Pharmaceutical preparation for subcutaneous administration

Abstract

To provide a composition that is suitable for treating Parkinson disease, and for consistently maintaining a desirable dopamine level in a brain.SOLUTION: A stable liquid aqueous pharmaceutical composition consists of levodopa 4'-monophosphoric acid and carbidopa 4'-monophosphoric acid having a weight ratio of approximately 20:1, where Parkinson disease and an associated state are treated by subcutaneously administering the composition.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present disclosure relates to stable pharmaceutical formulations of levodopa and carbidopa prodrugs for subcutaneous administration. [Background technology]

[0002] Parkinson's disease is a chronic, progressive neurodegenerative condition characterized by reduced brain levels of the neurotransmitter dopamine (ie, 3,4-dihydroxyphenethylamine).

[0003] Administration of levodopa (i.e., L-3,4-dihydroxyphenylalanine) is currently the most effective therapy for treating patients with Parkinson's disease. Coadministration of carbidopa with levodopa inhibits the peripheral metabolism of levodopa to dopamine, thereby significantly reducing the dosage of levodopa required for a therapeutically effective clinical response and reducing associated side effects.

[0004] Oral administration of tablets containing levodopa and carbidopa (especially those with a weight (w / w) ratio of levodopa to carbidopa of 4:1) has long been used to treat Parkinson's disease. For example, Sinemet® is a registered trademark of a preparation of levodopa and carbidopa manufactured by Merck Sharp and Dohme Corp., USA, with a weight (w / w) ratio of levodopa to carbidopa of 4:1. However, due to the short half-life of levodopa, even when co-administered with carbidopa, it is difficult to consistently maintain desirable dopamine levels in the brain using these oral tablets.

[0005] Oral ingestion of levodopa tablets is associated with variable exposure to plasma levodopa. One approach that has been effective in reducing fluctuations in dopamine levels compared to oral administration of levodopa and carbidopa tablets is continuous intestinal delivery of levodopa / carbidopa gel. The product manufactured by "AbbVie Inc., USA", known under the trade name Duodopa® in Europe and Duopa® in the United States, is a suspension of levodopa / carbidopa monohydrate (4:1 (w / w) ratio of levodopa to carbidopa monohydrate) in an aqueous gel (sodium carboxymethylcellulose). The gel is delivered to the proximal small intestine through a jejunal tube inserted through a surgically implanted percutaneous endoscopic gastrostomy port. It would be beneficial to deliver levodopa continuously to provide therapeutic dopamine levels in the brain without the use of surgical implants.

[0006] Levodopa and carbidopa each have low aqueous solubility at neutral pH. Because levodopa and carbidopa are relatively insoluble, it is difficult to achieve stable, more soluble formulations containing levodopa (or compounds that can be bioconverted to levodopa in vivo). Previous prodrug approaches to deliver levodopa subcutaneously have failed due to various technical challenges, such as poor chemical stability, poor solubility, in vivo bioconversion problems, and toxicity, to name a few. There are no commercially available subcutaneously administered levodopa products, and subcutaneous administration of levodopa, with or without carbidopa, has not yet been successfully commercialized.

[0007] Certain prodrugs of levodopa and carbidopa suitable for subcutaneous administration are described in WO2016 / 065019A1, the administration, methods of manufacture, and use of which are incorporated by reference. However, it would be beneficial to provide a safe and stable composition for administering such prodrugs.

[0008] One approach to formulating a prodrug of levodopa is described in WO2018 / 154447A1. This approach requires the use of one or more antioxidants, which increases the complexity of maintaining the quality of the product. The composition described contains 1.36% carbidopa phosphate (CD-p) and 5.64% levodopa phosphate (LD-p).

[0009] Another approach for subcutaneous delivery of levodopa is described in WO2015 / 136538A1.This approach describes a dopa decarboxylase inhibitor composition that requires carbidopa arginine complex combined with levodopa.However, no evidence is reported that the composition described therein is delivered subcutaneously. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2016 / 065019 [Patent Document 2] International Publication No. 2018 / 154447 [Patent Document 3] International Publication No. 2015 / 136538 Summary of the Invention [Problem to be solved by the invention]

[0011] To date, there remains a need for commercially viable pharmaceutical compositions suitable for subcutaneous delivery of levodopa and carbidopa prodrugs for the treatment of Parkinson's disease. [Means for solving the problem]

[0012] The present disclosure relates to a safe and stable aqueous pharmaceutical composition suitable for subcutaneous administration comprising a levodopa acid prodrug and a carbidopa acid prodrug in a ratio of about 20:1. The composition provides a stable liquid suitable for subcutaneous administration. In certain embodiments, such compositions, when administered to a human subject, achieve a pharmacokinetic plasma exposure of levodopa similar to oral levodopa / carbidopa therapy comparable to Sinemet® products. Such pharmacokinetic plasma exposure is maintained over an extended period of time. Moreover, such compositions are safe and well tolerated in human subjects. In view of this aspect, the present disclosure provides a pharmaceutical composition suitable for subcutaneous administration comprising a levodopa acid prodrug and a carbidopa acid prodrug as described herein, and at least one pharma- ceutically acceptable carrier, the weight ratio of levodopa acid prodrug to carbidopa acid prodrug being about 20:1, and can be administered to a human subject. In some embodiments, the composition is an aqueous liquid composition having a pH of about 6.5 to about 9.0.

[0013] Thus, the present disclosure: formula:

[0014] [ka] A compound represented by the formula: formula:

[0015] [ka] The present invention relates to a stable liquid aqueous pharmaceutical composition comprising a compound represented by the formula: the weight ratio of compound (A-1) to compound (B-1) is about 20:1; Suitable for subcutaneous administration.

[0016] In another aspect, the present disclosure provides a method for the preparation of a formula:

[0017] [ka] A compound represented by the formula: formula:

[0018] [ka] The present invention relates to a stable liquid aqueous pharmaceutical composition comprising a compound represented by the formula: The concentration of compound (A-1) is about 240 mg / mL, and the concentration of compound (B-1) is about 12 mg / mL; The pharmaceutical composition is suitable for subcutaneous administration, The pharmaceutical composition, when administered to an adult human, has an AUC (0-t) vs. AUC (0-t) This provides a mean plasma exposure ratio of levodopa to carbidopa of approximately 7.30 to 1 as measured by

[0019] In another aspect, the present disclosure provides a method for the preparation of a formula:

[0020] [ka] A compound represented by the formula: formula:

[0021] [ka] A compound represented by the formula: A stable liquid pharmaceutical composition comprising water, The concentration of compound (A-1) was about 240 mg / mL, and the concentration of compound (B-1) was about 12 mg / mL. The pharmaceutical composition is suitable for subcutaneous administration, The composition is substantially free of antioxidants.

[0022] In another aspect, the present disclosure provides a method for the preparation of a formula:

[0023] [ka] A compound represented by the formula: formula:

[0024] [ka] The present invention relates to a stable liquid aqueous pharmaceutical composition comprising a compound represented by the formula: The concentration of compound (A-1) was about 240 mg / mL, and the concentration of compound (B-1) was about 12 mg / mL. The pharmaceutical composition is suitable for subcutaneous administration, The composition contains less than about 5.4% w / w DHPPA-P at pH 6.5-9.0 after 5 days at 25°C followed by 30 days at 5°C.

[0025] As disclosed herein, the present disclosure relates to the following embodiments:

[0026] Embodiment 1. Formula:

[0027] [ka] A compound represented by the formula: formula:

[0028] [ka] A stable liquid aqueous pharmaceutical composition comprising a compound represented by the formula: the weight ratio of compound (A-1) to compound (B-1) is about 20:1; Suitable for subcutaneous administration The stable liquid aqueous pharmaceutical composition.

[0029] Embodiment 2. The stable liquid aqueous pharmaceutical composition according to embodiment 1, wherein the concentration of compound (A-1) is from about 216 mg / mL to about 264 mg / mL.

[0030] Embodiment 3. The stable liquid aqueous pharmaceutical composition according to embodiment 1 or 2, wherein the concentration of compound (B-1) is 9.6 mg / mL to 13.2 mg / mL.

[0031] Embodiment 4. The stable liquid aqueous pharmaceutical composition according to embodiment 1, wherein the concentration of compound (A-1) is about 240 mg / mL and the concentration of compound (B-1) is about 12 mg / mL.

[0032] Embodiment 5. The stable liquid aqueous pharmaceutical composition according to any one of Embodiments 1 to 4, having a pH of about 6.5 to about 9.0.

[0033] Embodiment 6. The stable liquid aqueous pharmaceutical composition according to embodiment 1, wherein the concentration of compound (A-1) is 324 mg / mL to 396 mg / mL, and the concentration of compound (B-1) is 16.2 mg / mL to 19.8 mg / mL.

[0034] Embodiment 7. The stable liquid aqueous pharmaceutical composition according to embodiment 6, wherein the concentration of compound (A-1) is about 360 mg / mL and the concentration of compound (B-1) is about 18 mg / mL.

[0035] Embodiment 8. The stable liquid aqueous pharmaceutical composition according to embodiment 6 or 7, having a pH of about 6.5 to about 9.0.

[0036] Embodiment 9. The pharmaceutical composition, when administered to an adult human, has an AUC (0-t) vs. AUC (0-t) 6. The stable liquid aqueous pharmaceutical composition according to any one of embodiments 1 to 5, wherein the composition provides a mean plasma exposure ratio of levodopa to carbidopa of 6.57 to 8.03 levodopa to about 1 carbidopa as measured by HPLC.

[0037] Embodiment 10. The pharmaceutical composition, when administered to an adult human, has an AUC (0-t) vs. AUC (0-t) 10. The stable liquid aqueous pharmaceutical composition of embodiment 9, providing a mean plasma exposure ratio of levodopa to carbidopa of about 7.30 levodopa to about 1 carbidopa as measured by HPLC.

[0038] Embodiment 11. Continuous subcutaneous administration of the pharmaceutical composition to a population of human adults achieves a mean plasma concentration of levodopa having a variability of about 0.3 or less over a period of 2 to 16 hours after administration, the variability being less than or equal to about 0.5 for a given period ([C max -C min ] / C ave 6. The stable liquid aqueous pharmaceutical composition according to any one of embodiments 1 to 5, wherein

[0039] Embodiment 12. Continuous subcutaneous administration of the composition to a population of human adults achieves a mean plasma concentration of levodopa having a variability of about 0.40 over a period of 2 to 72 hours after administration, the variability being ([C max -C min ] / C ave 6. The stable liquid aqueous pharmaceutical composition according to any one of embodiments 1 to 5, wherein

[0040] Embodiment 13. The stable liquid aqueous pharmaceutical composition of any one of embodiments 1 to 5, wherein the pharmaceutical composition is in a vial having a gas headspace containing no more than about 5.5% oxygen.

[0041] Embodiment 14. The stable liquid aqueous pharmaceutical composition of embodiment 13, wherein the pharmaceutical composition has a pH of about 6.8 to about 7.8.

[0042] Embodiment 15. The stable liquid aqueous pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is substantially free of antioxidants.

[0043] Embodiment 16 The stable liquid aqueous pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is substantially free of arginine.

[0044] Embodiment 17. The stable liquid aqueous pharmaceutical composition of any one of the preceding embodiments, wherein the composition contains less than about 5.4% w / w DHPPA-P relative to carbidopa 4'-monophosphate at pH 6.5-9.0 after 5 days at 25°C followed by 30 days at 5°C.

[0045] Embodiment 18. The stable liquid aqueous pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is substantially free of ascorbic acid or a pharma- ceutically acceptable salt of ascorbic acid.

[0046] Embodiment 19. The stable liquid aqueous pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition is substantially free of L-cysteine ​​or a pharma- ceutically acceptable salt thereof, N-acetylcysteine ​​(NAC) or a pharma- ceutically acceptable salt thereof, glutathione or a pharma- ceutically acceptable salt thereof, diacetylcysteine ​​or a pharma- ceutically acceptable salt thereof, and sodium bisulfite, or any combination thereof.

[0047] Embodiment 20. The stable liquid aqueous pharmaceutical composition of any one of the preceding embodiments, wherein the composition is substantially free of antioxidants and contains less than about 15 micrograms / mL of hydrazine after storage under pH-neutral conditions at 25° C. for 5 days, followed by storage at 5° C. for 30 days.

[0048] EMBODIMENT 21. formula:

[0049] [ka] A compound represented by the formula: formula:

[0050] [ka] A compound represented by the formula: and water. A stable liquid aqueous pharmaceutical composition comprising: The concentration of compound (A-1) was about 240 mg / mL, and the concentration of compound (B-1) was about 12 mg / mL. Suitable for subcutaneous administration When administered to adult humans, AUC (0-t) vs. AUC (0-t)providing a mean plasma exposure ratio of levodopa to carbidopa of about 7.30 to 1 as measured by The stable liquid aqueous pharmaceutical composition.

[0051] Embodiment 22. The stable liquid aqueous pharmaceutical composition of embodiment 21, which is stable for at least 3 months in a 10 cc vial at a temperature between 2°C and 8°C, at 1 atmosphere pressure, and with less than about 9% oxygen.

[0052] Embodiment 23. The stable liquid aqueous pharmaceutical composition of embodiment 22, having a pH of about 6.5 to about 9.0.

[0053] Embodiment 24. The stable liquid aqueous pharmaceutical composition of embodiment 23, having a pH of about 6.8 to about 7.8.

[0054] Embodiment 25. The stable liquid aqueous pharmaceutical composition according to any one of Embodiments 22 to 24, wherein the vial has less than about 5.5% oxygen in the vial headspace.

[0055] 26. formula:

[0056] [ka] A compound represented by the formula: formula:

[0057] [ka] A compound represented by the formula: and water. A stable liquid aqueous pharmaceutical composition comprising: The concentration of compound (A-1) was about 240 mg / mL, and the concentration of compound (B-1) was about 12 mg / mL. Suitable for subcutaneous administration Substantially free of antioxidants, The stable liquid aqueous pharmaceutical composition.

[0058] In embodiment 27, when administered to an adult human, the AUC (0-t) vs. AUC (0-t) 27. The stable pharmaceutical composition of embodiment 26, providing a mean plasma exposure ratio of levodopa to carbidopa of about 7.30 to 1 as measured by HPLC.

[0059] Embodiment 28. The stable liquid aqueous pharmaceutical composition of embodiment 27, which is stable for at least 3 months in a 10 cc vial at a temperature between 2°C and 8°C, at 1 atmosphere and with less than about 9% oxygen.

[0060] Embodiment 29. The stable liquid aqueous pharmaceutical composition according to any one of Embodiments 26 to 28, having a pH of about 6.5 to about 9.0.

[0061] Embodiment 30. The stable liquid aqueous pharmaceutical composition of embodiment 29, having a pH of about 6.8 to about 7.8.

[0062] Embodiment 31. The stable liquid aqueous pharmaceutical composition according to any one of Embodiments 28 to 30, wherein the vial has less than about 5.5% oxygen.

[0063] EMBODIMENT 32. formula:

[0064] [ka] A compound represented by the formula: formula:

[0065] [ka] A stable liquid aqueous pharmaceutical composition comprising a compound represented by the formula: The concentration of compound (A-1) was about 240 mg / mL, and the concentration of compound (B-1) was about 12 mg / mL. Suitable for subcutaneous administration After 5 days at 25° C., followed by 30 days at 5° C., at a pH of 6.5-9.0, containing less than about 5.4% w / w DHPPA-P; The stable liquid aqueous pharmaceutical composition.

[0066] Embodiment 33. A stable liquid aqueous pharmaceutical composition according to embodiment 32, which is stable for at least 3 months in a 10 cc vial at a temperature between 2°C and 8°C, at 1 atmosphere pressure and with less than about 9% oxygen by volume.

[0067] Embodiment 34. The stable liquid aqueous pharmaceutical composition according to embodiment 32 or 33, having a pH of about 6.5 to about 9.0.

[0068] Embodiment 35. The stable liquid aqueous pharmaceutical composition according to embodiment 34, having a pH of about 6.8 to about 7.8.

[0069] Embodiment 36. The stable liquid aqueous pharmaceutical composition according to any one of Embodiments 33 to 35, wherein the vial has less than about 5.5% oxygen.

[0070] Embodiment 37. When administered to adult humans, the AUC (0-t) vs. AUC (0-t) 37. The stable pharmaceutical composition of any one of embodiments 32-36, providing a mean plasma exposure ratio of levodopa to carbidopa of about 7.30 to 1 as measured by ELISA.

[0071] Embodiment 38. A method of treating Parkinson's disease in a subject, comprising subcutaneously administering to a patient in need of such treatment a pharmaceutical composition of any one of Embodiments 1 to 37.

[0072] Embodiment 39. A method of treating Parkinson's disease in a subject, comprising subcutaneously administering to a patient in need of treatment for Parkinson's disease a pharmaceutical composition of embodiment 32, the composition comprising: (0-t) vs. AUC (0-t) The method comprises providing a mean plasma exposure ratio of levodopa to carbidopa of about 7.30 to 1 as measured by

[0073] Embodiment 40. A method of improving "off" time of Parkinson's disease symptoms in a subject from a baseline score, comprising subcutaneously administering to a patient in need of treatment for Parkinson's disease an amount of a pharmaceutical composition of any one of embodiments 1-37 effective to reduce Parkinson's disease symptoms by at least 46% from baseline.

[0074] Embodiment 41. A method of improving a Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score in a subject having a baseline MDS-UPDRS score, comprising subcutaneously administering to a subject in need of treatment for Parkinson's disease an amount of the pharmaceutical composition of claim 21 effective to reduce the baseline MDS-UPDRS total score by at least 9 units.

[0075] Embodiment 42. A method of improving quality of life in a subject with a baseline Parkinson's Disease Questionnaire-39 (PDQ-39) summary index score, comprising subcutaneously administering to a subject in need of treatment for Parkinson's disease an amount of the pharmaceutical composition of claim 21 effective to reduce the baseline PDQ-39 score by at least 6.9 units.

[0076] Embodiment 43. A method of improving sleep in a subject having a baseline Parkinson's Disease Sleep Scale-2 (PDSS-2) total score, comprising subcutaneously administering to a subject in need of treatment for Parkinson's disease an amount of the pharmaceutical composition of claim 21 effective to reduce the baseline PDSS-2 total score by at least 2 units.

[0077] Embodiment 44 The method of any one of embodiments 38-43, wherein the subject is treated for at least 10 days without developing skin nodules.

[0078] Embodiment 44. A method of reducing the incidence of "off" time in Parkinson's disease symptoms in a subject compared to a subject receiving oral administration of a tablet comprising levodopa and carbidopa, comprising subcutaneously administering to a patient in need of treatment for Parkinson's disease a pharmaceutical composition according to any of embodiments 1-21.

[0079] Embodiment 45. The method of embodiment 44, wherein the incidence of Parkinson's disease symptom "off" time in the subject is reduced and "on" time is increased without problematic dyskinesias.

[0080] Further advantages of the present disclosure will be apparent to those skilled in the art upon reading this patent application. The embodiments of the present disclosure described in the following paragraphs are intended to illustrate the present invention and should not be construed as narrowing the scope of the present invention. [Brief description of the drawings]

[0081] [Figure 1] 1 is a plasma time concentration profile of levodopa and carbidopa levels in healthy human volunteers after subcutaneous administration of a pharmaceutical composition consisting of levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a 4:1 ratio. [Diagram 2] 1 is a plasma time concentration profile of levodopa and carbidopa levels in healthy human volunteers after subcutaneous administration of a pharmaceutical composition consisting of a 10:1 ratio of levodopa 4'-monophosphate and carbidopa 4'-monophosphate. [Diagram 3] 1 is a plasma time concentration profile of levodopa and carbidopa levels in healthy human volunteers after subcutaneous administration of a pharmaceutical composition consisting of levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a ratio of 20:1. [Figure 4] 1 is a plasma time concentration profile of levodopa and carbidopa levels in healthy human volunteers after oral administration of a pharmaceutical composition consisting of levodopa and carbidopa in a 4:1 ratio. [Diagram 5]FIG. 1 is a plasma time concentration profile of levodopa plasma levels (± standard deviation) in healthy human volunteers receiving a subcutaneous bolus dose of a pharmaceutical composition consisting of levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a 20:1 ratio, followed by a continuous subcutaneous infusion of the pharmaceutical composition for 72 hours. [Figure 6] 1 is a plasma concentration time profile of levodopa levels in a human patient following enteral administration of Duodopa®, a 4:1 ratio of levodopa to carbidopa. [Figure 7] 1 is a comparison of plasma time concentration profiles of levodopa levels in healthy human volunteers administered subcutaneous levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a 20:1 ratio and orally administered levodopa and carbidopa in a 4:1 ratio. Oral levodopa plasma concentrations were increased by 2-fold. [Figure 8] Graphical representation of DHPPA-P levels (% w / w) versus carbidopa 4'-monophosphate concentration based on pH after 5 days at 25°C and 30 days at 5°C, where % w / w is the amount of DHPPA-P relative to 100 times the amount of carbidopa 4'-monophosphate. [Figure 9] Graphical representation of DHPPA-P levels (% w / w) versus carbidopa 4'-monophosphate concentration based on pH after 5 days at 25°C followed by 65 days at 5°C, where % w / w is the amount of hydrazine per 100 times the amount of carbidopa 4'-monophosphate. [Figure 10] 1 is a graphical representation of hydrazine levels (% w / w) versus carbidopa 4'-monophosphate concentration based on pH after 5 days at 25°C followed by 30 days at 5°C. [Figure 11] 1 is a graphical representation of hydrazine levels (% w / w) versus carbidopa 4'-monophosphate concentration based on pH after 5 days at 25°C followed by 65 days at 5°C. [Figure 12]FIG. 1 is a graphical representation of the percentage of subjects with the highest grade based on the Infusion Site Evaluation Numeric Scale received during any of the 10 days for pharmaceutical compositions (levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a ratio of 20:1) and placebo. [Figure 13] FIG. 1 is a graphical representation of the percentage of subjects with the highest grade based on the Infusion Site Evaluation Letter Grade Scale received during any 10 day period for a pharmaceutical composition consisting of levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a ratio of 20:1 and placebo. [Figure 14A] 1 is a graphical representation of the study design for Clinical Trial A to evaluate the safety and tolerability of 4-week continuous subcutaneous infusion in patients of a pharmaceutical composition consisting of levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a ratio of 20:1. [Figure 14B] 1 is a graph showing the results for Clinical Trial A of injection site grading using a numerical scale in patients. [Figure 14C] 1 is a graph showing the results for Clinical Trial A of injection site grading using a letter scale in patients. [Figure 14D] 1 is a graph showing the mean (SD) change from baseline in MDS-UPDRS total score for Clinical Trial A in patients. [Figure 14E] FIG. 1 is a graph showing the Mean (SD) Change from Baseline in "Off" Time at Regularly Scheduled Visits for Clinical Trial A in Patients. [Figure 15] FIG. 2 is a plasma time concentration profile of levodopa plasma levels (± standard deviation) in healthy human volunteers after subcutaneous administration of a bolus dose of a pharmaceutical composition consisting of levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a 20:1 ratio, followed by continuous subcutaneous administration of the pharmaceutical composition for 24 hours (Clinical Trial B). [Figure 16A]FIG. 1 is a plasma time concentration profile of levodopa plasma levels in Parkinson's disease patients after an initial bolus dose is administered subcutaneously followed by continuous subcutaneous administration over 72 hours at various doses of a pharmaceutical composition having a 20:1 levodopa 4' monophosphate to carbidopa 4' monophosphate ratio. [Figure 16B] FIG. 1 is a plasma time concentration profile of carbidopa plasma levels in Parkinson's disease patients after an initial bolus dose is administered subcutaneously followed by continuous subcutaneous administration over 72 hours at various doses of a pharmaceutical composition having a 20:1 levodopa 4' monophosphate to carbidopa 4' monophosphate ratio. [Figure 17] FIG. 2 is a plasma time concentration profile of carbidopa plasma levels (± standard deviation) in healthy human volunteers after subcutaneous administration of a bolus dose of a pharmaceutical composition consisting of levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a ratio of 20:1, followed by continuous subcutaneous administration of the pharmaceutical composition for 24 hours (Clinical Trial B). [Figure 18] 1 is a plasma concentration time profile of carbidopa levels in a human patient following enteral administration of Duodopa®, a 4:1 ratio of levodopa to carbidopa, over a 24 hour period. [Figure 19] 1 is a graph comparing the mean levodopa pharmacokinetic profiles following subcutaneous injection into the abdomen, arm, and thigh in healthy human volunteers (Clinical Trial B). [Figure 20] 1 is a graph comparing the mean carbidopa pharmacokinetic profiles following subcutaneous injection into the abdomen, arm, and thigh in healthy human volunteers (Clinical Trial B). [Figure 21] 4 shows the percentage of patients who experienced "off" time during the day who received the pharmaceutical composition compared to patients who received oral Sinemet® (Clinical Trial B). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0082] The present disclosure describes the unexpected discovery that subcutaneous administration to humans of a pharmaceutical composition having a dose ratio of levodopa acid prodrug to carbidopa acid prodrug of about 20:1 w / w provides an effective level of levodopa to carbidopa exposure. Such compositions incorporate surprisingly less than expected, yet still therapeutically relevant amounts of carbidopa. The reduced loading of carbidopa drug in the composition is beneficial to patients in that it reduces by-products associated with carbidopa degradation, thus resulting in increased stability and improved safety profile of the composition. Thus, the present disclosure provides stable aqueous pharmaceutical formulations of levodopa and carbidopa acid prodrug for subcutaneous administration.

[0083] As discussed above, the inherently low aqueous solubility of levodopa at physiologically acceptable pH for subcutaneous injection presents significant technical challenges to the development of improved pharmaceutical compositions and methods of treatment. Such challenges include, for example, the difficulty of achieving adequate dosage and formulation stability within the required pH limits. These challenges are further complicated by the requirement that pharmaceutical compositions and methods of treatment provide pharmacokinetically relevant and pharmacokinetically consistent control of dopamine levels in the patient's brain.

[0084] The pharmaceutical compositions of the present disclosure overcome the problems of previous approaches for administering levodopa with or without carbidopa. Such pharmaceutical compositions can be administered to patients suffering from Parkinson's disease and related conditions.

[0085] In various embodiments of the present disclosure, the pharmaceutical composition comprises a levodopa prodrug and a carbidopa prodrug that convert in vivo to levodopa and carbidopa. The pharmaceutical composition of the present disclosure allows for delivery by continuous subcutaneous administration. Such subcutaneous administration can maintain sustained levodopa steady-state plasma concentrations similar to the commercially available enteral gel formulation with a 4:1 ratio of levodopa to carbidopa currently sold under the trade name Duodopa® / Duopa®. Furthermore, this continuous administration achieves a steady-state plasma drug concentration (C ) of levodopa that is comparable to that of the 4:1 ratio oral tablet formulation sold under the trade name Sinemet®. SS ) essentially eliminating significant variations in the carbidopa concentration. The pharmaceutical formulation also has a reduced relative concentration of carbidopa compared to intraduodenally administered gel and oral therapy. The pharmaceutical compositions and methods of the present disclosure represent an advancement in the treatment of Parkinson's disease and other related conditions.

[0086] The pharmaceutical compositions of the present disclosure provide the same or similar effects as those observed with oral therapy, including the steady-state concentration of levodopa (C SS ) without significant changes in the C-reactive protein level, and sustained C-reactive protein levels similar to those achieved with currently available intraduodenal gel therapy. SS Moreover, such sustained levodopa steady-state plasma concentrations are achieved using the pharmaceutical compositions of the present disclosure without the need for surgically implanting a percutaneous endoscopic gastrostomy port, which is necessary for intraduodenal administration. Furthermore, the pharmaceutical compositions of the present disclosure achieve low levels of hydrazine and DHPPA-P degradants at near-neutral pH levels, substantially free of antioxidants. For example, the pharmaceutical compositions release less than about 15 micrograms / mL of hydrazine after storage at 25° C. for about 5 days and at 5° C. for about 30 days. Such pharmaceutical compositions are advantageous over compositions that use antioxidants and have pH levels above 9.1, as described in WO2018 / 15447.

[0087] Levodoparinic acid prodrugs are

[0088] [ka] Compound (A-1) has the chemical name levodopa-4'-monophosphate and has been assigned the CAS Registry Number 97321-87-4. The international nonproprietary name for levodopa-4'-monophosphate is foslevodopa.

[0089] Carbidoparinic acid prodrugs are

[0090] [ka] Compound (B-1) has the chemical name carbidopa-4'-monophosphate and has been assigned the CAS registry number 28860-95-9. The international nonproprietary name for carbidopa-4'-monophosphate is foscarbidopa.

[0091] As used herein, certain terms may be used within the disclosure.

[0092] Where numerical ranges are recited herein, each number within the range is expressly contemplated to the same degree of precision. For example, in the range from 6 to 9, the values ​​7 and 8 are contemplated in addition to 6 and 9, and in the range from 6.0 to 7.0, the values ​​6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are expressly contemplated.

[0093] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0094] As used herein, the term "and / or" in phrases such as "A and / or B" is intended to mean "A and B," "A or B," "A" or "B."

[0095] The term "about" generally indicates a range of numbers that one of ordinary skill in the art would consider equivalent to the recited value (i.e., having the same function or result). In many cases, the term "about" can include numbers that are rounded to the nearest significant figure. In some cases, the term "about" can be used to indicate values ​​within ±20% of the stated value, for example, values ​​within ±15%, ±10%, ±7.5%, ±5%, ±4%, ±3%, ±2% or ±1% of the stated value.

[0096] The term "substantially free" means not added as an excipient.

[0097] The term "neutral pH conditions" means a pH of about 6.8 to about 7.8.

[0098] The term "stable" means that the pharmaceutical composition contains less than about 15 micrograms / mL of hydrazine after storage under pH-neutral conditions at 25° C. for 5 days followed by 30 days at 5° C.

[0099] The term "baseline" refers to the first measurement of a target variable immediately prior to administration of the therapy being tested.

[0100] The term "container" means any suitable container, coated or uncoated, manufactured using any suitable material, and includes, but is not limited to, vials, cartridges, syringes, bottles, and materials such as glass, plastic, and / or any combination thereof.

[0101] Unless the context otherwise requires, the terms "comprise", "comprises" and "comprising" are used with the express understanding that they are to be interpreted inclusively and not exclusively, and thus, they indicate the inclusion of recited features but do not exclude one or more other such features.

[0102] The terms "patient," "subject," "individual," and the like refer to a human.

[0103] The term "carrier" used in connection with pharmaceutical excipients refers to any and all solvents, dispersion media, preservatives, coatings, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.

[0104] The term "pharmaceutical acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include, but are not limited to, (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2] ... (2) acid addition salts formed with organic acids such as 1,2-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; and (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion); or when an acidic proton present in the parent compound is coordinated with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine). Such salts are disclosed in WO2016 / 065019A1.

[0105] In one embodiment, the pharmaceutical composition comprises a levodopa acid prodrug and carbidopa acid in an aqueous carrier, and the pharmaceutical composition is suitable for subcutaneous administration. The pharmaceutical composition comprises a ratio of levodopa 4'-monophosphate to carbidopa 4'-monophosphate of about 20 to about 1. In one embodiment, the pharmaceutical composition comprises about 240 mg / mL levodopa 4'-monophosphate and about 12 mg / mL carbidopa 4'-monophosphate. In another embodiment, the pharmaceutical composition comprises about 360 mg / mL levodopa 4'-monophosphate and about 18 mg / mL carbidopa 4'-monophosphate. In another embodiment, the pharmaceutical composition comprises about 60 mg / mL 4'-monophosphate and about 3 mg / mL carbidopa 4'-monophosphate.

[0106] In one embodiment, the concentration of compound (A-1) in the composition is 216 mg / mL to 264 mg / mL. In another embodiment, the concentration of compound (A-1) is about 240 mg / mL. In one embodiment, the concentration of compound (B-1) in the composition is 9.6 mg / mL to 13.2 mg / mL. In another embodiment, the concentration of compound (B-1) is about 12 mg / mL. In one embodiment, the concentration of compound (A-1) in the composition is 216 mg / mL to 264 mg / mL, and the concentration of compound (B-1) in the composition is 9.6 mg / mL to 13.2 mg / mL. In another embodiment, the concentration of compound (A-1) is about 240 mg / mL, and the concentration of compound (B-1) is about 12 mg / mL. Thus, in one embodiment, the concentration of compound (A-1) in the composition is 216 mg / mL to 264 mg / mL. In another embodiment, the concentration of compound (A-1) is about 240 mg / mL. In one embodiment, the concentration of compound (B-1) in the composition is 9.6 mg / mL to 13.2 mg / mL. In another embodiment, the concentration of compound (B-1) is about 12 mg / mL. In one embodiment, the concentration of compound (A-1) in the composition is 216 mg / mL to 264 mg / mL, and the concentration of compound (B-1) in the composition is 9.6 mg / mL to 13.2 mg / mL. In another embodiment, the concentration of compound (A-1) is about 240 mg / mL, and the concentration of compound (B-1) is about 12 mg / mL. Thus, in one embodiment, the pharmaceutical composition comprises about 240 mg / mL of levodopa 4'-monophosphate and about 12 mg / mL of carbidopa 4'-monophosphate. In one embodiment, the concentration of compound (A-1) in the composition is 324 mg / mL to 396 mg / mL. In another embodiment, the concentration of compound (A-1) is about 360 mg / mL. In one embodiment, the concentration of compound (B-1) in the composition is 16.2 mg / mL to 19.8 mg / mL. In another embodiment, the concentration of compound (B-1) is about 18 mg / mL. In one embodiment, the concentration of compound (A-1) in the composition is 324 mg / mL to 396 mg / mL, and the concentration of compound (B-1) in the composition is 16.2 mg / mL to 19.8 mg / mL.In another embodiment, the concentration of compound (A-1) is about 360 mg / mL and the concentration of compound (B-1) is about 18 mg / mL.Thus, in one embodiment, the pharmaceutical composition comprises about 360 mg / mL levodopa 4'-monophosphate and about 18 mg / mL carbidopa 4'-monophosphate.

[0107] In one embodiment, the concentration of compound (A-1) is about 60 mg / mL and the concentration of compound (B-1) is about 3 mg / mL. Thus, in another embodiment, the pharmaceutical composition comprises about 60 mg / mL 4'-monophosphate and about 3 mg / mL carbidopa 4'-monophosphate.

[0108] In one embodiment, the pharmaceutical composition is prepared using a neutralizing agent. In one embodiment, the neutralizing agent is sodium hydroxide. In another embodiment, the neutralizing agent is potassium hydroxide. As described herein, the pharmaceutical composition can have a final pH of about 6.5 to about 9.2, which encompasses pH values ​​between 6.5 and 9.2 in increments of 0.1. In one embodiment, the pharmaceutical composition has a final pH (e.g., after reconstitution with water) of about 6.8 to about 7.8. Thus, the pharmaceutical composition can have a final pH selected from about 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, or 7.8. In one embodiment, the pharmaceutical composition has a final pH of about 7.0 to about 7.5. Thus, the pharmaceutical composition can have a final pH selected from about 7.0, 7.1, 7.2, 7.3, 7.4, or 7.5.

[0109] Formulations containing levodopa and carbidopa acid prodrugs may be oxidized and / or degraded to release various decomposition products, such as hydrazine and / or 2-methyl-3-(3,4-dihydroxyphenyl)-propionic acid (DHPPA-P). For example, hydrazine may result from oxidative decomposition of carbidopa-4'-monophosphate. Hydrazine is considered an impurity, and the release of hydrazine in the pharmaceutical composition should be controlled. In one embodiment, the pharmaceutical composition is stable and releases less than about 0.50 mg / mL of DHPPA-P after storage at room temperature (e.g., 25°C) for about 5 days and at refrigerated conditions (e.g., 5°C) for about 30 days.

[0110] In another embodiment, the pharmaceutical composition comprises less than about 5.4% w / w DHPPA-P at pH 6.5-9.0 after storage at 25° C. for 5 days followed by 30 days at 5° C. In one embodiment, the pharmaceutical composition releases less than about 15 micrograms / mL of hydrazine after storage at room temperature (e.g., 25° C.) for about 5 days and at refrigerated conditions (e.g., 5° C.) for about 30 days. Thus, for example, the pharmaceutical composition may comprise less than about 15 micrograms / mL of hydrazine after storage at 25° C. for 5 days followed by 30 days at 5° C. under neutral pH conditions.

[0111] In some embodiments, the composition is stable (e.g., under the above criteria) for at least 3 months under refrigerated conditions (e.g., at a temperature between 2°C and 8°C) and under conditions equivalent to those established in a 10 cc vial (e.g., using a 15 cc or 20 cc vial) having less than about 9% oxygen in the headspace at 1 atmosphere. Preferably, the vial (e.g., a 15 cc or 20 cc vial) contains less than about 5.5% oxygen at 1 atmosphere. The oxygen in the vial or another suitable container for storing the composition can be purged to less than about 9% oxygen by purging with nitrogen or any suitable inert gas.

[0112] The pharmaceutical compositions of the present disclosure exhibit desirable pharmacokinetics after administration to human subjects. In one embodiment, the pharmaceutical composition exhibits an AUC(0-t) vs. AUC (0-t) In another embodiment, the pharmaceutical composition, when administered to an adult human, provides a mean plasma exposure ratio of levodopa to carbidopa of 6.57 to 8.03 levodopa to about 1 as measured by AUC (0-t) vs. AUC (0-t) The pharmaceutical composition provides an average plasma exposure ratio of levodopa to carbidopa of about 7.30 to about 1 as measured by .times. ... max -C min ] / C ave In another embodiment, continuous subcutaneous administration of the composition to a population of adult humans achieves a mean plasma concentration of levodopa having a variability of about 0.40 over a period of 2 to 72 hours after administration, the variability being defined as ([C max -C min ] / C ave )

[0113] In one embodiment, the pharmaceutical composition of the present disclosure is substantially free of antioxidants. In another embodiment, the composition is substantially free of arginine. In another embodiment, the composition is substantially free of ascorbic acid or a pharma- ceutically acceptable salt of ascorbic acid. In another embodiment, the composition is substantially free of L-cysteine ​​or a pharma- ceutically acceptable salt thereof, N-acetylcysteine ​​(NAC) or a pharma- ceutically acceptable salt thereof, glutathione or a pharma- ceutically acceptable salt thereof, diacetylcysteine ​​or a pharma- ceutically acceptable salt thereof, and sodium bisulfite, or any combination thereof.

[0114] The present disclosure also relates to a method of treatment in which the pharmaceutical composition is used. In view of this aspect, the present disclosure provides a pharmaceutical composition disclosed herein for use as a medicament. Also provided is the use of the pharmaceutical composition disclosed herein in treatment. In particular, the present disclosure provides a method for treating a condition responsive to levodopa and carbidopa (e.g., Parkinson's disease) using a composition disclosed herein. In one aspect, the present disclosure provides a method for treating Parkinson's disease in a subject, the method comprising subcutaneously administering a pharmaceutical composition disclosed herein to a patient in need of such treatment. Also provided is a pharmaceutical composition disclosed herein for use in treating Parkinson's disease. Also provided is the use of a compound of formula (A-1) and a compound of formula (B-1) in the preparation of a pharmaceutical composition disclosed herein for use in treating Parkinson's disease. In one embodiment, the treatment comprises administering the pharmaceutical composition to a human adult patient, the administration reducing the AUC (0-t) vs. AUC (0-t)The present disclosure provides a plasma exposure ratio of levodopa to carbidopa of about 7.30 to 1 as measured by . In another aspect and embodiment, the present disclosure provides a method in which certain criteria of Parkinson's disease are improved. Thus, the present disclosure provides a method of improving the "off" time of Parkinson's disease symptoms in a subject, comprising subcutaneously administering to a patient in need of Parkinson's disease treatment an amount of a pharmaceutical composition disclosed herein effective to reduce Parkinson's disease symptoms by at least 46% from baseline. The present disclosure further provides a method of treating Parkinson's disease in a subject, comprising subcutaneously administering to a subject in need of Parkinson's disease treatment having a baseline Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score an amount of a pharmaceutical composition disclosed herein effective to reduce the baseline MDS-UPDRS total score by at least 9 units. The present disclosure further provides a method of treating Parkinson's disease in a subject, comprising administering subcutaneously to a subject in need of treatment for Parkinson's disease having a baseline Parkinson's Disease Questionnaire-39 (PDQ-39) Summary Index score an amount of a pharmaceutical composition disclosed herein effective to reduce the baseline PDQ-39 score by at least 6.9 units. The present disclosure further provides a method of treating Parkinson's disease in a subject, comprising administering subcutaneously to a subject in need of treatment for Parkinson's disease having a baseline Parkinson's Sleep Scale-2 (PDSS-2) total score an amount of a pharmaceutical composition disclosed herein effective to reduce the baseline PDSS-2 total score by at least 2 units. In an embodiment, the treatment disclosed herein can be continued for at least 10 days without the subject developing skin nodules.The present disclosure further provides a method of reducing the incidence of "off" time of Parkinson's disease symptoms in a subject as compared to a subject receiving oral administration of a tablet comprising levodopa and carbidopa, the method comprising subcutaneously administering to a patient in need of treatment for Parkinson's disease a pharmaceutical composition disclosed herein.

[0115] The present disclosure further relates to a ready-to-use vial or cartridge or container or enclosure suitable for containing liquid pharmaceutical dosage formulations. Such containment may serve to hold a liquid formulation (e.g., in a pharmaceutical composition disclosed herein) including one or more of levodopa acid prodrugs and carbidopa acid prodrugs. The vial may also serve as a storage container for a powder form of levodopa acid prodrugs and / or carbidopa acid prodrugs, so that the vial may be in a ready-to-use form that is ready to be removed or loaded for injection into the container by reconstitution with an aqueous vehicle. The stable pharmaceutical composition includes levodopa-4'-monophosphate in a concentration of about 216 mg / mL to about 264 mg / mL, and carbidopa-4'-monophosphate in a concentration of about 9.6 mg / mL to about 13.2 mg / mL.

[0116] The present disclosure further relates to a ready-to-use vial or cartridge or container or enclosure suitable for containing liquid pharmaceutical dosage formulations. Such a container may serve to hold a liquid formulation comprising one or more of a levodoparinic acid prodrug and a carbidoparinic acid prodrug. The vial may also serve as a storage container for a powder form of the levodoparinic acid prodrug and / or the carbidoparinic acid prodrug, so that the vial may be in a ready-to-use form that is ready to be withdrawn or loaded for injection into the container by reconstitution with an aqueous vehicle.

[0117] As described above, carbidopa is administered together with levodopa to improve the exposure of levodopa by inhibiting the aromatic L-amino acid decarboxylase (DDC) enzyme that metabolizes levodopa. Oral administration of levodopa and carbidopa in a ratio of 4:1 has been used to inhibit the DDC enzyme. An improved ratio of a composition containing levodopa acid prodrug and carbidopa acid prodrug for subcutaneous administration was found to be about 20:1 based on the plasma exposure ratio of levodopa to carbidopa observed in humans. The advantage of using a composition containing levodopa acid prodrug to carbidopa acid prodrug in a weight ratio of 20:1 is that excessive carbidopa prodrug administration is reduced. EXAMPLES

[0118] Example 1A Safety, tolerability and pharmacokinetics in healthy subjects This example demonstrates that a pharmaceutical composition consisting of levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a 20:1 ratio is safe and also evaluates its pharmacokinetics.

[0119] method A total of eight healthy elderly (ages 45-75 years) human subjects participated in a single-blind, placebo-controlled, three-period crossover design clinical trial to evaluate the safety, tolerability, and pharmacokinetics of levodopa 4'-monophosphate and carbidopa 4'-monophosphate delivered as a single continuous subcutaneous infusion (CSCI) over 16 hours. Each dose of levodopa 4'-monophosphate and carbidopa 4'-monophosphate composition or placebo was administered in a single-blind manner into the abdomen as a single CSCI, delivered at a constant rate over 16 hours via an infusion set connected to a portable pump. Regimen A, B, C, and D consisted of 640 / 160 mg levodopa 4'-monophosphate / carbidopa 4'-monophosphate, 640 / 64 mg levodopa 4'-monophosphate / carbidopa 4'-monophosphate CSCI, 640 / 32 mg levodopa 4'-monophosphate / carbidopa 4'-monophosphate CSCI, or placebo CSCI, delivered at a constant rate into the abdomen over 16 hours.For pharmacokinetic analysis, blood samples were drawn from each of eight healthy elderly (45-75 years) human subjects before priming of the catheter, before infusion (0 hours), and at 0.5, 1, 2, 4, 8, 12, 16, 20, 24, 26, and 28 hours after the start of the infusion.

[0120] Group Eligible subjects were healthy male and female volunteers between the ages of 45 and 75 years. If female, subjects must have been postmenopausal for at least one year or surgically sterile. Exclusion criteria included a history of significant skin conditions or disorders (e.g., psoriasis, atopic dermatitis, etc.) or evidence of recent sunburn, acne, scar tissue, tattoos, open wounds, branding or pigmentation.

[0121] Safety Results No patterns were evident regarding the nature or frequency of treatment-emergent adverse events following CSCI infusion or bolus injection of levodopa 4'-monophosphate and carbidopa 4'-monophosphate compositions compared to subjects receiving placebo. All regimens tested were well tolerated by subjects. No significant patterns of adverse events and laboratory findings were reported. There were no notable findings from individual measurements of blood pressure and pulse rate or from quantitative measurements from ECG.

[0122] Pharmacokinetic Results As shown in Figures 1-3, compositions of levodopa 4'-monophosphate and carbidopa 4'-monophosphate were delivered subcutaneously to healthy human volunteers at various weight ratios of 4:1 (regimen A, Figure 1); 10:1 (regimen B, Figure 2); and 20:1 (regimen C, Figure 3), respectively. The time concentration plasma level profiles for each of the ratios of subcutaneously delivered levodopa 4'-monophosphate and carbidopa 4'-monophosphate (Figures 1-3) were compared to the time concentration profile of levodopa and carbidopa plasma levels obtained from oral administration to the same humans of levodopa and carbidopa at a weight ratio of 4:1 levodopa:carbidopa (Figure 4). Furthermore, the time concentration profile of levodopa plasma levels in healthy human volunteers obtained by subcutaneous administration of levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a ratio of 20:1 (Figure 5) was compared with the time concentration profile of levodopa plasma levels in patients obtained by intraduodenal administration of Duodopa® in a weight ratio of levodopa to carbidopa of 4:1 (Figure 6). Furthermore, the time concentration profile of levodopa plasma levels in healthy human volunteers obtained by subcutaneous administration of levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a weight ratio of 20:1 was compared with the time concentration profile of levodopa plasma levels in patients obtained by oral administration of levodopa and carbidopa in a weight ratio of 4:1 (Figure 7).

[0123] FIG. 1 provides time concentration profiles of plasma levels of levodopa and carbidopa in healthy human volunteers following CSCI with subcutaneous administration of a composition containing levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a 4:1 weight ratio (640 mg levodopa 4'-monophosphate / 160 mg carbidopa 4'-monophosphate). Healthy elderly volunteers were administered a 4:1 ratio of levodopa 4'-monophosphate to carbidopa 4'-monophosphate. As shown in FIG. 1, the levodopa AUC( 0-t ) / Carbidopa AUC( 0-t ) was 1.79:1 compared to 7.39:1 for orally administered levodopa and carbidopa in a 4:1 weight ratio (Figure 4).

[0124] FIG. 2 provides time concentration profiles of plasma levels of levodopa and carbidopa in healthy elderly human volunteers following continuous subcutaneous infusion of a composition containing levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a 10:1 weight ratio (640 mg levodopa 4'-monophosphate / 64 mg carbidopa 4'-monophosphate). Results of the exposure ratio analysis showed that the plasma exposure ratio AUC( 0-t ) / Carbidopa AUC( 0-t ) was 3.94:1 compared to 7.39:1 for levodopa and carbidopa administered orally in a 4:1 weight ratio (FIG. 4).

[0125] Surprisingly, it has been found that a 20:1 dosing ratio (640 mg levodopa 4'-monophosphate / 32 mg carbidopa 4'-monophosphate) can provide a levodopa to carbidopa exposure ratio similar to oral levodopa and carbidopa administered at a 4:1 ratio (e.g., Sinemet®) for subcutaneously administered levodopa 4'-monophosphate and carbidopa 4'-monophosphate. Figure 3 provides time concentration profiles of plasma levels of levodopa and carbidopa in healthy human volunteers after continuous subcutaneous infusion of a pharmaceutical composition comprising levodopa-4'-monophosphate and carbidopa-4'-monophosphate in humans. As shown in Figure 3, CSCI administration of the composition unexpectedly resulted in a levodopa / carbidopa exposure ratio of 20:1 by weight (640 mg levodopa 4'-monophosphate to 32 mg carbidopa 4'-monophosphate) comparable to a 4:1 oral levodopa to carbidopa administration (Figure 4). 0-t / Carbidopa AUC 0-t The results from the exposure ratio analysis unexpectedly showed that the plasma exposure ratio of levodopa:carbidopa for a composition containing levodopa 4'-monophosphate and carbidopa 4'-monophosphate administered subcutaneously in a 20:1 weight ratio was 7.30:1 ng*h / mL, which is within about 99% or 0.09 (units) of the value of 7.39:1 for oral levodopa and carbidopa administered in a 4:1 weight ratio (e.g., Sinemet®). Additionally, the 20:1 levodopa 4'-monophosphate to carbidopa 4'-monophosphate composition results in an overall theoretical reduction in hydrazine exposure of about 80% compared to the 4:1 levodopa 4'-monophosphate to carbidopa 4'-monophosphate ratio, which further advantageously allows for more levodopa 4'-monophosphate in a fixed volume composition of levodopa 4'-monophosphate and carbidopa 4'-monophosphate.

[0126] Figure 4 provides time concentration profiles of plasma levels of levodopa and carbidopa in healthy elderly human volunteers after oral administration of a 4:1 weight ratio combination of levodopa and carbidopa. A total of 300 / 75 mg levodopa / carbidopa was administered orally to eight healthy elderly (45-75 years) human subjects in an open-label study as three divided doses of 100 / 25 mg levodopa / carbidopa. Doses were administered at 0, 5, and 10 hours. For pharmacokinetic analysis, blood samples were taken prior to the first dose (0 hours), and 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, prior to the second dose (5 hours), 5.25 hours, 5.5 hours, 5.75 hours, 6 hours, 6.5 hours, 7 hours, 8 hours, 9 hours, prior to the third dose (10 hours), 10.25 hours, 10.5 hours, 10.75 hours, 11 hours, 11.5 hours, 12 hours, 13 hours, 14 hours, 15 hours, 19 hours, and 24 hours after the initial dose on Day 1.

[0127] result FIG. 5 provides the time concentration profiles and Table 1 provides the pharmacokinetic parameters of levodopa and carbidopa plasma levels in healthy elderly human volunteers after a pharmaceutical composition consisting of levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a weight ratio of 20:1 was administered subcutaneously as an initial bolus infusion over 5 minutes, followed by a continuous subcutaneous infusion over 72 hours (960 mg / 48 mg levodopa 4'-monophosphate / carbidopa 4'-monophosphate).

[0128] [Table 1]

[0129] As shown in Table 2, continuous subcutaneous infusion of the composition (960 mg / 48 mg levodopa 4'-monophosphate / carbidopa 4'-monophosphate) over 72 hours achieved mean plasma concentrations of levodopa with a variability of about 0.3 or less over a period of 2 to 16 hours, where the variability was less than or equal to ([C max -C min ] / C ave ) is calculated as C max is the maximum (or peak) plasma concentration of levodopa achieved after continuous subcutaneous infusion of the composition (960 mg / 48 mg levodopa 4'-monophosphate / carbidopa 4'-monophosphate). min is the minimum observed plasma concentration of levodopa from 2 hours to 72 hours during continuous subcutaneous infusion of the composition (960 mg / 48 mg levodopa 4'-monophosphate / carbidopa 4'-monophosphate). ave is the mean plasma concentration of levodopa observed during continuous subcutaneous infusion of the composition (960 mg / 48 mg levodopa 4'-monophosphate / carbidopa 4'-monophosphate).

[0130] Continuous subcutaneous infusion of the composition (960 mg / 48 mg levodopa 4'-monophosphate / carbidopa 4'-monophosphate) for 72 hours achieves a stable plasma concentration of levodopa with a variability of about 0.4 or less over 2-72 hours during administration, where the variability is less than or equal to 0.01 for a given period ([C max -C min ] / C ave ) is defined as the low levodopa steady state (C ss ) Exposure variability (ng / mL) was similar to that seen with Duodopa® (4:1 ratio of levodopa to carbidopa monohydrate), the current standard of care that requires intraduodenal administration.

[0131] [Table 2]

[0132] Figure 6 provides the time-concentration profile of levodopa plasma levels in patients obtained by intraduodenal administration of Duodopa®, which has a levodopa to carbidopa ratio of 4:1. Comparison of Figures 5 and 6 shows that the time concentration profile of levodopa and carbidopa plasma levels in healthy elderly human volunteers after subcutaneous administration of a pharmaceutical composition containing levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a weight ratio of 20:1 provides a more stable concentration of levodopa in plasma over time as compared to Duodopa®.

[0133] FIG. 7 is a comparison of the time concentration profiles of levodopa plasma levels in healthy elderly human volunteers after continuous subcutaneous infusion of a pharmaceutical composition consisting of levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a weight ratio of 20:1 and oral administration of a pharmaceutical composition containing a combination of levodopa and carbidopa in a weight ratio of 4:1. The oral levodopa exposure data was scaled up (2-fold) to match the average levodopa exposure achieved by the pharmaceutical composition of levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a weight ratio of 20:1. As shown in FIG. 7, the pharmaceutical composition consisting of levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a ratio of 20:1 administered subcutaneously (solid line) demonstrated the ability to maintain levodopa plasma concentrations at steady state exposure with minimal steady state fluctuations and to maintain levodopa plasma exposure for 24 hours, whereas oral levodopa plasma concentrations (dotted line) fluctuated over time.

[0134] Example 1B Safety, tolerability, and pharmacokinetics of a 72-hour subcutaneous infusion in subjects with Parkinson's disease This example demonstrates that a pharmaceutical composition consisting of levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a 20:1 ratio is safe and also evaluates its pharmacokinetics over a 72 hour period.

[0135] method Subcutaneous infusions of a pharmaceutical composition consisting of levodopa 4'-monophosphate and carbidopa 4'-monophosphate and placebo were evaluated in a single-blind, single-ascending dose study in approximately 16 subjects with Parkinson's disease to evaluate the safety, tolerability, and pharmacokinetics of levodopa 4'-monophosphate and carbidopa 4'-monophosphate delivered as a single continuous subcutaneous infusion (CSCI) over a 72-hour period.

[0136] Four treatment groups, including up to four subjects in each group, received a bolus of a pharmaceutical composition consisting of levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a 20:1 ratio (200 mg / 10 mg), followed by 72-hour administration of a pharmaceutical composition consisting of levodopa 4'-monophosphate and carbidopa 4'-monophosphate in a 20:1 ratio by CSCI via an infusion pump: Group 1 received 960 / 48 mg, Group 2 received 2400 / 120 mg, Group 3 received 3600 / 180 mg, and Group 4 received 4800 / 240 mg of a pharmaceutical composition consisting of levodopa 4'-monophosphate and carbidopa 4'-monophosphate by CSCI via an infusion pump.

[0137] Group Eligible subjects were adult male and female subjects aged 45–85 years, diagnosed with idiopathic Parkinson's disease, who were levodopa-responsive, in generally good health, and on a stable oral levodopa regimen receiving at least three doses per day. As shown in Figures 16A and 16B, the mean measured concentrations of levodopa and carbidopa, respectively, from various doses of a pharmaceutical composition having a ratio of levodopa 4'-monophosphate to carbidopa 4'-monophosphate of 20:1 remained constant over 72 hours.

[0138] Example 2 stability This example demonstrates that a pharmaceutical composition consisting of a 20:1 ratio of levodopa 4'-monophosphate to carbidopa 4'-monophosphate is stable over time.

[0139] method Various aqueous pharmaceutical compositions containing levodopa 4'-monophosphate prodrug corresponding in structure to Formula (A-1) and carbidopa 4'-monophosphate prodrug corresponding in structure to Formula (B-1), water, and sufficient neutralizing agent to obtain the measured final pH were prepared as shown in Table 3. Pharmaceutical compositions having the formulations shown in Table 3 were prepared and filled into 10 cc vials (having a maximum fill volume of about 13.5 mL) for a total volume of about 11 mL, and the remainder of the vial volume was purged with nitrogen to leave an oxygen headspace of about 5.5%.

[0140] [Table 3]

[0141] The amounts of DHPPA-P and hydrazine were measured separately. Measurement of hydrazine levels was based on the derivatization of hydrazine to benzalazine, and the method involved gradient reversed-phase high performance liquid chromatography (HPLC) with ultraviolet (UV) detection to measure hydrazine and DHPPA-P.

[0142] Tables 4-7 show the release of DHPPA-P and hydrazine measured over time for Formulations 1-16, respectively, in Table 3. DHPPA-P was measured as mg / mL and % w / w. % w / w was calculated by multiplying the amount of DHPPA-P per amount of carbidopa 4'-monophosphate by 100. Hydrazine was measured as micrograms / mL and % w / w. % w / w was calculated by multiplying the amount of hydrazine per amount of carbidopa 4'-monophosphate by 100.

[0143] [Table 4]

[0144] [Table 5]

[0145] [Table 6]

[0146] [Table 7]

[0147] The results shown in Tables 4-7 were plotted as contour plots as shown in Figures 8-11. Figure 8 is a graphical representation of DHPPA-P levels (% w / w) versus the amount of carbidopa 4'-monophosphate after 5 days at 25°C and then 30 days at 5°C.

[0148] FIG. 9 is a graphical representation of DHPPA-P levels (% w / w) versus the amount of carbidopa 4'-monophosphate after 5 days at 25°C and further after 65 days at 5°C.

[0149] FIG. 10 is a graphical representation of hydrazine levels (% w / w) versus the amount of carbidopa 4'-monophosphate after 5 days at 25°C and further after 30 days at 5°C.

[0150] FIG. 11 is a graphical representation of hydrazine levels (% w / w) versus the amount of carbidopa 4'-monophosphate after 5 days at 25°C and further after 65 days at 5°C.

[0151] As shown in Figures 8 and 9, the higher the concentration of carbidopa 4'-monophosphate and the lower the pH, the lower the DHPPA-P levels.

[0152] The higher the pH, the lower the hydrazine levels, as shown in Figures 10 and 11. Formulations having concentrations of about 240 mg / mL levodopa 4'-monophosphate and 12 mg / mL carbidopa 4'-monophosphate (about 170 mg levodopa by molecular weight) showed low levels of DHPPA-P and hydrazine at final pH values ​​of about 6.5 to 9.0.

[0153] Example 3 24-Hour Continuous Subcutaneous Infusion of Levodopa and Carbidopa Prodrugs in Healthy Volunteers: Safety and Tolerability Over a 10-Day Period to Simulate a One-Year Exposure This study was designed to evaluate the safety and local tolerability of a 24-hour continuous subcutaneous infusion of an aqueous pharmaceutical composition containing a levodopa 4'-monophosphate prodrug corresponding in structure to Formula (A-1) and a carbidopa 4'-monophosphate prodrug corresponding in structure to Formula (B-1) (a prodrug combination), in which the pharmaceutical composition was administered to a limited area of ​​the abdomen of healthy volunteers for 10 consecutive days, simulating a one-year exposure.

[0154] method The study was a Phase 1, randomized, placebo-controlled study in healthy volunteers who received sufficient of the pharmaceutical composition to provide 600 mg of levodopa and an equal volume of saline by simultaneous 24-hour continuous subcutaneous infusion into both sides of the abdomen for 10 days. The study consisted of three periods, as shown in Table 8.

[0155] [Table 8]

[0156] As shown in Table 8, the screening period lasted 28 days and was conducted to ensure that patients met the eligibility and criteria, and further to collect medical history and baseline clinical evaluations. The next period was the confinement period, during which patients were confined to the study site for 13 days (days -1 to 12). During the confinement period, infusions were initiated on day 1, during which each patient received the pharmaceutical composition and an equal volume of placebo (saline) simultaneously. The infusions were administered into two areas of 5 cm diameter on either side of the abdomen. The subjects and the infusion site assessors were blinded to which treatment was administered on each side of the abdomen. The infusion sets were changed daily, and the catheters for each infusion set were placed within 5 cm diameter of the site used the previous day. The infusions continued 24 hours / day for 10 days, during which subjects received a dose of levodopa equivalent to about 600 to about 700 mg / day. A 28-day follow-up period was then conducted to allow for ad hoc reporting of adverse events. The infusion set was changed and reapplied to the same skin surface daily.

[0157] Rotating injection sites Good clinical practice and anecdotal data recommended that injection sites be rotated regularly, at least 2.5 cm apart, to reduce the risk of infection or irritation, fatty tissue buildup (hypertrophy), and scar formation (fibrosis). The infusion set selected for this study (Smith Cleo 90) recommended changing the set every 3 days to maintain sterility of the set. In clinical practice, patients are expected to adopt a clock-like rotation scheme that allows rotation to use the same injection site after using 11 alternate sites. Individuals will adopt a rotation schedule of injection sites around the navel (center). If the rotation begins at the 12 o'clock position and proceeds clockwise, assuming each injection site is used for 3 days, the patient will return to the 12 o'clock injection site after approximately 36 days - (12*3=)36 days, using the same injection site 10 times / year on average. This study provided an accelerated simulation of long-term use to evaluate local tolerance in healthy human volunteers with respect to the number of repeated injection sites the patient uses over a 1-year period.

[0158] Group The main inclusion criteria for this study were: Healthy adult male or female human volunteers aged 45–75 years; Body Mass Index (BMI) 18.0kg / m 2 from 32.0 kg / m 2 to; Generally good health based on medical history, physical examination, and clinically insignificant laboratory findings, electrocardiogram (ECG), or vital parameters; and No history of significant skin conditions or disorders identified by the investigator that may interfere with study evaluation.

[0159] Evaluation and Analysis Systemic and local safety and tolerability were assessed daily. Significant skin reactions were predefined as events not usually associated with predictable reactions from the use of an infusion set (grade ≥D or ≥6 on the Infusion Site Assessment Scale). Both subjects and assessors were blinded to the side of the abdomen into which the aqueous pharmaceutical composition containing levodopa 4'-monophosphate and carbidopa 4'-monophosphate and the placebo were infused. Specifically, the local skin tolerability of 10 days of 24-hour continuous subcutaneous infusion of the pharmaceutical composition into the abdomen was evaluated in 33 healthy human volunteers who completed the 10-day treatment period. Local skin tolerability was assessed by blinded assessors using the Infusion Site Assessment 2-part scale (Table 9). The assessment included a numeric grade (0-7) and a letter grade (A-G) scale. Significant skin reactions were predefined as events not usually associated with predictable reactions from the use of an infusion set (grade ≥D or ≥6). The primary endpoint was the number of healthy human volunteers who showed significant skin reactions at the injection site of the pharmaceutical composition more than 2 days out of the 10-day infusion.The 95% upper confidence limit for the proportion of the population who showed significant skin reactions more than 2 days out of the 10-day infusion was obtained by the Clopper-Pearson method.For each injection site assessment scale, a one-sided sign test was performed to test the hypothesis that there was no difference between the pharmaceutical composition and placebo at the final assessment against the alternative hypothesis that the pharmaceutical composition is more likely to have a higher grade.

[0160] [Table 9]

[0161] In addition to infusion site evaluations, safety assessments included: percent of subjects with treatment-emergent AEs and serious adverse events (SAEs); changes from baseline to end of study in clinical laboratory values, vital sign measurements, electrocardiogram (ECG), and physical examination findings.

[0162] result As shown in Table 10, the safety dataset included 34 subjects.

[0163] [Table 10]

[0164] Tolerability The highest grade reported for each healthy human volunteer subject (pharmaceutical composition site vs. placebo site) from days 1 to 10 of the study is summarized graphically for each injection site assessment scale in Figures 12 and 13. The percentage of subjects who completed 10 days of administration who reported significant skin reactions was 0% (0 / 33) at the pharmaceutical composition injection site and 3.0% (1 / 33) at the placebo injection site. The difference between the pharmaceutical composition and placebo on the dermatological assessment on day 10 of injection was not statistically significant on the numeric grade scale (P=0.828) or letter grade scale (P=0.363). The 95% upper confidence limit for the proportion of the population with significant skin reactions on 2 or more days of the 10-day injection of the pharmaceutical composition administered in this study is 0.087 (8.7% of the population). The 95% upper confidence limit for the proportion of the population experiencing significant skin reactions on 2 or more days of the 10-day placebo infusions administered in this study is 0.087 (8.7% of the population).

[0165] safety There were no clinically significant laboratory, vital sign, or ECG findings. Overall, 97% of subjects reported at least one adverse event (AE). There was one serious AE reported 4 days after study completion that was not considered potentially related to study drug. There were no discontinuations due to AEs (Table 11). The most frequently reported adverse events were injection site erythema (91%), injection site reactions (44%), and injection site pain (32%) (Table 12). All injection site AEs were mild or moderate in severity and quickly resolved.

[0166] [Table 11]

[0167] [Table 12]

[0168] A pharmaceutical composition comprising a levodopa 4'-monophosphate prodrug having a structure corresponding to formula (A-1) and a carbidopa 4'-monophosphate prodrug having a structure corresponding to formula (B-1) may provide the broad range of levodopa exposure required to adequately control motor symptoms and may represent an alternative treatment option for Parkinson's disease patients. This study demonstrated that the pharmaceutical composition was generally well tolerated and did not cause significant skin reactions at low (yet clinically relevant) doses administered subcutaneously to a limited area of ​​the abdomen for 10 consecutive days.

[0169] Example 4 Design of a Phase 1b Study to Evaluate the Safety and Tolerability of 4-Week Continuous Subcutaneous Infusions of Levodopa and Carbidopa Prodrugs in Patients with Parkinson's Disease This study was designed to evaluate the safety and tolerability of 4 weeks of continuous subcutaneous infusion of an aqueous pharmaceutical composition comprising a levodopa 4'-monophosphate prodrug corresponding in structure to Formula (A-1) and a carbidopa 4'-monophosphate prodrug corresponding in structure to Formula (B-1) in a weight ratio of 20:1. Additionally, the steady-state plasma levodopa levels achieved by continuous subcutaneous infusion of the pharmaceutical composition were evaluated, and exploratory efficacy was assessed by change from baseline in the endpoints listed in Table 18A.

[0170] method A single-arm, open-label, Phase 1b study was designed in Parkinson's disease patients treated with individualized therapeutic doses of the pharmaceutical composition by 24-hour continuous subcutaneous infusion for 28 days. Patients were recruited from US centers. The study consisted of four periods and is graphically depicted in FIG. 14A. The screening period included two visits to establish eligibility and a monitoring period to ensure that patients' current Parkinson's disease treatment was stable for 30 days. The screening period also included a 7-day monitoring period immediately following visit 2. Patients recorded their Parkinson's disease medications using a subject's medication diary and monitored their motor symptoms using a wearable device.

[0171] The titration period was part of the enrollment period and followed the screening period. On day 1 of the titration period, patients received a bolus dose of the pharmaceutical composition, followed by a continuous infusion at a constant rate, with the dosage then adjusted at the discretion of the investigator based on the patient's clinical response. The therapeutic dose was defined as the dose that could elicit adequate control of motor symptoms by minimizing the number of "off" episodes, maximizing functional "on" time, and at the same time minimizing bothersome motor disorders. Patients continued to receive the therapeutic dose of the pharmaceutical composition established during the titration period until day 28 (treatment period). The main inclusion criteria for this study are summarized in Table 13.

[0172] [Table 13]

[0173] Systemic safety and tolerability were assessed by monitoring for adverse events, laboratory values, vital signs, electrocardiograms, and safety measures, including the Columbia-Suicide Rating Scale. The infusion site grading scale (Table 14A) and exploratory efficacy assessments (Table 14B) were used to assess study outcomes.

[0174] Subjects recorded their Parkinson's symptoms based on questionnaires in a Parkinson's diary. Each subject recorded whether they were "on", "off" or "asleep" and the severity of their dyskinesia (worrisome or not). Statistical significance of changes from baseline was shown at each visit for normalized "off" time, normalized "on" time without dyskinesia and normalized "on" time without bothersome dyskinesia. No statistical significance was shown at any visit for normalized "on" time with non-worrisome dyskinesia and normalized "on" time with bothersome dyskinesia.

[0175] The subject's MDS-UPDRS assessment consisted of the following sections: Part 1: Non-motor aspects of everyday life experiences (nM-EDL) Part 2: Motor Aspects of the Experience of Everyday Life (M-EDL) Part 3: Motor examination (including Hoehn and Yahr stages) · Part 4: Motor complications.

[0176] MDS-UPDRS total scores ranged from 0 to 176, with 176 representing worst (total) disability and 0 representing no disability. Mean total baseline scores ranged from about 45 to 47 across all visits, and mean visit total scores ranged from about 34 to 45 across all visits. Statistically significant changes from baseline were noted for total scores, Part 1 scores, and Part 2 scores at Day 7, Day 28, and the final visit, and for Part 4 scores at Day 28 and the final visit. There were no statistically significant changes in Part 3 "on" scores at any visit.

[0177] The PDQ-39 measured aspects of health relevant to subjects with Parkinson's disease. Each item was scored on a 5-point scale: 0=never, 1=occasionally, 2=sometimes, 3=often, 4=always (or never, if applicable). Higher scores are consistently associated with more severe symptoms of the disease, such as tremors and stiffness. The majority of subjects answered "never" or "sometimes", while seven subjects answered "always" or "never". The results are expressed as a summary index. The PDQ-39 summary index ranges from 0 to 100, where lower scores indicate better perceived health. The domains and indexes used for the assessment are as follows: Summary Index Motor Domain Score Activities in the area of ​​daily living Emotional well-being domain score Symptom Domain Score Social support domain score Cognitive domain score Communication Area Score Physical Discomfort Domain Score.

[0178] Statistically significant changes from baseline were demonstrated for summary indexes at all visits.

[0179] The PDSS-2 scale characterizes different aspects of nocturnal sleep disturbance in subjects suffering from Parkinson's disease. The PDSS-2 consisted of 15 questions assessing motor and non-motor symptoms at night and during awakening, as well as sleep disturbances categorized into three domains (nocturnal motor symptoms, nocturnal PD symptoms, and sleep disturbances). Scores were calculated for each domain and for a total score. Regarding sleep problems, their frequency was assessed on a 5-point Likert-type scale ranging from 0 (never) to 4 (very often). The majority of subjects answered "never" or "sometimes", while 7 subjects answered "always" or "never".

[0180] The KPPS assessed pain in subjects with Parkinson's disease. The scale measured the frequency and severity of seven domains of pain (musculoskeletal pain, chronic pain, fluctuating referred pain, night pain, orofacial pain, localized limb pain / edema / swelling, and radicular pain). A total score was also assessed. Statistically significant changes from baseline were demonstrated at day 28 and final visit for the total score and at day 28 for the fluctuating referred pain score.

[0181] The PAS measured the severity of anxiety in subjects with Parkinson's disease. Scores for persistent anxiety, momentary anxiety and avoidance behavior, as well as a total score, were assessed. Statistically significant changes from baseline were noted for the total score and avoidance behavior at day 28 and the final visit.

[0182] All subjects wore the Kinesia 360 device, which continuously recorded data for the assessment of tremor, dyskinesis, and mobility. There were no statistically significant changes from baseline at any visit for tremor, dyskinesis, and slowness.

[0183] Injection Site Assessment Grade Scale and exploratory efficacy assessments were performed and are presented below in Tables 14A and 14B.

[0184] [Table 14]

[0185] [Table 15]

[0186] Exploratory analyses were performed to evaluate the efficacy of the pharmaceutical composition in reducing "off" time and on motor and non-motor symptoms of Parkinson's disease.

[0187] result Twenty-one patients were enrolled. The study population was primarily male (61.9%) and Caucasian (100%): one (4.8%) subject was Hispanic or Latino. Mean (SD) age was 61.6 (10.3) years. Mean (SD) Parkinson's disease duration since diagnosis was 9.0 (4.0) years, and mean (SD) duration of motor fluctuations was 6.0 (4.1) years. Mean "off" time per day at baseline was 6.54 hours, ranging from 3.77 to 9.46 hours. Seven subjects (33%) discontinued prematurely. Two subjects discontinued due to adverse events.

[0188] Subject baseline demographic and disease characteristics are shown in Table 15.

[0189] [Table 16]

[0190] The results of the injection site grading are shown in Figures 14B and 14C and in Table 16 below.

[0191] [Table 17]

[0192] In Parkinson's disease, "off" time refers to periods of the day when medication is not working well, resulting in recurrence or worsening of Parkinson's disease symptoms (tremor, stiffness, bradykinesia, and non-motor symptoms such as depression, pain, anxiety). In contrast, the term "on" time refers to periods when symptoms are adequately controlled. "Off" time can sometimes occur predictably and gradually ("wearing off"), or it can occur suddenly and unexpectedly ("sudden off", "yo-yo episode"). The frequency and timing of wearing off periods, as well as the number of hours of "off" time, are significantly correlated with the deterioration in quality of life of Parkinson's disease patients.

[0193] Quality of life in Parkinson's disease can be assessed using questionnaires and tools such as the Parkinson's Disease Questionnaire-39 (PDQ-39), a self-report questionnaire assessing the impact of Parkinson's disease on specific dimensions of functioning and well-being, and the PDSS-2, a revised version of the Parkinson's Disease Sleep Scale designed to characterize and quantify different aspects of nighttime sleep problems in Parkinson's disease. The severity of the disease was alternatively assessed by the Unified Parkinson's Disease Rating Scale (UPDRS) or the Movement Disorders Society revised version (MDS-UPDRS), tools consisting of rater-based interviews and clinical assessments designed to provide a quantifiable score for longitudinal assessment and follow-up of the disease.

[0194] Patient changes from baseline normalized "off" time were measured as shown in Table 17 and Figure 14E. A summary of pre-specified efficacy endpoints is provided in Table 18A, and efficacy assessments are shown in Table 18B.

[0195] [Table 18]

[0196] [Table 19]

[0197] [Table 20]

[0198] Analysis of efficacy data showed that "off" time improved in 17 of 20 patients. The mean (SD) reduction in "off" time from baseline to end of study was 3.24 (3.65) hours across subjects (46.2% improvement). Four subjects reported a greater than 90% reduction in daily "off" time at the end of the study. There was an average reduction in normalized "off" time, "on" time with non-problematic dyskinesis, and "on" time with bothersome dyskinesis, resulting in a mean (SD) improvement in normalized "on" time without dyskinesis of 3.99 (5.37) hours. As shown in Figure 14D, the mean (SD) reduction from baseline was 9.0 (11.87) for the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score, 6.9 (8.39) for the Parkinson's Disease Questionnaire 39 (PDQ-39) summary index, and 2.0 (11.48) for the Parkinson's Disease Sleep Scale-2 (PDSS-2) total score. After continuous subcutaneous infusion of the pharmaceutical composition, statistically significant changes from baseline were observed in the following: Parkinson's "on" and "off" time for movement disorders, MDS-UPDRS total score, non-motor aspects of daily living experience, motor aspects of daily living experience, and motor complications, and PDQ-39 summary index, as well as the domains of activities of daily living, emotional well-being, cognition, communication, mobility, symptoms, and physical discomfort.

[0199] Figure 21 and Table 18C show the percentage of patients receiving the pharmaceutical composition experiencing "off" time compared to patients receiving oral Sinemet®. As shown in Figure 21, patients receiving oral Sinemet® treatment show undesirable spikes in "off" time in the morning and around mealtime compared to patients receiving the CSCI pharmaceutical composition. Table 18C shows that at baseline, about 86.7% of the first morning symptom time upon waking was "off". Meanwhile, at the end of the 28-day study, about 84.2% of the first morning symptom time was "on" without movement disorder in patients receiving the CSCI pharmaceutical composition.

[0200] [Table 21]

[0201] Example 5 An algorithm was developed to convert oral levodopa into a pharmaceutical composition of carbidopa 4'-monophosphate and levodopa 4'-monophosphate to facilitate physician determination of the most appropriate starting dose for the study described in Example 4. The algorithm takes into account the low variability and fluctuation of levodopa exposure when delivered continuously subcutaneously, the 24-hour exposure, the pharmacokinetic profile of levodopa obtained from previous studies with the composition, and other clinical considerations.

[0202] Data obtained from patients who completed the treatment were used for dose evaluation. All patients who completed the study (N=14) achieved the desired dose range within 3 weeks after starting the pharmaceutical composition; 3 patients achieved the desired dose range on the same day after conversion from oral to the pharmaceutical composition, 7 subjects required 1 week, 1 subject required 2 weeks, and the remaining 3 patients required 3 weeks. The adjustments at each time point ranged from -0.04 mL / h to +0.08 mL / h (equivalent to -136 mg levodopa / day to 273 mg levodopa / day), and the difference in infusion rate from day 1 to day 28 (taking all adjustments into account) ranged from -0.06 mL / h to +0.08 mL / h (equivalent to -204 mg levodopa / day to +273 mg levodopa / day). Considering that all patient subjects were required to report motor fluctuations that were poorly controlled by their best oral medication at enrollment, these data suggest that the conversion algorithm is effective in guiding the starting dose of the pharmaceutical composition, as the magnitude of changes in continuous infusion rates appeared small (within 20% in all but one subject) and the desired dose range was achieved within 3 weeks.

[0203] Levodopa dosage levels by patient subjects at the beginning and end of the study are shown in Table 19. The dosage of the pharmaceutical composition delivered during the 24-hour treatment period ranged from about 28.8 / 576 mg to about 240 / 4800 mg of carbidopa 4'-monophosphate / levodopa 4'-monophosphate per day (which corresponds to about 400 mg to 3400 mg of levodopa, respectively, based on molecular weight). The mean and median dosages at the end of the study were about 117.5 / 2350 mg and 96 / 1920 mg (which corresponds to about 1670 mg and 1360 mg of levodopa, respectively, based on molecular weight).

[0204] [Table 22]

[0205] As described, if a patient has a levodopa equivalent dose of 2000 mg prior to study entry, the recommended starting dose of a pharmaceutical composition consisting of a levodopa 4'-monophosphate prodrug whose structure corresponds to formula (A-1) and a carbidopa 4'-monophosphate prodrug whose structure corresponds to formula (B-1) in a 20:1 weight ratio is 4032 mg of levodopa 4'-monophosphate delivered over 24 hours. Since the levodopa dose for each patient is determined by individualized patient titration, patients in these studies will be started on a dose (with the option of further dose modification to achieve optimal clinical response) that is expected to provide exposure close to their previous regimen of a pharmaceutical composition consisting of a levodopa 4'-monophosphate prodrug whose structure corresponds to formula (A-1) and a carbidopa 4'-monophosphate prodrug whose structure corresponds to formula (B-1). In this way, personalized titrable dosing can be achieved across a range of doses to address therapeutic needs.

[0206] Example 6 Pharmacokinetics of 24-h continuous subcutaneous infusion of levodopa and carbidopa prodrugs for Parkinson's disease in healthy human volunteers. This study was designed to characterize the pharmacokinetics of an aqueous pharmaceutical composition comprising a combination of a levodopa 4'-monophosphate prodrug corresponding in structure to Formula (A-1) and a carbidopa 4'-monophosphate prodrug corresponding in structure to Formula (B-1) (prodrug combination) following continuous subcutaneous infusion into the abdomen.

[0207] method The pharmaceutical composition prodrug was administered subcutaneously for 24 hours to eight healthy volunteers (ages 45-75) in an open-label study. Administration consisted of a loading dose of 100 mg levodoparinic acid followed by a continuous steady infusion of 850 mg levodoparinic acid over 24 hours. All injections of the pharmaceutical composition were administered into the subcutaneous space in the abdomen. Serial plasma samples were collected to assay for levodopa and carbidopa during and after injection of the pharmaceutical composition. Pharmacokinetic data for levodopa and carbidopa from a previous Duopa Phase 1 study (Nyholm, D., et al. AAPS Journal 2013; 15-2: 316-329) were used to compare pharmacokinetic data between the pharmaceutical composition of the present invention and Duopa. Safety and tolerability, including local adverse events (AEs) related to the subcutaneous injection site, were evaluated throughout the study. After administration of the pharmaceutical composition, the mean pharmacokinetic profile of levodopa over the first 16 hours is similar to that of a previous Phase 1 study of Duodopa in Parkinson's disease patients (Nyholm, D., et al. AAPS Journal 2013; 15-2: 316-329) (Figures 15 and 16).

[0208] result The mean pharmacokinetic profile of carbidopa over the first 16 hours in healthy human volunteers during and after administration of the pharmaceutical composition was found to provide a less variable pharmacokinetic profile than a previous Phase 1 study of Duodopa in Parkinson's disease patients (Nyholm, D., et al. AAPS Journal 2013; 15-2: 316-329) (Figures 17 and 18). Pharmacokinetic parameters of levodopa and carbidopa following infusion of the pharmaceutical composition are shown in Table 20.

[0209] [Table 23]

[0210] After injection of the pharmaceutical composition, the fluctuation of the levodopa concentration level is small, so that T maxThe range is 1 to 24 hours, which means that max can occur at any point during the injection. max -C min ] / C ave ) are often used to quantify pharmacokinetic variability. After administration, the pharmaceutical compositions appeared to have low variability (Table 21) for both levodopa and carbidopa relative to previously reported Duodopa data (Nyholm, D., et al. AAPS Journal 2013; 15-2: 316-329).

[0211] [Table 24]

[0212] After the study, the results were analyzed. Five subjects reported at least one adverse event. Mild injection site reactions and injection site irritation were observed in several subjects. All adverse events were transient and did not cause discontinuation of the study. There was no nodule formation at the injection site.

[0213] The pharmaceutical composition was able to provide stable levodopa and carbidopa exposure with very little fluctuation in levodopa concentration levels over a 24-hour period via subcutaneous delivery route, and had a favorable safety profile.

[0214] Example 7 To characterize the pharmacokinetics and safety and tolerability of an aqueous pharmaceutical composition comprising a levodopa 4'-monophosphate prodrug corresponding in structure to Formula (A-1) and a carbidopa 4'-monophosphate prodrug corresponding in structure to Formula (B-1) (prodrug combination) administered at different sites, the pharmaceutical composition was administered at three injection sites (abdomen, arm, and thigh of healthy volunteers).

[0215] method The pharmaceutical composition was administered subcutaneously to 12 healthy volunteers (ages 45-75) at three subcutaneous injection sites (abdomen, arm, and thigh) in a randomized crossover design for 24 hours. The dose consisted of 960 mg of levodopa 4'-monophosphate prodrug corresponding in structure to formula (A-1) delivered at a steady rate over 24 hours at each injection site. A minimum washout period of 24 hours was incorporated between the end of an injection of the pharmaceutical composition and the start of the next injection of the pharmaceutical composition. After injection of the pharmaceutical composition, serial plasma samples were collected to assay for levodopa and carbidopa. Safety and tolerability, including local adverse events related to the subcutaneous injection site, were evaluated throughout the study.

[0216] result During and after administration of the pharmaceutical composition, the mean PK profiles of both levodopa and carbidopa appeared to be similar among the three subcutaneous infusion sites (Figures 19 and 20). The PK parameters of levodopa and carbidopa after infusion of the pharmaceutical composition at the different subcutaneous infusion sites are shown in Table 22.

[0217] [Table 25]

[0218] The results shown in Table 22 and FIG. 19 indicate that the mean PK profile of levodopa is similar among the three subcutaneous injection sites (abdomen, arm, and thigh) after administration of the pharmaceutical composition. Furthermore, the results shown in Table 22 and FIG. 20 indicate that the mean PK profile of carbidopa is similar among the three subcutaneous injection sites (abdomen, arm, and thigh) after administration of the pharmaceutical composition. The results indicate that the pharmaceutical composition has a similar exposure of levodopa and carbidopa when injected into different injection sites. Furthermore, injection of the pharmaceutical composition was observed to be well tolerated with no significant pattern in adverse event profile across the three different injection sites. All adverse events were mild and did not cause discontinuation of the study. Based on these results, patients have the option of alternative subcutaneous injection sites for administering the pharmaceutical composition. It is understood that the foregoing detailed description and accompanying examples are merely illustrative and should not be considered as limiting the scope of the invention, which is defined only by the appended claims and their equivalents.

[0219] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including but not limited to those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, compositions, formulations, or methods of use of the invention, can be made without departing from the spirit and scope of the invention.

Claims

1. formula: [Formula 1] and a compound represented by the formula: formula: [Case 2] A stable liquid aqueous pharmaceutical composition comprising a compound represented by the formula: The weight ratio of compound (A-1) to compound (B-1) is about 20:1; Suitable for subcutaneous administration The stable liquid aqueous pharmaceutical composition.

2. 2. The stable liquid aqueous pharmaceutical composition according to claim 1, wherein the concentration of compound (A-1) is about 216 mg / mL to about 264 mg / mL.

3. 2. The stable liquid aqueous pharmaceutical composition according to claim 1, wherein the concentration of compound (B-1) is 9.6 mg / mL to 13.2 mg / mL.

4. 2. The stable liquid aqueous pharmaceutical composition according to claim 1, wherein the concentration of compound (A-1) is about 240 mg / mL, and the concentration of compound (B-1) is about 12 mg / mL.

5. 5. The stable liquid aqueous pharmaceutical composition according to claim 4, having a pH of about 6.5 to about 9.

0.

6. 2. The stable liquid aqueous pharmaceutical composition according to claim 1, wherein the concentration of compound (A-1) is 324 mg / mL to 396 mg / mL, and the concentration of compound (B-1) is 16.2 mg / mL to 19.8 mg / mL.

7. 7. The stable liquid aqueous pharmaceutical composition according to claim 6, wherein the concentration of compound (A-1) is about 360 mg / mL, and the concentration of compound (B-1) is about 18 mg / mL.

8. 8. The stable liquid aqueous pharmaceutical composition according to claim 7, having a pH of about 6.5 to about 9.

0.

9. When administered to adult humans, AUC （０－ｔ）vs. AUC （０－ｔ） 6. The stable liquid aqueous pharmaceutical composition of claim 5, providing a mean plasma exposure ratio of levodopa to carbidopa of 6.57 to 8.03 levodopa to about 1 carbidopa as measured by HPLC.

10. When administered to adult humans, AUC （０－ｔ） vs. AUC （０－ｔ） 10. The stable liquid aqueous pharmaceutical composition of claim 9, providing a mean plasma exposure ratio of levodopa to carbidopa of about 7.30 levodopa to about 1 carbidopa as measured by HPLC.

11. Continuous subcutaneous administration of the pharmaceutical composition to a population of adult humans achieves a mean plasma concentration of levodopa having a variability of about 0.3 or less over a period of 2 to 16 hours after administration, the variability being less than or equal to about 0.5 for a given period ([C ｍａｘ -C ｍｉｎ ] / C ａｖｅ 6. The stable liquid aqueous pharmaceutical composition according to claim 5, wherein said composition is defined as

12. Continuous subcutaneous administration of the composition to a population of human adults achieved mean plasma concentrations of levodopa with a variability of about 0.40 over a period of 2 to 72 hours after administration, with the variability being approximately 0.05 for a given period ([C ｍａｘ -C ｍｉｎ ] / C ａｖｅ 6. The stable liquid aqueous pharmaceutical composition according to claim 5, wherein said composition is defined as

13. 6. The stable liquid aqueous pharmaceutical composition of claim 5, in a vial having a gas headspace containing no more than about 5.5% oxygen.

14. 6. The stable liquid aqueous pharmaceutical composition according to claim 5, having a pH of about 6.8 to about 7.

8.

15. 6. The stable liquid aqueous pharmaceutical composition according to claim 5, which is substantially free of antioxidants.

16. 6. The stable liquid aqueous pharmaceutical composition according to claim 5, which is substantially free of arginine.

17. 6. The stable liquid, aqueous pharmaceutical composition of claim 5, comprising less than about 5.4% w / w DHPPA-P at pH 6.5-9.0 after 5 days at 25°C followed by 30 days at 5°C.

18. 6. The stable liquid aqueous pharmaceutical composition according to claim 5, which is substantially free of ascorbic acid or a pharma- ceutically acceptable salt of ascorbic acid.

19. 6. The stable liquid aqueous pharmaceutical composition according to claim 5, which is substantially free of L-cysteine ​​or a pharma- ceutically acceptable salt thereof, N-acetylcysteine ​​(NAC) or a pharma- ceutically acceptable salt thereof, glutathione or a pharma- ceutically acceptable salt thereof, diacetylcysteine ​​or a pharma- ceutically acceptable salt thereof, and sodium bisulfite, or any combination thereof.

20. 6. The stable liquid pharmaceutical composition of claim 5, containing less than about 15 micrograms / mL of hydrazine after storage under pH-neutral conditions at 25° C. for 5 days followed by storage at 5° C. for 30 days.

21. formula: [C3] A compound represented by the formula: formula: [C4] A compound represented by the formula: and water. A stable liquid aqueous pharmaceutical composition comprising: The concentration of compound (A-1) is about 240 mg / mL, and the concentration of compound (B-1) is about 12 mg / mL. Suitable for subcutaneous administration When administered to adult humans, AUC （０－ｔ） vs. AUC （０－ｔ） providing a mean plasma exposure ratio of levodopa to carbidopa of about 7.30 to 1 as measured by The stable liquid aqueous pharmaceutical composition.

22. 22. The stable liquid aqueous pharmaceutical composition according to claim 21, which is stable for at least 3 months in a 10 cc vial at a temperature between 2°C and 8°C, at 1 atmosphere pressure and with less than about 9% oxygen.

23. 23. The stable liquid aqueous pharmaceutical composition according to claim 22, having a pH of about 6.5 to about 9.

0.

24. 24. The stable liquid aqueous pharmaceutical composition according to claim 23, having a pH of about 6.8 to about 7.

8.

25. 25. The composition of claim 24, wherein the vial has less than about 5.5% oxygen.

26. formula: [C5] A compound represented by the formula: formula: [C6] A compound represented by the formula: and water. A stable liquid aqueous pharmaceutical composition comprising: The concentration of compound (A-1) is about 240 mg / mL, and the concentration of compound (B-1) is about 12 mg / mL. Suitable for subcutaneous administration Substantially free of antioxidants, The stable liquid aqueous pharmaceutical composition.

27. When administered to adult humans, AUC （０－ｔ） vs. AUC （０－ｔ） 27. The stable pharmaceutical composition of claim 26, providing a mean plasma exposure ratio of levodopa to carbidopa of about 7.30 to 1 as measured by HPLC.

28. 28. The stable liquid aqueous pharmaceutical composition according to claim 27, which is stable for at least 3 months in a 10 cc vial at a temperature between 2° C. and 8° C., at 1 atmosphere pressure, and with less than about 9% oxygen.

29. 29. The stable liquid aqueous pharmaceutical composition according to claim 28, having a pH of about 6.5 to about 9.

0.

30. 30. The stable liquid aqueous pharmaceutical composition according to claim 29, having a pH of about 6.8 to about 7.

8.

31. 31. The composition of claim 30, wherein the vial has less than about 5.5% oxygen.

32. formula: [C7] and a compound represented by the formula: formula: [C8] and a compound represented by the formula: and water. A stable liquid aqueous pharmaceutical composition comprising: The concentration of compound (A-1) is about 240 mg / mL, and the concentration of compound (B-1) is about 12 mg / mL. Suitable for subcutaneous administration Contains less than about 5.4% w / w DHPPA-P at pH 6.5-9.0 after 5 days at 25° C. followed by 30 days at 5° C. The stable liquid aqueous pharmaceutical composition.

33. 33. The stable liquid aqueous pharmaceutical composition according to claim 32, which is stable for at least 3 months in a 10 cc vial at a temperature between 2°C and 8°C, at 1 atmosphere pressure and with less than about 9% oxygen.

34. 34. The stable liquid aqueous pharmaceutical composition according to claim 33, having a pH of about 6.5 to about 9.

0.

35. 35. The stable liquid aqueous pharmaceutical composition according to claim 34, having a pH of about 6.8 to about 7.

8.

36. 36. The composition of claim 35, wherein the vial has less than about 5.5% oxygen.

37. When administered to adult humans, AUC （０－ｔ） vs. AUC （０－ｔ） 37. The stable pharmaceutical composition of claim 36, wherein the composition provides a mean plasma exposure ratio of levodopa to carbidopa of about 7.30 to 1 as measured by HPLC.

38. 34. A method of treating Parkinson's disease in a subject, comprising subcutaneously administering to a patient in need of treatment for Parkinson's disease the pharmaceutical composition of claim 32, comprising administering to an adult human an AUC （０－ｔ） vs. AUC （０－ｔ） providing a mean plasma exposure ratio of about 7.30 to 1 of levodopa to carbidopa as measured by

39. 22. A method for improving "off" time of Parkinson's disease symptoms in a subject from a baseline score, comprising subcutaneously administering to a patient in need of treatment for Parkinson's disease an amount of the pharmaceutical composition of claim 21 effective to reduce Parkinson's disease symptoms by at least 46% from baseline.

40. 22. A method of improving a Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score in a subject having a baseline MDS-UPDRS score, comprising subcutaneously administering to a subject in need of treatment for Parkinson's disease an amount of the pharmaceutical composition of claim 21 effective to reduce the baseline MDS-UPDRS total score by at least 9 units.

41. 22. A method of improving quality of life in a subject with a baseline Parkinson's Disease Questionnaire-39 (PDQ-39) summary index score, comprising subcutaneously administering to a subject in need of treatment for Parkinson's disease an amount of the pharmaceutical composition of claim 21 effective to reduce the baseline PDQ-39 score by at least 6.9 units.

42. 22. A method of improving sleep in a subject having a baseline Parkinson's Disease Sleep Scale-2 (PDSS-2) total score, comprising subcutaneously administering to a subject in need of treatment for Parkinson's disease an amount of the pharmaceutical composition of claim 21 effective to reduce the baseline PDSS-2 total score by at least 2 units.

43. 43. The method of any of claims 38-42, wherein the subject is treated for at least 10 days without an incidence of skin nodule development.

44. 22. A method for reducing the incidence of "off" time in Parkinson's disease symptoms in a subject compared to a subject receiving oral administration of a tablet comprising levodopa and carbidopa, the method comprising subcutaneously administering to a patient in need of treatment for Parkinson's disease a pharmaceutical composition according to claim 21.

45. 45. The method of claim 44, wherein the incidence of Parkinson's disease symptom "off" times in a subject is reduced and "on" times without problematic dyskinesias are increased.

Images