10, wherein the pharmaceutical composition does not comprise an antioxidant. 12. The method of claim 10, wherein the subject is treated for at least 10 days with no incidence of developing skin nodules. 13. The method of claim 10, wherein said therapeutically effective amount is an amount which, when continuously subcutaneously administered to a population of Parkinson's disease patients, provides a mean plasma exposure ratio of levodopa to carbidopa between 6.57 and 8.03 levodopa to about 1 carbidopa as measured by AUC(0-t) to AUC(0-t). 14. The method of claim 1, wherein said method improves sleep in a subject having a baseline Parkinson's Disease Sleep Scale-2 (PDSS-2) total score by at least 2 units; thereby improving said sleep. 15. The method of claim 14, wherein the pharmaceutical composition has a pH of between about 6.5 and about 9.2. 16. The method of claim 15, wherein the pharmaceutical composition has a pH of about 7.4. 17. The method of claim 16, wherein the pharmaceutical composition does not comprise an antioxidant. 18. The method of 16, wherein the subject is treated for at least 10 days with no incidence of developing skin nodules. 19. The method of claim 16, wherein said therapeutically effective amount is an amount which, when continuously subcutaneously administered to a population of Parkinson's disease patients, provides a mean plasma exposure ratio of levodopa to carbidopa between 6.57 and 8.03 levodopa to about 1 carbidopa as measured by AUC(0-t) to AUC(0-t). 20. A method of reducing motor fluctuations in a patient with Parkinson's disease comprising subcutaneously administering a therapeutically effective amount of an aqueous pharmaceutical composition comprising: about 240 mg/mL of a compound of formula: and about 12 mg/mL of a compound of formula: wherein the weight to weight ratio of compound (A-1) to compound (B-1) is about 20:1; and wherein said therapeutically effective amount is an amount which, when continuously administered to a population of Parkinson's disease patients, achieves an average percent improvement in off time from baseline of about 46%, thereby reducing the motor fluctuations. 21. The method of claim 20, wherein the pharmaceutical composition has a pH of between about 6.5 and about 9.2. 22. The method of claim 21, wherein the pharmaceutical composition has a pH of about 7.4. 23. The method of claim 22, wherein the pharmaceutical composition does not comprise an antioxidant. 24. The method of claim 22, wherein said effective amount is an amount which, when continuously subcutaneously administered to the population of Parkinson's disease patients, achieves a mean plasma concentration of levodopa having a degree of fluctuation of about 0.40 over a time period of 2-72 hours following administration, wherein the degree of fluctuation is defined as the ([Cmax−Cmin]/Cave) for the given time period. 25. The method of claim 22, wherein the subject is treated for at least 10 days with no incidence of developing skin nodules. 26. The method of claim 22, wherein said effective amount is an amount which, when continuously subcutaneously administered to the population of Parkinson's disease patients, provides a mean plasma exposure ratio of levodopa to carbidopa between 6.57 and 8.03 levodopa to about 1 carbidopa as measured by AUC(0-t) to AUC(0-t). 27. The method of claim 20, wherein said method improves quality of life in a subject having a baseline Parkinson's Disease Questionnaire-39 items (PDQ-39) summary index score by at least 6.9 units; thereby reducing the baseline PDQ-39 score by at least 6.9 units. 28. The method of claim 27, wherein the pharmaceutical composition has a pH of between about 6.5 and about 9.2. 29. The method of claim 28, wherein the pharmaceutical composition has a pH of about 7.4. 30. The method of claim 29, wherein the pharmaceutical composition does not comprise an antioxidant. 31. The method of 29, wherein the subject is treated for at least 10 days with no incidence of developing skin nodules. 32. The method of claim 29, wherein said therapeutically effective amount is an amount which, when continuously subcutaneously administered to a population of Parkinson's disease patients, provides a mean plasma exposure ratio of levodopa to carbidopa between 6.57 and 8.03 levodopa to about 1 carbidopa as measured by AUC(0-t) to AUC(0-t) when administered to adult humans. 33. A method for treatment of motor fluctuations in patients with Parkinson's disease, comprising continuously subcutaneously administering to said patients a therapeutically effective amount of an aqueous pharmaceutical composition which comprises a combination of a compound of formula: and a compound of formula: wherein the weight to weight ratio of compound (A-1) to compound (B-1) is about 20:1, thereby treating said motor fluctuations; and wherein the pharmaceutical composition has a pH of about 7.4. 34. The method of claim 33, wherein said treatment is safe. 35. The method of claim 34, wherein said treatment is a statistically significant treatment capable of generating statistically significant changes in clinical outcome from baseline in said patients. 36. The method of claim 33, wherein said pharmaceutical composition comprises about 240 mg of compound (A-1) and about 12 mg of compound (B-1).