Methods and compositions for treating Parkinson's disease

Abstract

Disclosed are methods of treating a neurological or movement disorder, e.g., Parkinson's disease, in an individual in need of such treatment by parenteral administration of levodopa, levodopa salts, levodopa prodrugs and dopa decarboxylase inhibitors (DDCIs), e.g., carbidopa, carbidopa salts, carbidopa prodrugs, benserazide, or any combination thereof, concomitant with oral administration of levodopa, a DDCI, e.g., carbidopa, benserazide, or any combination thereof.

Description

Related Applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 296,019, filed January 3, 2022, the contents of which are incorporated by reference in their entirety herein. [Technical field]

[0002]

[0002] The present invention provides a method for treating neurological or movement disorders, such as Parkinson's disease, by parenteral administration of levodopa or a prodrug thereof, and a dopa decarboxylase inhibitor (DDCI) or a prodrug thereof, such as carbidopa, benserazide, or any combination thereof, in conjunction with oral administration of levodopa or a prodrug thereof, a dopa decarboxylase inhibitor (DDCI) or a prodrug thereof, such as carbidopa, benserazide, or any combination thereof. [Background technology]

[0003]

[0003] Parkinson's disease is a degenerative condition characterized by reduced levels of the neurotransmitter dopamine in the brain. Levodopa (L-dopa or L-3,4-dihydroxyphenylalanine), which is an immediate metabolic precursor of dopamine that, unlike dopamine, can cross the blood-brain barrier, is the most commonly used drug to restore dopamine levels in the brain. Over the past 40 years, levodopa has remained the most effective therapy for the treatment of Parkinson's disease.

[0004]

[0004] However, levodopa has a short plasma half-life and, even under the best current standard of care, produces pulsed dopaminergic stimulation. Long-term treatment is therefore accompanied by motor fluctuations and movement disorders that may represent a significant source of disability for certain patients. A therapeutic strategy that can ultimately deliver levodopa / dopamine to the brain more continuously and physiologically, providing the benefits of standard levodopa with mitigated motor complications, is greatly needed by patients suffering from Parkinson's disease and other neurological or movement disorders. Summary of the Invention

[0005]

[0005] Provided herein are, inter alia, methods and pharmaceutical compositions for the treatment of neurological or movement disorders, including parenteral administration of levodopa, a prodrug or salt thereof (e.g., a pharma- ceutically acceptable prodrug salt thereof), a composition (e.g., a pharma- ceutically acceptable composition, e.g., a liquid pharmaceutical composition) comprising the same and a dopa decarboxylase inhibitor (DDCI), a prodrug or salt thereof (e.g., a pharma- ceutically acceptable prodrug or salt thereof), a composition (e.g., a pharma- ceutically acceptable composition, e.g., a liquid pharmaceutical composition) comprising the same, accompanied by oral administration of an active agent selected from the group consisting of levodopa, a levodopa salt, a levodopa prodrug, a dopa decarboxylase inhibitor (DDCI), a prodrug or salt thereof (e.g., a pharma- ceutically acceptable salt thereof), and a composition (e.g., a pharma- ceutically acceptable composition, e.g., a liquid pharmaceutical composition) comprising the same. Also disclosed are kits for administration of the described methods, and treatment regimens for administration of the described methods, specified by the time course and amount of the pharmaceutical composition.

[0006] An embodiment of the present invention is a method of treating Parkinson's disease in a patient in need thereof, comprising: subcutaneously administering to the patient a pharma- ceutically acceptable liquid composition comprising levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof, and carbidopa, a carbidopa salt, a carbidopa prodrug, or any combination thereof, in an amount to deliver about 720 mg of levodopa, a levodopa salt, a levodopa prodrug, or combination thereof, and about 90 mg of carbidopa, a carbidopa salt, a carbidopa prodrug, or combination thereof to the patient over a time course of at least about 24 hours; orally administering to the patient one or more immediate release tablets or capsules containing 100 mg of levodopa before or during the subcutaneous infusion time course; The present invention relates to a method comprising the steps of:

[0007] According to some embodiments, the pharma- ceutically acceptable liquid composition further comprises arginine. According to some embodiments, the pharma- ceutically acceptable liquid composition further comprises at least one antioxidant. According to some embodiments, the immediate release tablet or capsule further comprises carbidopa.

[0008]

[0008] In some embodiments, with subcutaneous and oral administration, the patient's plasma levodopa area under the curve (AUC) from time 0 to the end of the infusion period is higher compared to the combination of: i) the plasma levodopa AUC from time 0 to the end of the infusion period in which the patient is administered a pharma- ceutically acceptable liquid composition alone subcutaneously for at least about 24 hours; and ii) the plasma levodopa AUC in which the patient is administered oral levodopa alone.

[0009] A further embodiment of the present invention is a method of treating Parkinson's disease in a patient in need thereof, comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of at least about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising levodopa, carbidopa, arginine, and an antioxidant in an amount to deliver about 720 mg of levodopa and about 90 mg of carbidopa to the patient over at least about 24 hours; orally administering to the patient at least one oral dosage form containing levodopa prior to or during the subcutaneous infusion time course; The present invention relates to a method comprising the steps of:

[0010]

[0010] According to some embodiments, the oral dosage form contains one of: 50 mg levodopa, 75 mg levodopa, 95 mg levodopa, 100 mg levodopa, 125 mg levodopa, 145 mg levodopa, 150 mg levodopa, 195 mg levodopa, 200 mg levodopa, 245 mg levodopa, or 250 mg levodopa.

[0011] A further embodiment of the present invention is a method for treating Parkinson's disease in a patient currently receiving levodopa and carbidopa in the form of oral immediate release levodopa and carbidopa alone and in need of further treatment, comprising: subcutaneously administering to the patient a first Pharmaceutically acceptable liquid composition comprising levodopa, carbidopa, arginine, and an antioxidant in an amount to deliver about 720 mg of levodopa and about 90 mg of carbidopa to the patient over a 24 hour subcutaneous infusion time course for at least about 24 hours; administering to the patient at least one tablet or capsule daily orally containing 100 mg of levodopa and 25 mg of carbidopa before or during the subcutaneous infusion time course; The present invention relates to a method comprising the steps of:

[0012]

[0012] Disclosed herein is a method for treating a neurological or movement disorder in a patient in need of such treatment, comprising: parenterally administering to the patient a first pharmaceutical composition comprising: a) levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof; and b) a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, or any combination thereof; and concomitantly, orally administering to the patient a second pharmaceutical composition comprising an active agent selected from the group consisting of levodopa, a levodopa salt, a levodopa prodrug, a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, and any combination thereof.

[0013]

[0013] In some embodiments, the methods described herein include a DDCI that comprises, consists of, or consists essentially of carbidopa, benserazide, or any combination thereof.

[0014]

[0014] In some embodiments, the methods described herein include a DDCI in a first pharmaceutical composition that is the same as a DDCI in a second pharmaceutical composition.

[0015] In some embodiments, the methods described herein include a DDCI in a first pharmaceutical composition that is different from the DDCI in a second pharmaceutical composition.

[0015]

[0016] In some embodiments, the methods described herein include levodopa and a DDCI as the second pharmaceutical composition.

[0017] In some embodiments, the methods described herein include the DDCI carbidopa.

[0016]

[0018] In some embodiments, the methods described herein include subcutaneous, transdermal, intradermal, intravenous, intramuscular, intratracheal, intranasal, intrathecal, intragastric, or intraduodenal administration of the first pharmaceutical composition.

[0017]

[0019] In some embodiments, the methods described herein comprise subcutaneous administration of the first pharmaceutical composition.

[0020] In some embodiments, the methods described herein comprise administration of a pharmaceutical composition to a patient in need thereof via one or more sites.

[0018]

[0021] In some embodiments, the neurological or movement disorders related to the methods described herein include Parkinson's disease; secondary parkinsonism, such as drug-induced secondary parkinsonism, neuroleptic-induced parkinsonism, postencephalitic parkinsonism, and vascular parkinsonism; motor fluctuations; neurodegenerative disorders; movement disorders; reduced dopamine levels in the brain; levodopa-induced dyskinesia; rapid eye movement sleep behavior disorder (RBD); dystonia; morning akinesia; tremor symptoms, such as essential tremor and drug-induced Examples of conditions that may be present in the present invention include conditions such as: chronic tremor; myoclonus; chorea, e.g., drug-induced chorea; tics, e.g., drug-induced tics and organic tics; drug-induced dyskinesia; drug-induced akathisia; restless legs syndrome (RLS); stiff man syndrome; benign tremor attacks; malignant neuroleptic syndrome; Huntington's chorea; Shy-Drager syndrome; brain injury-induced conditions, e.g., carbon monoxide or manganese poisoning; or any combination thereof; for example, provided herein are methods of treating a patient suffering from Parkinson's disease.

[0019]

[0022] Usually, doctors assess the severity of Parkinson's disease patients according to subjective and objective signs and symptoms, for example using various scales, and prescribe the levodopa administration dose accordingly. One well-known and widely used scale for diagnosing and scaling the severity of Parkinson's disease is the Unified Parkinson's Disease Rating Scale (UPDRS). Modifications of the UPDRS may also be used to classify Parkinson's disease patients. Another known method of measuring the severity of Parkinson's disease is according to the Horn-Yarr (H&Y) stage, which includes a scale of five stages, with stages 1-2 considered to be mild or early Parkinson's disease patients, stage 3 considered to be moderate or intermediate Parkinson's disease patients, and stages 4-5 considered to be advanced Parkinson's disease patients. The daily levodopa dose may be determined and varied by the doctor according to the condition of a particular patient, the patient's response to treatment, etc., for example according to clinical findings and a "trial and error" method. Additionally, patients may be administered different daily doses on different days depending on signs and symptoms, and the range of daily doses administered may be determined by a physician, allowing for patient flexibility in treatment, where physicians generally refer to signs as objective measures and symptoms as subjective measures.

[0020]

[0023] According to some embodiments, provided herein is a method of treating a patient with advanced Parkinson's disease. According to some embodiments, provided herein is a method of treating a patient with advanced Parkinson's disease and / or a patient with moderate Parkinson's disease. According to some embodiments, provided herein is a method of treating a patient with motor fluctuations. According to some embodiments, provided herein is a method of treating a patient with Parkinson's disease with motor fluctuations.

[0021]

[0024] According to some embodiments, provided herein are methods of treating a Parkinson's disease patient in need of a dose of more than about 300 mg levodopa / day, more than about 400 mg levodopa / day, more than about 500 mg levodopa / day, more than about 600 mg levodopa / day, more than about 700 mg levodopa / day, more than about 800 mg levodopa / day, more than about 900 mg levodopa / day, or more than about 1000 mg levodopa / day.

[0022]

[0025] According to some embodiments, provided herein is a method for treating Parkinson's disease patients who require a high dose of levodopa at a certain time, for example in the morning, for example at the end (about the last time) of a low activity / evening period, for example at the beginning (about the first time) of a high activity / day period. For example, according to some embodiments, there may be a certain rate for the high activity / day period and a different rate for the low activity / evening period, and a high dose of levodopa may be administered at the end of the low activity / evening period, at the end of the low activity / evening period, at the beginning of the high activity / day period, etc. Such a high dose may be provided by oral administration of a second pharmaceutical composition, for example at the time mentioned above, which is provided concomitantly with a substantially continuous first pharmaceutical composition.

[0023]

[0026] According to some embodiments, provided herein are methods of treating a patient who has suffered from Parkinson's disease for more than about 4 years, more than about 5 years, more than about 6 years, more than about 7 years, more than about 8 years, more than about 9 years, or more than about 10 years.

[0024]

[0027] According to some embodiments, provided herein are methods of treating a Parkinson's disease patient suffering from at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours of "off time" per day, where "off time" refers to the recurrence of Parkinson's symptoms between administration of medication.

[0025]

[0028] In some embodiments, the methods described herein comprise substantially continuous administration of the first pharmaceutical composition.

[0029] In some embodiments, the methods described herein comprise administering the second pharmaceutical composition 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times per day.

[0026]

[0030] In some embodiments, the methods described herein include administration of a second pharmaceutical composition when symptoms from said neurological or movement disorder require said administration.

[0031] In some embodiments, the methods described herein include administration of a second pharmaceutical composition at a predefined number of times, at predefined intervals, or both.

[0027]

[0032] In some embodiments, the methods described herein include multiple administrations of the second pharmaceutical composition, wherein the dose administered is the same in all administrations.

[0033] In some embodiments, the methods described herein include multiple administrations of the second pharmaceutical composition, wherein the administered dose is different in at least two of the administrations.

[0028]

[0034] In some embodiments, the methods described herein include administering the second pharmaceutical composition at a dose of about 25 mg to about 400 mg of levodopa, or a salt or prodrug thereof, in each administration.

[0029]

[0035] In some embodiments, the methods described herein include as a first pharmaceutical composition a levodopa moiety, a carbidopa moiety, and arginine.

[0036] In some embodiments, the methods described herein include as a first pharmaceutical composition a levodopa moiety, a carbidopa moiety, arginine, and at least one antioxidant.

[0030]

[0037] In some embodiments, the methods described herein include as a first pharmaceutical composition a levodopa moiety, a carbidopa moiety, arginine, and at least two antioxidants.

[0031]

[0038] In some embodiments, the methods described herein include, as a first pharmaceutical composition, a composition comprising a levodopa moiety, a carbidopa moiety, and a base selected from the group consisting of arginine, lysine, NaOH, tris(hydroxymethyl)aminomethane (TRIS), and any combination thereof.

[0032]

[0039] In some embodiments, the methods described herein include, as a first pharmaceutical composition, a composition having a pH in the range of about 6 to about 10, in the range of about 8 to about 10, in the range of about 8 to about 9, in the range of about 8.5 to about 9.5, in the range of about 9 to about 10, in the range of about 9.1 to about 9.8, or about 9.5.

[0033]

[0040] In some embodiments, the methods described herein include, as a first pharmaceutical composition, a composition comprising about 1% to about 40% w / v, about 1% to about 20% w / v, about 1% to about 10% w / v, about 2% to about 8% w / v, about 4% to about 8% w / v, about 5% to about 7% w / v, about 10% to about 20% w / v, about 15% to about 25% w / v, about 20% to about 30% w / v, about 25% to about 35% w / v, about 30% to about 40 w / v, about 30 w / v, or about 6% w / v of levodopa, levodopa prodrug, levodopa salt, or any combination thereof.

[0034]

[0041] In some embodiments, the methods described herein include, as a first pharmaceutical composition, a composition comprising about 0.5% w / v to about 10% w / v, about 0.5% w / v to about 6% w / v, about 0.5% w / v to about 4% w / v, about 0.5% w / v to about 2% w / v, about 0.5% w / v to about 1% w / v, about 0.75% w / v, about 1.0% w / v, about 1.3% w / v, about 1.5% w / v of carbidopa, a carbidopa salt, a carbidopa prodrug, or any combination thereof.

[0035]

[0042] In some embodiments, the methods described herein include an antioxidant selected from the group consisting of ascorbic acid or a salt thereof, cysteine, e.g., N-acetylcysteine, bisulfite or a salt thereof, glutathione, a tyrosinase inhibitor, a divalent cation, butylated hydroxytoluene (BHT), beta hydroxy acid (BHA) tocopherol, gentisic acid, tocopherol, tocopherol derivatives, thioglycerol, and any combination thereof.

[0036]

[0043] In some embodiments, the methods described herein include, as a first pharmaceutical composition, a composition comprising about 0.05% w / v to about 2.0% w / v, about 0.5% to about 1.5 w / v, 0.75 w / v, about 0.9 w / v, about 1.0 w / v, about 1.1 w / v, or about 1.25 w / v% of an antioxidant or combination of antioxidants.

[0037]

[0044] In some embodiments, the methods described herein include a composition comprising about 5 w / v% to about 30 w / v%, about 10 w / v% to 20 w / v%, about 20 w / v% to about 30 w / v%, about 12.5 w / v% to 17.5 w / v%, about 15 w / v%, about 20 w / v%, about 25 w / v%, about 24 w / v%, or about 15.2 w / v% of a base as a first pharmaceutical composition.

[0038]

[0045] In some embodiments, the methods described herein include administration of the first pharmaceutical composition via one or two sites.

[0046] In some embodiments, the methods described herein include administration of a first pharmaceutical composition in a volume of about 1 ml to about 30 ml per site daily, about 2 ml to about 20 ml per site daily, about 3 ml to about 10 ml per site daily, about 5 ml to about 7 ml per site daily, about 9 ml per site daily, about 10 ml per site daily, about 11 ml per site daily, about 12 ml per site daily, or about 6 ml per site daily.

[0039]

[0047] Also disclosed herein is a first pharmaceutical composition comprising levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof, and a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, or any combination thereof, and a second pharmaceutical composition comprising levodopa, a levodopa salt, a levodopa prodrug, a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, or any combination thereof, for use as a combination in the treatment of a neurological or movement disorder, wherein the first pharmaceutical composition is formulated as a parenteral composition and the second pharmaceutical composition is formulated as an oral composition.

[0040]

[0048] Also disclosed herein is a kit comprising a first pharmaceutical composition in parenteral form comprising levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof; and a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, or any combination thereof, a second pharmaceutical composition in oral form comprising levodopa, a levodopa salt, a levodopa prodrug; a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug; or any combination thereof, and instructions for concomitant administration of the first pharmaceutical composition and the second pharmaceutical composition for the treatment of a neurological or movement disorder.

[0041]

[0049] Disclosed herein, in other embodiments, is a method of treating a neurological or movement disorder in a patient in need of such treatment, comprising: subcutaneously administering to the patient a first pharma- ceutically acceptable liquid composition comprising levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof, and a carbidopa, a carbidopa salt, a carbidopa prodrug, or any combination thereof, in an amount to deliver to the patient about 100-800 mg of levodopa, a levodopa salt, a levodopa prodrug, or combination thereof, and about 12 to about 50 mg of carbidopa, a carbidopa salt, a carbidopa prodrug, or combination thereof, over a subcutaneous infusion time course of about 7 to about 10 or more hours (e.g., a time course of about 8 hours); and orally administering to the patient an immediate release tablet or capsule comprising levodopa and carbidopa prior to or during the subcutaneous infusion time course. Contemplated immediate release tablets may contain, for example, 50 mg, 75 mg, 100 mg, 125 mg, or 150 mg of levodopa and / or 2.5 mg, 18.57 mg, 25 mg, 31.25 mg, 37.5 mg, or 50 mg of carbidopa. In some embodiments, the methods described herein include initial and / or simultaneous oral administration of an immediate release tablet or capsule at the start of the infusion time course, for example, oral administration of an immediate release tablet or capsule may occur substantially simultaneously when the infusion administration begins, and / or about 1, 2, 3, 4, or 5 hours after the start of the infusion time course (e.g., about 0 hours or about 4 hours after the start of the infusion time course), and / or about 4 hours after the start of the infusion time course, and / or about 4 hours and about 8 hours after the start of the infusion time course, and / or about 1, 2, 3, 4, or 5 hours before the start of the infusion time course (e.g., about 0 hours or about 4 hours before the start of the infusion time course).

[0042]

[0050] In some embodiments, the methods described herein include an immediate release tablet or capsule containing 100 mg of levodopa and 25 mg of carbidopa.

[0051] The methods described herein may include subcutaneous administration of a first pharma- ceutically acceptable liquid composition comprising levodopa and carbidopa in an amount to deliver to a patient about 140-170 mg of levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof, and about 16 to about 24 mg of carbidopa, a carbidopa salt, a carbidopa prodrug, or any combination thereof. A contemplated first pharma-ceutically acceptable liquid composition may include a liquid composition comprising about 6% by weight levodopa, about 0.75% by weight carbidopa, and about 10% to about 20% by weight arginine.

[0043]

[0052] In some embodiments, the methods described herein may include subcutaneous administration of a first pharma- ceutically acceptable liquid composition comprising a levodopa prodrug and carbidopa, a carbidopa salt, a carbidopa prodrug, or any combination thereof, in an amount to deliver to the patient about 550-650 mg of levodopa prodrug and about 24 to about 28 mg of carbidopa, a carbidopa salt, or a carbidopa prodrug. A contemplated first pharma-ceutically acceptable liquid composition comprises about 30% by weight of levodopa prodrug, about 1.3% by weight of carbidopa, and about 20% to about 30% by weight of arginine.

[0044]

[0053] For example, the methods described herein may include concomitant subcutaneous administration of a first composition and oral administration of a tablet or capsule, where the patient's area under the curve (AUC) of levodopa from time 0 to the end of the infusion period is higher compared to the combination of the patient's levodopa AUC from time 0 to the end of the infusion period where the first composition alone is administered subcutaneously, and the patient's levodopa AUC when the tablet or capsule is administered alone, and the amount of levodopa administered subcutaneously and orally concomitantly is about the same as the combined amount of levodopa administered subcutaneously alone and orally alone.

[0045]

[0054] Also disclosed herein is a method of treating a neurological or movement disorder in a patient in need thereof, comprising: subcutaneously administering to the patient a first Pharmaceutically acceptable liquid composition comprising about 6% by weight of levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof, and about 0.75% by weight of carbidopa, a carbidopa salt, a carbidopa prodrug, or any combination thereof, over a subcutaneous infusion time course of about 7 to about 10 hours or more; and orally administering to the patient an immediate release tablet or capsule comprising 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, or 250 mg of levodopa before or during the subcutaneous infusion time course, wherein the immediate release tablet or capsule optionally further comprises carbidopa.

[0046]

[0055] Also disclosed herein is a method of treating a neurological or movement disorder in a patient in need of such treatment, comprising: subcutaneously administering to the patient, over a subcutaneous infusion time course of about 24 hours or more, a first pharma- ceutically acceptable liquid composition comprising levodopa and carbidopa in an amount to deliver about 720 mg of levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof, and about 90 mg of carbidopa, a carbidopa salt, a carbidopa prodrug, or any combination thereof, to the patient over about 24 hours; and orally administering to the patient, before or during the subcutaneous infusion time course, a tablet or capsule, e.g., immediate release or modified release, e.g., extended release tablet or capsule, comprising levodopa and carbidopa.

[0047]

[0056] In some embodiments, the methods disclosed herein include administration of subcutaneous infusions over about 18 hours at a high activity rate and over about 6 hours at a low activity rate, where about 691.2 mg of levodopa, levodopa salt, levodopa prodrug, or any combination thereof, and about 86.4 mg of carbidopa, carbidopa salt, carbidopa prodrug, or any combination thereof are administered over the 18 hours at the high activity, and about 28.8 mg of levodopa, levodopa salt, levodopa prodrug, or any combination thereof, and 3.6 mg of carbidopa, carbidopa salt, carbidopa prodrug, or any combination thereof are administered over the 6 hours at the low activity.

[0048]

[0057] According to some embodiments, the tablet or capsule is orally administered substantially simultaneously with the start of the infusion time course. The tablet or capsule may be administered at predefined intervals during the infusion or when desired or required based on feedback, e.g., to the patient, caregiver, physician, sensor, etc. The intervals at which the tablet or capsule is administered may be substantially the same as each other or different. According to some embodiments, the tablet or capsule is orally administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after the start of the infusion time course, and any number of tablets or capsules may be administered as detailed herein. According to some embodiments, the tablet or capsule contains 100 mg of levodopa and 25 mg of carbidopa.

[0049]

[0058] According to some embodiments, the first Pharmaceutically acceptable liquid composition administered over 24 hours according to the methods of the present invention comprises about 6% by weight of levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof, about 0.75% by weight of carbidopa, a carbidopa salt, a carbidopa prodrug, or any combination thereof, and about 10% to about 20% by weight of arginine.

[0050]

[0059] According to some embodiments, the first pharma- ceutically acceptable liquid composition administered over 24 hours according to the methods of the present invention comprises about 30% by weight of a levodopa prodrug, about 1.3% by weight of carbidopa, or any combination thereof, and about 20% to about 30% by weight of arginine.

[0051]

[0060] According to some embodiments, whether the first pharmaceutically acceptable liquid composition is administered for 24 hours or more according to the methods of the present invention in conjunction with oral administration of a tablet or capsule as detailed herein, the patient's area under the curve (AUC) of levodopa from time 0 to the end of the infusion period is higher than the patient's AUC of levodopa from time 0 to the end of the infusion period when the patient is subcutaneously administered the first composition alone compared to the patient's AUC of levodopa from time 0 to the end of the infusion period when the patient is administered the first composition alone compared to the combination together when the tablet or capsule is administered alone and when the amount of levodopa administered concomitantly subcutaneously and orally is approximately the same as the combined amount of levodopa administered alone subcutaneously and alone orally.

[0052]

[0061] An embodiment of the present invention relates to a method of treating Parkinson's disease in a patient in need thereof, the method comprising: levodopa prodrugs; and dopa decarboxylase inhibitors (DDCI), DDCI salts, DDCI prodrugs, or any combination thereof parenterally administering a first pharmaceutical composition comprising: In addition, Levodopa, levodopa salts, levodopa prodrugs; dopa decarboxylase inhibitors (DDCI), DDCI salts, DDCI prodrugs, or any combination thereof orally administering a morning oral dose composition comprising Includes.

[0053]

[0062] An embodiment of the present invention relates to a method of treating Parkinson's disease in a patient in need thereof, the method comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising a levodopa prodrug, carbidopa, arginine, and an antioxidant in an amount to deliver about 900 mg of levodopa prodrug and about 30 mg of carbidopa to the patient over about 24 hours; orally administering to the patient at least one oral dosage form containing levodopa prior to or during the subcutaneous infusion time course; Includes.

[0054]

[0063] An embodiment of the present invention relates to a method of treating Parkinson's disease in a patient in need thereof, the method comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising a levodopa prodrug, carbidopa, arginine, and an antioxidant in an amount to deliver about 1800 mg of levodopa prodrug and about 78 mg of carbidopa to the patient over about 24 hours; orally administering to the patient at least one oral dosage form containing levodopa prior to or during the subcutaneous infusion time course; Includes.

[0055]

[0064] An embodiment of the present invention relates to a method of treating Parkinson's disease in a patient in need thereof, the method comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising a levodopa prodrug, carbidopa, arginine, and an antioxidant in an amount to deliver about 1800 mg of levodopa prodrug and about 60 mg of carbidopa to the patient over about 24 hours; orally administering to the patient at least one oral dosage form containing levodopa prior to or during the subcutaneous infusion time course; Includes.

[0056]

[0065] An embodiment of the present invention relates to a method of treating Parkinson's disease in a patient in need thereof, the method comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising a levodopa prodrug, carbidopa, arginine, and an antioxidant in an amount to deliver about 2700 mg of levodopa prodrug and about 90 mg of carbidopa to the patient over about 24 hours; orally administering to the patient at least one oral dosage form containing levodopa prior to or during the subcutaneous infusion time course; Includes.

[0057]

[0066] An embodiment of the present invention relates to a method of treating Parkinson's disease in a patient in need thereof, the method comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising a levodopa prodrug, carbidopa, arginine, and an antioxidant in an amount to deliver about 2700 mg of levodopa prodrug and about 117 mg of carbidopa to the patient over about 24 hours; orally administering to the patient at least one oral dosage form containing levodopa prior to or during the subcutaneous infusion time course; Includes.

[0058]

[0067] An embodiment of the present invention relates to a method of treating Parkinson's disease in a patient in need thereof, the method comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising a levodopa prodrug, carbidopa, arginine, and an antioxidant in an amount to deliver about 3500 mg of levodopa prodrug and about 120 mg of carbidopa to the patient over about 24 hours; orally administering to the patient at least one oral dosage form containing levodopa prior to or during the subcutaneous infusion time course; Includes.

[0059]

[0068] An embodiment of the present invention relates to a method of treating Parkinson's disease in a patient in need thereof, the method comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising a levodopa prodrug, carbidopa, arginine, and an antioxidant in an amount to deliver about 3000 mg of levodopa prodrug and about 130 mg of carbidopa to the patient over about 24 hours; orally administering to the patient at least one oral dosage form containing levodopa prior to or during the subcutaneous infusion time course; Includes.

[0060]

[0069] An embodiment of the present invention relates to a method of treating Parkinson's disease in a patient in need thereof, the method comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising a levodopa prodrug, carbidopa, arginine, and an antioxidant in an amount to deliver about 4200 mg of levodopa prodrug and about 150 mg of carbidopa to the patient over about 24 hours; orally administering to the patient at least one oral dosage form containing levodopa prior to or during the subcutaneous infusion time course; Includes.

[0061]

[0070] An embodiment of the present invention relates to a method of treating Parkinson's disease in a patient in need thereof, the method comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising a levodopa prodrug, carbidopa, arginine, and an antioxidant in an amount to deliver about 3300 mg of levodopa prodrug and about 143 mg of carbidopa to the patient over about 24 hours; orally administering to the patient at least one oral dosage form containing levodopa prior to or during the subcutaneous infusion time course; Includes.

[0062]

[0071] An embodiment of the present invention relates to a method of treating Parkinson's disease in a patient in need thereof, the method comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising a levodopa prodrug, carbidopa, arginine, and an antioxidant in an amount to deliver about 3600 mg of levodopa prodrug and about 156 mg of carbidopa to the patient over about 24 hours; orally administering to the patient at least one oral dosage form containing levodopa prior to or during the subcutaneous infusion time course; Includes.

[0063]

[0072] According to some embodiments, the oral dosage form is a morning oral dose.

[0073] An embodiment of the present invention relates to a method of treating Parkinson's disease in a patient in need thereof, the method comprising: administering to the patient subcutaneously a first pharmaceutical composition comprising a levodopa portion and a carbidopa portion over a subcutaneous infusion time course of about 24 hours or more; Accompanying orally administering to the patient at least one oral dosage form containing levodopa prior to or during the subcutaneous infusion time course; Includes.

[0064]

[0074] According to some embodiments, the first pharmaceutical composition comprises a levodopa portion and a carbidopa portion in a ratio of about 30:1 w / w. According to some embodiments, the treatment comprises treatment of motor fluctuations. According to some embodiments, the first pharmaceutical composition comprises up to about 4200 mg of a levodopa portion and up to about 150 mg of a carbidopa portion, the levodopa portion and the carbidopa portion being in a ratio of about 30:1 w / w. According to some embodiments, the oral dosage form is a morning oral dose.

[0065]

[0075] An embodiment of the present invention relates to a method of treating Parkinson's disease in a patient in need thereof, the method comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising levodopa prodrug and carbidopa in an amount to deliver to the patient a ratio of about 30:1 w / w to about 8:1 w / w of levodopa prodrug and carbidopa over about 24 hours; orally administering to the patient at least one oral dosage form containing levodopa prior to or during the subcutaneous infusion time course; Includes.

[0066]

[0076] An embodiment of the present invention relates to a method of treating Parkinson's disease in a patient in need thereof, the method comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising a levodopa portion and a carbidopa portion in an amount to deliver to the patient over about 24 hours a ratio of about 30:1 w / w of the levodopa portion and the carbidopa portion; orally administering to the patient at least one oral dosage form containing levodopa prior to or during the subcutaneous infusion time course; Includes.

[0067]

[0077] An embodiment of the present invention relates to a method of treating Parkinson's disease in a patient in need thereof, the method comprising: subcutaneously administering to the patient a first pharmaceutical composition comprising a levodopa prodrug and a carbidopa prodrug over a subcutaneous infusion time course of about 24 hours or more; Accompanying orally administering to the patient at least one oral dosage form containing levodopa before or during the subcutaneous infusion time course, wherein up to about 4260 mg of levodopa is administered to the patient daily; Includes.

[0068]

[0078] According to some embodiments, the methods provided herein may further include administering one or more loading doses to the patient. According to some embodiments, the loading dose is administered by subcutaneous injection. According to some embodiments, the loading dose is administered orally.

[0069]

[0079] According to some embodiments, the methods provided herein may further include administering one or more additional doses to the patient. According to some embodiments, the additional doses are administered by subcutaneous injection. According to some embodiments, the additional doses are administered orally. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0070] Detailed Description of the Invention

[0080] The features and other details of the present disclosure will now be described in more detail.Specific terms used in the specification, examples, and appended claims are collected here.These definitions should be read in light of the remainder of this disclosure and understood by those skilled in the art.Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0071]

[0081] The terms "treat," "treatment," "treating," and the like are used herein generally to refer to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic in that it partially or completely cures the disease and / or the adverse effects caused by the disease. The term "treatment" as used herein encompasses any treatment of a disease in a mammal, particularly a human, including: (a) inhibiting the disease, i.e., preventing the disease from increasing in severity or extent; (b) relieving the disease, i.e., causing partial or complete remission of the disease; or (c) preventing recurrence of the disease, i.e., preventing the disease from returning to an active state, following a previous successful treatment of the symptoms of the disease or treatment of the disease.

[0072]

[0082] "Prevention" includes delaying the onset of clinical symptoms, complications, or biochemical signs of a condition, disorder, disease, or condition that manifests in a subject who may be afflicted with or prone to the condition, disorder, disease, or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder, disease, or condition. "Prevention" includes prophylactically treating a condition, disorder, disease, or condition in or that manifests in a subject, including prophylactically treating clinical symptoms, complications, or biochemical signs of a condition, disorder, disease, or condition that manifests in or that manifests in a subject.

[0073]

[0083] The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient," as used interchangeably herein, refer to any and all solvents, dispersion media, coatings, isotonic agents, absorption delaying agents, and the like, compatible with pharmaceutical administration.

[0074]

[0084] As used herein, the terms "pharmaceutical composition" and "pharmaceutical formulation" refer to a composition or formulation containing at least one biologically active compound, e.g., levodopa or carbidopa, or a pharmaceutically acceptable salt or prodrug thereof, formulated with one or more pharmaceutically acceptable excipients.

[0075]

[0085] As used herein, the term "pharmaceutically acceptable salts" refers to salts of acidic or basic groups that may be formed by the conjugates used in the compositions disclosed herein.

[0076]

[0086] "Individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or non-human primates, and humans. In some embodiments, the mammal treated by the methods of the invention is a human suffering from a neurodegenerative condition, e.g., Parkinson's disease.

[0077]

[0087] The term "about" as used herein is considered to cover a range of ±10% of the stated value unless specifically stated otherwise or understood otherwise by a person skilled in the art. Furthermore, any value provided may also be considered to cover a range of ±10% of the value without the use of the term "about". This includes values ​​in the Examples section, which may vary according to the instruments and apparatus used, the purity of the compounds, etc.

[0078]

[0088] The term "maximum" as used herein, when appearing as part of a range, is defined such that the range does not include "none", "nothing", or "0", unless specifically stated otherwise or understood otherwise by one of ordinary skill in the art. That is, if an ingredient is in a maximum specified amount, e.g., 720 mg, 0 mg is not considered part of the range. Thus, if a composition contains, e.g., up to 360 mg, up to 370 mg, up to 720 mg of levodopa, the composition must contain more than 0 levodopa. Similarly, if a composition contains, e.g., up to 45 mg, up to 46 mg, up to 90 mg of carbidopa, the composition must contain more than 0 carbidopa.

[0079]

[0089] The term "levodopa moiety" as used herein includes any moiety that contains levodopa, including, for example, levodopa itself, levodopa prodrugs, levodopa salts, and levodopa prodrug salts, unless specifically stated otherwise or understood otherwise by one of ordinary skill in the art. Similarly, the term "carbidopa moiety" as used herein includes any moiety that contains carbidopa, including, for example, carbidopa itself, carbidopa prodrugs, carbidopa salts, and carbidopa prodrug salts, unless specifically stated otherwise or understood otherwise by one of ordinary skill in the art.

[0080]

[0090] The term "liquid" as used herein refers to any type of fluid, including gels, aqueous compositions and non-aqueous compositions, unless specifically stated otherwise or understood otherwise by one of ordinary skill in the art.

[0081]

[0091] The term "concomitant" as used herein, unless specifically stated otherwise or understood otherwise by a person skilled in the art, refers to any kind of combined administration of two or more active ingredients by the same composition, and simultaneous administration of active ingredients by separate compositions, and administration of two or more active ingredients sequentially, consecutively, on the same day, with a predefined period separating the administration of the active ingredients from each other, etc. The term "concomitant" may also be used herein to refer to any kind of combined administration of two separate pharmaceutical compositions, where each composition may be administered by various routes of administration, at various time intervals, doses, etc. For example, as detailed herein, one composition may be administered parenterally, e.g., subcutaneously, substantially continuously, while the second composition is administered concomitantly with the first composition by non-sequential, oral administration. Moreover, the concomitant administration of two or more separate compositions may be dependent on each other or independent of each other.

[0082]

[0092] The terms "continuously" and "substantially continuously" as used herein, unless specifically stated otherwise or understood otherwise by one of skill in the art, refer to a period during which the composition is administered over a period of about 24 hours, about 12 hours, about 5 hours, about 3 hours, about 1 hour, about 30 minutes, about 15 minutes, about 5 minutes, or less than about 1 minute of interruption. The period during which the composition is administered may be at least about 6 hours, about 8 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, 3 days, 7 days, 2 weeks, 1 month, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, 10 years, etc.

[0083]

[0093] As used herein, the term "physiologically acceptable pH value" and the like, unless specifically stated otherwise or understood otherwise by one of ordinary skill in the art, refers to a pH value within the range of about 4.5 to about 10. Furthermore, when pH values ​​are provided, for example in the examples, the values ​​may be within about ±0.1 and / or ±10% of the stated value, and it is noted that if the measured pH is 8.1, the same formulation may be prepared to provide a pH of about 8.0 or 8.2. Such differences may be due to temperature changes, different measuring equipment, etc.

[0084]

[0094] Neuropathies are disorders of the body's nervous system, and the term "movement disorder" as used herein refers to a condition of the nervous system that causes abnormal voluntary or involuntary movements, or slow, sluggish movements. According to some embodiments, the neurological or movement disorder is Parkinson's disease; secondary parkinsonism, such as drug-induced secondary parkinsonism, neuroleptic-induced parkinsonism, postencephalitic parkinsonism, and vascular parkinsonism; motor fluctuations; neurodegenerative disorders; movement disorders; reduced dopamine levels in the brain; levodopa-induced dyskinesia; rapid eye movement sleep behavior disorder (RBD); dystonia; morning akinesia; tremor symptoms, such as essential tremor and drug-induced tremor; myoclonus; chorea, such as drug-induced chorea; tics, such as drug-induced tics and organic tics; drug-induced dyskinesia; drug-induced akathisia; restless legs syndrome (RLS); stiff man syndrome; benign tremor attacks; malignant neuroleptic syndrome; Huntington's chorea; Shy-Drager syndrome; brain injury-induced conditions, such as carbon monoxide or manganese poisoning; or any combination thereof. According to some embodiments, the methods relate to the treatment of Parkinson's disease and / or motor fluctuations, including motor fluctuations resulting from Parkinson's disease, motor fluctuations in patients with Parkinson's disease, etc.

[0085]

[0095] The term "dopa decarboxylase inhibitor" as used herein refers to an agent capable of inhibiting the peripheral metabolism of levodopa to dopamine by aromatic L-amino acid decarboxylase, such as carbidopa, benserazide, methyldopa, 3',4',5,7-tetrahydroxy-8-methoxyisoflavone, alpha-difluoromethyldopa, or any combination thereof.

[0086]

[0096] The terms "morning dose" and "morning oral dose" as used herein, unless specifically stated otherwise or understood otherwise by one of skill in the art, are interchangeable and refer to an oral dosage form containing levodopa that is administered, in particular, in the morning hours, e.g., within 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours of the patient's waking hours. According to some embodiments, a morning dose refers to an oral dosage form containing levodopa that is administered within 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes of the patient's waking hours.

[0087]

[0097] The term "loading dose" refers to a dose of a pharmaceutical composition comprising levodopa or a levodopa moiety, e.g., a levodopa prodrug (e.g., a bolus dose of levodopa or a levodopa moiety, e.g., a levodopa prodrug) that may be administered to rapidly achieve symptomatic control or a desired therapeutic state when the patient is, for example, in an "off" state (e.g., when administration of a therapeutic agent has been discontinued for an extended period of time, e.g., 3 hours or more, and / or when the patient exhibits undesirable Parkinsonian symptoms, e.g., decreased motor control, decreased motor ability, tremor and / or rigidity, "off" states, dyskinesias). A loading dose can be, for example, - before starting a continuous infusion, - Between two consecutive continuous infusion sessions separated by a period of 2, 3, 4, 5 hours or more during which no continuous infusion is administered, - After a period of relatively small continuous infusion doses, e.g. after morning or evening hours It should be noted that the loading dose may be administered as an infusion bolus or by oral administration of a pharmaceutical composition containing any known oral form of levodopa or a levodopa equivalent.

[0088]

[0098] The term "booster dose" refers to a dose of a pharmaceutical composition comprising levodopa, a levodopa moiety, or, e.g., a levodopa prodrug (e.g., a bolus dose of levodopa, a levodopa moiety, e.g., a levodopa prodrug) that can be administered as needed for symptomatic control or to rapidly achieve a desired therapeutic state, e.g., to manage acute "off" symptoms experienced during continuous infusion.

[0089]

[0099] Any type of bolus dose, whether referred to herein as a loading dose, a top-up dose, a bolus, or any other related term, may be administered about 1, 2, 3, 4, 5 or more times per day, or as prescribed by a physician, or as determined necessary by a patient, a caregiver, or a physician. The number and duration of various bolus doses may be varied accordingly. Bolus doses may be administered by infusion, for example via a subcutaneous infusion pump, or by oral administration.

[0090]

[0100] The loading dose, booster dose, or any other bolus dose may be administered subcutaneously in a volume of up to about 5 ml per dose. The loading dose, booster dose, or any other bolus dose may be administered subcutaneously in a volume of about 0.1 ml, about 0.15 ml, about 0.2 ml, about 0.25 ml, about 0.3 ml, about 0.4 ml, about 0.5 ml, about 0.6 ml, about 0.9 ml, about 1.2 ml, about 1.5 ml, about 1.8 ml, about 2.0 ml, about 2.5 ml, about 3.0 ml, about 3.5 ml, about 4.0 ml, about 4.5 ml, or about 5.0 ml per dose.

[0091]

[0101] The loading dose, booster dose, or any other bolus dose may be administered subcutaneously, orally, or both subcutaneously and orally in an amount that provides up to about 500 mg of levodopa or levodopa equivalent per dose. The loading dose, booster dose, or any other bolus dose may be administered subcutaneously, orally, or both subcutaneously and orally in an amount of about 5 mg, about 10 mg, about 15 mg, about 17 mg, about 20 mg, about 25.5 mg, about 30 mg, about 34 mg, about 40 mg, about 42.5 mg, about 45 mg, about 50 mg, about 51 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg per dose.

[0092]

[0102] As known in the art, the amount of levodopa equivalents is calculated to evaluate the levodopa dose. For example, the levodopa equivalents are calculated using a dose multiplication factor of 1 for immediate release levodopa, a dose multiplication factor of 0.75 for either sustained release levodopa, controlled release levodopa, or extended release levodopa, a dose multiplication factor of 1.33 for COMT inhibitors, and so on. In addition, various calculations may involve various levodopa moieties, such as levodopa prodrugs. For example, the bioavailability of the prodrug may differ from that of levodopa itself and must therefore be considered. The prodrug may not completely switch to levodopa, so that the theoretical amount of levodopa is less than expected. This must also be considered in the calculation of the levodopa equivalents. The calculation of the levodopa equivalents may help determine the daily dose to be administered to the patient, as well as the loading dose, top-up dose, or any other bolus dose.

[0093]

[0103] According to some embodiments, the morning oral dose comprises one of: 25 mg levodopa, 50 mg levodopa, 75 mg levodopa, 95 mg levodopa, 100 mg levodopa, 125 mg levodopa, 145 mg levodopa, 150 mg levodopa, 195 mg levodopa, 200 mg levodopa, 245 mg levodopa, or 250 mg levodopa.

[0094]

[0104] An embodiment of the present invention relates to a method of treating a neurological or movement disorder, e.g., Parkinson's disease, in a patient in need of such treatment, the method comprising: levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof; and dopa decarboxylase inhibitors (DDCI), DDCI salts, DDCI prodrugs, or any combination thereof parenterally administering a first pharmaceutical composition comprising: In addition, Levodopa, levodopa salts, levodopa prodrugs; dopa decarboxylase inhibitors (DDCI), DDCI salts, DDCI prodrugs; or any combination thereof and orally administering a second pharmaceutical composition comprising Includes.

[0095]

[0105] According to some embodiments, the concomitant administration of the first and second pharmaceutical compositions provides a synergistic effect such that the concomitant administration provides a higher levodopa blood level than the expected additive effect of providing the first and second pharmaceutical compositions without the concomitant administration. According to some embodiments, the synergistic effect between the first and second pharmaceutical compositions provides an increase in levodopa blood levels of about 5% to about 50% compared to the expected additive value. According to some embodiments, the synergistic effect between the first and second pharmaceutical compositions provides an increase in levodopa blood levels of about 10% to 40%, about 15% to 35% of levodopa blood levels, about 20% to 40%, about 25% to 35% of levodopa blood levels, or about 20%, 25%, or 30% of levodopa blood levels compared to the expected additive value.

[0096]

[0106] According to some embodiments, the first pharmaceutical composition comprises a levodopa moiety and a carbidopa moiety. According to some embodiments, at least one of the levodopa moiety and the carbidopa moiety in the first pharmaceutical composition is levodopa or a carbidopa prodrug. According to some embodiments, both of the levodopa moiety and the carbidopa moiety in the first pharmaceutical composition are levodopa prodrug and carbidopa prodrug, respectively. According to some embodiments, the second pharmaceutical composition comprises levodopa and carbidopa. According to some embodiments, the second pharmaceutical composition comprises only levodopa as an active ingredient. According to some embodiments, the second pharmaceutical composition further comprises a catechol O-methyltransferase (COMT) inhibitor, such as entacapone or tolcapone.

[0097]

[0107] According to some embodiments, the first pharmaceutical composition and / or the second pharmaceutical composition comprises (1) levodopa, a levodopa salt, and / or a levodopa prodrug, and / or (2) carbidopa, a carbidopa salt, and / or a carbidopa prodrug. According to some embodiments, the levodopa prodrug is any of the prodrugs disclosed in PCT / IL2020 / 050960 or PCT / IL2022 / 050269, which applications are incorporated herein by reference in their entirety. According to some embodiments, the levodopa prodrug and / or the carbidopa prodrug is any of the prodrugs disclosed in PCT / JP2022 / 012484.

[0098]

[0108] According to some embodiments, the levodopa prodrug has the general formula (I):

[0099] [ka]

[0100] (In the formula, R is an amino acid side chain, R1 and R2 are each independently selected from the group consisting of H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, C3-C6 cycloalkyl, phenyl, -OC(=O)-R', -C(=O)-OR', -C(=O)-R', -C(=S)-R', -OC(=O)-NR'R', -OC(=S)-NR'R', or -OC(=O)-R''; R3 and R4 are each independently selected from the group consisting of H, (C1-C3) alkyl, C3-C6 cycloalkyl, phenyl, or -P(=O)(OR')2; R5 is selected from the group consisting of H, (C1-C3) alkyl, C3-C6 cycloalkyl, and phenyl; R' are each independently selected from the group consisting of H attached to the nitrogen through a ring carbon, (C1-C6) alkyl, (C2-C6) alkenyl, C3-C6 cycloalkyl, phenyl, and heteroaryl; R″ is selected from the group consisting of (C1-C6) alkyl, (C2-C6) alkenyl, and (C2-C6) alkynyl. Levodopa amino acid conjugates (LDAA), enantiomers, diastereomers, racemates, ions, zwitterions, pharma- ceutically acceptable salts thereof, or any combination thereof.

[0101]

[0109] According to some embodiments, R is an amino acid side chain of any natural, synthetic, non-natural, or non-proteinogenic amino acid, such as, for example, arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, lanthionine, selenocysteine, pyrrolidine, ADDA amino acids ((2S,3S,4E,6E,8S,9S)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldec-4,6-dienoic acid), beta-alanine, 4-aminobenzoic acid, gamma-aminobutyric acid, S-aminoethyl-L-cysteine, 2-aminoisobutyric acid, aminolevulinic acid, azetidine-2-carboxylic acid, canaline, canavanine, carboxyglutamic acid, chloroalanine, citrulline, cysteine, dehydroalanine, diaminopimelic acid, hydroxyphenylglycine, enduracidin, homocysteine, homoserine, 4-hydroxyphenylglycine, hydroxyproline, hypusine, beta-leucine, norleucine, norvaline, ornithine, penicillamine, placohypaforine, pyroglutamic acid, quisqualic acid, sarcosine, theanine, tranexamic acid, tricolominic acid, or the side chain of any isomer thereof. In this regard, it should be noted that R may be any of the known isomers of lanthionine, one of which is referred to herein as lanthionine-1 or lanthionine-peak 1, and the other of which is referred to herein as lanthionine-2 or lanthionine-peak 2. Additionally, the levodopa lanthionine conjugates may be referred to herein as LD-LA, LD-LA1 (for the first isomer), LD-LA2 (for the second isomer), LD-lanthionine 1 (for the first isomer), LD-lanthionine 2 (for the second isomer), and the like.

[0102]

[0110] According to some embodiments, R is an amino acid side chain of arginine, tyrosine, lysine, aspartic acid, asparagine, tryptophan, glutamine, glutamic acid, glycine, or lanthionine. According to some embodiments, R is an amino acid side chain of arginine, tyrosine, lysine, lanthionine-2, tryptophan, glutamic acid, or glycine. According to some embodiments, R is an amino acid side chain of arginine, tyrosine, lysine, or lanthionine-2. According to some embodiments, R is an amino acid side chain of arginine, tyrosine, or lysine. According to some embodiments, R is an amino acid side chain of lanthionine-2.

[0103]

[0111] According to some embodiments, each of R1, R2, R3, R4 and R5 is H. According to some embodiments, R'' has at least 10 carbon atoms. According to some embodiments, the pharmaceutical composition comprises a mixture of two or more LDAA compounds.

[0104]

[0112] According to some embodiments, the levodopa prodrug has the general formula (II):

[0105] [ka]

[0106] (In the formula, R X is an amino acid side chain or a 0 phosphorylated amino acid side chain thereof; R1 and R2 are each independently selected from the group consisting of H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, C3-C6 cycloalkyl, phenyl, -OC(=O)-R', -C(=O)-OR', -C(=O)-R', -C(=S)-R', -OC(=O)-NR'R', -OC(=S)-NR'R', or -OC(=O)-R''; R3 and R4 are each independently selected from the group consisting of H, (C1-C3) alkyl, C3-C6 cycloalkyl, phenyl, or -P(=O)(OR')2; R5 is selected from the group consisting of H, (C1-C3) alkyl, C3-C6 cycloalkyl, and phenyl; R' are each independently selected from the group consisting of H attached to the nitrogen through a ring carbon, (C1-C6) alkyl, (C2-C6) alkenyl, C3-C6 cycloalkyl, phenyl, and heteroaryl; and R″ is selected from the group consisting of (C1-C6) alkyl, (C2-C6) alkenyl, and (C2-C6) alkynyl. Levodopa amino acid conjugates (LDAA), enantiomers, diastereomers, racemates, ions, zwitterions, pharma- ceutically acceptable salts thereof, or any combination thereof.

[0107]

[0113] According to some embodiments, the levodopa prodrug has the general formula (III):

[0108] [ka]

[0109] (In the formula, R X is an amino acid side chain selected from the group consisting of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, ornithine, lanthionine, and 3,4-dihydroxyphenylalanine side chains; or a 0-phosphorylated amino acid side chain thereof; R1 and R2 are each independently selected from the group consisting of H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, C3-C6 cycloalkyl, phenyl, -OC(=O)-R', -C(=O)-OR', -C(=O)-R', -C(=S)-R', -OC(=O)-NR'R', -OC(=S)-NR'R', or -OC(=O)-R''; R3 and R4 are each independently selected from the group consisting of H, (C1-C3) alkyl, C3-C6 cycloalkyl, phenyl, or -P(=O)(OR')2; R5 is selected from the group consisting of H, (C1-C3) alkyl, C3-C6 cycloalkyl, and phenyl; R' are each independently selected from the group consisting of H attached to the nitrogen through a ring carbon, (C1-C6) alkyl, (C2-C6) alkenyl, C3-C6 cycloalkyl, phenyl, and heteroaryl; R″ is selected from the group consisting of (C1-C6) alkyl, (C2-C6) alkenyl, and (C2-C6) alkynyl. Levodopa amino acid conjugates (LDAA), enantiomers, diastereomers, racemates, ions, zwitterions, pharma- ceutically acceptable salts thereof, or any combination thereof.

[0110]

[0114] For example, in the embodiments described herein, R x The amino acid side chains of:

[0111] [ka]

[0112] [ka]

[0113] [ka]

[0114] It may be.

[0115] According to some embodiments of the general formula (III), R x is an amino acid side chain selected from the group consisting of arginine, lysine, serine, glycine, alanine, valine, phenylalanine, tyrosine, ornithine, and 3,4-dihydroxyphenylalanine; or a 0-phosphorylated amino acid side chain thereof.

[0115]

[0116] According to some embodiments of general formula (III), each of R1, R2 and R5 is H; R3 and R4 are independently H or -P(=O)(OR')2; and R' is H.

[0116]

[0117] According to a preferred embodiment of the general formula (III), R x is an amino acid side chain selected from the group consisting of arginine, lysine, serine, glycine, alanine, valine, phenylalanine, tyrosine, ornithine, and 3,4-dihydroxyphenylalanine; or a phosphorylated amino acid side chain thereof; each of R1, R2, and R5 is H; R3 and R4 are independently H or -P(=O)(OR')2; and R' is H.

[0117]

[0118] According to some embodiments, the LDAA has the formula (IV):

[0118] [ka]

[0119] (In the formula, R 10a is an amino acid side chain or a 0 phosphorylated amino acid side chain thereof; R 11a and R 12a are the same or different and each is optionally substituted hydrogen, alkyl, cycloalkyl, phenyl, P(=O)(OR')2, S(=O)(OH), or glycosyl; R 13a and R 14a are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, -OC(=O)-R', -C(=O)-OR', -C(=O)-R', -C(=S)-R', -OC(=O)-NR'R'', -OC(=S)-NR'R'', or OC(=O)-R''; R 15a is hydrogen, alkyl, cycloalkyl or phenyl; R' and R" are the same or different and each is hydrogen, alkyl, alkenyl, cycloalkyl, or phenyl, or R' and R" together with the adjacent nitrogen atom form a group which forms a heteroaryl; R''' is hydrogen, alkyl, alkenyl or alkynyl. or a pharma- ceutically acceptable salt thereof.

[0120] According to some embodiments, the LDAA has the formula (V):

[0121] [ka]

[0122] (In the formula, R 20a is an optionally substituted amino acid side chain; R 21a and R 22a are the same or different and each is optionally substituted hydrogen, alkyl, alkanoyl, P(=O)(OH), S(=O)(OH) or glycosyl; R 23a , R 24a , and R 25a are the same or different and each is hydrogen or alkyl. or a pharma- ceutically acceptable salt thereof.

[0123] In some embodiments, the LDAA has the formula (IV-1):

[0124] [ka]

[0125] (In the formula, R 10a is an amino acid side chain; R 11a and R 12aare the same or different and each is optionally substituted hydrogen, S(=O)(OH) or glycosyl, while R 11a and R 12a are not both hydrogen at the same time); or a pharmacologically acceptable salt thereof.

[0126]

[0121] Exemplary embodiments of the aforementioned levodopa prodrugs are listed below in Tables 1 and 2:

[0127] [Table 1]

[0128] [Table 2-1]

[0129] [Table 2-2]

[0130] [Table 2-3]

[0131] [Table 2-4]

[0132] [Table 2-5]

[0133] [Table 2-6]

[0134] [Table 2-7]

[0135]

Table 2-8

[0136]

Table 2-9

[0137]

Table 2-10

[0138]

Table 2-11

[0139]

Table 2-12

[0140]

Table 2-13

[0141]

Table 2-14

[0142]

Table 2-15

[0143]

Table 2-16

[0144]

Table 2-17

[0145] [Table 2-18]

[0146] [Table 2-19]

[0147] [Table 2-20]

[0148] [Table 2-21]

[0149] [Table 2-22]

[0150] Further embodiments of the present invention include: (2S)-2-amino-3-(3-hydroxy-4-phosphonooxyphenyl)propionamide; 2-[[(2S)-2-Amino-3-(3-hydroxy-4-phosphonooxyphenyl)propanoyl]amino]ethanesulfonic acid; (2S)-2-amino-6-[[(2S)-2-amino-3-(3-hydroxy-4-phosphonooxyphenyl)propanoyl]amino]hexanoic acid; or (2S)-2-amino-5-[[(2S)-2-amino-3-(3-hydroxy-4-phosphonooxyphenyl)propanoyl]amino]pentanoic acid The present invention relates to a levodopa amino acid conjugate (LDAA) selected from the group consisting of:

[0151]

[0123] An embodiment of the present invention is a compound represented by general formula (II-1) or (II-2):

[0152] [ka]

[0153] (In the formula, R1 and R2 are each independently selected from the group consisting of H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, C3-C6 cycloalkyl, phenyl, -OC(=O)-R', -C(=O)-OR', -C(=O)-R', -C(=S)-R', -OC(=O)-NR'R', -OC(=S)-NR'R', or -OC(=O)-R''; R3 and R4 are each independently selected from the group consisting of H, (C1-C3) alkyl, C3-C6 cycloalkyl, phenyl, or -P(=O)(OR')2; R5 is selected from the group consisting of H, (C1-C3) alkyl, C3-C6 cycloalkyl, and phenyl; R' are each independently selected from the group consisting of H attached to the nitrogen through a ring carbon, (C1-C6) alkyl, (C2-C6) alkenyl, C3-C6 cycloalkyl, phenyl, and heteroaryl; and R″ is selected from the group consisting of (C1-C6) alkyl, (C2-C6) alkenyl, and (C2-C6) alkynyl. The present invention relates to a levodopa-lanthionine conjugate (LD-LA) of the formula (I), an enantiomer, diastereomer, racemate, ion, zwitterion, a pharma- ceutically acceptable salt thereof, or any combination thereof.

[0154] According to some embodiments, each of R1, R2, R3, R4 and R5 is H. According to some embodiments, the levodopa prodrug has the general formula (VI):

[0155] [ka]

[0156] (wherein R is an optionally substituted amino acid side chain; R 1 and R 2 may be the same or different, and each independently represents an optionally substituted hydrogen atom, C1-C6 alkyl, C1-C6 alkanoyl, phosphono, sulfino, or glycosyl, provided that R 1 and R 2 is not a hydrogen atom at the same time; R 3 and R 4 may be the same or different and each independently represents a hydrogen atom or a C1-C6 alkyl; R 5 is a hydrogen atom, However, the following compounds: (2S)-2-[(2-aminoacetyl)amino]-3-(3,4-diacetyloxyphenyl)propanoic acid, (2S)-2-[[(2S)-2-amino-6-[(2-chlorophenyl)methoxycarbonylamino]hexanoyl]amino]-3-(3,4-dimethoxyphenyl)propanoic acid, (2S)-2-[[(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl]amino]-3-(4-hydroxy-3-methoxyphenyl)propanoic acid, (2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-3-(3,4-dimethoxyphenyl)propanoic acid, (2S)-2-[[(2R)-2-amino-3-phenylpropanoyl]amino]-3-(3,4-diacetyloxyphenyl)propanoic acid, and (2S)-2-[[(2S)-2-amino-5-methoxy-5-oxopentanoyl]amino]-3-(3,4-dimethoxyphenyl)propanoic acid are excluded), Contains levodopa amino acid conjugate (LDAA).

[0157]

[0126] In certain embodiments, the levodopa prodrug comprises a levodopa amino acid conjugate (LDAA) of general formula (VI) or a pharma- ceutically acceptable salt thereof, wherein R3, R4, and R5 are hydrogen atoms. 1 and R 2 are the same or different and each is a hydrogen atom, acetyl or phosphono, provided that R 1 and R 2 is not a hydrogen atom at the same time.

[0158] In certain embodiments, the present disclosure further provides that R, R and R are hydrogen atoms; 1 is a hydrogen atom, and R 2 is phosphono; and a pharma- ceutically acceptable salt thereof.

[0159]

[0128] In certain embodiments, the present disclosure further relates to an LDAA or a pharma- ceutically acceptable salt thereof according to any one of the above embodiments, wherein the amino acid of the amino acid side chain is glutamic acid, valine, alanine, lysine, 3,4-dihydroxyphenylalanine or tyrosine.

[0160] In certain embodiments, the LDAA is: (2S)-2-[[(2S)-2-amino-3-phosphonooxypropanoyl]amino]-3-(3,4-dihydroxyphenyl)propanoic acid, (2S)-2-[[(2S)-2-amino-3-(4-phosphonooxyphenyl)propanoyl]amino]-3-(3,4-dihydroxyphenyl)propanoic acid, (2S)-2-amino-5-[[(1S)-1-carboxy-2-(3,4-diacetoxyphenyl)ethyl]amino]-5-oxopentanoic acid, (2S)-3-(3,4-dihydroxyphenyl)-2-[(2-methyl-2-phosphonooxypropanoyl)amino]propanoic acid, and (2S)-2-[[(2S)-2-amino-3-[4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]propanoyl]amino]-3-(3,4-dihydroxyphenyl)propanoic acid is selected from the group consisting of:

[0161] In certain embodiments, the LDAA is: (2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-(3-hydroxy-4-phosphonooxyphenyl)propanoic acid, (2S)-2-[[(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl]amino]-3-(3-hydroxy-4-phosphonooxyphenyl)propanoic acid, (2S)-2-[[(2S)-2,6-diaminohexanoyl]amino]-3-(3-hydroxy-4-phosphonooxyphenyl)propanoic acid, and (2S)-2-[[(2S)-2-amino-3-(4-phosphonooxyphenyl)propanoyl]amino]-3-(3,4-dihydroxyphenyl)propanoic acid and the levodopa amino acids are designated using IUPAC Japanese names.

[0162] In certain embodiments, the LDAA has the formula (VII-1):

[0163] [ka]

[0164] (wherein one of R1 and R2 is lysine or alanine, and the other is hydrogen). According to some embodiments, R1 is hydrogen and R2 is lysine or alanine.

[0165] In certain embodiments, the LDAA has the formula (VII-2):

[0166] [ka]

[0167] levodopa-tyrosine (LD-Tyr) conjugate of, an enantiomer, diastereomer, racemate, ion, zwitterion, a pharma- ceutically acceptable salt thereof, or any combination thereof.

[0168] In some embodiments, the first pharmaceutical composition comprising a levodopa moiety, e.g., LD-Tyr, may further comprise a stabilizer. In certain embodiments, the first pharmaceutical composition comprises about 0.1 to about 30% w / v of the stabilizer. In certain embodiments, the first pharmaceutical composition comprises about 1.5 to about 20% w / v of the stabilizer. For example, the first pharmaceutical composition may have a concentration of about 1.5 to about 5.0%, about 1.5 to about 10.0% w / v, about 1.5 to about 15.0% w / v, about 1.5 to about 20.0% w / v, about 1.5 to about 25.0% w / v, about 3.0 to about 5.0% w / v, about 3.0 to about 10.0% w / v, about 3.0 to about 15.0% w / v, about 3.0 to about 20.0% w / v, about 3 to about 25.0% w / v, about 3.0 to about 30.0% w / v, about 5.0 to about 10.0% w / v, about 5 to about 15.0% w / v, about 5.0 to about 20.0% w / v, about 5.0 to about 25.0% w / v, about 5.0 to about 30.0% w / v, about 7.0 to about 10.0% w / v, about 7.0 to about 15.0% w / v, about 7.0 to about 20.0% w / v, about 7.0 to about 25.0% w / v, about 7.0 to about 30.0% w / v, about 10.0 to about 15.0% w / v, about 10.0 to about 20.0% w / v, about 10 to about 25.0% w / v, about 10.0 to about 30.0% w / v, about 15.0 to about 20.0% w / v, about 15.0 to about 25.0% w / v, or about 15.0 to about 30.0% w / v of a stabilizer. In certain embodiments, the first pharmaceutical composition comprises a combination of two, three or four stabilizers, each separate stabilizer being present in the amounts described above, or the combination of stabilizers being present in the amounts described above.

[0169]

[0134] According to certain embodiments, the stabilizing agent comprises a base. In other embodiments, the first pharmaceutical composition comprises a stabilizing agent and further comprises a base, for example, to provide a predefined pH to the composition. According to some embodiments, the base is selected from NaOH, NH4OH, Ca(OH)2, ammonium hydroxide, arginine, lysine, magnesium hydroxide, potassium hydroxide, meglumine, tromethamine (TRIS), triethylamine, ethylenediamine, diethylamine, ethanolamine, diisopropylethylamine, diazabicycloundecene, or any combination thereof. The first pharmaceutical composition may comprise about 0.1 to about 30.0 w / v% of the base. According to some embodiments, the first pharmaceutical composition may comprise about 0.1 to about 1.0 w / v%, about 1.0 to about 2.0 w / v%, about 2.0 to about 3.0 w / v%, about 3.0 to about 4.0 w / v%, about 4.0 to about 5.0 w / v%, about 5.0 to about 6.0 w / v%, about 6.0 to about 7.0 w / v%, about 8.0 to about 9.0 w / v%, about 9.0 to about 10.0 w / v%, about 10.0 to about 11.0 w / v%, about 11.0 to about 12.0 w / v%, about 12.0 to about 13.0 w / v%, about 13.0 to about 14.0 w / v%, about 14.0 to about 15.0 w / v%, about 15.0 to about 16.0 w / v%, about 17.0 to about 18.0 w / v%, about 18.0 to about 19.0 w / v%, about 20.0 to about 21.0 w / v%, about 21.0 to about 22.0 w / v%, about 22.0 to about 23.0 w / v%, about 23.0 to about 24.0 w / v%, about 24.0 to about 25.0 w / v%, about 25.0 to about 26.0 w / v%, about 26.0 to about 27.0 w / v%, about 27.0 to about 28.0 w / v%, about 28.0 to about 30.0 w / v%, about 29.0 to about 31.0 w / v%, about 32.0 to about 33.0 w / v%, about 34.0 to about 35.0 w / v%, about 35.0 to about 36.0 w / v%, about 37.0 to 6.0 w / v%, about 16.0 to about 17.0 w / v%, about 17.0 to about 18.0 w / v%, about 18.0 to about 19.0 w / v%, about 19.0 to about 20.0 w / v%, about 20.0 to about 21.0 w / v%, about 21.0 to about 22.0 w / v%, about 22.0 to about 23.0 w / v%, about 23.0 to about 24.0 w / v%, about 24.0 to about 25.0 w / v%, about 25.0 to about 26.0 w / v%, about 26.0 to about 27.0 w / v%, about 27.0 to about 28.0 w / v%, about 28.0 to about 29.0 w / v%, or about 29.0 to about 30.0 w / v% of a base.

[0170]

[0135] In certain embodiments, the stabilizer comprises a base selected from the group consisting of arginine, lysine, NaOH, NH4OH, tris(hydroxymethyl)aminomethane (TRIS), ethylenediamine, diethylamine, ethanolamine, diethanolamine, meglumine, triethanolamine, and any combination thereof. In certain embodiments, the base is selected from the group consisting of arginine, lysine, NH4OH, ethylenediamine, diethylamine, ethanolamine, diethanolamine, meglumine, and combinations thereof. In certain embodiments, the base is selected from the group consisting of L-Arg, diethylamine, and combinations thereof. In certain embodiments, the base is selected from the group consisting of L-Arg, ethanolamine, and combinations thereof. In certain embodiments, the first pharmaceutical composition comprises about 0.1 to about 30.0 w / v% of the base. In certain embodiments, the first pharmaceutical composition comprises about 1.5% to about 20.0% w / v of the base. For example, the first pharmaceutical composition may have a concentration of about 1.5 to about 5.0% w / v, about 1.5 to about 10.0% w / v, about 1.5 to about 15.0% w / v, about 1.5 to about 20.0% w / v, about 1.5 to about 25.0% w / v, about 3.0 to about 5.0% w / v, about 3.0 to about 10.0% w / v, about 3.0 to about 15.0% w / v, about 3.0 to about 20.0% w / v, about 3.0 to about 25.0% w / v, about 3.0 to about 30.0% w / v, about 5.0 to about 10.0% w / v, about 5.0 to about 15.0% w / v, about 5.0 to about 20.0% w / v, about 5.0 to about 25.0% w / v, about 5 ...25.0% w / v, about 5.0 to about 25.0% w / v, about 5.0 to about 25.0% w / v, about 5.0 to about 25.0% w / v, about 5.0 to about 25.0% w / v, about 5.0 to about 25.0% w / v, about 5.0 to about 25.0% w / v, about 5.0 to about 25.0% w / v, about 5.0 to about The pharmaceutical composition may comprise about 0.0 to about 25.0% w / v, about 5.0 to about 30.0% w / v, about 7.0 to about 10.0% w / v, about 7.0 to about 15.0% w / v, about 7.0 to about 20.0% w / v, about 7.0 to about 25.0% w / v, about 7.0 to about 30.0% w / v, about 10.0 to about 15.0% w / v, about 10.0 to about 20.0% w / v, about 10.0 to about 25.0% w / v, about 10.0 to about 30.0% w / v, about 15.0 to about 20.0% w / v, about 15.0 to about 25.0% w / v, about 15.0 to about 30.0% w / v of the base. In certain embodiments, the first pharmaceutical composition comprises a combination of two, three or four stabilizers.For example, in certain embodiments, the pharmaceutical composition comprises arginine and an additional base selected from the group consisting of lysine, NH4OH, ethylenediamine, diethylamine, ethanolamine, diethanolamine, and meglumine. In certain embodiments, each separate stabilizer is present in the amounts described above, or a combination of stabilizers is present in the amounts described above. In certain embodiments, arginine is present in an amount of about 7.0 to about 8.0% w / v and the additional base is present in an amount of about 3.0 to about 8.0% w / v. In certain embodiments, the first pharmaceutical formulation comprises about 7.0 to about 8.0% (e.g., 7.2%) w / v L-Arg and about 3.0 to about 8.0% (e.g., about 5.4%) w / v diethylamine. In certain embodiments, the first pharmaceutical formulation comprises about 7.0 to about 8.0% (e.g., 7.2%) w / v L-Arg and about 2.0 to about 7.0% (e.g., about 4.5%) w / v ethanolamine.

[0171] In certain embodiments, the stabilizer includes polyethylene glycol (e.g., PEG-300, PEG-400, PEG-600), propylene glycol, choline, sodium or ammonium ions, amino acids (e.g., Lys or His), benzyl alcohol, ethanol, Group IIA metal complexes (e.g., Ca 2+ salts, e.g., CaCl2 and Ca ascorbate), citric acid, lactic acid, or acetic acid, electrophiles (e.g., Lewis acids, e.g., Na + , K + , Ca2 + , boron compounds, Fe 3+ , Al 3+ , Cu 2+ and α-β unsaturated carbonyls, e.g., maleic acid), phosphate buffer, Zn 2+ions, reducing sugars such as glucose, sodium acetate, hydroxypropyl beta cyclodextrin, soluble beta cyclodextrin, medium chain triglycerides such as octanoic acid, mixed micelles of glycocholate / lecithin, N-methylpyrrolidone, dimethylacetamide, soybean oil, sesame oil, castor oil, dimethylsulfoxide, glycerin, Tris buffer, ammonium acetate, or guanidine HCl. In certain embodiments, the stabilizing agent includes a surfactant, such as those described herein, e.g., poloxamer, Tween-80, Tween-20, and Kolliphor.

[0172]

[0137] In some embodiments, the stabilizer prevents or slows precipitation of the first pharmaceutical formulation and / or prevents or slows accumulation of impurities in the first pharmaceutical formulation.

[0173] [ka]

[0174] As shown in Figure 1, LD-Tyr is prone to forming diketopiperazine (DKP) impurities.

[0138] Thus, in certain embodiments, a stabilizer as described herein is added or included in the first pharmaceutical composition to prevent diketopiperazine formation. Thus, in certain embodiments, the pharmaceutical composition contains less than about 1.5% w / v LD-Tyr-diketopiperazine (LD-Tyr DKP) after 2 weeks at 2-8°C. In certain embodiments, the first pharmaceutical composition contains less than about 0.8% w / v LD-Tyr-diketopiperazine after 2 weeks at 2-8°C. For example, the pharmaceutical composition may contain less than about 0.8% w / v, 0.7% w / v, 0.6% w / v, 0.5% w / v, 0.4% w / v, 0.3% w / v, 0.2% w / v, or 0.1% w / v LD-Tyr-diketopiperazine after 2 weeks at 2-8°C. In certain embodiments, the first pharmaceutical composition comprises less than about 4.0% w / v LD-Tyr-diketopiperazine after 2 weeks at 25° C. For example, the first pharmaceutical composition may comprise less than about 5.0% w / v, 4.5% w / v, 4.0% w / v, 3.5% w / v, 3.0% w / v, 2.5% w / v, 2.0% w / v, 1.5% w / v, or 1.0% w / v LD-Tyr-diketopiperazine after 2 weeks at 25° C. In certain embodiments, the first pharmaceutical composition comprises less than about 4.0% w / v LD-Tyr-diketopiperazine after 2 weeks at 25° C. Methods for measuring DKP are known in the art and include, for example, high performance liquid chromatography (HPLC) and liquid chromatography mass spectrometry (LC-MS).

[0175] According to some embodiments, the levodopa moiety compound is present in the form of a pharma- ceutically acceptable salt. According to some embodiments, the salt of the levodopa moiety is trifluoroacetate (TFA), HCl, fumarate, lactate, maleate, gluceptate, phosphate, sulfate, HBr, nitrate, acetate, propionate, hexanoate, cyclopentanepropionate, glycolate, pyruvate, lactate, hippurate, methanesulfonate, ascorbate, malonate, oxalate, maleate, tartrate, citrate, succinate, benzoate, cinnamate, sulfonate, lauryl sulfate, gluconate, gluconate, glycerol ... glutamate, hydroxynaphthoate, salicylate, stearate, muconate, alkali metal salts, such as the lithium, sodium or potassium salts, alkaline earth metal salts, such as the calcium or magnesium salts, aluminium salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, N-methylglucamine salts, dicyclohexylamine salts, adipate salts, alginate salts, ascorbate salts, aspartate salts, benzenesulfonate salts, bisulfate salts, borates, butyrate salts, cam salts Folate butyrate salt, camphorsulfonate butyrate salt, digluconate butyrate salt, dodecylsulfate butyrate salt, ethanesulfonate butyrate salt, glucoheptonate butyrate salt, glycerophosphate butyrate salt, gluconate butyrate salt, hemisulfate butyrate salt, heptanoate butyrate salt, hydrogen iodide butyrate salt, 2-hydroxyethanesulfonate butyrate salt, lactobionate butyrate salt, laurate butyrate salt, methanesulfonate butyrate salt, 2-naphthalene In some embodiments, the butyrate salt may be selected from sulfonate butyrate salts, nicotinate butyrate salts, oleate butyrate salts, palmitate butyrate salts, pamoate butyrate salts, pectinate butyrate salts, persulfate butyrate salts, 3-phenylpropionate butyrate salts, phosphate butyrate salts, picrate butyrate salts, pivalate butyrate salts, tartrate butyrate salts, thiocyanate butyrate salts, p-toluenesulfonate butyrate salts, undecanoate butyrate salts, valerate salts, or any combination thereof.

[0176]

[0140] The first pharmaceutical composition may contain about 2.5 to about 70% w / v of a levodopa moiety, enantiomer, diastereomer, racemate, ion, zwitterion, pharma- ceutically acceptable salt thereof, or any combination thereof, or any combination of two or more levodopa moieties, enantiomers, diastereomers, racemates, ions, zwitterions, pharma- ceutically acceptable salts thereof, or any combination thereof. According to some embodiments, the first pharmaceutical composition may be at about 2.5 to about 5% w / v, about 5 to about 10% w / v, about 10 to about 15 w / v%, about 15 to about 20 w / v%, about 20 to about 25 w / v%, about 25 to about 30 w / v%, about 30 to about 35 w / v%, about 35 to about 40 w / v%, about 40 to about 45 w / v%, about 45 to about 50 w / v%, about 50 to about 55 w / v%, about 55 to about 60 w / v%, about 60 to about 65 w / v%, or about 70 to about 75 w / v. / v%, about 65 to about 70w / v%, about 10 to about 12.5w / v%, about 12.5 to about 17.5w / v%, about 17.5 to about 22.5w / v%, about 22.5 to about 27.5w / v%, about 27.5 to about 32 .5w / v%, about 32.5 to about 37.5w / v%, about 37.5 to about 42.5w / v%, about 42.5 to about 45w / v%, about 10%w / v, about 12.5w / v%, about 15w / v%, about 17.5w / v %, about 20w / v%, about 22.5w / v%, about 25w / v%, about 27.5w / v%, about 30w / v%, about 32.5w / v%, about 35w / v%, about 37.5w / v%, about 40w / v%, about 42.5 w / v%, approximately 45w / v%, approximately 47.5w / v%, approximately 50w / v%, approximately 52.5w / v%, approximately 55w / v%, approximately 57.5w / v%, approximately 60w / v%, approximately 62.5w / v%, approximately 65w / v%, approximately 6 7.5% w / v, about 70% w / v of a levodopa moiety, enantiomer, diastereomer, racemate, ion, zwitterion, pharma- ceutically acceptable salt thereof, or any combination thereof, or any combination of two or more levodopa moieties, enantiomers, diastereomers, racemates, ions, zwitterions, pharma- ceutically acceptable salts thereof, or any combination thereof.

[0177] In some embodiments, the first pharmaceutical composition comprises a carbidopa moiety, e.g., carbidopa and / or a carbidopa prodrug, which may be selected from the group consisting of any of Formulas (VIII)-(XIV) or a pharmacologiciZably acceptable salt thereof:

[0142] Compounds represented by formula (VIII):

[0178] [ka]

[0179] (In the formula, R 10b is an amino acid side chain; R 11b and R 12b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl; R 13b is hydrogen or alkyl)

[0143] Compounds represented by formula (IX):

[0180] [ka]

[0181] (In the formula, R 20b is an amino acid side chain; R 21b and R 22b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl; R 23b is hydrogen or alkyl)

[0144] A compound represented by formula (X):

[0182] [ka]

[0183] (In the formula, R 30b is an amino acid side chain; R 31b and R 32b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl; R 33b is hydrogen or alkyl)

[0145] Compounds represented by formula (XI):

[0184] [ka]

[0185] (In the formula, R 41b and R 42b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl; R 43b and R 44b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl, or R 43b and R 44b together form a group which forms an optionally substituted alkylene; R 45b is hydrogen or alkyl)

[0146] Compounds represented by formula (XII):

[0186] [ka]

[0187] (In the formula, R 51b and R 52b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl; R 53b and R54b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl, or R 53b and R 54b together form a group which forms an optionally substituted alkylene; R 55b is hydrogen or alkyl)

[0147] Compounds represented by formula (XIII):

[0188] [ka]

[0189] (In the formula, R 61b and R 62b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl; R 63b and R 64b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl, or R 63b and R 64b together form a group which forms an optionally substituted alkylene; R 65b is hydrogen or alkyl) and

[0148] Compounds represented by formula (XIV):

[0190] [ka]

[0191] (In the formula, R 71b and R 72b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl; R73b and R 74b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl, or R 73b and R 74b together form a group which forms an optionally substituted alkylene; R 75b is hydrogen or alkyl).

[0192]

[0149] In some embodiments, the first pharmaceutical composition comprises any combination of levodopa and carbidopa prodrugs described above. In some embodiments, the first pharmaceutical composition comprises any combination of levodopa and carbidopa prodrugs described herein. According to further embodiments, the first pharmaceutical composition comprises any of carbidopa and levodopa prodrugs described herein. It should be noted that the first pharmaceutical composition may comprise any number of levodopa and / or carbidopa moieties. Thus, according to some embodiments, the first pharmaceutical composition comprises any combination of at least one levodopa moiety and at least one carbidopa moiety, such as a combination of levodopa and a carbidopa prodrug, a combination of carbidopa and a levodopa prodrug, a combination of levodopa, a levodopa prodrug and a carbidopa, a combination of a levodopa prodrug, a carbidopa prodrug and a carbidopa, a combination of levodopa, carbidopa, a levodopa prodrug and a carbidopa prodrug, a combination of levodopa, carbidopa, a levodopa prodrug and a carbidopa prodrug, etc.

[0193] In some embodiments, the first pharmaceutical composition comprises R 10b is an amino acid side chain; R 11b and R 12b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl; R 13b In certain embodiments, R is hydrogen or alkyl.11b and R 12b are the same or different and each is hydrogen or P(=O)(OH), R 13b is hydrogen.

[0194] In some embodiments, the first pharmaceutical composition comprises R 20b is an amino acid side chain; R 21b and R 22b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl; R 23b In some embodiments, R is hydrogen or alkyl. 21b and R 22b are the same or different and each is hydrogen or P(=O)(OH), R 23b is hydrogen.

[0195] In some embodiments, the first pharmaceutical composition comprises R 30b is an amino acid side chain; R 31b and R 32b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl; R 33b In some embodiments, R is hydrogen or alkyl. 31b and R 32b are the same or different and each is hydrogen or P(=O)(OH), R 33b is hydrogen.

[0196] In some embodiments, the first pharmaceutical composition comprises R 41b and R 42b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl; R 43band R 44b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl; or R 43b and R 44b together form a group which forms an optionally substituted alkylene; R 45b In some embodiments, R is hydrogen or alkyl. 41b and R 42b are the same or different and each is hydrogen or P(=O)(OH), R 45b is hydrogen.

[0197] In some embodiments, the first pharmaceutical composition comprises R 51b and R 52b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl; R 53b and R 54b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl; or R 53b and R 54b together form a group which forms an optionally substituted alkylene; R 55b In some embodiments, R is hydrogen or alkyl. 51b and R 52b are the same or different and each is hydrogen or P(=O)(OH), R 55b is hydrogen.

[0198] In some embodiments, the first pharmaceutical composition comprises R 61b and R 62bare the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl; R 63b and R 64b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl; or R 63b and R 64b together form a group which forms an optionally substituted alkylene; R 65b In some embodiments, R is hydrogen or alkyl. 61b and R 62b are the same or different and each is hydrogen or P(=O)(OH), R 65b is hydrogen.

[0199] In some embodiments, the first pharmaceutical composition comprises R 71b and R 72b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl; R 73b and R 74b are the same or different and each is optionally substituted hydrogen, alkyl, P(=O)(OH), S(=O)(OH), or glycosyl; or R 73b and R 74b together form a group which forms an optionally substituted alkylene; R 75b In some embodiments, R is hydrogen or alkyl. 71b and R 72b are the same or different and each is hydrogen or P(=O)(OH), R 75b is hydrogen.

[0200] In some embodiments, alkyl is an alkyl group having 1 to 6 carbon atoms (C 1~6 It refers to a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms (C 1~4 ) is preferred. Specific examples thereof include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, i-pentyl, and n-hexyl.

[0201]

[0158] In some embodiments, alkoxy refers to a monovalent group in which the alkyl group is attached to an oxygen atom, examples of which include alkyl groups having 1 to 6 carbon atoms (C 1~6 ) straight-chain or branched alkyl-O-. Specific examples thereof include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.

[0202] In some embodiments, alkenyl refers to a straight or branched unsaturated hydrocarbon chain having 2 to 6 carbon atoms with one carbon-carbon double bond, examples of which include vinyl, propenyl, butenyl, and various branched chain isomers thereof.Preferably, alkenyl refers to a straight or branched unsaturated hydrocarbon chain having 2 to 4 carbon atoms.

[0203]

[0160] In some embodiments, alkynyl refers to a linear or branched monovalent hydrocarbon chain group having one or more triple bonds, for example, linear or branched alkynyl having 2 to 6 carbon atoms. Specific examples thereof include 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl, etc.

[0204] In some embodiments, alkylene is an alkylene having 1 to 6 carbon atoms (C 1~6) and specific examples thereof include methylene, ethylene, trimethylene, tetramethylene, and the like.

[0205]

[0162] Here, R 43b and R 44b R is alkylene 53b and R 54b R is alkylene 63b and R 64b Alkylene of R 73b and R 74b Examples of the alkylene are preferably methylene and ethylene, each of which may be substituted. Examples of such substituents include alkyl and alkoxy, which may be substituted with 1 to 3 identical or different substituents.

[0206]

[0163] In some embodiments, alkanoyl refers to a monovalent group in which an alkyl, as described above, is attached to a carbonyl, examples of which include alkyl groups having 1 to 6 carbon atoms (C 1~6 ) straight-chain or branched alkyl-CO-. Specific examples thereof include acetyl, propionyl, butyryl, pivaloyl, pentanoyl, hexanoyl, and heptanoyl.

[0207] In the present invention, cycloalkyl is a group having 3 to 8 carbon atoms (C 3~8 ) refers to a monocyclic saturated hydrocarbon group. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0208] In some embodiments, amino acid side chain refers to the amino acid side chain of a natural, synthetic, non-natural, or non-proteinogenic amino acid, examples of which include arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, lanthionine, selenocysteine, pyrrolidine, ADDA amino acids ((2S,3S,4E,6E,8S,9S)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldec-4,6-dienoic acid), β-amino ... -alanine, 4-aminobenzoic acid, γ-aminobutyric acid, S-aminoethyl-L-cysteine, 2-aminoisobutyric acid, aminolevulinic acid, azetidine-2-carboxylic acid, canaline, canavanine, carboxyglutamic acid, chloroalanine, cysteine, dehydroalanine, diaminopimelic acid, hydroxyphenylglycine, enduracidin, homoserine, 4-phenylglycine, hydroxyproline, hypusine, β-leucine, norleucine, norvaline, ornithine, penicillamine, placohypaforine, pyroglutamic acid, quisqualic acid, sarcosine, theanine, tranexamic acid, trichromate, 3,4-dihydroxyphenylalanine, etc. 10a Examples of R preferably include the amino acid side chains of arginine, lysine, alanine, valine, tyrosine and 3,4-dihydroxyphenylalanine. 20a Examples of R preferably include the amino acid side chains of glutamic acid, valine, alanine, lysine, 3,4-dihydroxyphenylalanine and tyrosine. 10b Examples of R preferably include the amino acid side chains of tyrosine and lysine. 20b Examples of R preferably include the amino acid side chains of alanine and lysine. 30b Examples of, preferably, include the amino acid side chains of alanine and lysine.

[0209] For example, R 10a , R 20a , R10b , R 20b , and R 30b The amino acid side chain represented by is represented by:

[0210] [ka]

[0211] [ka]

[0212] [ka]

[0213] [ka]

[0214] [ka]

[0215] [ka]

[0216] [ka]

[0217] [ka]

[0218] [ka]

[0219] [ka]

[0220] [ka]

[0221] [ka]

[0222] [ka]

[0223] (amino acid side chain of proline, R 10a , R 20a , R 10b , R 20b , R 30b each forms a bond with a nitrogen atom of a peptide bond of each compound);

[0224] [ka]

[0225] [ka]

[0226] [ka]

[0227] [ka]

[0228] [ka]

[0229] [ka]

[0230]

change

[0231]

change

[0232]

change

[0233]

change

[0234]

change

[0235]

[0192] Here, the amino acid side chain of the present invention may be substituted, and examples thereof include -P(O)(OR6)2 (wherein R6 is hydrogen, alkyl, etc.), glucosyl groups (e.g., [(2R,3S,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]), and groups that bond to another adjacent group to form an alkylene group which may be substituted (examples of the substituent include alkyl groups, alkoxy groups, etc.). Examples of substituted amino acid side chains include tyrosine side chains, serine side chains, threonine side chains, or substituted amino acid side chains bearing hydroxy, e.g., (3,4-dihydroxyphenyl)methyl, specific examples of which include phosphonooxymethyl, (4-phosphonooxyphenyl)methyl, [4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxyphenyl]methyl, (2,2-dimethyl-1,3-benzodioxol-5-yl)methyl, (2-ethoxy-2-methyl-1,3-benzodioxol-5-yl)methyl, and the like.

[0236]

[0193] In the present invention, the monosaccharides that are the glycosyl source include aldoses such as glucose (grape sugar), ribose, erythrose, xylose, arabinose, mannose, and galactose, and ketoses such as ribulose, psicose, fructose, sorbose, and tagatose. These monosaccharides may be in the d-, l-, or dl-form.

[0237]

[0194] The monosaccharides described herein may be substituted, and examples of the substituents include carbonyl groups, acetylamino groups, sulfinoxy groups, phosphonooxy groups, etc. Specific examples of substituted polysaccharides include glucuronic acid, N-acetylglucosamine, α-D-glucopyranose-6-(hydrogen sulfate), etc.

[0238]

[0195] In some embodiments, the group in which R' and R'' are taken together and together with the nitrogen atom to form a heteroaryl refers to a 5-10 membered aromatic heterocyclic group containing 1-4 heteroatoms independently selected from the group consisting of sulfur atoms, oxygen atoms, and nitrogen atoms, with monocyclic or bicyclic heteroaryl being preferred. A 5-10 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of sulfur atoms, oxygen atoms, and nitrogen atoms is more preferred. Specific examples thereof include pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazinyl, triazinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolyl, isoquinolyl, imidazopyridyl, benzopyranyl, and the like. Preferred are pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazinyl, triazinyl, etc. Particularly preferred are pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, etc.

[0239]

[0196] When a compound has an asymmetric carbon atom in its molecule, the compound may exist as multiple stereoisomers (i.e., diastereoisomers and optical isomers) based on the asymmetric carbon atom. However, the intended compound includes any of these stereoisomers and mixtures thereof.

[0240]

[0197] The compounds of the present invention may be isotopically labeled compounds (e.g., 3 H, 13 C. 14 C. 15 N, 18 F, 32 P, 35 S, 125 I, etc.), including deuterium conversions.

[0198] Examples of pharmacologically acceptable salts of the compounds of the present invention include inorganic acid addition salts (e.g., salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), organic acid addition salts (e.g., salts of methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid, methylsulfuric acid, etc.), inorganic base addition salts (e.g., salts of sodium, potassium, calcium, magnesium, etc.), and amino acid salts (e.g., salts of glutamic acid, aspartic acid, arginine, lysine, etc.).

[0241]

[0199] The compound of the present invention or a pharmacologically acceptable salt thereof includes an internal salt or an adduct thereof, a solvate or a hydrate thereof, etc. Any of the compounds disclosed herein, including any modification such as a labeled compound, a salt, a hydrate, a prodrug, etc., may be included in the first pharmaceutical composition.

[0242]

[0200] Exemplary embodiments of the aforementioned carbidopa prodrugs are listed in Table 3 below.

[0243] [Table 3-1]

[0244] [Table 3-2]

[0245] [Table 3-3]

[0246] [Table 3-4]

[0247] [Table 3-5]

[0248] [Table 3-6]

[0249] [Table 3-7]

[0250] [Table 3-8]

[0251]

[0201] According to some embodiments, the DDCI is carbidopa, a carbidopa prodrug, a carbidopa salt, benserazide, a benserazide prodrug, a benserazide salt, or any combination thereof. According to some embodiments, the DDCI is carbidopa. According to some embodiments, the DDCI is a carbidopa prodrug, for example, selected from the carbidopa prodrugs disclosed herein. The DDCI in the first pharmaceutical composition may be the same as or different from the DDCI in the second pharmaceutical composition. Furthermore, the levodopa moiety in each of the first and second pharmaceutical compositions may be the same or different. That is, according to some embodiments, the first pharmaceutical composition and the second pharmaceutical composition both contain levodopa, while according to other embodiments, the first pharmaceutical composition may contain one type of levodopa moiety, such as a levodopa prodrug and / or a levodopa salt, while the second pharmaceutical composition contains a different type of levodopa moiety, such as levodopa. It is further noted that the concentration or amount of each moiety in a first pharmaceutical composition may differ from the concentration or amount of that moiety in a second pharmaceutical composition.

[0252]

[0202] According to some embodiments, the first pharmaceutical composition may be administered by any parenteral administration route, for example, subcutaneously, transdermally, intradermally, intravenously, intramuscularly, intratracheally, intranasally, intrathecally, intragastrically, or intraduodenally. According to some embodiments, the first pharmaceutical composition is administered subcutaneously. According to some embodiments, the first pharmaceutical composition is liquid. According to some embodiments, the first pharmaceutical composition is aqueous.

[0253] According to some embodiments, the first pharmaceutical composition is administered substantially continuously. According to some embodiments, the first pharmaceutical composition is administered subcutaneously via a designated pump device.

[0254]

[0204] The specified pump embodiments are described in, for example, US10,603,430, US10,463,787, US10,463,572, US2020 / 0093984, WO2019 / 008529, USD887,577, USD921,187, USD921,188, USD865,665, USD868,689, USD921,189, USD921,190, USD935,478, US2020 / 0368448, USD

[0023] The present invention may be any of the pump embodiments disclosed in US Pat. No. 2,993,333, ...

[0255] According to some embodiments, the method of the present invention includes administering the first pharmaceutical composition at one site, two sites, or three or more sites, and the location of the sites can be changed at any suitable, possibly pre-determined, interval. According to some embodiments, once administered via a particular site, administration via the same site or nearby the site can only be after a possibly pre-defined period of time. According to some embodiments, the location of any one of the sites is changed after 12, 24, 36, 48, 60, or 72 hours. According to some embodiments, the location of any one of the sites is changed after up to 24 hours, up to 48 hours, or up to 72 hours. According to some embodiments, the location of the site is changed after 4, 5, 6, or 7 days. According to some embodiments, the location of the site is changed after 2, 3, or 4 weeks. According to some embodiments, the location of the site is changed when needed or desired, e.g., according to subjective data received from the patient and / or according to objective data received, e.g., from a sensor positioned at or near the injection site.

[0256] According to some embodiments, each injection site should be located at least 3 cm, 5 cm, 7 cm, or 10 cm from the umbilicus. According to some embodiments, any new injection site selected should be at least 1 cm, 1.5 cm, 2 cm, 2.5 cm, 5 cm, 7.5 cm, or 10 cm away from any previous site used within the past 5, 7, 10, 12, 15, or 20 days.

[0257] According to some embodiments, the dosage volume and / or dosage rate is the same for all or at least two of the sites. According to other embodiments, the dosage rate and / or dosage volume varies from site to site. Each site may or may not be administered independently, and all sites may be administered dependently on one another.

[0258]

[0208] According to some embodiments, the method of the present invention comprises subcutaneously administering a first pharmaceutical composition of the present invention for about 5 to about 24 hours or more, such as about 5 to about 12 hours or more, about 7 to about 10 hours or more, or for example about 8 hours or about 24 hours.

[0259] According to some embodiments, the dosage of the carbidopa moiety in the first pharmaceutical composition is from about 10 mg to about 25 mg per administration, from about 10 mg to about 50 mg per administration, from about 10 mg to about 75 mg per administration, from about 12 mg to about 25 mg per administration, from about 12 mg to about 50 mg per administration, from about 12 mg to about 75 mg per administration, from about 15 mg to about 2 ... The dosage of the carbidopa moiety in the first pharmaceutical composition is about 90 mg, for example, administered for about 5 to about 24 hours or more. According to some embodiments, the dosage of the carbidopa moiety in the first pharmaceutical composition is about 46 mg to about 90 mg per administration. According to some embodiments, the dose of the carbidopa portion in the first pharmaceutical composition is about 90 mg, for example, administered over about 24 hours. According to some embodiments, the dose of the carbidopa portion in the first pharmaceutical composition is about 46 mg to about 90 mg, for example, administered over about 24 hours. According to some embodiments, the dose of the carbidopa portion in the first pharmaceutical composition is about 24 mg to 28 mg, for example, administered over about 7 to about 10 hours or more. According to some embodiments, the dose of the carbidopa portion in the first pharmaceutical composition is about 78 mg, for example, administered over about 24 hours. According to some embodiments, the dose of the carbidopa portion in the first pharmaceutical composition is about 117 mg, for example, administered over about 24 hours. According to some embodiments, the dose of the carbidopa portion in the first pharmaceutical composition is about 130 mg, for example, administered over about 24 hours. According to some embodiments, the dosage of the carbidopa portion in the first pharmaceutical composition is about 143 mg, for example, administered over a period of about 24 hours.According to some embodiments, the dosage of the carbidopa portion in the first pharmaceutical composition is about 156 mg, for example, administered over a period of about 24 hours.

[0260] According to some embodiments, the dose of the levodopa moiety in the first pharmaceutical composition is from about 1000 mg to about 4000 mg per administration, from about 10 mg to about 800 mg per administration, from about 10 mg to about 25 mg per administration, from about 25 mg to about 50 mg per administration, from about 50 mg to about 75 mg per administration, from about 75 mg to about 100 mg per administration, from about 100 mg to about 150 mg per administration, from about 150 mg to about 200 mg per administration, from about 100 mg to about 250 mg per administration, from about 150 mg to about 200 mg per administration, from about 100 mg to about 300 mg per administration, from about 100 mg to about 350 mg per administration, from about 150 mg to about 400 mg per administration, from about 100 mg to about 400 mg per administration, from about 100 mg to about 50 mg per administration, from about 100 mg to about 50 mg per administration, from about 100 mg to about 60 mg per administration, from about 100 mg to about 70 mg per administration, from about 100 mg to about 80 mg per administration, from about 100 mg to about 90 mg per administration, from about 100 mg to about 150 mg per administration, from about 150 mg to about 200 mg per administration, from about 100 mg to about 250 mg per administration, from about 100 mg to about 350 mg per administration, from about 100 mg to about 400 mg per administration, from about 100 mg to about 50 mg per administration, from about 100 mg to about 50 mg per administration, from about 100 mg to about 60 mg per administration, from about 100 mg to about 150 mg per administration, from about 100 mg to about 2 The dosage of the levodopa moiety in the first pharmaceutical composition is about 200 mg to about 250 mg per administration, about 250 mg to about 300 mg per administration, about 300 mg to about 350 mg per administration, about 350 mg to about 400 mg per administration, about 400 mg to about 450 mg per administration, about 450 mg to about 500 mg per administration, about 500 mg to about 800 mg per administration, about 600 mg to about 800 mg per administration, about 700 mg to about 800 mg per administration, or about 720 mg per administration. In certain embodiments, the dosage of the levodopa moiety in the first pharmaceutical composition is about 370 mg to about 720 mg. In certain embodiments, the dosage is administered over about 5 to about 24 (e.g., about 7 to about 10, or about 8 hours or about 24 hours) or more hours. According to some embodiments, the dose of the levodopa portion in the first pharmaceutical composition is about 720 mg, for example, administered over about 24 hours. According to some embodiments, the dose of the levodopa portion in the first pharmaceutical composition is about 370 mg to about 720 mg, for example, administered over about 24 hours. According to some embodiments, the dose of the levodopa portion in the first pharmaceutical composition is about 360 mg to about 720 mg, for example, administered over about 24 hours. According to some embodiments, the dose of the levodopa portion in the first pharmaceutical composition is at most about 720 mg. According to some embodiments, the dose of the levodopa portion in the first pharmaceutical composition is about 550 mg to about 650 mg, for example, administered over about 7 to about 10 hours or more. According to some embodiments, the dose of the levodopa portion in the first pharmaceutical composition is about 1800 mg, for example, administered over about 24 hours. According to some embodiments, the dose of the levodopa portion in the first pharmaceutical composition is about 2700 mg, for example, administered over a period of about 24 hours.According to some embodiments, the dose of the levodopa portion in the first pharmaceutical composition is about 3000 mg, for example, administered over about 24 hours. According to some embodiments, the dose of the levodopa portion in the first pharmaceutical composition is about 3300 mg, for example, administered over about 24 hours. According to some embodiments, the dose of the levodopa portion in the first pharmaceutical composition is about 3600 mg, for example, administered over about 24 hours.

[0261]

[0211] In certain embodiments, the first pharmaceutical composition is administered in an amount that delivers about 500 to about 700 mg of levodopa and about 12 to about 50 mg of carbidopa to the patient. In certain embodiments, the first pharmaceutical composition is administered in an amount that delivers about 550 to about 650 mg of levodopa and about 24 to about 28 mg of carbidopa to the patient. In certain embodiments, the first pharmaceutical composition is administered in an amount that delivers about 100 to about 200 mg of levodopa and about 12 to about 50 mg of carbidopa to the patient. In certain embodiments, the first pharmaceutical composition is administered in an amount that delivers about 140 to about 170 mg of levodopa and about 16 to about 24 mg of carbidopa to the patient. In certain embodiments, the dose is administered over about 5 to about 24 (e.g., about 7 to about 10) hours or more. In certain embodiments, the first pharmaceutical composition is administered in an amount that delivers about 650 mg to about 800 mg, e.g., about 720 mg, of levodopa and about 80 mg to about 100 mg, e.g., about 90 mg, of carbidopa to the patient over about 24 hours. According to some embodiments, the dose of the carbidopa portion in the first pharmaceutical composition is about 46 mg to about 90 mg, e.g., administered over about 24 hours. According to some embodiments, the dose of the carbidopa portion in the first pharmaceutical composition is about 45 mg to about 90 mg, e.g., administered over about 24 hours. According to some embodiments, the dose of the carbidopa portion in the first pharmaceutical composition is at most about 90 mg. According to some embodiments, the dose of the carbidopa portion in the first pharmaceutical composition is about 24 mg to 28 mg, e.g., administered over about 7 to about 10 hours or more. According to some embodiments, the dose of the carbidopa portion in the first pharmaceutical composition is about 78 mg, for example, administered over about 24 hours. According to some embodiments, the dose of the carbidopa portion in the first pharmaceutical composition is about 117 mg, for example, administered over about 24 hours. According to some embodiments, the dose of the carbidopa portion in the first pharmaceutical composition is about 130 mg, for example, administered over about 24 hours. According to some embodiments, the dose of the carbidopa portion in the first pharmaceutical composition is about 143 mg, for example, administered over about 24 hours.According to some embodiments, the dosage of the carbidopa portion in the first pharmaceutical composition is about 156 mg, for example, administered over a period of about 24 hours.

[0262] According to some embodiments, the first pharmaceutical composition comprises levodopa and carbidopa in a ratio of about 8:1 w / w. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver about 720 mg LD and about 90 mg CD per day, about 360 mg LD and about 45 mg CD per day, about 370 mg LD and about 46 mg CD per day, wherein levodopa and carbidopa are in a ratio of about 8:1 w / w.

[0263]

[0213] According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver LD of more than 0 mg to about 720 mg and CD of more than 0 mg to about 90 mg per day, and the ratio of LD / CD administered is about 8:1 w / w. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver LD of about 8 mg to about 720 mg and CD of about 1 mg to about 90 mg per day, and the ratio of LD / CD administered is about 8:1 w / w. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver LD of about 360 mg to about 720 mg and CD of about 45 mg to about 90 mg per day, and the ratio of LD / CD is about 8:1 w / w. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver about 370 mg to about 720 mg of LD and about 46 mg to about 90 mg of CD per day, with an LD / CD ratio of about 8:1 w / w. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver about 370 mg to about 720 mg of LD and about 46 mg to about 90 mg of CD per day, with an LD / CD ratio of about 8:1 w / w.

[0264] According to some embodiments, the first pharmaceutical composition comprises up to about 60 mg / ml levodopa. According to some embodiments, the first pharmaceutical composition comprises up to about 7.5 mg / ml carbidopa. According to some embodiments, the first pharmaceutical composition comprises up to about 60 mg / ml levodopa and up to about 7.5 mg / ml carbidopa, the levodopa and carbidopa being in a ratio of about 8:1 w / w.

[0265]

[0215] According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver more than 0 mg up to about 2700 mg of LD-Tyr and more than 0 mg up to about 117 mg of carbidopa per day, and the ratio of administered LD-Tyr / CD is about 23:1 w / w. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver more than 0 mg up to about 3000 mg of LD-Tyr and more than 0 mg up to about 117 mg of carbidopa per day, and the ratio of administered LD-Tyr / CD is about 26:1 w / w. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver more than 0 mg up to about 3300 mg of LD-Tyr and more than 0 mg up to about 117 mg of carbidopa per day, and the ratio of administered LD-Tyr / CD is about 28:1 w / w. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver more than 0 mg up to about 3600 mg of LD-Tyr and more than 0 mg up to about 117 mg of carbidopa per day, and the ratio of administered LD-Tyr / CD is about 31:1 w / w. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver more than 0 mg up to about 2400 mg of LD-Tyr and more than 0 mg up to about 117 mg of carbidopa per day, and the ratio of administered LD-Tyr / CD is about 21:1 w / w. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver more than 0 mg up to about 2700 mg of LD-Tyr and more than 0 mg up to about 90 mg of carbidopa per day, and the ratio of administered LD-Tyr / CD is about 30:1 w / w. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver greater than 0 mg up to about 3000 mg of LD-Tyr and greater than 0 mg up to about 90 mg of carbidopa per day, with the ratio of LD-Tyr / CD administered being about 33:1 w / w. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver greater than 0 mg up to about 3300 mg of LD-Tyr and greater than 0 mg up to about 90 mg of carbidopa per day, with the ratio of LD-Tyr / CD administered being about 37:1 w / w.According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver more than 0 mg up to about 3600 mg of LD-Tyr and more than 0 mg up to about 90 mg of carbidopa per day, and the ratio of administered LD-Tyr / CD is about 40:1 w / w. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver more than 0 mg up to about 2400 mg of LD-Tyr and more than 0 mg up to about 90 mg of carbidopa per day, and the ratio of administered LD-Tyr / CD is about 27:1 w / w. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver more than 0 mg up to about 2700 mg of LD-Tyr and more than 0 mg up to about 75 mg of carbidopa per day, and the ratio of administered LD-Tyr / CD is about 36:1 w / w. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver more than 0 mg up to about 3000 mg of LD-Tyr and more than 0 mg up to about 75 mg of carbidopa per day, and the ratio of administered LD-Tyr / CD is about 40:1 w / w. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver more than 0 mg up to about 3300 mg of LD-Tyr and more than 0 mg up to about 75 mg of carbidopa per day, and the ratio of administered LD-Tyr / CD is about 44:1 w / w. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver more than 0 mg up to about 3600 mg of LD-Tyr and more than 0 mg up to about 75 mg of carbidopa per day, and the ratio of administered LD-Tyr / CD is about 48:1 w / w. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver from greater than 0 mg up to about 2400 mg of LD-Tyr and from greater than 0 mg up to about 75 mg of carbidopa per day, and the ratio of LD-Tyr / CD administered is about 32:1 w / w.

[0266]

[0216] According to some embodiments, the first pharmaceutical composition comprises about 300 mg / ml of LD-Tyr. According to some embodiments, the first pharmaceutical composition comprises about 13 mg / ml of carbidopa. According to some embodiments, the first pharmaceutical composition comprises up to about 300 mg of levodopa and up to about 13 mg of carbidopa, the levodopa and carbidopa being in a ratio of about 23:1 w / w. According to some embodiments, the first pharmaceutical composition comprises about 300 mg / ml of LD-Tyr. According to some embodiments, the first pharmaceutical composition comprises about 10 mg / ml of carbidopa. According to some embodiments, the first pharmaceutical composition comprises up to about 300 mg of levodopa and up to about 10 mg of carbidopa, the levodopa and carbidopa being in a ratio of about 30:1 w / w.

[0267]

[0217] According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver about 720 mg, about 660-670 mg, about 620-630 mg, about 560-570 mg, about 510-520 mg, about 470-480 mg, about 410-420 mg, or about 370-380 mg of levodopa per day. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver about 90 mg, about 85-90 mg, about 80-85 mg, about 75-80 mg, about 70-75 mg, about 65-70 mg, about 60-65 mg, about 55-60 mg, about 50-55 mg, or about 45-50 mg of carbidopa per day. According to some embodiments, the first pharmaceutical composition is administered in a daily dose of about 720 mg levodopa and about 90 mg carbidopa, about 660-670 mg levodopa and about 80-85 mg carbidopa, about 610-620 mg levodopa and about 75-80 mg carbidopa, about 560-570 mg levodopa and about 70-75 mg carbidopa, about 510-520 mg levodopa and about 560-570 mg levodopa and about 570-580 mg carbidopa, about 580-590 mg levodopa and about 590-600 mg carbidopa, about 600-610 mg levodopa and about 600-620 mg levodopa and about 600-650 mg carbidopa, about 610-620 mg levodopa and about 75-80 mg carbidopa, about 560-570 mg levodopa and about 70-75 mg carbidopa, about 510-520 mg levodopa and about 570-580 mg carbidopa, about 600-610 mg levodopa and about 600-650 mg carbidopa, about 610-620 mg levodopa and about 75-80 mg carbidopa, about 560-570 mg levodopa and about 70-75 mg carbidopa, about 510-520 mg levodopa and about 570-580 mg carbidopa, about 610-620 mg levodopa and about 600-650 mg carbidopa, about 620-630 mg levodopa and about 630-640 mg carbidopa, about 630-64 The compositions are administered in an amount to deliver about 60-70 mg of vodopa and about 60-70 mg of carbidopa, about 470-480 mg of levodopa and about 55-60 mg of carbidopa, about 410-420 mg of levodopa and about 50-55 mg of carbidopa, or about 370-380 mg of levodopa and about 45-50 mg of carbidopa, wherein the levodopa and carbidopa are administered in a ratio of about 8:1 w / w.

[0268]

[0218] According to some embodiments, the first pharmaceutical composition comprises a levodopa portion and a carbidopa portion in a ratio of about 2:1 w / w to about 40:1 w / w. According to some embodiments, the first pharmaceutical composition comprises a levodopa portion and a carbidopa portion in a ratio of about 2:1 w / w to about 4:1 w / w. According to some embodiments, the first pharmaceutical composition comprises a levodopa portion and a carbidopa portion in a ratio of about 4:1 w / w to about 6:1 w / w. According to some embodiments, the first pharmaceutical composition comprises a levodopa portion and a carbidopa portion in a ratio of about 6:1 w / w to about 8:1 w / w. According to some embodiments, the first pharmaceutical composition comprises a levodopa portion and a carbidopa portion in a ratio of about 8:1 w / w to about 10:1 w / w. According to some embodiments, the first pharmaceutical composition comprises a levodopa portion and a carbidopa portion in a ratio of about 10:1 w / w to about 15:1 w / w. According to some embodiments, the first pharmaceutical composition comprises a levodopa portion and a carbidopa portion in a ratio of about 15:1 w / w to about 20:1 w / w. According to some embodiments, the first pharmaceutical composition comprises a levodopa portion and a carbidopa portion in a ratio of about 20:1 w / w to about 25:1 w / w. According to some embodiments, the first pharmaceutical composition comprises a levodopa portion and a carbidopa portion in a ratio of about 25:1 w / w to about 30:1 w / w. According to some embodiments, the first pharmaceutical composition comprises a levodopa portion and a carbidopa portion in a ratio of about 30:1 w / w to about 35:1 w / w. According to some embodiments, the first pharmaceutical composition comprises a levodopa portion and a carbidopa portion in a ratio of about 35:1 w / w to about 40:1 w / w. According to some embodiments, the first pharmaceutical composition comprises a levodopa portion and a carbidopa portion in a ratio of about 20:1 w / w.

[0269] According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver about 100 mg, about 200 mg, about 240 mg, about 480 mg, about 720 mg, about 960 mg, about 1200 mg, about 1440 mg, about 1680 mg, about 1920 mg, about 2160 mg, about 2400 mg, about 2640 mg, about 2880 mg, about 3120 mg, about 3360 mg, about 3600 mg, about 3840 mg, about 4080 mg, about 4320 mg, about 4560 mg, about 4800 mg, about 5040 mg, about 5280 mg, about 5520 mg, about 5760 mg, or about 6000 mg of a levodopa portion over about 24 hours. According to some embodiments, the first pharmaceutical composition is administered in an amount that delivers about 100 mg to about 6000 mg of a levodopa portion over about 24 hours. According to some embodiments, the first pharmaceutical composition is administered in an amount that delivers about 240 mg to about 4800 mg of a levodopa portion over about 24 hours. According to some embodiments, the first pharmaceutical composition is administered in an amount that delivers about 8 mg to about 1600 mg of a levodopa portion over about 24 hours. According to some embodiments, the first pharmaceutical composition is administered in an amount that delivers about 8 mg to about 3200 mg of a levodopa portion over about 24 hours. According to some embodiments, the first pharmaceutical composition is administered in an amount that delivers about 8 mg to about 3440 mg of a levodopa portion over about 24 hours.

[0270]

[0220] According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver about 5 mg, about 6 mg, about 10 mg, about 12 mg, about 24 mg, about 36 mg, about 48 mg, about 60 mg, about 72 mg, about 84 mg, about 96 mg, about 108 mg, about 120 mg, about 132 mg, about 144 mg, about 156 mg, about 168 mg, about 180 mg, about 192 mg, about 204 mg, about 216 mg, about 228 mg, about 240 mg, about 252 mg, about 264 mg, about 276 mg, about 288 mg, or about 300 mg of carbidopa moiety over about 24 hours. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver about 12 mg to about 240 mg of carbidopa moiety over about 24 hours. According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver from about 1 mg to about 300 mg of a carbidopa moiety over about 24 hours.

[0271]

[0221] According to some embodiments, the first pharmaceutical composition is administered in an amount to deliver about 240 mg to about 4800 mg of a levodopa moiety and about 12 mg to about 240 mg of a carbidopa moiety over about 24 hours.

[0272] According to some embodiments, the method of the present invention comprises administering subcutaneously from about 1 to about 30 ml of the first pharmaceutical composition of the present invention over a 24 hour period. According to some embodiments, the method of the present invention comprises administering subcutaneously from about 1 to about 120 ml of the first pharmaceutical composition of the present invention over a 24 hour period. According to some embodiments, the method of the present invention may include administering to the subject a solution of about 1 ml to about 2 ml, about 2 ml to about 3 ml, about 3 ml to about 4 ml, about 4 ml to about 5 ml, about 5 ml to about 6 ml, about 6 ml to about 7 ml, about 7 ml to about 8 ml, about 8 ml to about 9 ml, about 9 ml to about 10 ml, about 10 ml to about 11 ml, about 11 ml to about 12 ml, about 12 ml to about 13 ml, about 13 ml to about 14 ml, about 14 ml to about 15 ml, about 15 ml to about 16 ml, about 16 ml to about 17 ml, about 17 ml to about 18 ml, about 18 ml to about 19 ml, about 19 ml to about 20 ml, about 20 ml to about The method includes subcutaneously administering about 21 ml, about 21 ml to about 22 ml, about 22 ml to about 23 ml, about 23 ml to about 24 ml, about 24 ml to about 25 ml, about 25 ml to about 26 ml, about 26 ml to about 27 ml, about 27 ml to about 28 ml, about 28 ml to about 29 ml, about 29 ml to about 30 ml, about 30 ml to about 40 ml, about 40 ml to about 50 ml, about 50 ml to about 60 ml, about 60 ml to about 70 ml, about 70 ml to about 80 ml, about 80 ml to about 90 ml, about 90 ml to about 100 ml, about 100 ml to about 110 ml, or about 110 ml to about 120 ml of the first pharmaceutical composition. According to some embodiments, the method includes subcutaneously administering about 9 ml of the first pharmaceutical composition of the present invention for about 24 hours. According to some embodiments, the method of the present invention comprises administering subcutaneously about 10 ml of the first pharmaceutical composition of the present invention for about 24 hours. According to some embodiments, the method of the present invention comprises administering subcutaneously about 11 ml of the first pharmaceutical composition of the present invention for about 24 hours. According to some embodiments, the method of the present invention comprises administering subcutaneously about 12 ml of the first pharmaceutical composition of the present invention for about 24 hours. According to some embodiments, the method of the present invention comprises administering subcutaneously about 20 ml of the first pharmaceutical composition of the present invention for about 24 hours.According to some embodiments, the method of the present invention comprises administering subcutaneously up to about 9 ml of the first pharmaceutical composition of the present invention for about 24 hours. According to some embodiments, the method of the present invention comprises administering subcutaneously up to about 10 ml of the first pharmaceutical composition of the present invention for about 24 hours. According to some embodiments, the method of the present invention comprises administering subcutaneously up to about 11 ml of the first pharmaceutical composition of the present invention for about 24 hours. According to some embodiments, the method of the present invention comprises administering subcutaneously up to about 12 ml of the first pharmaceutical composition of the present invention for about 24 hours. According to some embodiments, the method of the present invention comprises administering subcutaneously up to about 20 ml of the first pharmaceutical composition of the present invention for about 24 hours. According to some embodiments, the method of the present invention comprises administering subcutaneously up to about 120 ml of the first pharmaceutical composition of the present invention for about 24 hours.

[0273]

[0223] According to some embodiments, the first pharmaceutical composition is administered in a volume of about 1 ml to about 30 ml per site per day, about 2 ml to about 20 ml per site per day, about 3 ml to about 10 ml per site per day, about 5 ml to about 7 ml per site per day, or about 6 ml per site per day. According to some embodiments, the first pharmaceutical composition is administered in a volume of about 1 ml to about 2.5 ml per site per day, about 2.5 ml to about 5.0 ml per site per day, about 5.0 ml to about 7.5 ml per site per day, about 7.5 ml to about 10 ml per site per day, about 10 ml to about 12.5 ml per site per day, about 12.5 ml to about 15 ml per site per day, about 15 ml to about 17.5 ml per site per day, about 17.5 ml to about 20 ml per site per day, about 20 ml to about 22.5 ml per site per day, about 22.5 ml to about 25 ml per site per day, about 25 ml to about 27.5 ml per site per day, about 27.5 ml to about 30 ml per site per day. According to some embodiments, the first pharmaceutical composition is administered in a volume of about 6 ml per site per day. According to some embodiments, the first pharmaceutical composition is administered in a volume of about 9 ml per site per day. According to some embodiments, the first pharmaceutical composition is administered in a volume of about 4.5 ml per site per day. According to some embodiments, the first pharmaceutical composition is administered in a volume of about 10 ml per site per day. According to some embodiments, the first pharmaceutical composition is administered in a volume of about 5 ml per site per day. According to some embodiments, the first pharmaceutical composition is administered in a volume of about 11 ml per site per day. According to some embodiments, the first pharmaceutical composition is administered in a volume of about 5.5 ml per site per day. According to some embodiments, the first pharmaceutical composition is administered in a volume of about 12 ml per site per day. According to some embodiments, the first pharmaceutical composition is administered in a volume of about 6 ml per site per day.

[0274]

[0224] It should be noted that the administration rate may be constant over a 24-hour period or may vary over a 24-hour period. For example, according to some embodiments, there may be a constant rate for the high activity / daytime period and a different rate for the low activity / evening period. The high activity / daytime period may be, for example, about 15, about 16, about 17, about 18, or about 19 hours, while the low activity / evening period may be, for example, about 9, about 8, about 7, about 6, or about 5 hours, respectively. According to some embodiments, the high activity / daytime rate is implemented for about 18 hours, while the low activity / evening rate is implemented for about 6 hours. According to some embodiments, the high activity / daytime rate is implemented for about 16 hours, while the low activity / evening rate is implemented for about 8 hours. According to some embodiments, the administration rate is determined, at least in part, by input received from the patient, a caregiver, at least one sensor, or the like. According to some embodiments, the administration rate may be increased or decreased as needed, for example by a caregiver or patient, according to a predefined pattern that may be set periodically. According to other embodiments, the administration rate may be changed, for example increased or decreased, online, for example, according to input received from the patient, the caregiver, or at least one sensor indicating that a change in administration rate is required or beneficial. For example, if the patient wishes to rest at a certain point during the day, the rate may be decreased from a day rate to an evening rate, for example, by a command provided by the patient. In addition, the caregiver may give a command to the system, for example, to account for the patient resting during the day. Furthermore, the sensor may alert the system that the patient is sleeping (or falling asleep) and decrease the administration rate accordingly. The sensor may also provide sleep pattern data to enable the system to be notified in advance of the patient waking from sleep and responding, for example, increasing the administration rate. The administration rate may also be changed due to a monitored condition of the patient, for example, going into an "off episode", etc., which may increase the administration rate.

[0275]

[0225] The administration rate may be about 0.01 mL / site / hour to about 1 mL / site / hour. According to some embodiments, the administration rate is about 0.01 to 0.02 mL / site / hour. According to some embodiments, the administration rate is about 0.02 to 0.03 mL / site / hour. According to some embodiments, the administration rate is about 0.03 to 0.04 mL / site / hour. According to some embodiments, the administration rate is about 0.04 to 0.05 mL / site / hour. According to some embodiments, the administration rate is about 0.05 to 0.06 mL / site / hour. According to some embodiments, the administration rate is about 0.06 to 0.07 mL / site / hour. According to some embodiments, the administration rate is about 0.07 to 0.08 mL / site / hour. According to some embodiments, the administration rate is about 0.08 to 0.09 mL / site / hour. According to some embodiments, the administration rate is about 0.09 to 0.1 mL / site / hour. According to some embodiments, the administration rate is about 0.1 to 0.15 mL / site / hour. According to some embodiments, the administration rate is about 0.15 to 0.2 mL / site / hour. According to some embodiments, the administration rate is about 0.17 to 0.2 mL / site / hour. According to some embodiments, the administration rate is about 0.2 to 0.24 mL / site / hour. According to some embodiments, the administration rate is about 0.2 to 0.25 mL / site / hour. According to some embodiments, the administration rate is about 0.24 to 0.27 mL / site / hour. According to some embodiments, the administration rate is about 0.25 to 0.3 mL / site / hour. According to some embodiments, the administration rate is about 0.27 to 0.3 mL / site / hour. According to some embodiments, the administration rate is about 0.3 to 0.34 mL / site / hour. According to some embodiments, the administration rate is about 0.3 to 0.35 mL / site / hour. According to some embodiments, the administration rate is about 0.34 to 0.37 mL / site / hour. According to some embodiments, the administration rate is about 0.35 to 0.4 mL / site / hour. According to some embodiments, the administration rate is about 0.37 to 0.4 mL / site / hour. According to some embodiments, the administration rate is about 0.4 to 0.44 mL / site / hour. According to some embodiments, the administration rate is about 0.4 to 0.45 mL / site / hour.According to some embodiments, the administration rate is about 0.44-0.47 mL / site / hour. According to some embodiments, the administration rate is about 0.45-0.5 mL / site / hour. According to some embodiments, the administration rate is about 0.47-0.51 mL / site / hour. According to some embodiments, the administration rate is about 0.5-0.55 mL / site / hour. According to some embodiments, the administration rate is about 0.51-0.54 mL / site / hour. According to some embodiments, the administration rate is about 0.54-0.57 mL / site / hour. According to some embodiments, the administration rate is about 0.55-0.6 mL / site / hour. According to some embodiments, the administration rate is about 0.57-0.61 mL / site / hour. According to some embodiments, the administration rate is about 0.6-0.65 mL / site / hour. According to some embodiments, the administration rate is about 0.61-0.64 mL / site / hour. According to some embodiments, the administration rate is about 0.64-0.68 mL / site / hour. According to some embodiments, the administration rate is about 0.65-0.7 mL / site / hour. According to some embodiments, the administration rate is about 0.68-0.71 mL / site / hour. According to some embodiments, the administration rate is about 0.7-0.75 mL / site / hour. According to some embodiments, the administration rate is about 0.71-0.74 mL / site / hour. According to some embodiments, the administration rate is about 0.74-0.78 mL / site / hour. According to some embodiments, the administration rate is about 0.75-0.8 mL / site / hour. According to some embodiments, the administration rate is about 0.78-0.81 mL / site / hour. According to some embodiments, the administration rate is about 0.8 to 0.85 mL / site / hour. According to some embodiments, the administration rate is about 0.81 to 0.84 mL / site / hour. According to some embodiments, the administration rate is about 0.84 to 0.88 mL / site / hour. According to some embodiments, the administration rate is about 0.85 to 0.9 mL / site / hour. According to some embodiments, the administration rate is about 0.88 to 0.91 mL / site / hour. According to some embodiments, the administration rate is about 0.9 to 0.95 mL / site / hour. According to some embodiments, the administration rate is about 0.91 to 0.94 mL / site / hour.According to some embodiments, the administration rate is about 0.94-0.98 mL / site / hour. According to some embodiments, the administration rate is about 0.95-1.0 mL / site / hour. According to some embodiments, the administration rate is about 0.98-1.01 mL / site / hour. According to some embodiments, the administration rate is about 1.0-1.05 mL / site / hour. According to some embodiments, the administration rate is about 1.01-1.04 mL / site / hour. According to some embodiments, the administration rate is about 1.04 mL / site / hour. According to some embodiments, the administration rate is about 1.05-1.1 mL / site / hour. According to some embodiments, the administration rate is about 1.1-1.15 mL / site / hour. According to some embodiments, the administration rate is about 1.15-1.2 mL / site / hour.

[0276]

[0226] According to some embodiments, the administration rate of low activity / evening time is about 0.01-0.15 mL / site / hour. According to some embodiments, the administration rate of low activity / evening time is about 0.01-0.02 mL / site / hour. According to some embodiments, the administration rate of low activity / evening time is about 0.02-0.03 mL / site / hour. According to some embodiments, the administration rate of low activity / evening time is about 0.03-0.04 mL / site / hour. According to some embodiments, the administration rate of low activity / evening time is about 0.04-0.05 mL / site / hour. According to some embodiments, the administration rate of low activity / evening time is about 0.05-0.06 mL / site / hour. According to some embodiments, the administration rate of low activity / evening time is about 0.06-0.07 mL / site / hour. According to some embodiments, the administration rate of the low activity / evening time is about 0.07-0.08 mL / site / hour. According to some embodiments, the administration rate of the low activity / evening time is about 0.08-0.09 mL / site / hour. According to some embodiments, the administration rate of the low activity / evening time is about 0.09-0.1 mL / site / hour. According to some embodiments, the administration rate of the low activity / evening time is about 0.1-0.11 mL / site / hour. According to some embodiments, the administration rate of the low activity / evening time is about 0.11-0.12 mL / site / hour. According to some embodiments, the administration rate of the low activity / evening time is about 0.12-0.13 mL / site / hour. According to some embodiments, the administration rate of the low activity / evening time is about 0.13-0.14 mL / site / hour. According to some embodiments, the administration rate of the low activity / evening time is about 0.14-0.15 mL / site / hour. According to some embodiments, the administration rate of the low activity / evening time is about 0.04 mL / site / hour. According to some embodiments, the administration rate of the low activity / evening time is about 0.08 mL / site / hour.

[0277]

[0227] According to some embodiments, the administration rate of the high activity / daytime is about 0.15-1.0 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 0.15-0.2 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 0.2-0.25 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 0.25-0.3 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 0.3-0.35 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 0.35-0.4 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 0.4-0.45 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 0.45-0.5 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 0.5-0.55 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 0.55-0.6 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 0.6-0.65 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 0.65-0.7 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 0.7-0.75 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 0.75-0.8 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 0.8-0.85 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 0.85-0.9 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 0.9-0.95 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 0.95-1.0 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 1.0-1.05 mL / site / hour. According to some embodiments, the administration rate of the high activity / daytime is about 1.05-1.1 mL / site / hour.According to some embodiments, the administration rate of high activity / daytime is about 1.1 to 1.15 mL / site / hour. According to some embodiments, the administration rate of high activity / daytime is about 1.15 to 1.2 mL / site / hour. According to some embodiments, the administration rate of high activity / daytime is about 0.32 mL / site / hour. According to some embodiments, the administration rate of high activity / daytime is about 0.32 mL / hour to about 0.64 mL / hour. According to some embodiments, the administration rate of high activity / daytime is about 0.64 mL / hour, about 0.59 mL / hour, about 0.55 mL / hour, about 0.5 mL / hour, about 0.45 mL / hour, about 0.41 mL / hour, about 0.36 mL / hour, or about 0.32 mL / hour.

[0278]

[0228] As mentioned above, the low and high rates, while referred to as evening and day rates, respectively, may be used regardless of time of day (rather than patient condition, e.g., low activity and high activity). Furthermore, the rates may be changed over time and set at any suitable value and are not necessarily tied to one particular high rate and one particular low rate.

[0279]

[0229] According to some embodiments, the first composition is administered at a high activity rate for about 12 to about 20 hours (e.g., about 18 hours) and at a low activity rate for about 4 to about 12 hours (e.g., about 6 hours), with about 500 mg to about 800 mg (e.g., about 700 mg or about 691.2 mg) of levodopa and about 60 mg to about 100 mg (e.g., about 80 mg or about 86.4 mg) being administered during the high activity, and about 20 mg to about 40 mg (e.g., about 30 mg or about 28.8 mg) of levodopa and about 2 mg to about 5 mg (e.g., about 3 mg or about 3.6 mg) of carbidopa being administered during the low activity. According to some embodiments, the high activity rate and / or the low activity rate may be continuous periods during a 24-hour period. According to other embodiments, the high activity rate and / or the low activity rate may be administered in several non-continuous periods during a 24-hour period.

[0280]

[0230] It is further noted that the dosage volume and / or dosage rate may be constant throughout the treatment or may vary during different days and times, during different days, weeks, or months, etc. of treatment. According to some embodiments, the patient is monitored, e.g., independently, by an administrator, or electronically, e.g., by a sensor possibly found in a dedicated device, e.g., a watch-like device, a patch-like sensor, a dosage pump, etc. According to such embodiments, the dosage volume and / or rate is determined according to data received from such monitoring.

[0281] In certain embodiments, levodopa or a levodopa prodrug is administered at a high activity rate over a period of about 12 to about 20 hours (e.g., about 16 hours) at a dose of less than about 400 mg, about 400 mg to about 499 mg, about 500 mg to about 599 mg, about 600 mg to about 699 mg, about 700 mg to about 799 mg, about 800 mg to about 899 mg, about 900 mg to about 999 mg, about 1000 mg to about 1099 mg, about 1100 mg to about 1199 mg, about 1200 mg to about 1299 mg, about 1300 mg to about 1399 mg, about 1400 mg to about 1499 mg, about 1500 mg to about 1599 mg, about 1600 mg to about 1699 mg, about 1700 mg to about 1799 mg, or about 1800 mg to about 1999 mg. g, about 1800 mg to about 1899 mg, about 1900 mg to about 1999 mg, about 2000 mg to about 2099 mg, about 2100 mg to about 2199 mg, about 2200 mg to about 2299 mg, about 2300 mg to about 2399 mg, about 2400 mg to about 2499 mg, about 2500 mg to about 2599 mg, about 2600 mg to about 2699 mg, about 2700 mg to about 2799 mg, about 2800 mg to about 2899 mg, about 2900 mg to about 2999 mg, about 3000 mg to about 3099 mg, or more than about 3100 mg of levodopa, levodopa prodrug, or levodopa equivalent is administered to the patient over about 12 to about 20 hours (e.g., about 16 hours).

[0282]

[0232] Some embodiments relate to a method of administering a bolus subcutaneous injection of a first pharmaceutical composition of the present invention. According to some embodiments, the bolus injection comprises about 0.5 to about 2.0 mL / Kg of the first pharmaceutical composition. According to some embodiments, the bolus injection comprises about 0.5 to about 0.75 mL / Kg of the first pharmaceutical composition. According to some embodiments, the bolus injection comprises about 0.75 to about 1.0 mL / Kg of the first pharmaceutical composition. According to some embodiments, the bolus injection comprises about 1.0 to about 1.25 mL / Kg of the first pharmaceutical composition. According to some embodiments, the bolus injection comprises about 1.25 to about 1.5 mL / Kg of the first pharmaceutical composition. According to some embodiments, the bolus injection comprises about 1.5 to about 1.75 mL / Kg of the first pharmaceutical composition. According to some embodiments, the bolus injection comprises about 1.75 to about 2.0 mL / Kg of the first pharmaceutical composition. According to some embodiments, the bolus injection comprises about 0.75 to about 1.25 mL / Kg of the first pharmaceutical composition. According to some embodiments, the bolus injection comprises about 1.0 mL / Kg of the first pharmaceutical composition.

[0283] The bolus subcutaneous injection may be administered at any time, e.g., before, during, or after, any successive subcutaneous administrations that may occur. The bolus subcutaneous injection may be administered at any time during the day. The bolus subcutaneous injection may be administered once a day, once every 2, 3, 4, 5, or 6 days, once a week, or more. The bolus subcutaneous injection may be administered when needed / desired according to feedback received from the patient, caregiver, physician, sensor, etc., and / or according to a predefined regimen. The bolus subcutaneous injection may be administered over a period of about 5 minutes to about 40 minutes, about 5 minutes to about 10 minutes, about 10 minutes to about 15 minutes, about 15 minutes to about 20 minutes, about 20 minutes to about 25 minutes, about 25 minutes to about 30 minutes, about 30 minutes to about 35 minutes, about 35 minutes to about 40 minutes.

[0284]

[0234] According to some embodiments, the administered dose may be doubled, tripled or more by using multiple pumps, multiple injection sites per pump, and the like. According to some embodiments, the first pharmaceutical composition is administered for a defined period of time, such as days, weeks, months, or years. According to some embodiments, the first pharmaceutical composition is administered continuously for the treatment of a chronic condition.

[0285]

[0236] According to some embodiments, the first pharmaceutical composition comprises about 1% w / v to about 40% w / v of levodopa, a levodopa prodrug, a levodopa salt, or any combination thereof. According to some embodiments, the first pharmaceutical composition comprises about 1% w / v to about 5% w / v, about 5% w / v to about 10% w / v, about 10% w / v to about 15% w / v, about 15% w / v to about 20% w / v, about 20% w / v to about 25% w / v, about 25% w / v to about 30% w / v, about 30% w / v to about 35% w / v, about 35% w / v to about 40 w / v, about 2% w / v to about 10% w / v, about 4% w / v to about 8 w / v, about 5% w / v to about 7 w / v, about 6 w / v% levodopa, levodopa prodrug, levodopa salt, or any combination thereof.

[0286]

[0237] According to some embodiments, the first pharmaceutical composition comprises about 0.5 w / v% to about 10 w / v% carbidopa, carbidopa salt, carbidopa prodrug, or any combination thereof. According to some embodiments, the first pharmaceutical composition comprises about 0.5 w / v% to about 1 w / v%, about 1 w / v% to about 1.5 w / v%, about 1.5 w / v% to about 2 w / v%, about 2 w / v% to about 2.5 w / v%, about 2.5 w / v% to about 3 w / v%, about 3 w / v% to about 3.5 w / v%, about 3.5 w / v% to about 4 w / v%, about 4 w / v% to about 4.5 w / v%, about 4.5 w / v% to about 5 w / v%, about 5 w / v% to about 5.5 w / v%, about 5.5 w / v% about 6 w / v%, about 6 w / v% to about 6.5 w / v%, about 6.5 w / v% to about 7 w / v%, about 7 w / v% to about 7.5 w / v%, about 7.5 w / v% to about 8 w / v%, about 8 w / v% to about 8.5 w / v%, about 8.5 w / v% to about 9 w / v%, about 9 w / v% to about 9.5 w / v%, about 9.5 w / v% to about 10 w / v%, about 0.75 w / v% carbidopa, carbidopa salt, carbidopa prodrug, or any combination thereof.

[0287] For example, provided herein is a first pharmaceutical composition suitable for parenteral (e.g., subcutaneous) administration, comprising about 4 to about 10% by weight of levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof, about 0.5 to about 2% by weight of carbidopa, a carbidopa salt, a carbidopa prodrug, or any combination thereof, and about 10% to about 20% by weight of arginine. Another exemplary first pharmaceutical composition provided herein comprises about 6% by weight of levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof, about 0.75% by weight of carbidopa, a carbidopa salt, a carbidopa prodrug, or any combination thereof, and about 10% to about 20% by weight of arginine. According to some embodiments, arginine may be at least partially replaced by lysine.

[0288] According to some embodiments, the first pharmaceutical composition comprises about 0.05 w / v% to about 2.0 w / v%, about 0.05 w / v% to about 0.1 w / v%, about 0.1 w / v% to about 0.2 w / v%, about 0.2 w / v% to about 0.3 w / v%, about 0.3 w / v% to about 0.4 w / v%, about 0.4 w / v% to about 0.5 w / v%, about 0.5 w / v% to about 0.6 w / v%, about 0.6 w / v% to about 0.7 w / v%, about 0.7 w / v% to about 0.8 w / v%, about 0.8 w / v% to about 0.9 w / v%, about 0.9 w / v% to about 1.0 w / v%, about 1 w / v% to about 1.1 w / v%, about 1.1 w / v%, % to about 1.2 w / v%, about 1.2 w / v% to about 1.3 w / v%, about 1.3 w / v% to about 1.4 w / v%, about 1.4 w / v% to about 1.5 w / v%, about 1.5 w / v% to about 1.6 w / v%, about 1.6 w / v% to about 1.7 w / v%, about 1.7 w / v% to about 1.8 w / v%, about 1.8 w / v% to about 1.9 w / v%, about 1.9 w / v% to about 2.0 w / v%, about 0.75 w / v% to about 1.25 w / v%, about 0.75 w / v%, about 0.8 w / v%, about 0.85 w / v%, about 0.9 w / v%, about 0.95 w / v%, or about 1.0 w / v% of an antioxidant or a combination of antioxidants.

[0289]

[0240] According to some embodiments, the antioxidant is selected from the group consisting of ascorbic acid or a salt thereof, cysteine, e.g., N-acetylcysteine, bisulfite or a salt thereof, glutathione, tyrosinase inhibitors, divalent cations, butylated hydroxytoluene (BHT), beta hydroxy acid (BHA) tocopherol, gentisic acid, tocopherol, tocopherol derivatives, thioglycerol, and any combination thereof. According to some embodiments, the antioxidant is ascorbic acid. According to some embodiments, the antioxidant is N-acetylcysteine ​​(NAC). According to some embodiments, the first pharmaceutical composition comprises a combination of ascorbic acid and NAC. For example, provided herein is a first pharmaceutical composition suitable for, e.g., subcutaneous administration, comprising about 0.01% to about 1% by weight of an ingredient selected from the group consisting of about 0.1% to about 10% by weight of ascorbic acid or a pharma- ceutically acceptable salt thereof, NAC, L-cysteine, and a pharmacologically acceptable salt thereof, about 2% to about 16% by weight of levodopa or an ester thereof, and about 0.6% to about 2% by weight of carbidopa or an ester thereof.

[0290]

[0241] According to some embodiments, the first pharmaceutical composition comprises a base. According to some embodiments, the base is selected from the group consisting of arginine, lysine, NaOH, tris(hydroxymethyl)aminomethane (TRIS), NH4OH, ethylenediamine, diethylamine, ethanolamine, diethanolamine, meglumine, and any combination thereof. According to some embodiments, the base is arginine. According to some embodiments, the base is lysine.

[0291]

[0242] According to some embodiments, the first pharmaceutical composition includes about 5 w / v% to about 30 w / v% of the base. According to some embodiments, the first pharmaceutical composition includes about 5 w / v% to about 10 w / v%, about 10 w / v% to about 15 w / v%, about 15 w / v% to about 20 w / v%, about 20 w / v% to about 25 w / v%, about 25 w / v% to about 30 w / v%, about 12.5 w / v% to 17.5 w / v%, about 20 w / v%, about 25 w / v%, about 24 w / v%, about 15 w / v%, or about 15.2 w / v% of the base.

[0292]

[0243] According to some embodiments, the first pharmaceutical composition further comprises a catechol-O-methyltransferase (COMT) inhibitor. According to some embodiments, the COMT inhibitor is selected from entacapone, tolcapone, opicapone, or any combination thereof. According to some embodiments, the first pharmaceutical composition comprises about 0.1 to about 5.0% w / v of the COMT inhibitor. According to some embodiments, the first pharmaceutical composition comprises about 0.1 to about 1.0% w / v of the COMT inhibitor. According to some embodiments, the first pharmaceutical composition comprises about 1.0 to about 2.0% w / v of the COMT inhibitor. According to some embodiments, the first pharmaceutical composition comprises about 2.0 to about 3.0% w / v of the COMT inhibitor. According to some embodiments, the first pharmaceutical composition comprises about 3.0 to about 4.0% of the COMT inhibitor. According to some embodiments, the first pharmaceutical composition comprises about 4.0 to about 5.0% of a COMT inhibitor. According to some embodiments, the first pharmaceutical composition may be administered concomitantly with a COMT inhibitor.

[0293]

[0244] According to some embodiments, the first pharmaceutical composition further comprises a monoamine oxidase (MAO) inhibitor. The MAO inhibitor may be an MAO-A inhibitor or an MAO-B inhibitor. According to some embodiments, the first pharmaceutical composition comprises about 0.1 to about 5.0% w / v of the MAO inhibitor. According to some embodiments, the first pharmaceutical composition comprises about 0.1 to about 1.0% w / v of the MAO inhibitor. According to some embodiments, the first pharmaceutical composition comprises about 1.0 to about 2.0% w / v of the MAO inhibitor. According to some embodiments, the first pharmaceutical composition comprises about 2.0 to about 3.0% w / v of the MAO inhibitor. According to some embodiments, the first pharmaceutical composition comprises about 3.0 to about 4.0% of the MAO inhibitor. According to some embodiments, the first pharmaceutical composition comprises about 4.0 to about 5.0% of the MAO inhibitor. According to some embodiments, the MAO inhibitor is selected from moclobemide, rasagiline, selegiline, safinamide, or any combination thereof. According to some embodiments, the first pharmaceutical composition may be administered concomitantly with an MAO inhibitor.

[0294]

[0245] According to some embodiments, the first pharmaceutical composition includes a surfactant. According to some embodiments, the surfactant is selected from Tween-80, Tween-60, Tween-40, Tween-20, Tween-65, Tween-85, Span 20, Span 40, Span 60, Span 80, Span 85, polyoxyl 35 castor oil (Cremophor EL), polyoxyethylene-660 hydroxystearate (macrogol 660), or Poloxamer 188 (Pluronic® F-68), or any combination thereof. The first pharmaceutical composition of the present invention may include about 0.1 to about 3.0 w / v% of a surfactant or a combination of two or more surfactants. According to some embodiments, the first pharmaceutical composition comprises about 0.1 to about 0.2 w / v%, about 0.2 to about 0.3 w / v%, about 0.3 to about 0.4 w / v%, about 0.4 to about 0.5 w / v%, about 0.5 to about 0.6 w / v%, about 0.6 to about 0.7 w / v%, about 0.7 to about 0.8 w / v%, about 0.8 to about 0.9 w / v%, about 0.9 to about 1.0 w / v%, about 1.0 to about 1.5 w / v%, about 1.5 to about 2.0 w / v%, about 2.0 to about 2.5 w / v%, about 2.5 to about 3.0 w / v% of a surfactant or a combination of two or more surfactants.

[0295]

[0246] The first pharmaceutical composition may further comprise additional pharma- ceutically acceptable excipients, such as N-methylpyrrolidone (NMP), polyvinylpyrrolidone (PVP), propylene glycol, preservatives, pharma- ceutically acceptable vehicles, stabilizers, dispersants, suspending agents, amino sugars, calcium chelators, protease inhibitors, or any combination thereof. The first pharmaceutical composition of the present invention may comprise about 5.0 to about 80.0 w / v% additional pharma- ceutically acceptable excipients, such as solvents, such as NMP or buffers, or any other cosolvents. For example, provided herein is a pharma- ceutical acceptable first composition comprising about 6 wt% levodopa, about 0.75 wt% carbidopa, about 10 wt% to about 20 wt% arginine, about 0.5 wt% L-cysteine ​​or NAC, and / or about 0.5 wt% ascorbic acid or a salt thereof. An exemplary first pharmaceutical composition (e.g., Formulation A) may include about 6% by weight levodopa, about 0.75% by weight carbidopa, and about 14% to about 16% by weight arginine. Another exemplary pharmaceutical composition may include about 6% by weight levodopa, about 0.75% by weight carbidopa, about 14% to about 16% by weight arginine, about 0.5% ascorbic acid, and about 0.5% NAC.

[0296]

[0247] According to some embodiments, the first pharmaceutical composition of the present invention has a concentration of about 5.0 to about 10.0 w / v%, about 10.0 to about 15.0 w / v%, about 15.0 to about 20.0 w / v%, about 20.0 to about 25.0 w / v%, about 25.0 to about 30.0 w / v%, about 30.0 to about 35.0 w / v%, about 35.0 to about 40.0 w / v%, about 40.0 to about 45.0 w / v%, or about 50.0 to about 55.0 w / v%. 0.0 w / v%, about 45.0 to about 50.0 w / v%, about 50.0 to about 55.0 w / v%, about 55.0 to about 60.0 w / v%, about 60.0 to about 65.0 w / v%, about 65.0 to about 70.0 w / v%, about 70.0 to about 75.0 w / v%, about 75.0 to about 80.0 w / v% of a solvent, such as NMP, a buffer, or any other co-solvent.

[0297]

[0248] According to some embodiments, the first pharmaceutical composition further comprises a buffer. According to some embodiments, the buffer is selected from citrate buffer, citric acid buffer, sodium acetate buffer, acetate buffer, tartrate buffer, phosphate buffer, succinate buffer, Tris buffer, glycine buffer, hydrochloric acid buffer, potassium hydrogen phthalate buffer, sodium buffer, sodium citrate tartrate buffer, sodium hydroxide buffer, sodium dihydrogen phosphate buffer, disodium hydrogen phosphate buffer, tromethamine (TRIS), or any combination thereof. The first pharmaceutical composition may comprise about 0.1 to about 30.0 w / v % of the buffer. According to some embodiments, the first pharmaceutical composition comprises about 0.1 to about 1.0 w / v%, about 1.0 to about 2.0 w / v%, about 2.0 to about 3.0 w / v%, about 3.0 to about 4.0 w / v%, about 4.0 to about 5.0 w / v%, about 5.0 to about 6.0 w / v%, about 6.0 to about 7.0 w / v%, about 8.0 to about 9.0 w / v%, about 9.0 to about 10.0 w / v%, about 10.0 to about 15.0 w / v%, about 15.0 to about 20.0 w / v%, about 20.0 to about 25.0 w / v%, or about 25.0 to about 30.0 w / v% of the buffer.

[0298]

[0249] According to some embodiments, the first pharmaceutical composition further comprises an acid or a base, for example to provide a predefined pH to the composition. According to some embodiments, the acid is selected from HCl, HBr, methanesulfonic acid, ascorbic acid, acetic acid, citric acid, or any combination thereof. According to some embodiments, the base is selected from NaOH, Ca(OH)2, ammonium hydroxide, arginine, lysine, magnesium hydroxide, potassium hydroxide, meglumine, tromethamine (TRIS), triethylamine, diisopropylethylamine, diazabicycloundecane, or any combination thereof. The first pharmaceutical composition may comprise about 0.1 to about 30.0 w / v% of a base or acid. According to some embodiments, the first pharmaceutical composition may have a glycerol concentration of about 0.1 to about 1.0 w / v%, about 1.0 to about 2.0 w / v%, about 2.0 to about 3.0 w / v%, about 3.0 to about 4.0 w / v%, about 4.0 to about 5.0 w / v%, about 5.0 to about 6.0 w / v%, about 6.0 to about 7.0 w / v%, about 8.0 to about 9.0 w / v%, about 9.0 to about 10.0 w / v%, about 10.0 to about 11.0 w / v%, about 11.0 to about 12.0 w / v%, about 12.0 to about 13.0 w / v%, about 13.0 to about 14.0 w / v%, about 14.0 to about 15.0 w / v%, or about 15.0 to about 16. 0 w / v%, about 16.0 to about 17.0 w / v%, about 17.0 to about 18.0 w / v%, about 18.0 to about 19.0 w / v%, about 19.0 to about 20.0 w / v%, about 20.0 to about 21.0 w / v%, about 21.0 to about 22.0 w / v%, about 22.0 to about 23.0 w / v%, about 23.0 to about 24.0 w / v%, about 24.0 to about 25.0 w / v%, about 25.0 to about 26.0 w / v%, about 26.0 to about 27.0 w / v%, about 27.0 to about 28.0 w / v%, about 28.0 to about 29.0 w / v%, or about 29.0 to about 30.0 w / v% of a base or acid.

[0299]

[0250] It should be noted that any one or any combination of any of the ingredients disclosed herein may be added to the liquid pharmaceutical compositions of the present invention.

[0251] The pH of the first pharmaceutical composition of the present invention may be about 4.5 to about 10 at about 25°C. According to some embodiments, the pH of the first pharmaceutical composition is about 4.5 to about 5 at about 25°C. According to some embodiments, the pH of the first pharmaceutical composition is about 5 to about 6 at about 25°C. According to some embodiments, the pH of the first pharmaceutical composition is about 6 to about 7 at about 25°C. According to some embodiments, the pH of the first pharmaceutical composition is about 7 to about 8 at about 25°C. According to some embodiments, the pH of the first pharmaceutical composition is about 8 to about 9 at about 25°C. According to some embodiments, the pH of the first pharmaceutical composition is about 9 to about 10 at about 25°C. According to some embodiments, the pH of the first pharmaceutical composition is about 4.5 to about 5.5 at about 25°C. According to some embodiments, the pH of the first pharmaceutical composition is about 5.5 to about 6.5 at about 25° C. According to some embodiments, the pH of the first pharmaceutical composition is about 6.5 to about 7.5 at about 25° C. According to some embodiments, the pH of the first pharmaceutical composition is about 7.5 to about 8.5 at about 25° C. According to some embodiments, the pH of the first pharmaceutical composition is about 8.5 to about 9.5 at about 25° C. According to some embodiments, the pH of the first pharmaceutical composition is about 9.5 to about 10 at about 25° C. According to some embodiments, the pH of the first pharmaceutical composition is about 9.5 at about 25° C. According to some embodiments, an acid or base is added to the first pharmaceutical composition to provide the composition with a predefined pH value. According to some embodiments, the acid is selected from HCl, HBr, methanesulfonic acid, ascorbic acid, acetic acid, citric acid, or any combination thereof. According to some embodiments, the base is selected from NaOH, arginine, lysine, an amine base, any base previously mentioned herein, and any combination thereof.

[0300] According to some embodiments, the first pharmaceutical composition comprises:

[0301] [Table A]

[0302] and L-arginine may be at least partially replaced by lysine. Further, the concentration of arginine (and / or lysine) may be reduced to about 240mg / ml to about 230mg / ml, about 220mg / ml, about 210mg / ml, about 200mg / ml, about 190mg / ml, about 180mg / ml, about 170mg / ml, about 160mg / ml or about 150mg / ml. In addition, the concentration of carbidopa may be changed to about 7.5mg / ml, about 8.0mg / ml, about 8.5mg / ml, about 9.0mg / ml, about 9.5mg / ml, about 10mg / ml, about 11mg / ml, about 12mg / ml, about 14mg / ml or about 15mg / ml.

[0303] According to some embodiments, the second pharmaceutical composition is administered when desired and / or required, for example, when symptoms from said neurological or movement disorder require such administration, or according to a predefined treatment protocol. The assessment of the timing of administering the second pharmaceutical composition can be performed by the caretaker, the physician, the patient to whom the composition is being administered, or any combination thereof, resulting from consultation and / or joint decision-making, etc. According to some embodiments, a system assisted by any kind of sensor can provide data for determining the need to administer the second pharmaceutical composition. The data can be delivered to the caretaker, the physician, the patient, or any combination thereof, via any means, for example, electronic devices, for example, smartphones, dedicated consoles, tablets, email, dedicated or known applications, etc.

[0304] According to some embodiments, the second pharmaceutical composition is administered at predefined times, predefined intervals, or both, set, for example, according to a treatment protocol or according to data received from the patient, a caregiver, a physician, a sensor, etc. The predefined times and / or intervals may be reset at any time, for example, in consideration of data received from the patient, a caregiver, a sensor, a physician's evaluation, etc.

[0305] According to some embodiments, the second pharmaceutical composition is orally administered substantially simultaneously with the initiation of the infusion time course. According to some embodiments, the second pharmaceutical composition is orally administered about 1, 2, 3, 4, or 5 hours after the initiation of the infusion time course. It should be noted that the "initiation of the infusion time course" may be a time of day (an infusion cycle, e.g., when a new vial is introduced into the system, the cartridge is replaced, the infusion set is replaced, etc.).

[0306]

[0256] According to some embodiments, the second pharmaceutical composition administered orally is a morning oral dose. According to some embodiments, the morning oral dose comprises levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof. According to some embodiments, the morning oral dose comprises one of: 25mg levodopa, 50mg levodopa, 75mg levodopa, 95mg levodopa, 100mg levodopa, 125mg levodopa, 145mg levodopa, 150mg levodopa, 195mg levodopa, 200mg levodopa, 245mg levodopa, or 250mg levodopa.

[0307]

[0257] According to some embodiments, the morning oral dose comprises (a) levodopa, a levodopa salt, a levodopa prodrug, (b) a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, or (c) any combination thereof.

[0308] According to some embodiments, the second pharmaceutical composition is administered up to 20 times per day. According to some embodiments, the second pharmaceutical composition is administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times per day. According to some embodiments, the second pharmaceutical composition is administered about 3-7 times per day. According to some embodiments, the second pharmaceutical composition is administered about 4-6 times per day. According to some embodiments, the second pharmaceutical composition is administered at a frequency of about 30 minutes to about 24 hours. According to some embodiments, the second pharmaceutical composition is administered at a frequency of about 30 minutes to about 1 hour, about 1 hour to 2 hours, about 2 hours to 3 hours, about 3 hours to about 4 hours, about 4 hours to about 5 hours, about 5 hours to about 6 hours, about 6 hours to about 7 hours, about 7 hours to about 8 hours, about 8 hours to about 9 hours, about 9 hours to about 10 hours, about 11 hours to about 12 hours, about 10 hours to about 11 hours, about 13 hours to about 14 hours, about 12 hours to about 13 hours, about 15 hours to about 16 hours, about 14 hours to about 15 hours, about 17 hours to about 18 hours, about 16 hours to about 17 hours, about 19 hours to about 20 hours, about 18 hours to about 19 hours, about 21 hours to about 22 hours, about 20 hours to about 21 hours, about 23 hours to about 24 hours, or about 22 hours to about 23 hours.

[0309]

[0259] The interval between one administration and the next may similarly vary depending, for example, on patient / caregiver / physician observations and evaluations, on data received from any type of appropriate sensor, on predefined treatment protocols, on any combination thereof, etc.

[0310] According to some embodiments, the administered dose of the levodopa portion in the second pharmaceutical composition is the same for each administration. According to some embodiments, the dose of the levodopa portion in the second pharmaceutical composition may vary between different administrations. According to some embodiments, the dose of the levodopa portion in the second pharmaceutical composition is about 10 mg / day to about 3000 mg / day, about 10 mg / day to about 50 mg / day, about 50 mg / day to about 100 mg / day, about 100 mg / day to about 150 mg / day, about 150 mg / day to about 250 mg / day, about 250 mg / day to about 350 mg / day, about 350 mg / day to about 500 mg / day, about 500 mg / day to about 750 mg / day, about 750 mg / day to about 800 mg / day, about 800 mg / day to about 900 mg / day, about 900 mg / day to about 1000 mg / day, about 100 mg / day to about 250 mg / day, about 250 mg / day to about 350 mg / day, about 350 mg / day to about 500 mg / day, about 500 mg / day to about 750 mg / day, about 75 ...100 mg / day to about 3000 mg / day, about 100 mg / day to about 250 mg / day, about 100 g / day to about 1000 mg / day, about 1000 mg / day to about 1250 mg / day, about 1250 mg / day to about 1500 mg / day, about 1500 mg / day to about 1750 mg / day, about 1750 mg / day to about 2000 mg / day, about 2000 mg / day to about 2250 mg / day, about 2250 mg / day to about 2500 mg / day, about 2500 mg / day to about 2750 mg / day, or about 2750 mg / day to about 3000 mg / day. According to some embodiments, the dose in the levodopa portion of the second pharmaceutical composition is about 100 mg / day to about 1800 mg / day. According to some embodiments, the dose in the levodopa portion of the second pharmaceutical composition is about 350 mg / day to about 700 mg / day.

[0311]

[0261] It should be noted that the dosage is determined according to the time the composition is administered to the patient, so if several tablets, for example, four tablets, each containing 100 mg of levodopa, are administered to the patient at substantially the same time, the dosage of levodopa in the second pharmaceutical composition would be considered to be 400 mg in such an example. Furthermore, the daily dose may consist of several dosages that are not necessarily identical to each other, for example, the patient may be administered 100 mg at 8 am, 200 mg at 10 am, 100 mg at 3 pm, and 75 mg at 7 pm, so that the dosage of the levodopa portion in the second pharmaceutical composition would be considered to be 475 mg / day.

[0312]

[0262] According to some embodiments, the dose of the levodopa moiety in the second pharmaceutical composition is about 10 mg to about 500 mg per administration, about 10 mg to about 25 mg per administration, about 25 mg to about 50 mg per administration, about 50 mg to about 75 mg per administration, about 75 mg to about 100 mg per administration, about 100 mg to about 150 mg per administration, about 150 mg to about 200 mg per administration, about 200 mg to about 250 mg per administration, about 250 mg to about 300 mg per administration, about 300 mg to about 350 mg per administration, about 350 mg to about 400 mg per administration, about 400 mg to about 450 mg per administration, about 450 mg to about 500 mg per administration. According to some embodiments, the dose varies between different administrations. According to other embodiments, the dose remains constant for at least two administrations, for example, for 24 hours, 3 days, a week, etc.

[0313]

[0263] In certain embodiments, the dose of the levodopa portion in the second pharmaceutical composition is, for example, about 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, or 250 mg of levodopa in an immediate release tablet or capsule. According to some embodiments, the amount of the levodopa portion in the second pharmaceutical composition is, for example, about 95 mg, about 145 mg, about 195 mg, or about 245 mg of levodopa in a sustained release form, for example, a tablet or capsule.

[0314]

[0264] As described above, the levodopa portion in the second pharmaceutical composition can be levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof. According to some embodiments, the levodopa portion in the second pharmaceutical composition is levodopa. According to some embodiments, the levodopa portion in the second pharmaceutical composition is a levodopa prodrug.

[0315] According to some embodiments, the dose of the carbidopa moiety in the second pharmaceutical composition is from about 2.5 mg to about 50 mg per administration, from about 2.5 mg to about 20 mg per administration, from about 2.5 mg to about 25 mg per administration, from about 2.5 mg to about 35 mg per administration, from about 2.5 mg to about 40 mg per administration, from about 15 mg to about 20 mg per administration, from about 15 mg to about 25 mg per administration, from about 15 mg to about 35 mg per administration, from about 15 mg to about 40 mg per administration, g, about 15 mg to about 50 mg per administration, about 20 mg to about 25 mg per administration, about 20 mg to about 35 mg per administration, about 20 mg to about 40 mg per administration, about 20 mg to about 50 mg per administration, about 25 mg to about 35 mg per administration, about 25 mg to about 40 mg per administration, about 25 mg to about 50 mg per administration, about 35 mg to about 40 mg per administration, about 35 mg to about 50 mg per administration, about 40 mg to about 50 mg per administration. According to some embodiments, the dose of the carbidopa portion in the second pharmaceutical composition comprises 2.5 mg, 18.57 mg, 25 mg, 31.25 mg, 37.5 mg, or 50 mg of carbidopa.

[0316] The second pharmaceutical composition may be in any suitable oral form, such as pills, hard or soft capsules, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, syrups, or elixirs. The second pharmaceutical composition may be in immediate release form, or any type of controlled release form, such as sustained release, extended release, delayed release, release over an extended period of time, etc. As mentioned above, the second pharmaceutical composition may contain at least two active moieties, such as levodopa and carbidopa. It should be noted that each active moiety in the second pharmaceutical composition may be formulated in a different release form, for example, levodopa may be in a controlled release form while carbidopa is in an immediate release form, or vice versa.

[0317] According to some embodiments, the second pharmaceutical formulation is administered during high activity / wake times, e.g., only during the day, such that the administration interval is narrower during high activity / wake times than during other parts of the day, e.g., low activity / evening times. According to further embodiments, the dose of the second pharmaceutical formulation provided during high activity / wake times is higher than the dose administered during other parts of the day, e.g., low activity / evening times. According to some embodiments, a dosing regimen over a 24-hour period is devised and may remain constant for a certain number of days, while within the same day, the regimen may differ based on wakefulness, activity, etc. According to some embodiments, the dosing regimen may vary from day to day and within the same day.

[0318]

[0268] Embodiments of the present invention further relate to a method of treating a neurological or movement disorder, e.g., Parkinson's disease, in a patient in need of such treatment, the method comprising: levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof; and dopa decarboxylase inhibitors (DDCI), DDCI salts, DDCI prodrugs, or any combination thereof parenterally administering a first pharmaceutical composition comprising: In addition, Levodopa, levodopa salts, levodopa prodrugs; dopa decarboxylase inhibitors (DDCI), DDCI salts, DDCI prodrugs, or any combination thereof orally administering a morning oral dose composition comprising The method includes:

[0319] A further embodiment of the invention is a combination of: levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof; and dopa decarboxylase inhibitors (DDCI), DDCI salts, DDCI prodrugs, or any combination thereof A first pharmaceutical composition comprising: Levodopa, levodopa salts, levodopa prodrugs; dopa decarboxylase inhibitors (DDCI), DDCI salts, DDCI prodrugs; or any combination thereof A second pharmaceutical composition comprising wherein the first pharmaceutical composition is formulated as a parenteral composition and the second pharmaceutical composition is formulated as an oral composition.

[0320]

[0270] A further embodiment of the present invention comprises: levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof; and dopa decarboxylase inhibitors (DDCI), DDCI salts, DDCI prodrugs, or any combination thereof a first pharmaceutical composition in parenteral form comprising Levodopa, levodopa salts, levodopa prodrugs; dopa decarboxylase inhibitors (DDCI), DDCI salts, DDCI prodrugs; or any combination thereof a second pharmaceutical composition in oral form comprising Instructions for the concomitant administration of a first pharmaceutical composition and a second pharmaceutical composition for the treatment of a neurological or movement disorder, such as Parkinson's disease. The present invention relates to a kit comprising:

[0321]

[0271] A further embodiment of the present invention is levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof; and dopa decarboxylase inhibitors (DDCI), DDCI salts, DDCI prodrugs, or any combination thereof a first pharmaceutical composition in parenteral form comprising Instructions for the concomitant administration of a first pharmaceutical composition and a second pharmaceutical composition for the treatment of a neurological or movement disorder, such as Parkinson's disease. and the second pharmaceutical composition is provided separately.

[0322] A further embodiment of the present invention is a method of treating Parkinson's disease in a patient in need of such treatment, wherein the patient has previously been administered a previous form of levodopa other than a 1:4 ratio immediate release carbidopa-levodopa tablet, switching the patient from their previous form of levodopa to oral immediate release levodopa-carbidopa 100 / 25 mg tablets; subcutaneously administering to the patient a first Pharmaceutically acceptable liquid composition comprising levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof over a subcutaneous infusion time course of at least about 24 hours or more; orally administering to the patient at least one oral dosage form comprising levodopa prior to or during the subcutaneous infusion time course; The present invention relates to a method comprising the steps of:

[0323] A further embodiment of the present invention is a method of treating Parkinson's disease in a patient in need of such treatment, wherein the patient has previously been administered a previous form of levodopa, switching the patient from a previous form of levodopa to an oral immediate release levodopa-carbidopa form; after said switching, subcutaneously administering to the patient a first Pharmaceutically acceptable liquid composition comprising levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof over a subcutaneous infusion time course of at least about 24 hours or more; orally administering to the patient at least one oral dosage form comprising levodopa prior to or during the subcutaneous infusion time course; The present invention relates to a method comprising the steps of:

[0324] A further embodiment of the present invention is a method of treating Parkinson's disease in a patient in need of such treatment, wherein the patient has previously been administered a previous form of levodopa, administering to the patient an amount of oral immediate release levodopa by switching the patient from a previous form of levodopa to an oral immediate release levodopa form; after said switching, subcutaneously administering to the patient a subcutaneous amount of a first Pharmaceutically acceptable liquid composition comprising levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof over a subcutaneous infusion time course of at least about 24 hours or more; Including, If the amount of the oral immediate release form of levodopa is greater than the subcutaneous amount of levodopa, then the amount of the oral immediate release form of levodopa is reduced by approximately the amount of the subcutaneous amount of levodopa and the patient is administered the remaining amount of oral immediate release levodopa; if the amount of the oral immediate release form of levodopa is less than the subcutaneous amount of levodopa, a levodopa salt, a levodopa prodrug, or a combination thereof, the patient is not administered an oral immediate release form of levodopa, except for a morning dose of oral immediate release levodopa, administered before or during the subcutaneous infusion time course; It concerns the method.

[0325] A further embodiment of the present invention is a method of treating Parkinson's disease in a patient in need of such treatment, where the patient has previously been administered a previous form of levodopa, the method comprising: administering to the patient an initial daily dose of oral immediate release levodopa by switching the patient from a previous form of levodopa to an oral immediate release levodopa form; after said switching, subcutaneously administering to the patient a first Pharmaceutically acceptable liquid composition over a subcutaneous infusion time course of at least about 24 hours or more in an amount to deliver about 720 mg of levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof to the patient over at least about 24 hours; Including, If the initial daily amount of oral immediate release levodopa is greater than about 700 mg, then the amount of oral immediate release levodopa is decreased by about 700 mg and the patient is administered a remaining amount of oral immediate release levodopa equal to the initial daily amount of oral immediate release levodopa minus 700 mg; If the initial daily amount of the oral immediate release form of levodopa is less than about 700 mg, the patient is administered only a morning dose of oral immediate release levodopa administered before or during the subcutaneous infusion time course. It concerns the method.

[0326]

[0276] In certain embodiments of the methods described herein, concomitant administration of a first composition (parenterally, e.g., subcutaneously) and a second composition (e.g., an oral tablet) to a patient results in a higher area under the curve (AUC) for levodopa from time 0 to the end of parenteral infusion, e.g., subcutaneous infusion, compared to the combined AUC for levodopa in the patient when the first composition and the second composition are not administered concomitantly, and the total amount of levodopa administered is the same whether administered concomitantly or non-concomitantly.

[0327]

[0277] Unless expressly stated, the method embodiments described herein are not bound to a particular order or sequence. In addition, some of the method embodiments described, or elements thereof, may occur or be performed at the same time, contemporaneously, or concurrently.

[0328]

[0278] It is also recognized that certain features of the invention may be provided in combination in a single embodiment. Conversely, various elements of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as appropriate with any other described embodiment of the invention. Moreover, certain features described in the context of various embodiments are not to be construed as essential features of that embodiment, unless the embodiment is ineffective without those elements.

[0329]

[0279] The various embodiments and aspects of the present invention, as precisely outlined above and claimed in the claims section below, can be supported by the following examples; however, they should not be limited by the examples. EXAMPLES

[0330] Example 1: Evaluation of plasma exposure of levodopa (LD) following co-administration of subcutaneous (SC) and oral forms of LD A study was run to evaluate the plasma exposure of levodopa (LD) and carbidopa (CD) following co-administration of LD by both subcutaneous (SC) and oral administration. Thus, results from combined SC+oral administration were compared to those from SC administration alone and from oral administration alone. Additive plasma exposure and PK profiles were expected; that is, SC+oral co-administration was expected to provide results equivalent to the additive results of SC and oral administration when each was administered separately.

[0331] method

[0281] Sixteen healthy subjects (aged 18-50 years) were treated in a crossover fashion, i.e. sequentially. The washout period was 6 days between the two subsequent treatments:

[0282] Treatment A: A total dose of 180 / 22.5 mg LD / CD (Formulation A) was administered by SC infusion over 8 hours at a steady infusion rate.

[0332]

[0283] Treatment B: Immediate release (IR) tablets of 100 / 25 mg LD / CD were administered orally at time 0 h. After a 32-hour washout period, the same 16 healthy subjects were administered LC / CD orally and subcutaneously according to the following treatment: Treatment C: 4 hours after the start of the infusion, a dose of 153.6 / 19.2 LD / CD (Formulation A) was administered by SC infusion over 8 hours at a steady infusion rate in combination with a single co-administration of oral IR LD / CD 100 / 25 mg tablets. Total LD / CD dose: 253.6 / 44.2 mg.

[0333]

[0286] Blood samples were collected at the following time points: Treatment A: 0 (before treatment started), 0.5h, 1h, 2h, 3h, 4h, 5h, 5.5h, 6h, 7h, 8h (before end of infusion).

[0334]

[0288] Treatment B: 0 (before the start of treatment), 0.5h, 1h, 2h, 3h, 4h. Treatment C: 0 (before start of treatment), 0.5h, 1h, 2h, 3h, 4h, 4.5h, 5h, 5.5h, 6h, 7h, 8h (before end of infusion).

[0335] result

[0290] Normalized AUC of LD and CD for Treatment C from combined SC and oral treatments as described above 0~8 was calculated to obtain the AUC from Treatment A (8 h SC injection) 0~8 ) and Treatment B (AUC from one IR oral tablet 0~4 ) and compared to the sum of normalized LD and CD AUCs obtained from the LD and CDAUCs. The results are shown in Tables 4 and 5 below.

[0336] [Table 4]

[0337] [Table 5]

[0338]

[0291] The combined / additive results of treatments A and B (combined, i.e., added to each other) were expected to be substantially the same as the results obtained from treatment C, which essentially combines treatments A and B within its treatment regime.

[0339] Surprisingly, as shown in the results above, the treatment C normalized AUC was significantly lower than the sum of the normalized AUCs for treatments A and B mentioned above. 0~8 A comparison of the LD AUC and CD AUC for treatment C demonstrated a higher than expected LD AUC, whereas in contrast, the CD AUC for treatment C was lower than expected.

[0340]

[0293] In particular, as shown in Table 4, the ratio of LD normalized AUC from treatment C compared to that obtained in treatment A+B (both added together to simulate SC+oral dosing in treatment C) for each individual was greater than 1.0, with a mean ratio of 1.245, ranging from 1.057 to 1.402. Furthermore, as shown in Table 5, for most individuals, the ratio of CD normalized AUC from treatment C compared to that obtained in treatment A+B was less than 1.0, with a mean ratio of 0.869, ranging from 0.773 to 1.080.

[0341] Thus, surprisingly, the combined SC+oral treatment achieves higher LD levels than would be expected from the addition of the two doses when each is given separately. In contrast, the CD levels obtained from the combined SC+oral treatment are lower than would be expected from the addition of the two doses when each is given separately. The lower CD results obtained in the combined treatment make the higher than expected LD levels even more surprising (the amount of CD is reduced, but the amount of LD is actually increased, which is the opposite of what would be expected, since in general, CD inhibits the peripheral metabolism of LD, so the lower the amount of CD, the lower the expected amount of LD).

[0342] Example 2: Pharmacokinetics (PK) of levodopa (LD) following SC administration of a LD prodrug in conjunction with oral administration of LD

[0295] The objective of this study was to determine the pharmacokinetics of levodopa in domestic pigs following continuous subcutaneous (SC) infusion of a levodopa (LD) prodrug administered concomitantly with oral levodopa, exemplified with LD-Tyr.

[0343]

[0296] Table 6 provides the LD-Tyr formulations tested in this study.

[0344] [Table 6]

[0345] Experimental procedure Test Design

[0297] The study consisted of three dosing sessions in which five sows (pig / Landrace x Large White, approximately 40-50 kg each) were treated with the LD-Tyr solution in Table 6 and / or Sinemet IR oral tablets (CD / LD 25 / 100 mg tablets) in a crossover design with a washout period of up to 4 days between dosing sessions, as detailed in the table below.

[0346] [Table 7]

[0347] [Table 8]

[0348] As shown above in Tables 7 and 8, the study included three test arms as follows: G1-SC received LD-TYR only (total daily dose of 600 mg); G2 - received only oral LD ​​(total daily dose of 300 mg); and He received both G3-SC LD-Tyr (total daily dose of 600 mg) and oral LD ​​(total daily dose of 200 mg).

[0349] Pharmacokinetics Blood collection

[0303] Blood samples for determination of LD-Tyr (in groups 1 and 3) and plasma levels of LD and CD (in all groups) were collected from pigs at the following time points: 0 (pre-dose), 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 5.5 h, 6 h, 7 h, 8.5 h, 9 h, 10 h, 11 h, 13 h, 15 h, 18 h after treatment initiation. Tablets were administered prior to blood collection (0, 4 and 8 h time points).

[0350] biochemical analysis

[0300] Plasma samples were analyzed for concentrations of LD-Tyr (groups 1 and 3) and LD and CD (all groups) using a validated LC-MS / MS analytical method.

[0351] Pharmacokinetic evaluation PK parameters of LD-Tyr, LD and CD (at least C max , t max , t 1 / 2 , AUC) were calculated by non-compartmental methods using appropriate software (e.g. Phoenix® WinNonlin®). Individual and mean quantitative parameters were calculated.

[0352] result LD AUC for all three test groups was calculated and is shown in Table 11 below. Note that the LD AUC from SC treatment of LD-Tyr is due to the in vivo dissociation of LD-Tyr into LD and tyrosine. The LD exposure obtained from SC injection is considered to be the baseline. Therefore, the additional exposure obtained in G3, in addition to that obtained from SC treatment alone (obtained in G1), is calculated according to both predicted and actual results according to the following formula.

[0353] 1) SC plus oral [[actual]] = G3(actual outcome) - G1(actual outcome); and 2) SC plus oral [[predicted]] = 2 / 3 * G2 (the multiplication by 2 / 3 is needed to normalize because G2 received a daily dose of 300 mg and the oral add-on in G3 results in a daily dose of 200 mg).

[0354] [Table 9]

[0355] After normalization, the exposure resulting from the addition of oral to SC administration (G3) is additive, i.e., at least approximately similar to oral treatment alone (G2). However, as shown above in Table 11, surprisingly, the predicted value for the addition of oral to SC administration is much lower than the actual results.

[0356] The ratio between actual and predicted values ​​is always above 1, starting at 1.14 and reaching as high as 2.15, with an average ratio of 1.57. Thus, these results show that the addition of an oral add-on increases the LD plasma exposure by an average of more than 50% over and above the LD exposure obtained from SC administration alone. This ratio indicates an unexpected synergistic effect between SC administration and oral treatment.

[0357] Equivalent

[0305] While specific embodiments of the subject invention have been discussed, the foregoing specification is illustrative and not limiting. Many variations of the invention will become apparent to those of skill in the art upon review of this specification. The full scope of the invention should be determined by reference to the claims, their full scope of equivalents, and the specification and such variations.

[0358]

[0306] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and the like used in the specification and claims are to be understood as being modified in all instances by the term "about." Furthermore, when a particular value is recited in the specification and claims, unless otherwise indicated, the term "about" means that an acceptable error range, e.g., up to 5% or 10% for the particular value, should be assumed.

[0359] Incorporation by Reference

[0307] The entire contents of all patents, designs, published patent applications, websites, and other references cited herein are expressly incorporated herein by reference in their entirety.

Claims

1. 1. A method for treating a neurological or movement disorder in a patient in need thereof, comprising: To the patient, a) a levodopa prodrug; and b) a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, or any combination thereof. and parenterally administering a first pharmaceutical composition comprising: In addition, orally administering to the patient a second pharmaceutical composition comprising an active agent selected from the group consisting of levodopa, a levodopa salt, a levodopa prodrug, a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, and any combination thereof; The method includes:

2. 2. The method of claim 1, wherein the DDCI is carbidopa, a carbidopa salt, a carbidopa prodrug, benserazide, or any combination thereof.

3. 3. The method of claim 1 or 2, wherein the DDCI in the first pharmaceutical composition is the same as the DDCI in the second pharmaceutical composition.

4. The method of any one of claims 1 to 3, wherein the DDCI in the first pharmaceutical composition is different from the DDCI in the second pharmaceutical composition.

5. The method of any one of claims 1 to 4, wherein the second pharmaceutical composition comprises levodopa and DDCI.

6. The method of any one of claims 1 to 5, wherein the DDCI is carbidopa.

7. 7. The method of any one of claims 1 to 6, wherein the first pharmaceutical composition is administered subcutaneously, transdermally, intradermally, intravenously, intramuscularly, intratracheally, intranasally, intrathecally, intragastrically, or intraduodenum.

8. The method of any one of claims 1 to 7, wherein the first pharmaceutical composition is administered subcutaneously.

9. The method of any one of claims 1 to 8, wherein the first pharmaceutical composition is administered to the patient in need of treatment for a neurological or movement disorder via one or more sites.

10. The neurological or movement disorder is selected from the group consisting of Parkinson's disease; secondary parkinsonism, such as drug-induced secondary parkinsonism, neuroleptic-induced parkinsonism, postencephalitic parkinsonism, and vascular parkinsonism; motor fluctuations; neurodegenerative disorders; movement disorders; reduced dopamine levels in the brain; levodopa-induced dyskinesia; rapid eye movement sleep behavior disorder (RBD); dystonia; morning akinesia; tremor symptoms, such as essential tremor and drug-induced tremor.

10. The method of any one of claims 1 to 9, wherein the condition is selected from the group consisting of: myoclonus; chorea, e.g. drug-induced chorea; tics, e.g. drug-induced tics and organic tics; drug-induced dyskinesia; drug-induced akathisia; restless legs syndrome (RLS); stiff man syndrome; benign tremor attacks; malignant neuroleptic syndrome; Huntington's chorea; Shy-Drager syndrome; brain injury induced conditions, e.g. carbon monoxide or manganese poisoning; or any combination thereof.

11. The method of any one of claims 1 to 10, wherein the first pharmaceutical composition is administered substantially continuously.

12. 12. The method of any one of claims 1-11, wherein the second pharmaceutical composition is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times daily.

13. The method of any one of claims 1 to 12, wherein said second pharmaceutical composition is administered when symptoms from said neurological or movement disorder require said administration.

14. The method of any one of claims 1 to 13, wherein the second pharmaceutical composition is administered at predefined times, at predefined intervals, or both.

15. The method of any one of claims 1 to 14, wherein the second pharmaceutical composition is administered multiple times, and the administered dose is the same in all administrations.

16. The method of any one of claims 1 to 15, wherein the second pharmaceutical composition is administered multiple times, and the administered doses are different in at least two administrations.

17. 17. The method of any one of claims 1-16, wherein the second pharmaceutical composition is administered in a dose of about 25 mg of levodopa to about 400 mg of levodopa in each administration.

18. The method of any one of claims 1 to 17, wherein the first pharmaceutical composition comprises levodopa, carbidopa, and arginine.

19. The method of any one of claims 1 to 18, wherein the first pharmaceutical composition comprises levodopa, carbidopa, arginine, and at least one antioxidant.

20. 20. The method of any one of claims 1 to 19, wherein the first pharmaceutical composition comprises levodopa, carbidopa, arginine, and at least two antioxidants.

21. 21. The method of any one of claims 1-20, wherein the first pharmaceutical composition comprises levodopa, carbidopa, and a base selected from the group consisting of arginine, lysine, NaOH, tris(hydroxymethyl)aminomethane (TRIS), and any combination thereof.

22. 22. The method of any one of claims 1 to 21, wherein the pH of the first pharmaceutical composition is in the range of about 6 to about 10, in the range of about 8 to about 10, in the range of about 9 to about 10, in the range of about 9.1 to about 9.8, or about 9.

5.

23. 23. The method of any one of claims 1-22, wherein the first pharmaceutical composition comprises about 1% to about 40% w / v, about 1% to about 20% w / v, about 1% to about 10% w / v, about 2% to about 8% w / v, about 4% to about 8% w / v, about 5% to about 7% w / v, about 10% to about 20% w / v, about 15% to about 25% w / v, about 20% to about 30% w / v, about 25% to about 35% w / v, about 30% to about 40% w / v, about 30% w / v, or about 6% w / v of levodopa, levodopa prodrug, levodopa salt, or any combination thereof.

24. 24. The method of any one of claims 1-23, wherein the first pharmaceutical composition comprises about 0.5% to about 10% w / v, about 0.5% to about 6% w / v, about 0.5% to about 4% w / v, about 0.5% to about 2% w / v, about 0.5% to about 1% w / v, about 0.75% w / v, about 1.0% w / v, about 1.3% w / v, about 1.5% w / v of carbidopa, a carbidopa salt, a carbidopa prodrug, or any combination thereof.

25. 25. The method of any one of claims 1 to 24, wherein the antioxidant is selected from the group consisting of ascorbic acid or a salt thereof, cysteine, e.g., N-acetylcysteine, bisulfite or a salt thereof, glutathione, tyrosinase inhibitors, divalent cations, butylated hydroxytoluene (BHT), beta hydroxy acid (BHA) tocopherol, gentisic acid, tocopherol, tocopherol derivatives, thioglycerol, and any combination thereof.

26. 26. The method of any one of claims 1 to 25, wherein the first pharmaceutical composition comprises about 0.05% w / v to about 2.0% w / v, about 0.5% to about 1.5 w / v, 0.75% w / v, about 0.9% w / v, about 1.0% w / v, about 1.1% w / v, about 1.25% w / v of the antioxidant or combination of antioxidants.

27. 27. The method of any one of claims 1 to 26, wherein the first pharmaceutical composition comprises about 5% w / v to about 30% w / v, about 10% to 20% w / v, about 20% to about 30 w / v, about 12.5% ​​to 17.5 w / v, about 15% w / v, about 20% w / v, about 25% w / v, about 24% w / v, or about 15.2% w / v of base.

28. The method of any one of claims 1 to 27, wherein the first pharmaceutical composition is administered via one or two sites.

29. 29. The method of any one of claims 1-28, wherein the first pharmaceutical composition is administered in a volume of about 1 ml to about 30 ml per site daily, about 2 ml to about 20 ml per site daily, about 3 ml to about 10 ml per site daily, about 5 ml to about 7 ml per site daily, about 9 ml per site daily, about 10 ml per site daily, about 11 ml per site daily, about 12 ml per site daily, or about 6 ml per site daily.

30. For use in combination in the treatment of neurological or movement disorders, Levodopa prodrugs, and dopa decarboxylase inhibitors (DDCI), DDCI salts, DDCI prodrugs, or any combination thereof A first pharmaceutical composition comprising: Levodopa, a levodopa salt, a levodopa prodrug, a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug, or any combination thereof A second pharmaceutical composition comprising: A first pharmaceutical composition and a second pharmaceutical composition, wherein the first pharmaceutical composition is formulated as a parenteral composition and the second pharmaceutical composition is formulated as an oral composition.

31. levodopa prodrug; and dopa decarboxylase inhibitors (DDCI), DDCI salts, DDCI prodrugs, or any combination thereof a first pharmaceutical composition in parenteral form comprising levodopa, a levodopa salt, a levodopa prodrug; a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug; or any combination thereof. a second pharmaceutical composition in oral form comprising Instructions for the concomitant administration of a first pharmaceutical composition and a second pharmaceutical composition for the treatment of a neurological or movement disorder Kit including:

32. 1. A method for treating a neurological or movement disorder in a patient in need thereof, comprising: subcutaneously administering to the patient a first Pharmaceutically acceptable liquid composition comprising levodopa prodrug and carbidopa, a carbidopa salt, a carbidopa prodrug, or any combination thereof, in an amount to deliver about 100-800 mg of levodopa prodrug and about 12-50 mg of carbidopa, a carbidopa salt, or a carbidopa prodrug to the patient over a subcutaneous infusion time course of about 7 to about 10 hours or more; orally administering to the patient an immediate release tablet or capsule containing levodopa and carbidopa prior to or during the subcutaneous infusion time course; The method includes:

33. 33. The method of claim 32, wherein the immediate release tablet contains 50 mg, 75 mg, 100 mg, 125 mg, or 150 mg of levodopa.

34. 34. The method of claim 32 or 33, wherein the immediate release tablet contains 2.5 mg, 18.57 mg, 25 mg, 31.25 mg, 37.5 mg, or 50 mg of carbidopa.

35. 35. The method of any one of claims 32-34, wherein the subcutaneous infusion time course is about 8 hours.

36. 36. The method of any one of claims 32-35, wherein the immediate release tablet or capsule is orally administered substantially simultaneously with the initiation of the infusion time course.

37. 36. The method of any one of claims 32-35, wherein the immediate release tablet or capsule is orally administered about 1, 2, 3, 4, or 5 hours after the start of the infusion time course.

38. 36. The method of any one of claims 32-35, wherein the immediate release tablet or capsule is administered about 4 hours after the start of the infusion time course.

39. 36. The method of any one of claims 32-35, wherein the immediate release tablet or capsule is administered at about 4 hours and about 8 hours after the start of the infusion time course.

40. 40. The method of any one of claims 32-39, wherein the immediate release tablet or capsule contains 100 mg of levodopa and 25 mg of carbidopa.

41. 41. The method of any one of claims 32-40, wherein the step of subcutaneously administering a first Pharmaceutically Acceptable Liquid Composition comprises an amount of levodopa prodrug and carbidopa, a carbidopa salt, a carbidopa prodrug, or any combination thereof, to deliver to the patient about 550-650 mg of levodopa prodrug and about 24 to about 28 mg of carbidopa, a carbidopa salt, or a carbidopa prodrug.

42. The method according to any one of claims 32 to 41, wherein the neurological or movement disorder is Parkinson's disease.

43. 43. The method of any one of claims 32-42, wherein the first Pharmaceutically acceptable liquid composition comprises about 30% by weight of a levodopa prodrug, about 1.3% by weight of carbidopa, and about 20% to about 30% by weight of arginine.

44. 44. The method of any one of claims 32-43, wherein the concomitant subcutaneous administration of the first composition and oral administration of the tablet or capsule results in a patient's area under the curve (AUC) of levodopa from time 0 to the end of the infusion period that is greater than the patient's AUC of levodopa from time 0 to the end of the infusion period when the patient is administered the first composition alone subcutaneously compared to the patient's AUC of levodopa from time 0 to the end of the infusion period when the patient is administered the first composition alone subcutaneously compared to the combination together with the patient's AUC of levodopa when the tablet or capsule is administered alone and when the amount of levodopa concomitantly administered subcutaneously and orally is about the same as the combined amount of levodopa administered alone subcutaneously and alone orally.

45. 1. A method of treating Parkinson's disease in a patient in need thereof, comprising: levodopa prodrug; and dopa decarboxylase inhibitors (DDCI), DDCI salts, DDCI prodrugs, or any combination thereof and parenterally administering a first pharmaceutical composition comprising: In addition, Levodopa, levodopa salts, levodopa prodrugs; dopa decarboxylase inhibitors (DDCI), DDCI salts, DDCI prodrugs, or any combination thereof orally administering a morning oral dose composition comprising The method includes:

46. 1. A method of treating Parkinson's disease in a patient in need thereof, comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising a levodopa prodrug, carbidopa, arginine, and an antioxidant in an amount to deliver about 1800 mg of levodopa prodrug and about 78 mg of carbidopa to the patient over about 24 hours; orally administering to the patient at least one oral dosage form comprising levodopa prior to or during the subcutaneous infusion time course; The method includes:

47. 1. A method of treating Parkinson's disease in a patient in need thereof, comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising a levodopa prodrug, carbidopa, arginine, and an antioxidant in an amount to deliver about 2700 mg of levodopa prodrug and about 117 mg of carbidopa to the patient over about 24 hours; orally administering to the patient at least one oral dosage form comprising levodopa prior to or during the subcutaneous infusion time course; The method includes:

48. 1. A method of treating Parkinson's disease in a patient in need thereof, comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising a levodopa prodrug, carbidopa, arginine, and an antioxidant in an amount to deliver about 3000 mg of levodopa prodrug and about 130 mg of carbidopa to the patient over about 24 hours; orally administering to the patient at least one oral dosage form comprising levodopa prior to or during the subcutaneous infusion time course; The method includes:

49. 1. A method of treating Parkinson's disease in a patient in need thereof, comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising a levodopa prodrug, carbidopa, arginine, and an antioxidant in an amount to deliver about 3300 mg of levodopa prodrug and about 143 mg of carbidopa to the patient over about 24 hours; orally administering to the patient at least one oral dosage form comprising levodopa prior to or during the subcutaneous infusion time course; The method includes:

50. 1. A method of treating Parkinson's disease in a patient in need thereof, comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising a levodopa prodrug, carbidopa, arginine, and an antioxidant in an amount to deliver about 3600 mg of levodopa prodrug and about 156 mg of carbidopa to the patient over about 24 hours; orally administering to the patient at least one oral dosage form comprising levodopa prior to or during the subcutaneous infusion time course; The method includes:

51. 51. The method of any one of claims 45 to 50, wherein the oral dosage form is a morning oral dose.

52. 52. The method of any one of claims 45 to 51, wherein treatment comprises treatment of motor fluctuations.

53. 1. A method of treating Parkinson's disease in a patient in need thereof, comprising: subcutaneously administering to the patient over a subcutaneous infusion time course of about 24 hours or more a first Pharmaceutically acceptable liquid composition comprising levodopa prodrug and carbidopa in an amount to deliver a ratio of about 30:1 w / w to about 8:1 w / w of levodopa prodrug and carbidopa to the patient over about 24 hours; orally administering to the patient at least one oral dosage form comprising levodopa prior to or during the subcutaneous infusion time course; The method includes:

54. 54. The method of claim 53, wherein the treatment comprises treatment of motor fluctuations.

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