(12) Patent Application Publication (10) Pub. No.: US 2016/0022573 A1 Yacoby-Zeevi (43) Pub

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US 2016.0022573A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0022573 A1 Yacoby-Zeevi (43) Pub. Date: Jan. 28, 2016

(54) METHOD FOR TREATMENT OF Publication Classification PARKINSONS DISEASE (51) Int. Cl. (71) Applicant: NEURODERM LTD, Ness Ziona (IL) A619/00 (2006.01) A 6LX3L/277 (2006.01) (72) Inventor: Oron Yacoby-Zeevi, Moshav Bitsaron A63L/21 (2006.01) (IL) A63L/98 (2006.01) (52) U.S. Cl. (73) Assignee: NEURODERM, LTD., Rehovot (IL) CPC ...... A61K 9/0053 (2013.01); A61 K3I/198 (2013.01); A61 K3I/277 (2013.01); A61 K (21) Appl. No.: 14/774,938 3 1/121 (2013.01); A61 K9/0019 (2013.01) (22) PCT Fled: Mar. 13, 2014 (57) ABSTRACT (86) PCT NO.: PCT/L2O14/OSO261 The present invention provides a method for treatment of a S371 (c)(1), neurological or movement disorder, e.g., Parkinson's disease, (2) Date: Sep. 11, 2015 in an individual in need thereof, by parenteral administration of a composition comprising carbidopa and levopoda, or Related U.S. Application Data pharmaceutically acceptable salts thereof, and concomitant (60) Provisional application No. 61/779,357, filed on Mar. oral administration of a catechol-O-methyl transferase 13, 2013. (COMT) inhibitor, e.g., entacapone or tolcapone. Patent Application Publication Jan. 28, 2016 Sheet 1 of 6 US 2016/0022573 A1

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METHOD FOR TREATMENT OF about 0.4 to about 0.7 hours and a Y-phase half-life of about PARKINSONS DISEASE 2.4 hours and is therefore typically administered six to eight times per day. Tolcapone binds to the catalytic center of TECHNICAL FIELD COMT in both peripheral and central nervous systems with greater affinity than any of the three catecholamine, including 0001. The present invention provides a method for treat levodopa, and consequently prevents the 3-O-methylation of ment of neurological or movement disorders such as Parkin levodopa by COMT. Tolcapone thus improves the bioavail son's disease by parenteral administration of levodopa and ability and reduces the clearance of levodopa and Subse carbidopa, concomitantly with oral administration of a quently dopamine from the central nervous system. COMT inhibitor such as entacapone and tolcapone. 0006. The efficacy of levodopa’s metabolic pathways inhibitors, when concomitantly administered with levodopa, BACKGROUND in increasing the level of the latter in the blood is well docu 0002 Parkinson's disease is a degenerative condition mented, and various formulations of levodopa together with characterized by reduced concentration of the neurotransmit such inhibitors have been disclosed. For example, currently ter dopamine in the brain. Levodopa (L-dopa or L-3,4-dihy available oral drugs include SINEMETR) and sustained-re droxyphenylalanine) is an immediate metabolic precursor of lease SINEMETR) CR tablets that include levodopa and car dopamine that, unlike dopamine, is able to cross the blood bidopa, as well as MADOPAR(R) tablets containing levodopa brain barrier, and is most commonly used for restoring the and benserazide. Additional formulations of levodopa and dopamine concentration in the brain. For the past 40 years, carbidopa for Subcutaneous, preferably continuous, adminis levodopa has been remained the most effective therapy for tration are disclosed in International Publication Nos. WO treatment of Parkinson's disease. 2010/134074 and WO 2012/066538, the entire contents of 0003. However, levodopa has a short half-life in plasma each being herewith incorporated by reference in its entirety that, even under best common current standard of care, results as if fully disclosed herein. in pulsatile dopaminergic stimulation. Long-term therapy is 0007. An additional oral drug is STALEVOR tablets con therefore complicated by motor fluctuations and dyskinesia taining levodopa, carbidopa and entacapone, and formula that can represent a source of significant disability for some tions of these ingredients, e.g., for Subcutaneous administra patients. A therapeutic strategy that could ultimately deliver tion, are disclosed in the aforesaid WO 2012/066538, which levodopa? dopamine to the brain in a more continuous and further discloses oral administration of SINEMETR) and con physiologic manner would provide the benefits of standard comitant continuous Subcutaneous administration of either levodopa with reduced motor complications and is much entacapone or entacapone and carbidopa. needed by patients Suffering from Parkinson's disease and 0008 Nyholm et al. (European Journal of Neurology, other neurological or movement disorders (Olanow, Mov. 2012, 19, 820-826) shows that oral administration of 200 mg Dis., 2008, 23(Suppl. 3), S613-S622). Sustained-release oral entacapone and concomitant intraintestinal infusion of levodopa formulations have been developed but, at best, such levodopa and carbidopa at a dosage equal to 80% of the preparations have been found to be no more efficacious than optimized dose of a patient, allows maintaining a blood level standard tablets. Continuous administration of levodopa by of levodopa that is substantially the same as that achieved by intraduodenal administration or infusion has also been administration of the optimized dose of levodopa and carbi attempted by using ambulatory pumps or patches. Such treat dopa, without entacapone. In other words, Nyholm et al. ments, especially intraduodenal, are extremely invasive and shows that oral administration of entacapone allows reducing inconvenient. the initial dose of levodopa and carbidopa administered by 0004. The metabolic transformation of levodopa to 20% and still maintain the desired blood level of levodopa. dopamine is catalyzed by the aromatic L-amino acid decar 0009. Yet, the various formulations disclosed do not pro boxylase enzyme, a ubiquitous enzyme with particularly high vide the optimal treatment of Parkinson's disease due to still concentrations in the intestinal mucosa, liver, brain and brain relatively high level of side effects and levodopa blood level capillaries. Due to the extracerebral metabolism of levodopa, fluctuations. There is thus an ongoing and urgent need for it is necessary to administer large doses of levodopa leading to methods for treatment of movement disorders such as Parkin high extracerebral concentrations of dopamine that cause sons, that will provide patients with a constant blood unwanted side effects in some of the patients. Therefore, levodopa level that will lead to constant dopaminergic stimu levodopa is usually administered concurrently with oral lation in the brain, and at the same time limit the side effects administration of a dopa decarboxylase inhibitor, Such as caused by high peripheral levodopa concentration resulting carbidopa or benserazide, which reduces by 60-80% the from high dose levodopa administration. levodopa dose required for a clinical response, and thus pre vents certain of its side effects by inhibiting the conversion of SUMMARY OF INVENTION levodopa to dopamine outside of the brain. 0010. In one aspect, the present invention provides a 0005 Additional extracerebral metabolic pathways of method for treatment of Parkinson's disease in an individual levodopa are through monoamine oxidase (MAO), or cat in need thereof comprising parenterally administering a phar echol-O-methyl transferase (COMT) which converts maceutical composition comprising carbidopa and levopoda, levodopa to 3-methoxy-4-hydroxy-L-phenylalanine (3-O- or pharmaceutically acceptable salts thereof, to said indi methyldopa, 3-OMD), a metabolite that competes with vidual; and orally administering a catechol-O-methyl trans levodopa in crossing the blood-brainbarrier. Therefore, MAO ferase (COMT) inhibitor such as entacapone or tolcapone. inhibition by, e.g., moclobemide, rasagiline, selegiline or 0011. In another aspect, the present invention relates to safinamide, or COMT inhibition by, e.g., entacapone or tol carbidopa or a pharmaceutically acceptable salt thereof, capone, improves the efficacy of levodopa. Entacapone levodopa or a pharmaceutically acceptable salt thereof, and a exhibits short biphasic elimination, with a 3-phase half-life of COMT inhibitor for use as a combination in treatment of US 2016/0022573 A1 Jan. 28, 2016

Parkinson's disease, wherein the carbidopa and the levodopa has several drawbacks because oral administration results in (or salts thereof) are formulated as a sole parenteral compo fluctuations of blood levodopa level; and entacapone, when sition, and said COMT inhibitor is formulated as an oral present in one solution with carbidopa, e.g., after dissolution composition. of a tablet in the gastrointestinal tract), reduces carbidopa’s bioavailability. This is clearly indicated in Ahtila et al. (Clin BRIEF DESCRIPTION OF THE FIGURES Neuropharmacol., 1995, 18(1), 46-57), demonstrating that 0012 FIGS. 1A-1B show the effect of carbidopa on the high doses of entacapone (400 mg and 800 mg), concomi stability of levodopa in vitro and ex vivo: 1A. 6% by weight tantly orally administered with levodopa and carbidopa, levodopa and arginine Solution with various concentrations decrease the total amount of carbidopa in blood but do not (2, 1.5, 1, 0.5%) of carbidopa or no carbidopa were tested for affect the time to maximal concentration (T) of carbidopa. physical stability in vitro. The results show that carbidopa Ahtila et al. also show that the highest increase in the total prevented dark yellow color formation in the presence of air, amount of levodopa caused by the addition of entacapone to in a dose related manner (Small vials at the right hand side), oral administration of levodopa and carbidopa was about 33% and in the absence of air (with N in the head space) 0.5% (after 400 mg dose of entacapone). carbidopa was sufficient to inhibit this color formation (large 0019. The aforesaid suggests that it might be beneficial to vials in the left hand side of the figure). 1B. 7% by weight administer carbidopa separately from entacapone, i.e., using levodopa and arginine solution, with or without 2% carbidopa either different administration routes or by administering by weight, continuously administered into the Subcutaneous them in two different locations of the patient’s body. Indeed, tissue of a 5x5 cm fresh, full-thickness pig skin. The right as already shown by the present inventors and shown in WO hand side depicts the inhibition of oxidation with the use of a 2012/066538, oral administration of Sinemet(R) (levodopa/ levodopa formulation that includes carbidopa. carbidopa, 100/25 mg) and concomitant Subcutaneous administration of either entacapone or a combination of enta 0013 FIG. 2 shows that the presence of 1% carbidopa in a capone and carbidopa (formulated as different compositions) levodopa solution reduces the severity and extent of local resulted in increased blood levels of levodopa. As specifically levodopa dependent Subcutaneous toxicity in the pig. shown, entacapone and carbidopa, when continuously Sub 0014 FIGS. 3A-3C show the effect of carbidopa on the cutaneously co-administered with Sinemet(R), act in Synergy pharmacokinetics of levodopa in the pig. 3A: the plasma on the plasma pharmacokinetics of levodopa. concentration of levodopa following continuous Subcutane ous administration of 6% levodopa with various amounts of 0020. In another approach disclosed in the aforesaid carbidopa. 3B: The correlation between plasma steady state Nyholm et al., entacapone is orally administered while a concentrations of levodopa, obtained following continuous combination of levodopa and carbidopa is administered con Subcutaneous administration of levodopa/carbidopa formula comitantly by intraintestinal infusion, and as shown, oral tions and the formulation concentration of carbidopa. 3C: The administration of entacapone allows reducing the initial dose correlation between plasma steady state concentration of car of levodopa and carbidopa administered by 20% while main bidopa following continuous Subcutaneous administration of taining the desired blood level of levodopa. According to levodopa/carbidopa formulations and the formulation con Nyholm et al., the administration route disclosed may allow centration of carbidopa. an increase of up to 33% in the level of levodopa. 0015 FIGS. 4A-4B show the effect of continuous subcu 0021. It has now been found, in accordance with the taneous (SC) entacapone (E) and/or carbidopa (CD) (40 present invention, that continuous Subcutaneous administra mg/24 h) administration on the plasma concentrations of tion of a composition comprising both levodopa and carbi levodopa (LD, ng/ml) following oral administration of dopa, and concomitant oral administration of a catechol-O- Sinemet (100/25 levodopa/carbidopa) in pigs (4A); and the methyl transferase inhibitor, in particular, entacapone, to effect of continuous SC CD (40 mg/24 h) and/or LD (140 Parkinson's patients unexpectedly increases the blood level mg/24 h) administration on the plasma concentrations of LD of levodopa by more than 40%, more particularly from about following oral administration of Sinemet in pigs (4B). 420 ng/ml to about 620 ng/ml, while maintaining a constant blood level of levodopa with no substantial fluctuations, and 0016 FIG. 5 shows the effect of carbidopa on the local therefore allows significantly reducing the initial dose of Subcutaneous toxicity of levodopa following 24h continuous levodopa administered to Parkinson's patients and Subse Subcutaneous administration, at 0.16 ml/h, in pigs. quently reducing the side effects of the drug. Moreover, the 0017 FIG. 6 show the effect of oral administration of experimental data provided herein show that the subcutane entacapone (200 mg every 2h) on the plasma concentrations ous administration of a sole composition comprising of levodopa (LD), carbidopa (CD), and 3-O-methyldopa levodopa and carbidopa have additional benefits compared (3-OMD) during continuous SC administration of levodopa with separate administrations thereof due to reduced local (360 mg/24 h) and carbidopa (90 mg/24 h) in human volun side effects caused by levodopa when administered together teerS. with carbidopa. 0022. These findings show that oral administration of a DETAILED DESCRIPTION OF THE INVENTION COMT inhibitor concomitantly with a parenteral, e.g., sub 0.018. As stated above, the concomitant administration of cutaneous, administration, in particular continuous levodopa and an active agent capable of inhibiting a meta parenteral administration, of levodopa and a dopa decarboxy bolic pathway of levodopa is well known, and one of the lase inhibitor such as carbidopa leads to levodopa blood level commercially available drugs for treatment of Parkinson's that is remarkably higher than those shown in any one of the disease is STALEVOR) that, in fact, comprises a combination prior art utilizing a different administration regimen, Suggest of levodopa, carbidopa and entacapone. Nevertheless, despite ing that the administration regimen demonstrated herein of the advantages associated with a joint oral administration allows to utilize to the fullest the inhibitory potentials of both of the three ingredient, this specific route of administration inhibitors. US 2016/0022573 A1 Jan. 28, 2016

0023 The present invention thus provides a strategy for individual; and the COMT inhibitor, e.g., entacapone or tol treatment of a neurological or movement disorder Such as capone, is formulated as a pharmaceutical composition orally Parkinson's disease, comprising parenteral (e.g., continuous) administered to said individual (herein “the oral composi administration of a combination of levodopa and a dopa tion'). decarboxylase inhibitor, or pharmaceutically acceptable salts 0029. The term “pharmaceutical composition” as used of the aforesaid, concomitantly with oral administration of a herein refers to a composition comprising at least one active COMT inhibitor. Such a strategy allows providing high component as disclosed hereinformulated together with one plasma levodopa level thereby Substantially continuous or more pharmaceutically acceptable carriers or pharmaceu stimulation of the dopaminergic system in the brain, and may tically acceptable excipients. The terms “pharmaceutically allow decreasing the COMT inhibitor oral dosing regimen acceptable carrier” and “pharmaceutically acceptable excipi from 5-8 times/day to 2-3 times/day, and/or reduce daily dose ent as used herein refer to any and all solvents, dispersion of levodopa and/or COMT inhibitor. media, preservatives, antioxidants, coatings, isotonic and 0024. A neurological disorder is a disorder of the body’s absorption delaying agents, and the like, that are compatible nervous system, and the term “movement disorder as used with pharmaceutical administration. The use of Such media herein refers to a nervous system condition that causes abnor and agents for pharmaceutically active substances is well mal voluntary or involuntary movements, or slow, reduced known in the art. The compositions may also contain other moVementS. active compounds providing Supplemental, additional, or 0025. The neurological or movement disorder treatable enhanced therapeutic functions. “Pharmaceutically or phar according to the treatment strategy disclosed herein includes, macologically acceptable' include molecular entities and without being limited to, Parkinson's disease, secondary par compositions that do not produce an adverse, allergic or other kinsonism, restless leg syndrome, Huntington's disease, Shy untoward reaction when administered to an animal, or a Drager syndrome, and dystonia, as well as various conditions human, as appropriate. For human administration, prepara resulting from brain injury Such as, without limiting, carbon tions should meet Sterility, pyrogenicity, safety and purity monoxide or manganese intoxication. In one embodiment, standards as required by, e.g., the U.S. FDA Office of Bio the neurological disease to be treated according to this strat logics standards. egy is Parkinson's disease. 0030. In one aspect, the present invention thus provides a 0026. The term "dopa decarboxylase inhibitor as used method for treatment of a neurological or movement disorder herein refers to an agent capable of inhibiting the peripheral such as Parkinson's disease in an individual in need thereof metabolism of levodopa to dopamine by aromatic L-amino comprising parenterally administering a pharmaceutical acid decarboxylase such as carbidopa and benserazide. In a composition comprising carbidopa and levopoda, orpharma particular embodiment, the dopa decarboxylase inhibitor ceutically acceptable salts thereof, to said individual; and used according to the treatment strategy disclosed herein is orally administering to said individual a COMT inhibitor. In carbidopa or a pharmaceutically acceptable salt thereof. an alternative method, carbidopa and levodopa, or pharma 0027. The term “catechol-O-methyl transferase (COMT) ceutically acceptable salts thereof, are parenterally adminis inhibitor as used herein refers to an agent capable of inhib tered from two different pharmaceutical compositions, iting the degradation of levodopa to 3-O-methyldopa wherein one of those compositions comprises carbidopa or a (3-OMD) by catechol-O-methyl transferase and thus pro pharmaceutically acceptable salt thereof, and another one of longing the half-life of levodopa in the circulation. Examples said compositions comprises levodopa or a pharmaceutically of COMT inhibitors include, without being limited to, enta acceptable salt thereof. capone, that is only peripherally active, as well as tolcapone 0031. The parenteral composition may be administered by and nitecapone that are active in both the periphery and cen any parenteral administration route, e.g., Subcutaneously, tral nervous system. Preferred COMT inhibitors to be admin transdermally, intradermally, intravenously, intramuscularly, istered according to the treatment strategy disclosed herein intratracheally, intranasally, intrathecally, intragastrically or are entacapone and tolcapone. The dose of COMT inhibitor intraduodenally, and in one or more sites on the individuals administered is determined so as to allow obtaining Substan body. In particular embodiments, the parenteral composition tially constant inhibition of COMT activity upon administra is Substantially continuously administered, e.g., Substantially tion, thereby increasing the half-life of administered continuously Subcutaneously, transdermally, intradermally, levodopa and Substantially reducing the pulsatility of intragastrically or intraduodenally administered to said indi levodopa plasma levels to avoid low trough levels of plasma vidual. Continuous administration of the parenteral compo levodopa. sition may be accomplished using, e.g., an infusion pump, or 0028. According to the treatment strategy disclosed a dermal patch, namely, a device Suitable for transdermal or herein, the combination of levodopa and dopa decarboxylase Subcutaneous administration of the parenteral composition, inhibitor, e.g., carbidopa, parenterally administered to the i.e., capable of delivering said composition through the skin treated individual, may be formulated as two separate phar or mucous membrane into the bloodstream of a patient. Der maceutical compositions (herein “the parenteral composi mal patches Suitable for use according to the method of the tions') wherein one of said compositions comprises levodopa invention may have one or more compartments containing the or a pharmaceutically acceptable salt thereof, and another of parenteral composition or compositions to be administered, said compositions comprises said dopa decarboxylase inhibi and are described, e.g., in the aforesaid WO 2012/066538. tor or a pharmaceutically acceptable salt thereof, or as a sole 0032. The weight ratio between the levodopa and dopa pharmaceutical composition comprising both active compo decarboxylase inhibitor, e.g., carbidopa, administered nents (herein “the parenteral composition'). In a particular according to the method of the present invention may be any embodiment, the combination of levodopa and dopa decar weight ratio that, together with the COMT inhibitor concomi boxylase inhibitor is formulated as a sole pharmaceutical tantly administered, would be sufficient to maintain therapeu composition that is parenterally administered to the treated tic plasma levels of levodopa, no matter whether said US 2016/0022573 A1 Jan. 28, 2016

levodopa and dopa decarboxylase inhibitor are formulated as 9.2, 9.3, 9.4, 9.5, 9.6, 9.7 or 9.8, at 25° C. Such compositions a sole parenteral composition or as two separate parenteral may have a molar ratio of active components, i.e., carbidopa compositions. In certain embodiments, the levodopa: carbi and levodopa, to arginine of about 1:1.8 to about 1:3.5, or dopa weight ratio is in a range of about 20:1 to about 1:1. about 1:2.2 to about 1:2.5. More particular such compositions 0033. In certain embodiments, the parenteral composition comprise about 4% to about 12%, or about 5% to about 30%, further comprises arginine. According to particular Such by weight levodopa, and/or about 1% to about 6%, or about embodiments, the parenteral composition comprises carbi 1% to about 2%, by weight carbidopa. dopa and levodopa in an overall molar ratio to arginine of 0038. In some embodiments, the parenteral composition about 1:2 to about 1:3.5. As previously shown by the present comprises arginine, carbidopa, and at least about 4% by inventors and disclosed in WO 2010/134074 and WO 2012/ weight levodopa, as defined hereinabove, and further com 066538, such compositions are significantly more stable than prises meglumine. Certain particular such compositions are compositions where no arginine is used, or compositions those wherein the molar ratio of active components to the where basic amino acid other than arginine, e.g., lysine or arginine is about 1:1.1 to about 1:1.9, and/or the molar ratio of histidine, are used. active components to the meglumine is about 1:0.3 to about 0034. In some particular such embodiments, the 1:1.2, about 1:0.3 to about 1:1.5, about 1:0.4, or about 1:1.1. parenteral composition according to the method of the inven Other particular Such compositions are those comprising tion comprises (i) arginine, about 0.1% to about 2% by weight about 2.0% to about 11% by weight meglumine, and/or about carbidopa, and about 4% to about 8% by weight levodopa; or 10% to about 35% by weight arginine. (ii) arginine, about 0.6% to about 1.5% by weight carbidopa, 0039. In more particular embodiments, the parenteral and about 6% by weight levodopa. Such compositions may be composition comprises arginine, carbidopa, at least about 4% administered at a rate of about 0.1 to about 1000 ul/hour/site: by weight levodopa, and optionally meglumine, as defined in or at a volume of about 2 to about 10 ml/24 hour/site, e.g., any one of the embodiments above, and further comprises at about 4 to about 6 ml/24 hour? site; or at a dose of about 80 to least one agent capable of inhibiting the formation of oxida about 800 mg levodopa/day and about 20 to about 200 mg tion products, e.g., ascorbic acid or a pharmaceutically carbidopa/day; or at a rate of about 240 to about 360 mg acceptable salt thereof such as sodium ascorbate, calcium levodopa and about 60 to about 90 mg carbidopa/day/site. ascorbate, potassium ascorbate, ascorbyl palmitate, or ascor More specific Such parenteral compositions are administered byl stearate, L-cysteine, N-acetylcysteine (NAC), gluthatione Subcutaneously, transdermally, intradermally, intravenously, (GSH), Na-EDTA, Na-EDTA-Ca, or a combination intramuscularly, intratracheally, intranasally or intrathecally. thereof. 0035. In other particular such embodiments, the parenteral 0040. According to the present invention, parenteral com composition comprises (i) arginine, about 1% to about 4% by positions comprising arginine, carbidopa, at least about 4% weight carbidopa, and about 6% to about 16% by weight by weight levodopa, and optionally meglumine, as defined in levodopa; or (ii) arginine, about 1.5% to about 2.5% by any one of the embodiments above, may further comprise weight carbidopa, and about 12% by weight levodopa. Such sodium bisulfite. compositions may be administered at a rate of about 0.2 to 0041. In certain specific embodiments, the parenteral about 2000 ul/hour/site; or at a volume of about 10 to about 24 composition according to the method of the present invention ml/24 hour/site, e.g., about 12 to about 16 ml/24 hour/site; or comprises about 6% by weight levodopa, about 0.6% to about at a dose of about 600 to about 4000 mg levodopa/day and 1.4% by weight carbidopa, about 15% to about 16% by about 60 to about 500 mg carbidopa/day; or at a rate of about weight arginine, and about 0.5% by weight ascorbic acid; 800 to about 1600 mg levodopa and about 200 to about 400 may further comprise about 0.4% by weight L-cysteine and/ mg carbidopa/day/site. More specific Such parenteral compo or about 0.5% by weight NAC; and has a pH of about 9.4 to sitions are administered intragastrically or intraduodenally. about 9.6. 0036. In certain particular embodiments, the parenteral 0042. In other specific embodiments, the parenteral com composition according to the method of the invention com position according to the method of the present invention prises arginine, levodopa and carbidopa, wherein the comprises about 12% to about 15% by weight levodopa, parenteral composition has levodopacarginine molar ratio about 1.2% to about 4% by weight carbidopa, about 32% to selected from about 1:1.5 to about 1:2.5, respectively, and a about 42% by weight of either arginine or meglumine; and pH of about 8.5 to about 10, i.e., about 8.5, 8.6, 8.7, 8.8, 8.9, about 1.0% to about 1.3% by weight sodium ascorbate; may 9.0, 9.19.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10, at 25° C. further comprise about 0.1% to about 0.5% by weight L-cys Such compositions may comprise, e.g., about 1% to about teine and/or NAC and/or cysteine-HCl; and has a pH of about 20% or more, by weight, carbidopa, preferably at least about 9.6 to about 9.8. 1%, 2%, 4% or 6% by weight carbidopa; or at least about 1%, 0043. According to the present invention, a parenteral preferably about 2%. 3%, 4%, 5% or 6%, by weight levodopa. composition having any one of the various compositions More particular such compositions may further comprise a defined above is administered concomitantly with an oral pharmaceutically acceptable excipient such as N-methylpyr composition comprising a COMT inhibitor. The COMT rolidone, polyvinylpyrrolidone, propylene glycol, or a com inhibitor may be administered at a dosage of e.g., about 10 to bination thereof, and may still further comprise water. In about 1600 mg per day, about 50 to about 400 mg per day, specific embodiments, such parenteral compositions have a about 100 to about 600 mg per day, about 400 to about 1200 pH of about 8.5 to about 9.8 at 25° C. mg per day, about 1000 to about 1400 mg per day, or about 0037. In certain particular embodiments, the parenteral 1200 mg to about 1600 mg per day. The oral composition may composition according to the method of the invention com be administered 1, 2, 3, 4 or 5 times a day. In particular prises arginine, carbidopa, at least about 4% by weight embodiments, the COMT inhibitor is administered at a lower levodopa, and optionally meglumine, wherein the parenteral frequency than presently recommended, e.g., two to three composition has a pH of about 9.1 to about 9.8, i.e., about 9.1. times per day, or in a lower daily dosage amount. US 2016/0022573 A1 Jan. 28, 2016

0044. In certain embodiments, the oral composition com ments, the compositions have fewer undesirable by-products, prises entacapone, and it is administered concomitantly with e.g., toxic by-products, or contaminants, e.g., hydrazine, the parenteral composition at a dose of about 200 mg to about when carbidopa and levodopa are present at the same time, 600 mg, e.g., about 200, 250,300,350, 400, 450, 500, 550 or and when prepared using certain antioxidants, e.g., ascorbic 600 mg. twice or three times a day. In more particular Such acid or salts thereof, rather than others, e.g., Sodium bisulfite. embodiments, the oral composition is administered at a dose In other embodiments, the compositions have fewer undesir of about 350 to about 450 mg, e.g., about 400 mg. twice a day. able by-products when pre-heated water is added as disclosed 0045. In other embodiments, the oral composition com above, as compared to formulations prepared without the prises tolcapone, and it is administered concomitantly with addition of pre-heated water. In further embodiments, the the parenteral composition at a dose of about 50 mg to about levodopa and/or carbidopa may not dissolve unless the prepa 200 mg, e.g., about 50, 75, 100, 125, 150, 175 or 200 mg, ration procedure described above is used. Such preparations once, twice or three times a day. In more particular Such as described above may provide more stable formulations as embodiments, the oral composition is administered at a dose compared to formulations prepared without adding hot water of about 75 to about 125 mg, e.g., about 100 mg. twice a day. or heating. 0046 Oral compositions of the COMT inhibitor may be in 0050 Oral compositions of the COMT inhibitor may be any suitable form. For example, the oral composition may be prepared according to any method known in the art for the formulated as a pill, hard or soft capsule, tablet, troches, manufacture of pharmaceutical compositions and may fur lozenges, aqueous or oily Suspensions, dispersible powders ther comprise one or more ingredients selected from Sweet or granules, emulsions, syrups or elixirs. The oral formulation ening agents, flavoring agents, coloring agents and preserving may comprise, e.g., about 200 mg to about 600 mg, about 50 agents in order to provide pharmaceutically elegant and pal mg to about 200 mg. or 100 mg. of the COMT inhibitor per atable preparations. Tablets contain the active component, dose. In some cases, the oral formulation may be a controlled i.e., the COMT inhibitor, in admixture with non-toxic phar release formulation, i.e., formulated for controlled (sus maceutically acceptable excipients, which are suitable for the tained, extended, or prolonged) or delayed release of the manufacture of tablets. These excipients may be, e.g., inert COMT inhibitor. diluents such as calcium carbonate, Sodium carbonate, lac 0047. The various pharmaceutical compositions utilized tose, calcium phosphate, or sodium phosphate; granulating according to the method of the invention may be prepared by and disintegrating agents, e.g., corn starch or alginic acid: conventional techniques, e.g., as described in Remington: binding agents, e.g., starch, gelatin or acacia; and lubricating The Science and Practice of Pharmacy, 19" Ed., 1995. The agents, e.g., magnesium Stearate, Stearic acid, or talc. The compositions can be prepared, e.g., by uniformly and inti tablets may be either uncoated or coated utilizing known mately bringing the active component/components into asso techniques to delay disintegration and absorption in the gas ciation with a liquid carrier, a finely divided solid carrier, or trointestinal tract and thereby provide a Sustained action over both, and then, if necessary, shaping the product into the a longer period. For example, a time delay material Such as desired formulation. The compositions may be in liquid, Solid glyceryl monostearate or glyceryl distearate may be or semisolid form and may further include pharmaceutically employed. They may also be coated using the techniques acceptable fillers, carriers, diluents or adjuvants, and other described in the U.S. Pat. Nos. 4,256,108, 4,166,452 and inert ingredients and excipients. In one embodiment, the 4.265,874 to form osmotic therapeutic tablets for control pharmaceutical composition of the present invention is for release. The oral compositions may also be in the form of mulated as nanoparticles. oil-in-water emulsion. 0048. The parenteral compositions utilized may be pre 0051. The oral compositions may be formulated for either pared by mixing levodopa and a dopa decarboxylase inhibi immediate or controlled release of the COMT inhibitor. Such tor, e.g., carbidopa, optionally together with arginine and/or controlled release compositions may be formulated as con meglumine and/or one or more antioxidants, in amounts as trolled-release matrix, e.g., as controlled-release matrix tab disclosed above, to form a powder mixture. Water may be lets in which the release of a soluble active agent is controlled added to the mixture to form a Suspension. The Suspension by having the active diffuse through a gel formed after the may be heated, e.g., to about 60-90° C., more particularly to Swelling of a hydrophilic polymer brought into contact with about 72-5°C., e.g., by adding pre-heated water and/or by dissolving liquid (in vitro) or gastro-intestinal fluid (in vivo). placing the mixture in a hot (e.g., 72-5°C.) water bath for a Many polymers have been described as capable of forming Sufficient time period, e.g., for about 3 minutes, about 5 Such gel, e.g., derivatives of cellulose, in particular the cellu minutes, about 10 minutes or more, to form a solution, with lose ethers such as hydroxypropyl cellulose, hydroxymethyl optional stirring, and cooling the solution to form the com cellulose, methylcellulose or methyl hydroxypropyl cellu position. N may be provided the head space of the container. lose, and among the different commercial grades of these For example, the mixture can be removed from the hot water ethers are those showing fairly high viscosity. In other bath and cooled to room temperature (RT), and an antioxidant embodiments, the compositions comprise the active compo may then be added under N atmosphere and Subsequent nent formulated for controlled release in microencapsulated stirring. A preparation Such as that above, e.g., where dosage form, in which small droplets of the COMT inhibitor levodopa, carbidopa, and arginine are mixed together as pow are surrounded by a coating or a membrane to form particles ders first, and a Suspension with water is then formed and in the range of a few micrometers to a few millimeters. heated, may result in a more stable solution as compared to a 0052. Other contemplated formulations are depot sys preparation that includes a stepwise preparation of individual tems, based on biodegradable polymers, wherein as the poly water Suspensions of ingredients and later combination. mer degrades, the active component is slowly released. The 0049. The parenteral compositions may be sterilized, e.g., most common class of biodegradable polymers is the hydro using 0.2 uM filters such as filters with nylon or polyvi lytically labile polyesters prepared from lactic acid, glycolic nylidene difluoride (PVDF) membranes. In some embodi acid, or combinations of these two molecules. Polymers pre US 2016/0022573 A1 Jan. 28, 2016

pared from these individual monomers include poly (D.L- for either immediate or controlled release of the COMT lactide) (PLA), poly (glycolide) (PGA), and the copolymer inhibitor as described above, and may be in any one of the poly (D.L-lactide-co-glycolide) (PLG). forms described above. 0053. The treatment strategy disclosed herein is aimed at 0059. In certain embodiments, either the parenteral or oral increasing the half-life of administered levodopa and Substan composition included in the kit disclosed, or both, may be tially reducing the pulsatility of plasma levels thereof, by provided in a container(s), i.e., a pre-filled cartridge(s), Suit co-administering levodopa and a dopa decarboxylase inhibi able for use by a patient or a physician. For example, provided tor Such as carbidopa, and Substantially constantly inhibiting herein is a kit comprising a prefilled cartridge containing a COMT activity, thus providing the individual treated with a parenteral liquid composition comprising carbidopa, constant plasma levodopa level that will lead to constant levodopa and arginine; and an oral composition, e.g., one or dopaminergic stimulation in the brain, and at the same time more tablets or pills, of a COMT inhibitor, e.g., entacapone or limiting the side effects caused by high plasma levodopa tolcapone; and optionally instructions for use. levels resulting from high dose levodopa administration. 0060. The invention now being generally described, will Contemplated administration of levodopa, a dopa decarboxy be more readily understood by reference to the following lase inhibitor, and a COMT inhibitor according to the method examples which are included merely for purposes of illustra of the present invention can typically be carried out over a tion of certain aspects and embodiments of the present inven defined time period, e.g., days, weeks, months and even years, tion, and are not intended to limit the invention in any way. depending on the state of the patient, and as deemed appro priate by the practitioner. EXAMPLES 0054. In another aspect, the present invention relates to a dopa decarboxylase inhibitor or a pharmaceutically accept Example 1 able salt thereof, levodopa or a pharmaceutically acceptable salt thereof, and a COMT inhibitor, e.g., entacapone or tol Preparation of Solutions/Formulation for capone, for use as a combination in treatment of a neurologi Subcutaneous Administration cal or movement disorder, wherein the dopa decarboxylase 0061 A. A 2% carbidopa solution/formulation was pre inhibitor and the levodopa, or said pharmaceutically accept pared by adding pre-heated 0.1% Na-bisulfite solution to able salts thereof, are formulated, either separately or as a carbidopa LASSIA Ltd.. Arginine (Merck) was added to combination, as a parenteral composition(s), and saidCOMT obtain a final molar ratio of 1:1.2 CD (carbidopa): Arg(argi inhibitor is formulated as an oral composition. nine). The mixture was stirred at 60° C. until complete dis 0055. In a particular such aspect, the invention relates to Solution was obtained. Heating was stopped and the prepara carbidopa, levodopa and a COMT inhibitor, more particularly tion was allowed to cool down to RT; pH of 8.5. Solution was entacapone or tolcapone, for use as a combination in treat filtered using a sterile 0.22 LM PVDF membrane. ment of Parkinson's disease, wherein the carbidopa and the 0062 B. A 10% tolcapone solution/formulation was pre levodopa are formulated as a sole parenteral composition as pared as follows: a solution containing 10% tolcapone was defined above, and said COMT inhibitor is formulated as an prepared by adding the respective amount of H2O to tolca oral composition as defined above. pone (Synfine Research), slowly adding arginine while stir 0056. In certain embodiments, the parenteral composition ring to obtain a final molar ratio of 1:1. The mixture was (s) is formulated as a subcutaneous, transdermal, intradermal, stirred until complete dissolution was obtained. After cooling intravenous, intramuscularly, intratracheally, intranasally, down, the pH of the solution was 7.8. intrathecal, intragastrical or intraduodenal composition. Par 0063 C. A solution containing 10% entacapone was pre ticular such parenteral compositions are suitable for Substan pared by adding the respective amount of HO to entacapone tially continuous administration. (Suven Life Sciences), stirring at 30-35°C. and slowly adding 0057 Also contemplated herein is a kit comprising: (i) a arginine to obtain a final molar ratio of 1:1. The mixture was parenteral composition as defined above, i.e., a pharmaceuti stirred until complete dissolution was obtained. After cooling cal composition formulated for parenteral, e.g., transdermal, down, the pH of the solution was 6.9. The pH of less concen intradermal or Subcutaneous, administration, preferably con trated solutions (6%) was 7.8. After preparation, such enta tinuous parenteral administration, said parenteral composi capone solution can be diluted to a 2%. 3% or 4% by weight tion comprising a dopa decarboxylase inhibitor, e.g., carbi formulation. dopa, and levodopa, or pharmaceutically acceptable salts 0064. Entacapone did not dissolve (at concentrations thereof, e.g., meglumine or arginine salts thereof; (ii) an oral >1%) with other amino acids such as histidine and glutamic composition as defined above, i.e., a pharmaceutical compo acid or in buffers at various pHs. sition formulated for oral administration, said oral composi 0065 D. A 7% levodopa/2% carbidopa solution was pre tion comprising a COMT inhibitor, e.g., entacapone or tolca pared by adding pre-heated 0.1% Na-bisulfite solution to pone; and (iii) instructions for concomitant administration of arginine. Levodopa was added to obtain a final molar ratio of the pharmaceutical compositions for treatment of a neuro 1:2 LD: Arg. The mixture was stirred at 75-80°C. until com logical or movement disorder Such as Parkinson's disease. plete dissolution was obtained. After cooling down to 60°C., 0058. The parenteral composition included in the kit dis carbidopa and arginine were added to obtain a final molar closed may be liquid or a lyophilized powder that can be ratio of 1:1.2 CD(carbidopa): Arg(arginine). The mixture was reconstituted into a liquid formulation, or may form part of a stirred at 60° C. until complete dissolution was obtained. dermal patch, and/or may be designed for continuous admin After cooling, about 12.5% more arginine was added to the istration by any suitable parenteral administration route Such solution. The pH of the solution was about 9.2. as transdermally, intravenously, Subcutaneously, intrader 0.066 E. A 7% weight percent levodopa solution was pre mally, intramuscularly, intragastrically or intraduodenally. pared by adding pre-heated 0.1% Na-bisulfite solution to The oral composition included in the kit may be formulated arginine. Levodopa was added to obtain a final molar ratio of US 2016/0022573 A1 Jan. 28, 2016 7

1:2 LD: Arg. The mixture was stirred at 75-80°C. until com- stirring for 13 min at 75° C. until fully dissolved. LD/CD plete dissolution was obtained. After cooling down, the pH of solution was kept at RT for 10 minto cool down. the solution was about 9.4. (0073 Method 3 (Same as 2 without Na-Bis Pre-Heating). 0067 F.A.2% or 4% entacapone ortolcapone solution was 10074 All powders (LD, CD and L-Arg) were weighed prepared by dissolving entacapone or tolcapone in a solution together and water was added. Suspension was heated with containing 1 equivalent of meglumine (molar ratio of entaca- E, E,R t Rio s Aliyed LD/CD pone/tolcapone:meglumine was 1:1) at a pH of 8.23. (0075 Method 4 (Preparation in Steps). Example 2 0076 LD and the respective amount of L-Arg were weighed; water and Na-Bissolution were added. The suspen sion was heated for 7 min at 75° C. until fully dissolved Formulation Preparation Procedure followed by 7 min at RT. CD and the respective amount of 0068 Levodopa (LD) and carbidopa (CD) formulations L-Arg were weighed, and added to the LD/Arg solution at 60° can be prepared as follows. However, as shown in Table A, the C. until fully dissolved. Finally, extra L-Arg was added. method of preparation has significant impact on the resulting (0077 Method 5 (Same as 4 without Na-Bis Pre-Heating). physical and chemical stability of the composition. (0078 LD and the respective amount of L-Arg were weighed; water was added. The suspension was heated for 7 0069 Method 1 (L-Arg Solution). min at 75° C. until fully dissolved followed by 7 min at RT. 10070l. L-Arg and Na-Bis (Na-bisulfate) were dissolved in CD and the respective amount of L-Arg were weighed, and water. The solution was added to the LD and CD powders. added to the LD/Arg solution at 60° C. until fully dissolved. The mixture was heated with stirring for 13 min at 75° C. until Finally, extra L-Arg was added. fully dissolved. LD/CD solution was kept at RT for 10 minto 0079. After cooling down, all formulations from all meth cool down. ods were divided in to 3 vials, and water, Na-Bissolution or (0071 Method 2 (all Powders Together). Na-Bis-Arg solution was added to each vial. The physical and 0072 All powders (LD, CD and L-Arg) were weighed and chemical stability were evaluated and are presented in Tables water with Na-Bis was added. Suspension was heated with A1 and A2. TABLE A1 Physical stability

First test Second test

Metho 24 hours 48 hours 72 hours 24 hours 48 hours

1 Water ------NR NR --- NR Na-Bissolution ------Na-Bissolution ------titrated with L-Arg 2 Water ------NR +f- Na-Bissolution -- +f- Na-Bissolution +f- +f- titrated with L-Arg 3 Water -- Very few Na-Bissolution + (more than particles at the 13, 15) bottom Na-Bissolution -- titrated with L-Arg 4 Water -- NR NR -- NR Na-Bissolution -- -- Na-Bissolution +f- -- titrated with L-Arg 5 Water ---- NR NR -- NR Na-Bissolution ------Na-Bissolution ------titrated with L-Arg

- No precipitate + Precipitate

0080. The formulations were sampled for HPLC analysis at the end of the preparation and after 5 days at RT. The recovery after 5 days at RT was calculated and compared to T=0. I0081. The results in Table A1 and A2 clearly show that the method of formulation preparation has a significantimpact on its physical and chemical stability. The formulation of Method 3 shows significantly more stability. US 2016/0022573 A1 Jan. 28, 2016

TABLE A2 Chemical stability First test Second test LD recovery CD recovery LD recovery CD recovery after 5 days after 5 days after 5 days after 5 days Metho (%) (%) (%) (%)

e 90.6 98.0 89.5 100.4 Bissoluti 90.6 98.6 87.O 101.3 Bissoluti 90.8 98.0 88.9 99.9 ed with e 98.4 98.2 99.1 100.1 Bissoluti 98.2 98.1 99.4 10O.S Bissoluti 99.0 98.5 98.9 99.5 ed with e 99.7 97.5 95.5 (al 96.5 Bissoluti 99.2 97.7 97.7 (b) 99.1 Na Bissoluti 99.5 98.1 94.9) 96.2 itra ed with 4 Wa e 97.7 97.5 96.3 99.3 Na Bissoluti 96.O 95.8 94.9 97.6 Na Bissoluti 97.7 97.9 96.3 100.0 itra ed with S Wa e 97.9 96.3 98.1 100.9 Na Bissoluti 98.2 98.0 98.2 102.2 Na Bissoluti 97.4 96.7 98.3 100.6 itra ed with lThe recovery values were lower at the second test compared to the first test, due to technical problem which scurred during the sampling, PlThe recovery values were lower at the second test compared to the first test, due to technical problem which occurred during the sampling, Example 3 Effect of Arginine on Long Term Stability of Levodopa and Levodopa/Carbidopa Compositions 0082 Liquid formulations with levodopa, carbidopa and arginine were prepared using the procedure outlined in Example 2, and comparative studies on formulations with a different concentration of arginine and/or an amino Sugar (e.g., meglumine), and/or a Sugar (e.g. dextrose), and/or a base (NaOH), or another basic amino acid (e.g., lysine, his tidine) were prepared. The results are shown in Table B. TABLE B

Amino Acid (AA Other

LD, CD Molar Molar Conc. Conc. ratio Conc. ratio Physical (%) Name (%) (API:Arg) Name (%) (API:CI) Dissolution stability at RT 1OO Lys 8.5 :2.5 NA 5.0 Lys 9.25 :2.5 NA 3.3.0 Lys 6.2 :2.5 NA 3.0 Lys S.6 :2.5 2.S.O Lys 4.6 :2.5 5.0 His 9.8 :2.5 2.S.O His 4.9 :2.5 NA 1.2SiO His 2.5 :2.5 14 days 9:O 8.2 :1 NA 4.7.0 4.0 :1 NA 9.S.O 15.9 :19 days 4.8.1.4 11.0 :20 months 4.8.1.4 12.1 :22 months 4.8.1.4 12.7 :2.4 months S.4f1.5 13.5 :2.1 months S.4f1.5 14.8 2.3 months 6.1.5 14.8 :2.1 month 6.1.5 16.0 2.3 months 7.2 17.8 :22 month 71.5 14.1 :18 Color change US 2016/0022573 A1 Jan. 28, 2016

TABLE B-continued

Amino Acid (AA Other

LD, CD Molar Molar Conc. Conc. ratio Conc. ratio Physical (%) Name (%) (API:Arg) Name (%) (API:CI) Dissolution stability at RT 8/1.5 Arg 15.7 1:19 Dex S.O Yes Color change 10/1.5 Arg 19.2 1:19 Dex S.O Yes Color change 6/1.5 Arg 9.3 1:1.5 NaOH 4.6 1:O.S Yes e3 months 5.0 Meg S.O 1:1 NA 5.0 Meg 5.9 1:12 NA 5.0 Meg 10.8 1:22 NA 8/1.5 Arg 15.7 1:19 Meg 3.2 1:04 e4.5 months 8/1.5 Arg 12.2 1:15 Meg 7.9 1:1 e4.5 months 10/1.5 Arg 19.2 1:19 Meg 4.0 1:04 e4.5 months 10/1.5 Arg 14.6 1:15 Meg 9.9 1:1 e4.5 months 7/1.5 Arg 14.1 1:19 Meg 2.8 1:04 e4.5 months 7/1.5 Arg 10.7 1:1.5 Meg 6.9 1:1 e4.5 months *Lys—lysine; His—histidine; Arg-arginine; Dex—dextrose; Meg meglumine; NA-not available,

0083 Table B indicates that arginine forms stable solu TABLE C1-continued tions with high concentrations of levodopa and carbidopa (>2.5%) at molar ratios <1:2.5, whereas with other basic Stability amino acids LD does not even dissolve under these condi tions. At molar ratios of LD/CD to arginine 1:<2, the solutions L-Arg Physical (% from T = 0) at RT do not have long term stability, unless meglumine or another counterion is used, and meglumine may be used to reduce the concentration stability 5 days 2 months molar ratio of arginine to LD/CD. 0084. Liquid formulations were prepared by weighing all Formulation (%) at RT LD CD LD CD powders (LD, CD and L-Arg) and the addition of water pre heated to 73+3° C. Suspension was put in a water bath at 4.81.4% 11.0 At least 2 99.4 97.3 100.1 93.7 73+3° C. and stirred for 10 min until fully dissolved. LD/CD LD, CD 11.6 months 98.9 97.4 100.6 96.2 solution was kept at RT for 10 min to cool down. Then, (1% Na-Asc) 12.1 99.1 97.0 100.3 94.3 ascorbic acid was added. Solutions were divided into glass 12.7 99.4 97.2 99.0 92.4 vials and kept at +25° C. and at -20° C. for the indicated period of time. Prior to analyses, frozen vials were placed at RT until fully thawed. Formulations were then mixed and Subjected to stability analyses. TABLE C2 0085 Tables C1-C6 indicate the effect of L-Argon physi Stability (% from T = 0) cal and chemical long term stability at +25°C. and at -20°C. 2 weeks at -20 + 5°C. In particular, these Tables show that there is a correlation L-Arg Immediately 24 hours between the molar ratio of arginine to LD/CD and stability concentration Physical after thawing at RT where generally compositions having more arginine, have longer stability: LD/CD:arginine solutions (at molar ratios of Formulation (%) stability LD CD LD CD 1:-2.1) are stable for at least 1 month at RT and at -20+5°C. 6.1.5% LD, CD 13.5 At least 99.7 98.4 100.0 99.1 The solutions are stable even at very high Solid concentrations (1% Na-Asc) 14.2 24h after 99.8 98.1 101.O. 99.4 at -20°C. 14.8 thawing 1OO.O 98.9 99.9 98.9 (total of >45%). 16.0 99.9 98.8 100.3 99.3 TABLE C1

Stability TABLE C3 L-Arg Physical (% from T = 0) at RT L-Arg concentration Physical stability (at RT concentration stability 5 days 2 months Formulation (%) 1% Na-Asc 1% Asc Formulation (%) at RT LD CD LD CD 6.1.5% LD, CD 14.8 At least 3 weeks At least 3 days 15.8 16.8 6.1.5% LD, CD 13.5 6 days 10O.O 97.5 S.4f1.5% LD, CD 12.3 At least 3 days (1% Na-Asc) 14.2 At least 100.8 96.7 13.5 14.8 7 days 99.6 96.6 14.8 16.O 99.5 96.6 US 2016/0022573 A1 Jan. 28, 2016

TABLE C4 L-Arg Physical stability Stability (% from T = O) at RT

conc. (after 2 month at 1 weeks 2 weeks 1 month Formulation (%) RT) LD CD LD CD LD CD

S.4f1.5% LD, CD 13.5 -- 101.4 100.4 101.7 98.4 98.8 103.1 (1% Asc) 14.8 -- 101.4 101.4 102.0 100.1 99.0 1042 6.1.5% LD, CD 14.8 -- 101.8 101.5 101.6 99.6 99.0 1042 (1% Asc) 16.0 101.1 100.4 102.8 100.6 99.4 1042 7.2% LD, CD 17.8 -- 101.7 101.0 102.7 99.7 98.7 103.1 (1% Asc) 7.2% LD, CD 1006 NA 101.9 99.2 98.4 103.6 (1% Na-Asc)

TABLE C5 TABLE C6 Stability Stability (% from (% from LD, CD L-Arg T = 0) T = 0) concentration concentration (%) Physical stability at 25°C. 2 weeks at 5 weeks at –20 + 5° C., -20 + 5° C., Physical immediately immediately 12.3% 24.4 Considerable precipitate on Day 5 stability (11 after after L-Arg days after thawin thawin 29.6 Slight precipitate on Day 5 32.1 No precipitate on Day 7 Formulation conc. (%) thawing) LD CD LD CD S.4f1.5% LD, CD 13.5 -- 102.3 99.5 99.4 104.3 (1% Asc) 14.8 102.7 101.3 99.6 104.6 6.1.5% LD, CD 14.8 102.6 101.1 99.1 104.2 (1% Asc) 16.O 103.2 100.9 99.2 104.3 7.2% LD, CD 17.8 -- 102.8 101.O. 99.2 104.3 I0086 Formulations containing 6/1.5% and 5.4/1.5% (1% Asc) LD/CD and varying L-Arg concentrations were titrated with 7.2%(1% Na-Asc) LD, CD 102.9 101.O. 99.4 104.4 acetic acid (100%)O or lactic acid (85%),O to study the effect of pH and L-Arg concentration on the physical stability of the solutions (Table D). TABLED L-Arginine Asci pH Lactic pH after (%) Na-Asc before (%) lactic pH drop 4 hours 24 hours

6.1.5% 4.8 Na-Asc 9.53 .1 9.25 -0.28 OK -- LD, CD 9.53 7 9.16 -0.37 -- -- 9.53 2.3 9.02 -0.51 ------4.8 Asc 941 O.85 9.24 -0.17 OK -- 942 3 9.14 -0.28 -- -- 941 7 9.06 -0.35 -- -- 5.8 Na-Asc 9.S2 .1 9.33 -0.19 OK OK 9.SO 7 9.21 -0.32 OK -- 9.53 2.3 9.08 -0.45 -- -- 5.8 Asc 9.44 O.85 9.27 -0.17 OK OK 9.45 3 9.19 -0.26 OK -- 9.45 7 9.11 -0.34 -- -- 6.8 Na-Asc 9.S6 .1 9.36 -0.20 OK OK 9.S6 7 9.23 -0.33 OK OK 9.S6 2.3 9.09 -0.47 OK -- 6.8 Asc 946 O.85 9.30 -0.16 OK OK 946 3 9.20 -0.26 OK OK 9.47 7 9.11 -0.36 OK --

L-Arginine Asc pH Lactic Acetic pH 2 3 10 (%) Na-Asc before (%) (%) after pH drop days days days

S.4f1.5% 12.3 Na-Asc 9.41 O.36 9.35 -0.06 OK -- -- LD, CD 9.43 1.O 9.18 -0.25 ------9.43 O.35 929 -0.14 OK -- -- 12.3 ASc 9.28 O.36 9.20 -0.08 ------9.29 1.O 9.05 -0.24 ------9.29 O.35 9.14 -0.15 ------US 2016/0022573 A1 Jan. 28, 2016 11

TABLE D-continued 13.5 Na-Asc 9.SO O.36 9.38 -0.12 OK OK OK 9.48 1.O 9.25 -0.23 ------949 O3S 9.35 -0.14 OK OK OK 13.5 Asc 9.32 O.36 9.25 -0.07 ------9.33 1.O 9.11 -0.22 ------9.34 O3S 920 -0.14 ------14.8 Na-Asc 9.51 943 -0.08 OK OK OK 9.51 9.28 -0.23 OK OK OK 9.51 O3S 9.38 -0.13 OK OK OK 14.8 Asc 9.36 929 -O.O7 OK OK OK 9.37 9.13 -0.24 +f- -- -- 9.36 O3S 9.23 -0.13 OK OK OK * OK-no precipitate; +- very few particles; + slight precipitate; ++ considerable precipitate

0087 Table D indicates that ascorbic acid reduces the pH TABLE F-continued by 0.1-0.15 units as compared to Na-ascorbate and that other organic acids can further reduce the pH of the formulations. Stability (% from T = 0 But the physical stability test results indicate that formula Physical 3 days 15 days tions are not generally stable at pH-9.15-0.5. Formulations with Na-ascorbate appear more stable than formulations with Formulation N, +/- stability LD CD LD CD ascorbic acid at a given L-arginine concentration. Thus, it is 296 CD -- 4 days 98.9 94.5 102.9 103.3 Suggested that excess of acid may cause precipitation in the 98.3 94.8 absence of adequate amount of L-Arg. 0088 Table E shows the physical and chemical stability 3 0090 The experimental results shown in FIG. 1A indicate weeks post-preparation of the 6/1.5/14.8% LD/CD/Arg for that carbidopa prevented dark yellow color formation in the mulation used for the stability tests shown in Table D. presence of air, in a dose related manner. In the absence of air (with N in the head space) 0.5% CD was sufficient to inhibit TABLE E this color formation. It is suggested that CD inhibits oxidation Stability of LD in vitro. The experimental results shown in Table F Physical % of To indicate that carbidopa does not have a significant effect on the chemical stability of levodopa. It also shows that the ratio Formulation Asc/Na-Asc (1%) stability (at RT) LD CD between arginine and the total active ingredients is important 6/1.5% LD/CD, Asc e3 weeks 103.1 98.9 to prevent precipitation, i.e., the physical stability of the for 14.8% L-Arg Na-Asc 101.1 97.4 mulation is depended on the relative concentration of arginine 0091. In an additional experiment, LD formulations were prepared with 0, 0.5, 1 and 2% CD and respective concentra tions of arginine. Physical and chemical stability were evalu Example 4 ated, and results are shown in Table G. Stability of Levodopa Formulations with Carbidopa TABLE G In-Vitro and Ex-Vivo Chemical stability at Physical RT (% of to stability at 0089. The effect of carbidopa on levodopa formulations was investigated. Levodopa (LD) formulations were prepared 1 month after RT1 month with 0, 0.5, 1, 1.5 and 2% by weight carbidopa (CD) and a L-Arg 3 days thawing after constant concentration of arginine. Physical and chemical Formulation (%) LD CD LD CD thawing LD stabilities were evaluated, as shown in Table F. 6% LDiO% CD 13.5 102.3 - 6% LD 13.5 102.3 O% CD TABLE F 6%. L.D.O.5% 14.2 103.3 100.4 6% LD 14.2 103.3 CD O.S90 CD Stability (90 from T = 0 6% LD.1% CD 14.8 103.S 101.3 6% LD, 14.8 103.5 196 CD Physical 3 days 15 days 6%. L.D.2% CD 16.5 103.3 101.66% LD, 16.5 103.3 2% CD Formulation N2 +/- stability LD CD LD CD 7%LD wo CD + Stable 99.2 NA 103.4 NA - Stable 98.1 NA - NA 0092. In the presence of adequate concentrations of O.S90 CD + Stable 98.6 94.7 104.1 108.1 L-arginine, all formulations ex-vivo were stable for at least a - Stable 98.7 95.6 month at RT following thawing, as shown in Table G. 196 CD + Stable 98.9 95.2 102.5 104.4 (0093. The effect of carbidopa on the stability of levodopa - Slight 97.9 94.0 - precipitate formulations is shown in FIG.1. A 7% LD/arginine solution, 1.5% CD + 7 days 98.1 94.2 103.7 104.8 with or without 2% CD, was continuously administered at 99.6 96.O - 0.08 ml/hx 18 h, 37°C. into a 5x5 cm fresh, full-thickness pig skin. The right hand side of FIG. 1 indicates the lack of black US 2016/0022573 A1 Jan. 28, 2016 by-products formation, Suggesting that CD inhibits oxidation after. FIG. 2 shows that the presence of 1% carbidopa reduces of LD ex vivo and may also inhibit the formation of o-quino the severity and extent of levodopa dependent toxicity, in nes and melanin. V1VO. 0097. The effect of carbidopa on the pharmacokinetics of Example 5 levodopa and carbidopa were investigated. Solutions contain ing 6%. LD and 0,0.5, 1 or 2% CD and the respective amount Stability of Carbidopa Formulations with Levodopa of arginine (13.5, 14.2, 14.8 or 16.5%, respectively) were 0094. The effect of levodopa on the stability of carbidopa continuously administered SC to pigs at 0.16 ml/h 24h. FIG. was investigated. Table H indicates results. 3 shows that CD has a significant effect on the pharmacoki 0095 Table H indicates that CD was less sensitive to oxi netics of LD. This effect was dose dependent and linear dation and degradation and was more stable in the presence of between 0.3 and 1.2% CD. LD: the area of impurities at retention time (R.T.) 4.82, 5.65, Example 7 12.7, 13.53 and 14.55 were significantly increased under aerobic conditions when LD was not present, and the area of Plasma Levels of Levodopa Following Subcutaneous impurities at R.T. at 4.82 and 13.53 were increased even in the Administration absence of oxygen. It appears that LD may protect CD from 0098. In this experiment, the purpose was to determine the degradation. plasma levels of LD (levodopa) following continuous Subcu TABLE H

T = O T = 4 days at 25° C.

LD CD LD CD Recovery of CD Formulation (mg/g) (mg/g) (mg/g) (mg/g) (% of tO)

6%. L.D.2% CD 60.3 19.4 Air 63.2 18.9 97.4 N 62.9 19.0 97.9 296 CD NA 19.5 Air NA 15.9 81.5 N NA 19.0 97.4

T = O Retention time (area of impurity)

Formulation 3.38 3.54 4.2 485 S.2 S.S2 S.77 12.10 13.3S 13.6O 14.60

6%. L.D.2% NA NA 1.08 3.15 1.67 O.34 0.86 NA 148 0.95 1.63 CD 296 CD 1.30 O2S NA 1.79 NA NA. O.95 0.35 NA 1.4S 3.83 CD vs. CDLD O.6 1.1 1.5 2.3

T = 4 days Retention time (area of impurity) at 25°C. 3.15 3.32 4.12 4.82 S6S 11.92 12.10 12.27 12.70 13.53. 14.SS

6%. L.D.2% Air 12.23 1.00 2.10 3.57 1.94 0.79 0.69 0.89 1.34 134 16.82 CD N 8.09 (0.82 1.48 363 1.61 O.44 OS3 O.S6 O.56 1.08 1182 296 CD Air NA 1.59 NA 9.49 1.18 NA NA NA 7.54 24.04 70.22 N, NA 1.65 NA 6.63 1.07 0.23 NA NA O.SO 3.62 25.45 CD vs. CDLD Air 1.6 2.7 O.6 S. 6 17.9 4.2 N 2.O 1.8 O.7 O.S O.9 3.4 2.2

Example 6 taneous administration of carbidopa, levodopa or entacapone and combinations thereof with oral LD/CD in pigs. 0099 LandracexLarge White female pigs weighing about Toxicity and Pharmacokinetics of Levodopa 22 kg were treated, starting on Day 1 at 15:00 as per Table I, Formulations with Carbidopa with oral LD/CD 100/25 and with the respective test formu lations, containing carbidopa, levodopa or entacapone and 0096. The effect of carbidopa on levodopa local toxicity combinations thereof, formulated with arginine, as described was investigated in pigs: Solutions containing 6% LD and 0. above, and administered continuously Subcutaneously via a 0.5 or 1% CD with the respective amount of arginine (13.5. dermal patch (OmnipodR) at a rate of 0.08 ml/h. 14.2 or 14.8%, respectively) were continuously administered 0100 Table I indicates the treatment protocol of each SC to pigs at 0.16 ml/hx24 h. Each formulation was admin group. The formulations were prepared as in Example 1 and istered to 2 pigs. Skin samples were collected 8+1 days there 2. US 2016/0022573 A1 Jan. 28, 2016 13

TABLE I

Treatment group

None CD CD - E E LD - CD LD

l 3 3 3 2 2 1 SC route of No SC 2% 2% carbidopa + 10% 79% 79% administration treatment carbidopa 10% entacapone levodopa + levodopa entacapone 2% carbidopa Oral treatment 100/25 levodopacarbidopa

I0101 Blood samples were collected following the 3' oral plasma concentrations of LD following the continuous SC dose at pre-determined time points and plasma levels of administration of CD and entacapone each alone (FIG. 1A levodopa, carbidopa and 3-OMD were analyzed by HPLC and Table 2, C vs. B+D). Results also show that there is an ECD. additive effect between levodopa (140 mg/24 h) and CD (40 0102 FIG. 4 indicates the mean levodopa plasma concen mg/24 h) on the plasma PK of levodopa (ng/ml) when co trations following oral administration of Sinemet (oral 100/ administered continuously subcutaneously, as compared to 25LD/CD) with continuous SC administration of entacapone the calculated LD plasma PK obtained after adding the (200 mg/24 h)+CD (40 mg/24 h), as two separate composi plasma concentrations of LD following the continuous SC tions (FIG. 4A); or LD (140 mg/24 h)+CD (40 mg/24 h) in administration of CD and LD each alone (FIG. 1B and Table pigs (FIG. 4B) (all Subcutaneous formulations included argi 2, E vs. D+F). Moreover, the results suggest that continuous nine, as above). SC administration of LD and CD may be sufficient to main (0103 Results show that there is a synergistic effect tain constant, continuous levodopa plasma concentrations between entacapone (200 mg/24 h) and CD (40 mg/24 h) on even in the absence of oral LD/CD administration (FIG. 4B the plasma pharmacokinetics (PK) of levodopa (ng/ml) when dotted line and Table J E minus A). Table J presents concen co-administered continuously subcutaneously, as compared trations of plasma levodopa 6/2 and 8 h post-oral LD/CD to the calculated LD plasma PK obtained after adding the administration. TABLEJ

SC treatment

(LD + CD) - None LD - CD E - CD Time calculated calculated calculated point (h) None A E B E + CDC CD D LD + CDE E - A LD F D - F B - D

6.5 51 179 1695 998 1226 1174 322 132O 1177 8 O O 1474 868 1227 1227 413 1281 868

* E-entacapone; CD-carbidopa; LD—levodopa; NA-not Available

0104 FIG. 5 shows tissue biopsies from the application site of the levodopa-carbidopa arginine combination formu lation and the levodopa?arginine formulation. No visible tis Sue irritation or damage was apparent in the levodopa-carbi dopa arginine formulation. The site administered with levodopa-arginine formulation appears to have some black ening of tissue. Without being limited by any theory, it is thought that having carbidopa and arginine together with levodopa (arginine) formulation protects the local tissue from local damage of levodopa by preventing oxidation of levodopa into irritant by products, and that carbidopa is a potent anti-oxidant. US 2016/0022573 A1 Jan. 28, 2016 14

Example 8 Additional Exemplary Carbidopa and Levodopa/Carbidopa Formulations 01.05 In Tables K and L. additional non-limiting exem plary carbidopa and levodopa/carbidopa formulations are provided. TABLE K Additional carbidopa formulations Property 1 2 3 API concentration 2 & 4% 4% O6-20% CD:arginine ratio 1:1.1-1.2 1:1.5 1:1 Excipients NMP 3.5% O 0-15% concentration Na-bisulfite O.1% O O-O.2% Ascorbic Acid O 0.75% 0-2% or more L-Cysteine O O.1% 0-0.2% or more Other anti-oxidants O-290 Osmolality 650-750 300-400 200-1800 for SC No limits for ID pH 82-86 8.6-9.1 8-9.8 Stability 25o C. 48-72 hours e21 days 2 wks-e2 years 4° C. Not stable e21 days 2 wks-e2 years -20°C. e1 year e21 days 2 wks-e2 years SC infusion 24 hours 2 ml 2 ml 0.1-6 ml

TABLEL Additional levodopa/carbidopa formulations Property 4 5 6 API CD O or 1 or 2% 1-2% O-4% up to 8% concentration LD 3-7% 5-79% 2.5-12% up to 24% Ratios LD to CD ratio 6:1–6:3 or LD alone 3.5-4:1 1:1-10:0.5 CD:arginine ratio 1:1-2 1:9-14 1:1 LD:arginine ratio 1:1.8-2.2 1:2-3.5 1:1.8 API: arginine ratio 1:1.2 CD:Arg-- 1:23-25 1:1.8 1:2 LD: Arg) + 12.5% Arg Excipients NMP O O O Na-bisulfite O.O75-0.15% O O-O.2% Ascorbic acid O 0.75 0-2% or more Other anti-oxidants O-290 Osmolality 9.1% LD, CD 1300-1500 200-1800 for SC 7.2% LD, CD 950-11SO 1200-1300 No limits for ID 6.1.5% LD, CD 800-850 940-98O S$1.25% LD, CD NT 790-830 pH 8.5-9.5 9.2-9.6 9.1-9.8 Stability 25o C. e2 days e2 months e2 days 4° C. <2 days e2 days e2 days -20°C. e2 days e2 months e2 months SC infusion 24 hours 2 ml 2-6 ml 0.1-10 ml site Intraduodenal 24 hours 4-24 ml Intrathecal 1-1000 uliday

Example 9 0107 A single center, double-blind, randomized, placebo controlled, study was conducted with six healthy Caucasian males volunteers, aged 18-40 years old. LD (6%)/CD (1.5%) Plasma Levels of Levodopa, Carbidopa, and was administered at a rate of 240 ul/h, corresponding to 360 3-O-Methyldopa Following Continuous mg of LD and 90 mg of CD per 24 hours. Entacapone (200 Subcutaneous Administration of Carbidopa and mg) was administered orally every 2 hours, starting 15 h after Levodopa and Oral Administration of Entacapone infusion initiation of LD/CD. Plasma LD, CD and 3-OMD 0106. In this experiment, the purpose was to determine the concentrations were quantified at pre-determined time points. plasma levels of levodopa (LD), carbidopa (CD), and 3-O- 0108. As shown in FIG. 6, the results demonstrate that oral methyldopa (3-OMD) following continuous subcutaneous entacapone increased the plasma concentrations of LDattain administration of carbidopa and levodopa, and oral adminis able with the continuous SC administration of LD/CD by tration of entacapone in human Volunteers. 50% within 9 hours after the initiation of entacapone dosing. US 2016/0022573 A1 Jan. 28, 2016

The plasma concentrations of LD did not reach a steady state 9. The method of claim 8, wherein said composition is by the time the study was terminated 24 hours after LD/CD administered Subcutaneously, transdermally, intradermally, infusion initiation and 9 hours after entacapone dosing initia intravenously, intramuscularly, intratracheally, intranasally tion. The plasma concentrations of 3-OMD were significantly or intrathecally. reduced. These results suggest that rather than administering 10. The method of claim 6, wherein said composition com 200 mg of entacapone 6-8 times daily, as is typically done prises (i) arginine, about 1% to about 4% by weight carbi with oral LD/CD administration, 400 mg entacapone can dopa, and about 6% to about 16% by weight levodopa; or (ii) instead be administered, e.g., twice or three times daily. arginine, about 1.5% to about 2.5% by weight carbidopa, and about 12% by weight levodopa. EQUIVALENTS 11. The method of claim 10, wherein said composition is 0109 While specific embodiments of the subject inven administered at a rate of about 0.2 to about 2000 ul/h/site; or tion have been discussed, the above specification is illustra at a volume of about 10 to about 24, preferably about 12 to tive and not restrictive. Many variations of the invention will about 16 ml/24 h/site; or at a dose of about 600 to about 4000 become apparent to those skilled in the art upon review of this mg levodopa/day and about 60 to about 500 mg carbidopa/ specification. The full scope of the invention should be deter day; or at a rate of about 800 to about 1600 mg levodopa and mined by reference to the claims, along with their full scope about 200 to about 400 mg carbidopa/day/site. of equivalents, and the specification, along with Such varia 12. The method of claim 11, wherein said composition is tions. administered intragastrically or intraduodenally. 0110. Unless otherwise indicated, all numbers expressing 13. The method of any one of claims 1 to 12, wherein said quantities of ingredients, reaction conditions, and so forth COMT inhibitor is entacapone or tolcapone, and is adminis used in the specification and claims are to be understood as tered 1, 2, 3, 4 or 5 times a day. being modified in all instances by the term “about'. It should 14. The method of claim 13, wherein said COMT inhibitor be noted that where particular values are described in the is entacapone, and is administered at a dose of about 200 mg description and claims, unless otherwise stated, the term to about 600 mg, preferably about 400 mg. twice or three "about’ means that an acceptable error range, e.g., up to 5% times a day. or 10%, for the particular value should be assumed. 15. The method of claim 14, wherein the entacapone is administered twice a day. INCORPORATION BY REFERENCE 16. The method of claim 13, wherein said COMT inhibitor 0111. The entire contents of all patents, published patent is tolcapone, and is administered at a dose of about 50 mg to applications, websites, and other references cited herein are about 200 mg, preferably about 100 mg. once or twice or three hereby expressly incorporated herein in their entireties by times a day. reference. 17. The method of claim 16, wherein the tolcapone is 1. A method for treatment of Parkinson's disease in an administered twice a day. individual in need thereof comprising parenterally adminis 18. Carbidopa, levodopa and a COMT inhibitor for use as tering a pharmaceutical composition comprising carbidopa a combination in treatment of Parkinson's disease, wherein and levopoda to said individual; and orally administering a the carbidopa and the levodopa are formulated as a sole catechol-O-methyl transferase (COMT) inhibitor. parenteral composition, and said COMT inhibitor is formu 2. The method of claim 1, wherein said composition is lated as an oral composition. administered Subcutaneously, transdermally, intradermally, 19. The use of claim 18, wherein the carbidopa and the intravenously, intramuscularly, intratracheally, intranasally, levodopa are formulated as a subcutaneous, transdermal, intrathecally, intragastrically or intraduodenally. intradermal, intravenous, intramuscularly, intratracheally, 3. The method of claim 1, wherein said composition is intranasally, intrathecal, intragastrical or intraduodenal com administered in one or more sites on the individual’s body. position. 4. The method of any one of claims 1 to 3, wherein said 20. The use of claim 18, wherein said parenteral composi composition is Substantially continuously administered. tion is Suitable for Substantially continuous administration. 5. The method of claim 4, wherein said composition further 21. The use of any one of claims 18 to 20, wherein said comprises arginine. parenteral composition further comprises arginine. 6. The method of claim 5, wherein said composition has a 22. The use of claim 21, wherein the composition has a molar ratio of carbidopa and levodopa to arginine of about 1:2 molar ratio of carbidopa and levodopa to arginine of about 1:2 to about 1:3.5. to about 1:3.5. 7. The method of claim 6, wherein said composition com 23. The use of claim 22, wherein said composition com prises (i) arginine, about 0.1% to about 2% by weight carbi prises (i) arginine, about 0.1% to about 2% by weight carbi dopa, and about 4% to about 8% by weight levodopa; or (ii) dopa, and about 4% to about 8% by weight levodopa; (ii) arginine, about 0.6% to about 1.5% by weight carbidopa, and arginine, about 0.6% to about 1.5% by weight carbidopa, and about 6% by weight levodopa. about 6% by weight levodopa; (iii) arginine, about 1% to 8. The method of claim 7, wherein said composition is about 4% by weight carbidopa, and about 6% to about 16% by administered at a rate of about 0.1 to about 1000 ul/h/site; or weight levodopa; or (iv) arginine, about 1.5% to about 2.5% at a volume of about 2 to about 10, preferably about 4 to about by weight carbidopa, and about 12% by weight levodopa. 6, ml/24 h/site; or at a dose of about 80 to about 800 mg levodopa/day and about 20 to about 200 mg carbidopa/day; or 24. The use of any one of claims 18 to 23, wherein the at a rate of about 240 to about 360 mg levodopa and about 60 COMT inhibitor is entacapone or tolcapone. to about 90 mg carbidopa/day/site. k k k k k