Levodopa polymer conjugates, formulations thereof, and their use for the treatment of Parkinson's disease - Patents.com

Abstract

A compound of formula I: or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein R1 is a pharmaceutically acceptable polymer moiety comprising a pharmaceutically acceptable polymer chain, wherein a carbonyl group is bonded to R1 through an ester, amide, carbonate, or carbamate bond; R2 is hydrogen, or -(C=0)R5, wherein R5 is C 1-3 a straight or branched chain alkyl group; and R3 and R4 are independently hydrogen, C 1-3 selected from a straight or branched chain alkyl group, or -(C=0)R6, where R6 is -(0-CH2-CH2) n -OCH3 or C 1-3 is a straight or branched chain alkyl group, and n is 1 to 5. The compositions of the present invention are useful for treating Parkinson's disease when administered alone or in combination with carbidopa and / or entacapone.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 868,134, filed June 28, 2019, the contents of which are incorporated herein by reference in their entirety. [Technical field]

[0002] The present invention relates to polymer conjugates of levodopa and its prodrugs, and polymeric nanoparticle / microparticle formulations of the polymer conjugates. These compounds and compositions are useful in the treatment of Parkinson's disease. [Background technology]

[0003] Levodopa is (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid [ka] It is the common name for an aromatic amino acid derivative that is the main source of dopamine. In humans and other animals, levodopa is synthesized from the amino acid L-tyrosine and serves as a precursor in the synthesis of the neurotransmitters dopamine, norepinephrine (noradrenaline) and epinephrine (adrenaline), collectively known as catecholamines.

[0004] Parkinson's disease (PD) is a progressive neurodegenerative disease that affects approximately 1-2% of the population over 60 years of age. Symptoms include resting tremor, rigidity, slowness of movement and postural instability caused by selective degeneration of dopaminergic neurons in the substantia nigra, leading to the destruction of the nigrostriatal pathway and reduced striatal dopamine levels. Non-patent literature 1.

[0005] The efficacy of high-dose levodopa (3-16 g / day) in the treatment of PD was first reported in 1969 (Non-Patent Document 2 and Non-Patent Document 3). The U.S. Food and Drug Administration ("FDA") approved levodopa for the treatment of PD in 1970. Levodopa, unlike dopamine, can cross the blood-brain barrier (BBB) ​​and is converted to dopamine in the central nervous system as well as the peripheral circulation. Most commonly, levodopa is used as a dopamine replacement agent for the treatment of PD and is particularly effective in controlling the bradykinesia symptoms that are evident in PD. Levodopa is recommended for the symptomatic treatment of all stages of Parkinson's disease and is administered multiple times daily by the oral route. Levodopa is usually administered with carbidopa, a dopamine decarboxylase inhibitor, to reduce the amount of levodopa that is converted to dopamine in the periphery. This combination therapy allows more levodopa to cross the BBB. Once converted to dopamine, it activates postsynaptic dopaminergic receptors, compensating for the decline in endogenous dopamine.

[0006] Levodopa is absorbed in the small intestine, and 95% of the administered oral dose is presystemically decarboxylated to dopamine by aromatic L-amino acid decarboxylase (AADC) enzymes in the stomach, intestinal lumen, kidneys, and liver. Levodopa can also be methoxylated by the hepatic catechol-O-methyltransferase (COMT) enzyme system to 3-O-methyldopa (3-OMD), which cannot be converted to central dopamine. Thus, only a small portion of an oral dose of levodopa is transported across the BBB to the central nervous system (CNS), where it is converted to the neurotransmitter dopamine by brain AADC enzymes. Dopamine is further converted to sulfated or glucuronidated metabolites and homovanillic acid through various metabolic processes. The major metabolites of levodopa are 3,4-dihydroxyphenylacetic acid (13–47%) and homovanillic acid (23–39%).

[0007] Gastric AADC and COMT enzymes break down levodopa, so the drug is given: i) a peripheral dopamine decarboxylase inhibitor (carbidopa), without which 90% of levodopa is metabolized in the intestinal wall, and ii) COMT inhibitors (entacapone) which reduce peripheral loss of levodopa by approximately 5%.

[0008] Inhibitors of AADC and COMT inhibit the decarboxylation of levodopa in the stomach and periphery, making more levodopa available for transport across the BBB and increasing brain dopamine content. Carbidopa, when administered with levodopa, reduces the amount of levodopa required to produce a given response by 75%. Coadministration of a 200 mg dose of entacapone with levodopa / carbidopa increases levodopa plasma exposure by 35-40%.

[0009] The plasma half-life of levodopa alone is approximately 50 minutes. When administered with carbidopa (Sinemet® and Sinemet® CR50-200), its half-life increases to 1.5 hours (Sinemet label, NDA 17555). The time to peak plasma concentration (T max ) is approximately 0.5 hours for Sinemet and 2 hours for Sinemet CR, and the peak plasma concentration (C max ) was 1151 ng / mL vs. 3256 ng / mL for Sinemet vs. Sinemet CR (Sinemet CR label, NDA019856). After administration of Stalevo® (combination of carbidopa, levodopa and entacapone, 37.5 / 150 / 200 mg), t max is about 1.5 hours, and C max is 1270±329ng / mL (STALEVO label, NDA21485).

[0010] Common side effects of levodopa include nausea, vomiting, dry mouth, loss of appetite, heartburn, diarrhea, constipation, dizziness, muscle pain, numbness or tingling, and sleep disorders. Serious side effects include mood changes, increased blinking / twitching, and worsening involuntary movements / convulsions. Fluctuations in motor symptoms, including dyskinesia and abnormal involuntary movements, are closely related to the pharmacokinetics of levodopa, its erratic uptake, short half-life, low bioavailability, and significant fluctuations in plasma concentrations. Non-Patent Document 4 and Non-Patent Document 5.

[0011] The development of dyskinesias can be avoided by using lower doses of levodopa and by maintaining stable dopamine levels. Research is ongoing to find a route of delivery of levodopa to achieve continuous dopaminergic stimulation. Intrajejunal infusion developed by Abbvie (Duopa®) is given by continuous infusion for the treatment of motor fluctuations in patients with advanced Parkinson's disease, approved by the FDA in 2015. Levodopa inhalation powder, Inbrija® by Acorda Therapeutics, Inc., was approved by the FDA in 2018. Several other formulations for continuous subcutaneous (SC) infusion are in development, such as ABBV-951 (Abbvie) and ND6012 (Neuroderm / Mitsubishi Tanabe).

[0012] Levodopa has been modified into water-soluble ester and amide derivatives for better brain uptake. Many prodrugs have been reported for levodopa, as it has three active functional groups to modify as prodrug derivatives. There are two benzyl hydroxyl groups at the 3- and 4-positions, one amine group at the 2-position, and one active carboxyl group at the terminal. The two hydroxyl groups of levodopa can be modified into ester derivatives. The methyl ester of levodopa (Levomet®) is already on the market. However, the ethyl ester derivative (Etilevodopa, TV-1203) was found to be less effective than levodopa in phase III clinical trials. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Olanow et al., Neurology.2009;72(21Suppl4):S1-136 [Non-Patent Document 2] Cotzias et al.,N.Engl.J.Med.1969;280(7):337-345 [Non-Patent Document 3] Yahr et al., Arch. Neurol. 1969;21(4):343-354 [Non-Patent Document 4] LeWitt,Mov.Disord.2015;30(1):64-72 [Non-Patent Document 5] Tambasco et al.,CurrNeuropharmacol.2018;16(8):1239-1252 Summary of the Invention [Means for solving the problem]

[0014] The present invention provides specific polymer conjugates of levodopa and its prodrugs with linear, branched and spherical biocompatible polymers. These compounds provide sustained release properties compared to free levodopa, which has a very short half-life. The present invention also provides nanoparticle / microparticle formulations of the polymer conjugates of levodopa and its prodrugs using biocompatible pharma- ceutically acceptable polymers.

[0015] The compounds and compositions of the present invention provide improved bioavailability, reducing the dosing frequency and total dose of levodopa, thereby improving the side effect profile of levodopa used alone or in combination with carbidopa and / or entacapone.

[0016] In some embodiments, the present invention provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt, hydrate, and / or solvate thereof; R 1 is a pharma- ceutically acceptable polymer moiety comprising a pharma- ceutically acceptable polymer chain, wherein the carbonyl group is connected to R via an ester, amide, carbonate or carbamate bond. 1 Combined into; R 2 is hydrogen or -(C=0)R 5 where R 5 is C 1-3 is a straight or branched chain alkyl group; and R 3 and R 4 are independently hydrogen, C 1-3 A straight or branched chain alkyl group, or -(C=0)R 6 Selected from R 6 HA-(0-CH 2 -CH 2 ) n -OCH 3 or C 1-3 It is a straight or branched chain alkyl group, and n is 1-5.

[0017] Yet another embodiment of the present invention is a pharmaceutical composition comprising micro- or nanoparticles comprising: a pharma- ceutical effective amount of a compound of formula I; and A second pharma- ceutically acceptable polymer. Provide The compound of formula I is encapsulated in a second pharma- ceutically acceptable polymer.The pharma- ceutically acceptable polymers used in the present invention can be linear, branched or globular.

[0018] In some embodiments of the invention, the pharma- ceutically acceptable polymer and / or the second pharma-ceutically acceptable polymer are independently selected from the group consisting of polyethylene glycol (PEG), poly(glycolide) (PGA), poly(lactide) (PLA), poly(caprolactone), poly(lactide-co-caprolactone), poly(lactide-co-glycolide) (PLGA), and poly(lactic acid)-butanol, poly(vinylpyrrolidone), poly(vinyl alcohol) (PVA), poly(ethyleneimine), poly(malic acid), poly(L-lysine), poly(L-glutamic acid), and poly((N-hydroxyalkyl)glutamine), dextrin, hydroxyethyl starch, polysialic acid, polyacetal, N-(2-hydroxypropyl)methacrylamide copolymer, poly(amidoamine) dendrimers, and mixtures, combinations, and copolymers thereof. In some embodiments of the present invention, the pharma- ceutically acceptable polymer and / or the second pharma-ceutically acceptable polymer used for encapsulation are selected from the group consisting of PLA, PGA, PLGA, PVA, and combinations thereof in different proportions.

[0019] Certain embodiments of the present invention provide compositions comprising a pharma- ceutical effective amount of a compound of formula I and one or more pharma- ceutical acceptable carriers or excipients.In particular, castor oil or its derivatives can be used as an excipient.In some embodiments, the compositions are in the form of liposomes or micelles using pharma- ceutical acceptable amphiphilic compounds.

[0020] In certain embodiments of the invention, the micro- or nanoparticle compositions comprising the polymer-encapsulated compound of formula I further comprise one or more pharma- ceutically acceptable carriers or excipients.

[0021] The composition of the present invention is useful for the treatment of PD. In particular, the composition is useful for the same treatment as levodopa used alone or in combination with carbidopa and / or entacapone, such as the indications approved by the USFDA or other national drug regulatory authorities for levodopa alone or in combination with carbidopa and / or entacapone.

[0022] In some embodiments, the compositions of the invention can be administered by parenteral routes, such as intravenously, intramuscularly, intraperitoneally, or subcutaneously. In certain other embodiments, the compositions of the invention can be administered topically, such as in the form of transdermal patches, creams, foams, gels, lotions, ointments, sprays, and eye drops, which are applied transdermally, conjunctivally, or by inhalation.

[0023] In some embodiments, the compositions of the invention may be administered once daily, or two or three times weekly, hi other embodiments, the compositions of the invention may be administered once weekly, once every other week, or once monthly.

[0024] The compositions of the present invention provide improved chemical and pharmaceutical properties, such as superior pharmacokinetic properties compared to levodopa, and require substantially reduced dosages to achieve therapeutic plasma concentrations due to the structure of the compound of formula I, the nature of the composition, and / or the mode of administration. The compositions of the present invention reduce adverse events and pharmacokinetic variability. Detailed Description of the Invention

[0025] Prodrugs of levodopa are obtained by using appropriate chemical moieties that mask one or both reactive hydroxyl groups of the phenyl ring and / or amine group of levodopa. In some embodiments, O-diacetyl derivatives or short polyethylene glycol (PEG) units (repeating units n=1-5) at positions 3 and 4 of levodopa can be used to generate ester bonds, which are eventually converted to free levodopa in the body system. The two hydroxyl groups can also be converted to O-methoxy groups to extend the duration of action. Amide prodrugs of levodopa in the form of acetamide, where the amine group is converted to acetamide, have better C-reactivity compared to levodopa upon systemic administration. max , t max It has been established that the C in plasma is 0.1 and AUC (area under the curve representing the change in drug concentration in plasma as a function of time) (Jiang et al., J. Pharm. Biomed. Anal. 2010;53:751-754). Thus, N-acetylation reactions can be performed with levodopa to use the acetamide group for improved efficacy. It is worth noting here that in most of the prodrug formulations of levodopa, the C in plasma is 0.1 and AUC is 0.1. max , AUC and t max The value of C is known. Better C in plasma for a particular prodrug formulation is max It is not necessary to have better brain uptake than the plasma C max and t max It has been demonstrated that elevated amounts of dopamine were observed in the brain with such prodrugs compared to levodopa, even when there was no difference in dopamine levels (Ishikura et al., Int. J. Pharm. 1995;116:51-63).

[0026] The carboxylic acid functional group of levodopa is used to generate an in vivo cleavable bond to the biocompatible polymer, so that the polymer allows levodopa to circulate in plasma for a longer time without clearance. It also reduces the chance of peripheral degradation of levodopa to dopamine by AADC and COMT enzymes, thereby increasing the subsequent availability of levodopa in the brain. The conjugate compound of formula I provides sustained plasma levels of levodopa with increased delivery of levodopa to the brain, resulting in improved efficacy.

[0027] The pharma- ceutically acceptable polymer used in the present invention can be non-toxic, non-immunogenic, non-antigenic, highly soluble in water and FDA (The Food and Drug Administration) approved.The covalent attachment of polymer to drug can increase its hydrodynamic size (size in solution), which prolongs its circulation time by reducing renal clearance (Knop et al., Angew.ChemieInt.Ed.2010;49(36):6288-6308; Vonese et al., Drug Discov Today.2005;10(21):1451-1458; and Harris et al., Nat Rev Drug Discov.2003;2(3):214-221). The polymer conjugate compounds of the invention and the polymer encapsulated compositions of the invention have several advantages, including: increased bioavailability at lower doses; predictable drug release profile over a defined period of time following each administration; better patient compliance; ease of application; improved systemic availability due to avoidance of first-pass metabolism; reduced dosing frequency without compromising efficacy of treatment; reduced incidence of side effects; and reduced overall cost of healthcare.

[0028] The polymer conjugate of formula I can be prepared by methods known in the art, for example, Sk UH et al., Biomacromolecules. 2013; 14(3): 801-810. The polymer-encapsulated micro / nanoparticles can be prepared by methods known in the art, for example, Han et al., Front Pharmacol. 2016; 7: 185; Qutachi O et al., Acta Biomater. 2014; 10(12): 5090-5098.

[0029] In some embodiments, the pharma- ceutically acceptable polymer chain in the compound of formula I comprises 15 to 75 monomer units, 20 to 70 monomer units, or 25 to 65 monomer units, in other embodiments, the polymer has a molecular weight in the range of 1 kDa to 75 kDa, 2 kDa to 60 kDa, or 3 kDa to 50 kDa.

[0030] In certain other embodiments, the pharma- ceutically acceptable polymer chain in the compound of formula I is a linear or branched PEG comprising 4-120 monomer units, 4-75 monomer units, 4-50 monomer units, or 4-30 monomer units. In certain other embodiments, the polymer is a linear or branched PEG comprising 12-120 monomer units, 12-75 monomer units, 12-75 monomer units, or 12-30 monomer units. In some other embodiments, the polymer chain is a linear or branched PEG comprising 11-20 monomer units, 26-42 monomer units, 49-64 monomer units, or 72-111 monomer units. In certain other embodiments, the polymer chain is a linear or branched PEG having a molecular weight in the range of 0.4 kDa to 50 kDa, 0.5 kDa to 50 kDa, 0.8 kDa to 50 kDa, or 1 kDa to 50 kDa.

[0031] The term "encapsulated" in the context of the present invention means coated, covered, or surrounded such that about 20% to about 80% of the compound of formula I is enclosed / covered / coated by the polymer.

[0032] In some embodiments, PLGA and mixtures of PLGA with other polymers, such as PLA, PGA and PVA in different ratios, are used to encapsulate the compounds of the present invention to form microparticles. Due to its excellent biocompatibility, PLGA is a pharma- ceutically acceptable biodegradable polymer that is widely used to encapsulate a wide range of therapeutic agents, including hydrophilic and hydrophobic small molecule drugs, DNA, and proteins. Other additives, such as PEG, poly(orthoesters), chitosan, alginate, caffeic acid, hyaluronic acid, etc., can be used to enhance drug loading and efficiency in PLGA microparticles. PLGA can be of various compositions of PLA and PGA, with the ratio of PGA in PLA ranging from 20 to 80%, and vice versa.

[0033] In some embodiments, the amount of the compound of formula I in the composition of the invention ranges from 100 mg to 2000 mg equivalent of levodopa administered once daily. A composition containing 10 to 200 mg of carbidopa and / or 200 to 1600 mg of entacapone can be used in combination with the composition of the invention for the treatment of PD. In some embodiments, the composition of the invention can contain carbidopa and / or entacapone in addition to the compound of formula I. The amount of carbidopa co-administered with levodopa can be in a ratio of 1:10 to 1:4 relative to the amount of levodopa. Entacapone can be co-administered with levodopa in a dose of 200 mg, the dose of which can be repeated as necessary. Carbidopa in an amount of 10 mg to 200 mg / day and / or entacapone in an amount of 200 mg to 1600 mg / day can be co-administered with the compound or composition of the invention.

[0034] In some embodiments, the dosage form of the composition of the present invention is adapted for parenteral administration to patients, including subcutaneous injection, intramuscular injection, intraperitoneal injection, intravenous injection or intradermal injection.In other embodiments, the composition can be administered as a depot.When parenterally injected, the levodopa polymer conjugate of formula I can undergo enzymatic cleavage to generate levodopa and / or its prodrug, and the respective polymers used in conjugation.

[0035] In some embodiments, the compositions of the invention further comprise one or more pharma- ceutically effective carriers or excipients. Pharmaceutical compositions suitable for parenteral administration include: aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0036] The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. EXAMPLES

[0037] a) Preparation of the polymer conjugate of formula I Levodopa can be prepared by methods known in the art or obtained from commercial sources. All prodrugs of levodopa (esters at the 3,4 position and amides at the 2 position) can also be prepared by methods known in the art.

[0038] Levodopa or its prodrug is dissolved in anhydrous dimethylformamide (DMF) under nitrogen atmosphere. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) and dimethylamino)pyridine (DMAP) dissolved in DMF are added to the reaction mixture and the reaction mixture is stirred for 30 minutes. A calculated amount of linear, branched PEG or any other carboxylate-functionalized globular polymer dissolved in DMF is added to the reaction mixture and the reaction mixture is stirred under nitrogen atmosphere for 2 days. The solvent is evaporated and the resulting reaction mixture is dialyzed with a dialysis membrane (MWCO 1 kDa) for 24 hours and then with water. The resulting water is lyophilized to obtain the final levodopa polymer conjugate. The purity of the conjugate is checked by reversed-phase high performance liquid chromatography (HPLC) and the loading of the polymer conjugate is characterized / calculated by proton nuclear magnetic resonance (NMR) and matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry.

[0039] b) Preparation of Microparticles of the Compound of Formula I For the preparation of levodopa microparticles, a nanoprecipitation technique is used. Briefly, either levodopa or a levodopa prodrug and a polymer (e.g., PLGA) are dissolved in different ratios in an appropriate solvent (e.g., dichloromethane) and, if necessary, the mixture is subjected to sonication for 5-10 min to achieve dissolution. A hydrophilic non-ionic surfactant such as Pluronic F127 (e.g., a triblock copolymer) is dissolved in 50 mL of deionized water and the levodopa / PLGA solution is added dropwise using a syringe at a flow rate of 1 mL / 10 min while stirring at various speeds. Centrifuge and lyophilize the resulting nanosuspension in a cryoprotectant (e.g., 2% sucrose). Characterize the microparticles using scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray diffraction (XRD).

Claims

1. Formula I: 【Chemistry 1】 or a pharma- ceutically acceptable salt, hydrate, and / or solvate thereof, R １ is a pharma- ceutically acceptable polymer moiety comprising a pharma- ceutically acceptable polymer chain, wherein the carbonyl group is connected to R via an ester, amide, carbonate or carbamate bond. １ coupled to R ２ is hydrogen or -(C=0)R ５ Wherein R ５ is C １－３ is a straight or branched chain alkyl group; and R ３ and R ４ are independently hydrogen, C １－３ A straight or branched chain alkyl group, or -(C=0)R ６ is selected from R ６ is -(0-CH ２ -CH ２ ) ｎ -OCH ３ Or C １－３ is a linear or branched alkyl group, n is 1 to 5; The pharma- ceutically acceptable polymer chain comprising the polymer moiety R1 is selected from the group consisting of polyethylene glycol, poly(glycolide), poly(lactide), poly(caprolactone), poly(lactide-co-caprolactone), poly(lactide-co-glycolide), and poly(lactic acid)-butanol, poly(vinylpyrrolidone), poly(vinyl alcohol), poly(ethyleneimine), poly(malic acid), poly(L-lysine), poly(L-glutamic acid), and poly((N-hydroxyalkyl)glutamine), dextrin, hydroxyethyl starch, polysialic acid, polyacetal, N-(2-hydroxypropyl)methacrylamide copolymer), poly(amidoamine) dendrimers, and mixtures, combinations, and copolymers thereof. A compound characterized in that

2. 13. A composition comprising a pharma- ceutically effective amount of a compound of claim 1 and one or more pharma- ceutically acceptable carriers or excipients.

3. The composition of claim 2, wherein the composition is injectable, inhalable, or topical.

4. The composition according to claim 2, characterized in that the composition is in the form of a liposome or a micelle.

5. The composition according to claim 2, characterized in that the pharma- ceutically acceptable carrier is castor oil or a derivative thereof.

6. a pharma- ceutical effective amount of a compound of formula I according to claim 1; and A second pharma- ceutically acceptable polymer. A pharmaceutical composition comprising micro- or nanoparticles comprising The compound of formula I is encapsulated in the second pharma- ceutically acceptable polymer. A pharmaceutical composition comprising:

7. 7. The pharmaceutical composition of claim 6, wherein the second pharma- ceutically acceptable polymer is selected from the group consisting of polyethylene glycol, poly(glycolide), poly(lactide), poly(caprolactone), poly(lactide-co-caprolactone), poly(lactide-co-glycolide), and poly(lactic acid)-butanol, poly(vinylpyrrolidone), poly(vinyl alcohol), poly(ethyleneimine), poly(malic acid), poly(L-lysine), poly(L-glutamic acid), and poly((N-hydroxyalkyl)glutamine), dextrin, hydroxyethyl starch, polysialic acid, polyacetal, N-(2-hydroxypropyl)methacrylamide copolymer), poly(amidoamine) dendrimers, and mixtures, combinations, and copolymers thereof.

8. 8. The pharmaceutical composition of claim 7, further comprising one or more pharma- ceutically acceptable carriers or excipients.

9. 9. The pharmaceutical composition of claim 8, wherein the composition is injectable, inhalable, or topical.

10. The composition according to claim 2, for use in the treatment of Parkinson's disease.

11. The composition of claim 10, characterized in that the composition is for intravenous, intramuscular, intraperitoneal, or subcutaneous use.

12. 11. The composition according to claim 10, characterized in that the composition is for use in combination with carbidopa and / or entacapone.

13. 12. The composition according to claim 11, characterized in that the composition is for once daily use.

14. 12. The composition according to claim 11, characterized in that the composition is for use at most two or three times a week.

15. The composition of claim 11, wherein the composition is for use once every week or every other week.

16. 12. The composition according to claim 11, characterized in that the composition is for once-monthly use.

17. The composition according to claim 6, for use in the treatment of Parkinson's disease.

18. 18. The composition according to claim 17, characterized in that the composition is for use in combination with carbidopa and / or entacapone.

19. 18. The composition of claim 17, wherein the composition is for intravenous, intramuscular, intraperitoneal, or subcutaneous use.

20. 18. The composition of claim 17, characterized in that the composition is for once-daily use.

21. 18. The composition according to claim 17, characterized in that the composition is for use at most two or three times a week.

22. 18. The composition of claim 17, wherein the composition is for weekly or biweekly use.

23. 18. The composition of claim 17, characterized in that the composition is for once-monthly use.

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