DOPA DECARBOXYLASE INHIBITOR COMPOSITIONS

BACKGROUND

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

[002] However, levodopa has a short half-life in plasma that, even under best common current standard of care, results in pulsatile dopaminergic stimulation. Long-term therapy is therefore complicated by motor fluctuations and dyskinesia that can represent a source of significant disability for some patients. A therapeutic strategy that could ultimately deliver levodopa/dopamine to the brain in a more continuous and physiologic manner, would provide the benefits of standard levodopa levels with reduced motor complications, and is much needed by patients suffering from Parkinson's disease and other neurological or movement disorders (Olanow CW; Mov. Dis. 2008, 23(Suppl. 3):S613-S622). Sustained-release oral L-dopa formulations have been developed, but, at best, such preparations have been found to be no more efficacious than standard tablets. Continuous administration of levodopa by intraduodenal administration or infusion has also been attempted by using ambulatory pumps or patches. Such treatments, especially intraduodenal, are extremely invasive and inconvenient.

[003] The metabolic transformation of L-dopa to dopamine is catalyzed by the aromatic L- amino acid decarboxylase enzyme, a ubiquitous enzyme with particularly high concentrations in the intestinal mucosa, liver, brain, and brain capillaries. Due to the possibility of extracerebral metabolism of L-dopa, it is necessary to administer large doses of L-dopa leading to high extracerebral concentrations of dopamine that cause nausea in some patients. Therefore, L-dopa is usually administered concurrently with oral administration of a L-dopa decarboxylase inhibitor, such as carbidopa or benserazide, which reduces by 60-80% the L-dopa dose required for a clinical response, and prevents certain of its side effects by inhibiting the conversion of levodopa to dopamine outside the brain.

[004] Various oral formulations together with inhibitors of enzymes associated with the metabolic degradation of levodopa are well known, for example, decarboxylase inhibitors such as carbidopa and benserazide, monoamine oxidase (MAO)-A or MAO-B inhibitors such as moclobemide, rasagiline, selegiline, and safinamide, and catechol-O-methyl transferase (COMT) inhibitors such as tolcapone and entacapone. Currently available oral drugs include SINEMET ^® and SINEMET ^® CR sustained-release tablets that include carbidopa or levodopa; MADOPAR ^® tablets containing levodopa and benserazide; and STALEVO ^® tablets containing carbidopa, entacapone, and levodopa.

[005] Carbidopa is a non-competitive inhibitor of L-dopa decarboxylase. When mixed with levodopa, carbidopa inhibits the peripheral conversion of levodopa to dopamine. This results in increased levodopa available for transport to the CNS. Carbidopa also inhibits the metabolism of levodopa in the gastrointestinal (GI) tract, thus, increasing levodopa bioavailability. It is used in Parkinson's disease to reduce the peripheral effect of dopamine. The loss of the hydrazine functional group represents the major metabolic pathway for carbidopa.

[006] Hydrazine (N2H4), or its salts, are used in the production of pharmaceutical products.

However, it has been the cause of severe adverse effects on the central nervous system, liver, and kidneys. In addition to these effects, experimental animals have also shown the following symptoms: loss of body weight, anemia, hypoglycaemia, fatty degeneration of the liver, and convulsions. Hydrazine has also been shown to cause DNA damage, gene mutations, and chromosome aberrations (Environmental health criteria No. 68 hydrazine (1987)), and has induced tumor growth in mice, hamsters, and rats after oral, intraperitoneal, and inhalation administration (MacEwan JD, Vernot EH, Haun CC, et al. (1981)). Hydrazine and its salts are used in the pharmaceutical industry as an intermediate to produce drugs with different therapeutic effects including decarboxylase inhibitors, anti-hypertensives, and anti-bacterials. Since hydrazine is toxic and thought to be a possible human carcinogen, its presence is limited in some of these drug substances in the monographs of the European Pharmacopoeia (Ph. Eur.). [007] Accordingly, there is an ongoing and urgent need for liquid formulations and compositions that can achieve continuous dopaminergic stimulation to treat movement disorders such as Parkinson's disease more effectively, containing a safe and tolerable amount of hydrazine.

SUMMARY

[008] This disclosure is directed, at least in part, relates to pharmaceutical compositions which include a prodrug of carbidopa or pharmaceutically acceptable salts thereof, and further including at least one antioxidant. Such compositions have shown to be more stable than those containing no antioxidants at all. Moreover, compositions comprising at least two antioxidants have shown to be more stable than corresponding pharmaceutical compositions comprising only a single antioxidant. Disclosed formulations have improved resistance to degradation (e.g., have minimal amounts of a degradation species, for example, hydrazine), and are significantly stable.

[009] Accordingly, in a first aspect, the disclosure contemplates, at least in part, a pharmaceutically acceptable formulation comprising:

a) a compound of formula (I) represented by:

(I), or a pharmaceutically acceptable salt thereof, wherein

R ¹ and R ² are each independently selected from the group consisting of H, C1-C4 alkyl, - P(0)(OH) ₂ , and -R ⁵ -0-P-(0)(OH) ₂ ;

R ⁵ is a Ci-C ₆ alkyl or a C3-C6 cycloalkyl; and

R ⁶ is selected from the group consisting of H, -P(0)(OH) ₂ , or a C1-C4 alkyl,

provided that at least one of R ¹ , R ² and R ⁶ is not H;

b) a first antioxidant;

c) optionally, a second antioxidant; and

d) a pharmaceutically acceptable carrier, wherein the pharmaceutical composition has lower level of hydrazine as compared to a similar pharmaceutical composition comprising one or no antioxidants. Such a pharmaceutical composition may have less than about 10 μg/ml (10 ppm) hydrazine, less than about 5 μg/ml (50 ppm) hydrazine, or less than about 1 μg/ml (1 ppm) hydrazine.

[010] A disclosed pharmaceutical composition may comprise from about 0.1 % to about 10% by weight of the compound of formula (I), for example, from about 0.5% to about 6% by weight, about 1% to about 4% by weight, about 0.75% by weight, about 1.4% by weight, about 3% by weight, about 3.3% by weight, or about 4% by weight of the compound of formula (I).

[01 1 ] In some embodiments, the first antioxidant is ascorbic acid or a pharmaceutically acceptable salt thereof, for example sodium ascorbate, potassium ascorbate, calcium ascorbate, ascorbyl stearate and ascorbyl palmitate, or a combination thereof. In exemplary embodiments, the pharmaceutically acceptable salt of ascorbic acid is sodium ascorbate. In some embodiments, the first antioxidant is sodium bisulfite.

[012] A disclosed pharmaceutical composition may comprise from about 0.1 % to about 10% by weight ascorbic acid or a pharmaceutically acceptable salt thereof, for example, from about 0.2% to about 2%, from about 0.4% to about 1.3%, about 0.5%, about 0.6%, about 0.75%, about 0.85%, about 1.0%, or about 1.2% by weight ascorbic acid or a pharmaceutically acceptable salt thereof.

[013] In some embodiments, a disclosed pharmaceutical composition comprises a second antioxidant.

[014] The second antioxidant in a disclosed pharmaceutical composition may be, for example, L-cysteine or a pharmaceutically acceptable salt thereof, N-acetylcysteine (NAC) or a pharmaceutically acceptable salt thereof, glutathione or a pharmaceutically acceptable salt thereof, diacetylcysteine or a pharmaceutically acceptable salt thereof, and sodium bisulfite, or any combination thereof. In exemplary embodiments, the second antioxidant is selected from the group consisting of cysteine hydrochloride, NAC, and sodium bisulfite, or any combination thereof.

[015] In some embodiments, a disclosed pharmaceutical composition may comprise: (i) from about 0.001% to about 5%, from about 0.01% to about 1%, from about 0.1% to about 0.6%, about 0.3%, or about 0.4% by weight L-cysteine or a pharmaceutically acceptable salt thereof;

(ii) from about 0.001% to about 5%, from about 0.01% to about 1%, about 0.1%, about 0.2%, about 0.3%, or about 0.4% by weight NAC;

(iii) from about 0.01% to about 2%, from about 0.075% to about 0.75%, or about 0.1% by weight sodium bisulfite;

(iv) from about 0.001% to about 5%, or from about 0.1% to about 1% by weight glutathione; and/or

(v) from about 0.001% to about 5%, or from about 0.01% to about 1% by weight diacetylcysteine or a pharmaceutically acceptable salt thereof.

[016] Exemplary embodiments relate to a pharmaceutical composition comprising from about 0.1% to about 10% by weight of the compound of formula (I), from about 0.1% to about 10% by weight ascorbic acid or a pharmaceutically acceptable salt thereof, and

(i) from about 0.001 % to about 5% by weight L-cysteine or a pharmaceutically acceptable salt thereof;

(ii) from about 0.001 % to about 5% by weight NAC; or

(iii) from about 0.01% to about 2% by weight sodium bisulfite.

[017] In exemplary embodiments, a disclosed pharmaceutical composition may comprise from about 0.5% to about 6%, or from about 1% to about 4% by weight of the compound of formula (I), from about 0.2% to about 2%, or from about 0.4% to about 1.3% by weight ascorbic acid or a pharmaceutically acceptable salt thereof, and

(i) from about 0.01 % to about 1 %, or from about 0.1 % to about 0.6% by weight of L-cysteine or a pharmaceutically acceptable salt thereof;

(ii) from about 0.01% to about 1%, or from about 0.1% to about 0.4% by weight NAC; or

(iii) from about 0.075% to about 0.75% by weight sodium bisulfite. [018] In some embodiments, a disclosed pharmaceutical composition may comprise a levodopa and/or prodrug of levodopa or a pharmaceutically acceptable salt thereof, for example, a compound of formula (II) represented by:

(II),

or a pharmaceutically acceptable salt thereof, wherein

R ³ and R ⁴ are each independently selected from the group consisting of H, -P(0)(OH) ₂ , and -R ⁵ -0-P(0)(OH) ₂ ;

R ⁵ is a Ci-C ₆ alkyl or a C3-C6 cycloalkyl; and

R ⁶ is H or a Ci-C ₄ alkyl,

provided that at least one of R ³ , R ⁴ and/or R ⁶ is not H.

[019] For example, the levodopa prodrug may be a levodopa 4' -monophosphate and/or a pharmaceutically acceptable salt thereof.

[020] In some embodiments, a disclosed pharmaceutical composition may comprise either less than about 1% by weight, or form about 1% to about 20% by weight of a levodopa and/or levodopa prodrug or a pharmaceutically acceptable salt thereof, for example, from about 2% to about 16%, about 4%, about 6%, about 12%, or about 13.2% by weight of a levodopa and/or levodopa prodrug or a pharmaceutically acceptable salt thereof.

[021 ] A disclosed pharmaceutical composition may further comprise arginine, meglumine, or a combination thereof, and optionally further comprising a surfactant. The surfactant may be, for example, polysorbate 80.

[022] In exemplary embodiments, a disclosed pharmaceutical composition may comprise from about 0.01% to about 5%, from about 0.1 % to about 0.5%, or about 0.3% by weight surfactant such as polysorbate 80, and/or and from 0% to about 42% by weight arginine, meglumine, or a combination thereof.

[023] Exemplary embodiments relate to a pharmaceutical composition comprising:

(i) from about 0.1% to about 10% by weight of a compound of formula (I);

(ii) from about 0.1% to about 10% by weight, ascorbic acid or a pharmaceutically acceptable salt thereof;

(iii) from about 0.001 % to about 5% by weight L-cysteine or a pharmaceutically acceptable salt thereof; from about 0.001% to about 5% by weight NAC; or from about 0.01% to about 2% by weight sodium bisulfite;

(iv) from about 1% to about 20% by weight of a levodopa and/or levodopa prodrug or a pharmaceutically acceptable salt thereof;

(v) from about 0% to about 42% by weight arginine, meglumine, or a combination thereof; and, optionally

(vi) from about 0.01% to about 5% by weight polysorbate 80,

wherein the composition comprises less than about 10 μg/ml (10 ppm), less than about 5 μg/ml (5 ppm), or less than about 1 μg/ml (1 ppm) hydrazine.

[024] A disclosed pharmaceutical composition may comprise less than about 10 μg/ml (10 ppm) or less than about 1 μg/ml (1 ppm) of hydrazine after storage for a period of 1 to 24 hours, 1 to 30 days, 1 to 12 months, or 1 to 3 years, at a temperature in a range of from about -20°C to about 25°C, for example, about -20°C, between about 2°C to about 8°C, or about 25°C. In an exemplary embodiment, the pharmaceutical composition may comprise less than 1 μg/ml (1 ppm) of hydrazine after 7 days at a temperature of 25°C.

[025] In some embodiments, a disclosed pharmaceutical composition is formulated as a liquid.

[026] In an aspect, the disclosure, at least in part thereof, relates to a method for treating a disease, disorder or condition associated with loss of dopamine or dopaminergic neurons in a subject, the method comprising administering to the subject an effective amount of a disclosed pharmaceutical composition as described herein, thereby treating the subject. [027] For example, the disease, disorder or condition may be Parkinson's disease.

[028] In some embodiments, a contemplated pharmaceutical composition used in a disclosed method may be administered substantially continuous.

[029] In an aspect, the disclosure, at least in part thereof, relates to a kit comprising one, two, or more containers, wherein each container includes a disclosed pharmaceutical composition as described herein, wherein the pharmaceutical composition is present in an amount sufficient to treat a disease, disorder or condition associated with loss of dopamine or dopaminergic neurons in an individual in need thereof for at least 1 day, at least 1 week, at least 1 month, at least 2 months, at least 6 months or for at least one year. For example, the disease, disorder or condition may be Parkinson's disease.

[030] This Summary introduces a selection of concepts in a simplified form that are further described below in the Brief Description of the Drawings and the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.

[031 ] Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

BRIEF DESCRIPTION OF THE DRAWINGS

[032] Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced. [033] In the drawings:

[034] Fig. 1 is a bar graph showing the hydrazine concentrations measured in formulations comprising a carbidopa phosphoester (4-carbidopa monophosphate) without antioxidant (Fl), with one antioxidant such as ascorbic acid or sodium bisulfite (F2 and F4, respectively), or with two antioxidants such as ascorbic acid and N-acetylcysteine (NAC) (F3). All formulations were kept at room temperature under N ₂ atmosphere.

[035] Fig. 2 is a bar graph showing the hydrazine concentrations measured in formulations comprising a carbidopa monophosphoester (4-carbidopa monophosphate) and a 4-levodopa monophosphoester without antioxidant (F5) or with two antioxidants such as ascorbic acid and NAC (F6). All formulations were kept at RT without N ₂ .

DETAILED DESCRIPTION

[036] The disclosure relates, at least in part, to formulations comprising a prodrug of carbidopa and/or a prodrug of levodopa and, optionally, one, two, or more antioxidation agents.

[037] It has been established by the present inventors that formulations with a carbidopa prodrug such as, but not limited to, a carbidopa phosphate, and at least one, but preferably two, antioxidants such as ascorbic acid, L-cysteine, or N-acetylcysteine (NAC), can result in substantially lower levels of hydrazine release as compared to corresponding formulations with no antioxidants. It has been further established by the present inventors that formulations comprising at least two antioxidants contain less hydrazine as compared to formulations comprising only one antioxidant.

[038] Moreover, it has been established herein that the level of hydrazine correlates with the amounts of antioxidant(s) in the formulation, wherein increased amounts of antioxidant(s) may result in decreased release of hydrazine. This tendency or dependence of hydrazine release in presence and amount of antioxidant(s) has been established in formulation further comprising a prodrug of levodopa, such as but not limited to, a levodopa phosphate. Pharmaceutical compositions

[039] In one aspect of the present disclosure, a pharmaceutical composition is provided, comprising a prodrug of carbidopa and/or a levodopa and/or prodrug of levodopa and one or more antioxidation agents, and, optionally, a pharmaceutically acceptable carrier.

[040] The terms "pharmaceutical composition" and "formulation" are interchangeable and, as used herein, refer to a medicinal preparation which encompass a mixture of different components, including one or more active agents as disclosed herein, combined or formulated together with one or more pharmaceutically acceptable carriers, which can be administered in a specific form, such as, but not limited to, a tablet, linctus, ointment, infusion or injection. The formulation may comprise solid and/or non-solid, e.g., liquid, gel, semi-solid (e.g. gel, wax) or gas components.

[041] In the context of some embodiments described herein, the term "pharmaceutical composition" pertains to compositions and formulations comprising at least one antioxidant. The term "similar pharmaceutical composition" denotes a composition that is identical to an embodied pharmaceutical composition in terms of all ingredients and amounts thereof it contains, except for being devoid of antioxidant(s).

[042] For example, liquid pharmaceutical compositions are contemplated herein.

[043] The term "active agent" refers to a compound, which is accountable for a desired biological effect, and in the context of embodiment described herein, the active agent may be at least one of a carbidopa prodrug or a pharmaceutically acceptable salt thereof, and/or levodopa, a prodrug thereof or a pharmaceutically acceptable salt thereof, and any combination thereof, and the biological desired effect is treatment, amelioration, prevention, mitigation and/or curing of a central nervous system (CNS) disease or disorder such as Parkinson's disease.

[044] As used herein, the terms "pharmaceutically acceptable", "pharmacologically acceptable" and "physiologically acceptable" are interchangeable and mean approved by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. These terms include formulations, molecular entities, and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by, e.g., the U.S. Food and Drug Administration (FDA) agency, and the European Medicines Agency (EMA).

[045] Herein, the phrase "physiologically suitable carrier" refers to an approved carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of a possible active agent. Physiologically suitable carriers encompass any and all solvents and dispersion media.

[046] Herein the term "excipient" refers to an inert substance added to a pharmaceutical composition (formulation) to further facilitate process and administration of the active ingredients. "Pharmaceutically acceptable excipients", as used herein, encompass preservatives, antioxidants, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents in combination with pharmaceutically active agents is well known in the art. The compositions can also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

[047] The term "physiologically acceptable pH" is understood to mean a pH of, e.g., a formulation or composition that facilitates administration of the formulation or composition to a patient without significant adverse effects, e.g., a pH of about 4 to about 9.8 (for example, about 4 ± 0.3 to about 9.5 ± 0.3).

[048] "Ambient temperature" as understood by a person of skill in the art refers to a temperature of from about 10°C to about 30°C. In exemplary embodiments, ambient temperature can be 25 °C.

[049] Percentages disclosed herein are by weight unless indicated otherwise. [050] The term "prodrug" herein refers to an inactive substance that is converted to a drug within the body. Hence, a prodrug may itself be biologically inactive and circulate harmlessly until activated by some metabolic process or clinically relevant event in the body, by the action of, for example, enzymes or other chemicals so as to produce an active therapeutic drug. Prodrug approaches include chemical modifications of drugs to improve, e.g., stability, permeability and/or bioavailability, in the circulation system and/or in the target cell and tissues, while minimally affecting the pharmacokinetic profile of the drug. For example, a prodrug may feature modification of the charge and lipophilicity of a drug in favor of blood brain barrier (BBB) permeability. An example of the prodrug approach is L-dopa (levodopa) in Parkinson's therapy. L-Dopa can cross the BBB and convert into the active therapeutic dopamine, which itself cannot cross the BBB.

[051] Chemical modifications to produce prodrugs include, for example, esterification (i.e. reacting a carboxylic group -COOH in the drug with an alcohol (ROH) to form an ester -COOR and water), amidation (i.e. formation of an amide group -CO-NH2 through the substitution of one or more of the hydrogen atoms by -R-CO-NH2, or replacing in a carboxylic group a carboxylic OH with NH ₂ ), and/or salt form formation of the active drug. Other modifications include linkage of a prodrug to a biologically active compound (e.g., coupling to phenylethylamine to nicotinic acid), derivatization of drugs to centrally acting amines, enclosing drugs in cyclodextrin caged complexes, and covalent attachment to cationic carriers or membrane -permeable peptides. The chemical group used for derivatization of the parent drug molecule, called the progroup, should be nontoxic.

Prodrugs of carbidopa

[052] In an aspect of some embodiments, the present disclosure provides formulations comprising a prodrug of carbidopa, wherein carbidopa is represented by the structural formula:

[053] Carbidopa is a non-competitive inhibitor of L-dopa decarboxylase, and when mixed with levodopa, it inhibits the peripheral conversion of levodopa to dopamine, resulting in increased levodopa available for transport to the CNS. Carbidopa also inhibits the metabolism of levodopa in the gastrointestinal (GI) tract, thus, increasing levodopa bioavailability as well. Carbidopa is used in Parkinson's disease to reduce the peripheral effect of dopamine.

[054] The carbidopa prodrug may be an ester derivative of carbidopa. For example, a carbidopa prodrug may be a carbidopa phosphoester, such as a carbidopa monophosphoester or a carbidopa di-phosphoseter.

[055] In some embodiments, a contemplated formulation comprises a carbidopa prodrug compound of formula (I) represented by the structural formula:

(I) or a pharmaceutically acceptable salt thereof, wherein

R ¹ and R ² are each independently selected from the group consisting of H, -P(0)(OH) ₂ , and -R ⁵ -0-P(0)(OH) ₂ ;

R ⁵ is a Ci-C ₆ alkyl or a C3-C6 cycloalkyl; and

R ⁶ is H or a Ci-C ₄ -alkyl,

provided that at least one of R ¹ , R ² and/or R ⁶ is not H.

[056] In some embodiments, a contemplated formulation comprises a compound corresponding in structure to a compound of formula (I). In some embodiments, a contemplated formulation comprises a compound which is a pharmaceutically acceptable salt of a compound corresponding in structure to a compound of formula (I). [ 057] For example, a compound corresponding in structure to a compound of formula (I) or to a pharmaceutically acceptable salt thereof may be a compound wherein R ¹ and R ² each independently is H or -P(0)(OH) ₂ ; and R ⁶ is H or a Ci-C4-alkyl, provided that at least one of R ¹ , R ² and/or R ⁶ is not H. For example, R ¹ may be H and R ² may be -P(0)(OH) ₂ , or R ¹ may be - P(0)(OH) ₂ and R ² may H or, alternatively, both R ¹ and R ² are -P(0)(OH) ₂ ; and R ⁶ is H.

[058] In some embodiments, a contemplated formulation comprises a compound of formula

(la) corresponding in structure to:

(la) or a pharmaceutically acceptable salt thereof.

[059] In some embodiments, a contemplated formulation comprises a compound of formula

(lb) corresponding in structure to:

(Ib) or a pharmaceutically acceptable salt thereof.

[060] In some embodiments, a contemplated formulation comprises a compound of formula

(Ic) corresponding in structure to:

(Ic) or a pharmaceutically acceptable salt thereof.

[061 1 A compound corresponding in structure to a compound of formula (I) or to a pharmaceutically acceptable salt thereof may be exemplified by a compound wherein R ¹ and R ² each independently is H or -R ⁵ -0-P(0)(OH)2, and R ⁶ is H or a Ci-C4-alkyl, provided that at least one of R ¹ , R ² and/or R ⁶ is not H. For example, R ¹ may be H and R ² may be -R ⁵ -0-P(0)(OH)2, or R ¹ may be -R ⁵ -0-P(0)(OH) ₂ and R ² may H, or, alternatively, both R ¹ and R ² are -R ⁵ -0-P(0)(OH) ₂ ; R ⁵ is a C1-C4 alkyl or a Cs-Ce cycloalkyl; and R ⁶ is H.

[062] For example, in a compound corresponding in structure to a compound of formula (I) or to a pharmaceutically acceptable salt thereof, at least one of R ¹ and R ² is -R ⁵ -0-P(0)(OH)2, and R ⁵ is an alkyl selected from methyl, ethyl, propyl, butyl, pentyl or hexyl, or a cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and R ⁶ is H. In an exemplary embodiment, R ⁵ is methyl. In a further exemplary embodiment, R ⁵ is ethyl. In further exemplary embodiments, R ⁵ is propyl such as propyl n-propyl or isopropyl, or R ⁵ is butyl selected from n- butyl, sec-butyl, isobutyl and/or tert-butyl.

[063] In some embodiments, a contemplated formulation comprises a compound of the formula (Id) corresponding in structure to:

(Id) or a pharmaceutically acceptable salt thereof.

[064] In some embodiments, a contemplated formulation comprises a compound of the formula (Ie) corresponding in structure to:

(Ie) or a pharmaceutically acceptable salt thereof.

[065] In some embodiments, a contemplated formulation comprises a compound of the formula (If) corresponding in structure to:

(If)

[066] A compound corresponding in structure to a compound of formula (I) or to a pharmaceutically acceptable salt thereof may be exemplified by a compound wherein R ¹ and R ² are each independently H or -P(0)(OH) ₂ ; and R ⁶ is a Ci-C4-alkyl. For example, R ¹ may be H and R ² may be -P(0)(OH) ₂ , or R ¹ may be -P(0)(OH) ₂ and R ² may H, or, alternatively, both R ¹ and R ² are -P(0)(OH) ₂ ; and R ⁶ is a Ci-C4-alkyl selected from methyl ethyl, propyl (e.g., n-propyl, isopropyl), and butyl (e.g., n-butyl, sec-butyl, isobutyl, tert-butyl).

[067] For example, in a compound corresponding in structure to a compound of formula (I) or to a pharmaceutically acceptable salt thereof, at least one of R ¹ and R ² is -P(0)(OH) ₂ , and R ⁶ is an alkyl selected from methyl, ethyl, propyl or butyl. In an exemplary embodiment, R ⁶ is methyl. In a further exemplary embodiment, R ⁶ is ethyl. In further exemplary embodiments, R ⁶ is propyl such as n-propyl or isopropyl, or R ⁶ is butyl selected from n-butyl, sec -butyl, isobutyl and/or tert- butyl.

[068] In some embodiments, a contemplated formulation comprises a compound of the formula (Ig) corresponding in structure to:

(Ig) or a pharmaceutically acceptable salt thereof.

[069] A compound corresponding in structure to a compound of formula (I) or to a pharmaceutically acceptable salt thereof may further be exemplified by a compound wherein R ¹ and R ² are each independently H or -R ⁵ -0-P(0)(OH) ₂ ; R ⁵ is a C1-C4 alkyl; and R ⁶ is a Ci-C ₄ -alkyl. For example, R ¹ may be H and R ² may be -R ⁵ -0-P(0)(OH) ₂ , or R ¹ may be -R ⁵ -0-P(0)(OH) ₂ and R ² may H, or, alternatively, both R ¹ and R ² are -R ⁵ -0-P(0)(OH) ₂ ; and R ⁵ and R ⁶ are each independently selected from ethyl, propyl (e.g., n-propyl, isopropyl), and butyl (e.g., n-butyl, sec- butyl, isobutyl and/or tert-butyl).

[070] For example, in a compound corresponding in structure to a compound of formula (I) or to a pharmaceutically acceptable salt thereof, at least one of R ¹ and R ² is -R ⁵ -0-P(0)(OH) ₂ , R ⁵ is methyl and R ⁶ is methyl, ethyl, propyl or butyl. In an exemplary embodiment, R ⁶ is methyl. In a further exemplary embodiment, R ⁶ is ethyl. In further exemplary embodiments, R ⁶ is propyl such as n-propyl or isopropyl, or R ⁶ is butyl selected from n-butyl, sec-butyl, isobutyl and/or tert-butyl.

[071 ] Further exemplary embodiments, feature further combinations of R ⁵ and R ⁶ , provided that of at least one of R ¹ and R ² is -R ⁵ -0-P(0)(OH)2. For example, R ⁵ may be ethyl and R ⁶ may be methyl, ethyl, propyl or butyl; or R ⁵ may be propyl and R ⁶ may be methyl, ethyl, propyl or butyl; or R ⁵ may be butyl and R ⁶ may be methyl, ethyl, propyl or butyl, or R ⁵ may be cyclopentyl or cyclohexyl and R ⁶ may be methyl, ethyl, propyl or butyl.

[072] A compound corresponding in structure to a compound of formula (I) or to a pharmaceutically acceptable salt thereof may be exemplified by a compound wherein one of R ¹ and R ² is independently -P(0)(OH) ₂ or -R ⁵ -0-P(0)(OH) ₂ , provided that R ¹ and R ² are not the same; R ⁵ is a C1-C4 alkyl; and R ⁶ is H or a Ci-C4-alkyl. For example, R ¹ may be -P(0)(OH) ₂ and R ² may be -R ⁵ -0-P(0)(OH) ₂ , or R ¹ may be -R ⁵ -0-P(0)(OH) ₂ and R ² may -P(0)(OH) ₂ ; R ⁵ is selected from ethyl, propyl (e.g., n-propyl, isopropyl), and butyl (e.g., n-butyl, sec -butyl, isobutyl and/or tert-butyl); and R ⁶ is H. Alternatively, R ¹ and R ² are different and each independently is - P(0)(OH) ₂ or -R ⁵ -0-P(0)(OH) ₂ , and R ⁵ and R ⁶ are each independently selected from ethyl, propyl (e.g., n-propyl, isopropyl), and butyl (e.g., n-butyl, sec -butyl, isobutyl and/or tert-butyl).

[073] For example, in a compound corresponding in structure to a compound of formula (I) or to a pharmaceutically acceptable salt thereof, R ¹ and R ² are not the same and each independently is -P(0)(OH) ₂ or -R ⁵ -0-P(0)(OH) ₂ , R ⁵ is methyl and R ⁶ is methyl, ethyl, propyl or butyl. In an exemplary embodiment, R ⁶ is methyl. In a further exemplary embodiment, R ⁶ is ethyl. In further exemplary embodiments, R ⁶ is propyl such as n-propyl or isopropyl, or R ⁶ is butyl selected from n-butyl, sec-butyl, isobutyl and/or tert-butyl.

[074] In some embodiments, a contemplated formulation comprises a compound of the formula (Hi) corresponding in structure to:

flh)

[075] Further exemplary embodiments, feature further combinations of R ⁵ and R ⁶ , wherein none of R ¹ and R ² is H, and R ¹ and R ² are different phosphoester groups as defined herein. For example, R ⁵ may be ethyl and R ⁶ may be methyl, ethyl, propyl or butyl; or R ⁵ may be propyl and R ⁶ may be methyl, ethyl, propyl or butyl; or R ⁵ may be butyl and R ⁶ may be methyl, ethyl, propyl or butyl.

Prodrugs of levodopa

[076] In an aspect of some embodiments, the disclosure provides a formulation with levodopa (L-dopa), a prodrug of levodopa (L-dopa), 3,4-dihydroxyphenylalanine, wherein L-dopa is represented by the structural formula:

L-Dopa is an amino acid that is made and used as part of the normal biology of humans, some animals and plants. Some animals and humans make it via biosynthesis from the amino acid L- tyrosine. Levodopa is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), which are collectively known as catecholamines. Furthermore, levodopa itself mediates neurotrophic factor release by the brain and CNS. L-Dopa can be manufactured and in its pure form is sold as a psychoactive drug used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.

[077] The levodopa prodrug may be an ester derivative of L-dopa. For example, a levodopa prodrug may be a L-dopa phosphoester, such as a L-dopa monophosphoester or L-dopa di- phosphoseter.

[078] In some embodiments, a contemplated formulation comprises a levodopa prodrug compound of formula (II), represented by the structural formula:

(II) or a pharmaceutically acceptable salt thereof, wherein

R ³ and R ⁴ are each independently selected from the group consisting of H, -P(0)(OH) ₂ , and -R ⁵ -0-P(0)(OH) ₂ ;

R ⁵ is a Ci-C ₆ alkyl or a C3-C6 cycloalkyl; and

R ⁶ is H or a Ci-C ₄ -alkyl,

provided that at least one of R ³ , R ⁴ and/or R ⁶ is not H.

[079] In some embodiment, a levodopa prodrug corresponds in structure to a compound of formula (II). In some embodiments, a levodopa prodrug is a pharmaceutically acceptable salt of a compound corresponding in structure to a compound of formula (II).

[080] For example, a compound corresponding in structure to a compound of formula (II) or to a pharmaceutically acceptable salt thereof may be a compound wherein R ³ and R ⁴ each independently is H or -P(0)(OH) ₂ ; and R ⁶ is H or a Ci-C ₄ -alkyl, provided that at least one of R ³ , R ⁴ and/or R ⁶ is not H. For example, R ³ may be H and R ⁴ may be -P(0)(OH) ₂ , or R ³ may be - P(0)(OH) ₂ and R ⁴ may H, or, alternatively, both R ³ and R ⁴ are -P(0)(OH) ₂ ; and R ⁶ is H. [ 0811 In some embodiments, a contemplated formulation comprises a compound of formula

(Ila), corresponding in structure to:

(Ila) or a pharmaceutically acceptable salt thereof.

[082] In some embodiments, a contemplated formulation comprises a compound of formula

(lib), corresponding in structure to:

(lib) or a pharmaceutically acceptable salt thereof.

[083] In some embodiments, a contemplated formulation comprises a compound of formula (lie), corresponding in structure to:

(lie) or a pharmaceutically acceptable salt thereof.

[084] A compound corresponding in structure to a compound of formula (II) or to a pharmaceutically acceptable salt thereof may be exemplified by a compound wherein R ³ and R ⁴ are each independently H or -R ⁵ -0-P(0)(OH) ₂ , for example, R ³ may be H and R ⁴ may be -R ⁵ -0- P(0)(OH) ₂ , or R ³ may be -R ⁵ -0-P(0)(OH) ₂ and R ⁴ may H, or, alternatively, both R ³ and R ⁴ are - R ⁵ -0-P(0)(OH) ₂ ; R ⁵ is a C1-C4 alkyl or a C ₅ -C ₆ cycloalkyl; and R ⁶ is H.

[085] For example, in a compound corresponding in structure to a compound of formula (II) or to a pharmaceutically acceptable salt thereof, at least one of R ³ and R ⁴ is -R ⁵ -0-P(0)(OH) ₂ , and R ⁵ is an alkyl selected from methyl, ethyl, propyl or butyl, pentyl or hexyl, or a cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and R ⁶ is H. In an exemplary embodiment, R ⁵ is methyl. In a further exemplary embodiment, R ⁵ is ethyl. In further exemplary embodiments, R ⁵ is propyl such as propyl n-propyl or isopropyl, or R ⁵ is butyl selected from n- butyl, sec-butyl, isobutyl and/or tert-butyl.

[086] In some embodiments, a contemplated formulation comprises a compound of the formula (lid), corresponding in structure to:

(lid) or a pharmaceutically acceptable salt thereof.

[087] In some embodiments, a contemplated formulation comprises a compound of the formula (He), corresponding in structure to: HO

(He) or a pharmaceutically acceptable salt thereof.

[088] In some embodiments, a contemplated formulation comprises a compound of the formula (Ilf) corresponding in structure to:

(Ilf)

[089] A compound corresponding in structure to a compound of formula (II) or to a pharmaceutically acceptable salt thereof may be exemplified by a compound wherein R ³ and R ⁴ are each independently H or -P(0)(OH) ₂ ; and R ⁶ is a Ci-C4-alkyl. For example, R ³ may be H and R ⁴ may be -P(0)(OH) ₂ , or R ³ may be -P(0)(OH) ₂ and R ⁴ may H, or, alternatively, both R ³ and R ⁴ are -P(0)(OH) ₂ ; and R ⁶ is a Ci-C4-alkyl selected from methyl ethyl, propyl (e.g., n-propyl, isopropyl), and butyl (e.g., n-butyl, sec-butyl, isobutyl, tert-butyl).

[090] For example, in a compound corresponding in structure to a compound of formula (II) or to a pharmaceutically acceptable salt thereof, at least one of R ³ and R ⁴ is -P(0)(OH) ₂ , and R ⁶ is an alkyl selected from methyl, ethyl, propyl or butyl. In an exemplary embodiment, R ⁶ is methyl. In a further exemplary embodiment, R ⁶ is ethyl. In further exemplary embodiments, R ⁶ is propyl such as n-propyl or isopropyl, or R ⁶ is butyl selected from n-butyl, sec -butyl, isobutyl and/or tert- butyl.

[091 ] In some embodiments, a contemplated formulation comprises a compound of the formula (Ilg), corresponding in structure to:

dig) or a pharmaceutically acceptable salt thereof.

[092] A compound corresponding in structure to a compound of formula (II) or to a pharmaceutically acceptable salt thereof may further be exemplified by a compound wherein R ³ and R ⁴ are each independently H or -R ⁵ -0-P(0)(OH) ₂ ; R ⁵ is a C1-C4 alkyl; and R ⁶ is a Ci-C ₄ -alkyl. For example, R ³ may be H and R ⁴ may be -R ⁵ -0-P(0)(OH) ₂ , or R ³ may be -R ⁵ -0-P(0)(OH) ₂ and R ⁴ may H or, alternatively, both R ³ and R ⁴ are -R ⁵ -0-P(0)(OH) ₂ ; and R ⁵ and R ⁶ are each independently selected from ethyl, propyl (e.g., n-propyl, isopropyl), and butyl (e.g., n-butyl, sec- butyl, isobutyl or tert-butyl).

[093] For example, in a compound corresponding in structure to a compound of formula (II) or to a pharmaceutically acceptable salt thereof, at least one of R ³ and R ⁴ is -R ⁵ -0-P(0)(OH) ₂ , R ⁵ is methyl and R ⁶ is methyl, ethyl, propyl or butyl. In an exemplary embodiment, R ⁶ is methyl. In a further exemplary embodiment, R ⁶ is ethyl. In further exemplary embodiments, R ⁶ is propyl such as propyl n-propyl or isopropyl, or R ⁶ is butyl selected from n-butyl, sec-butyl, isobutyl and/or tert- butyl. [ 094] Further exemplary embodiments, feature further combinations of R ⁵ and R ⁶ , provided that of at least one of R ³ and R ⁴ is -R ⁵ -0-P(0)(OH)2. For example, R ⁵ may be ethyl and R ⁶ may be methyl, ethyl, propyl or butyl; or R ⁵ may be propyl and R ⁶ may be methyl, ethyl, propyl or butyl; or R ⁵ may be butyl and R ⁶ may be methyl, ethyl, propyl or butyl, or R ⁵ may be cyclopentyl or cyclohexyl and R ⁶ may be methyl, ethyl, propyl or butyl.

[095] A compound corresponding in structure to a compound of formula (II) or to a pharmaceutically acceptable salt thereof may be exemplified by a compound wherein one of R ³ and R ⁴ is each independently -P(0)(OH)2 or -R ⁵ -0-P(0)(OH)2, provided that R ³ and R ⁴ are not the same; R ⁵ is a C1-C4 alkyl; and R ⁶ is H or a Ci-C4-alkyl. For example, R ³ may be -P(0)(OH)2 and R ⁴ may be -R ⁵ -0-P(0)(OH) ₂ , or R ³ may be -R ⁵ -0-P(0)(OH) ₂ and R ⁴ may -P(0)(OH) ₂ ; R ⁵ is selected from ethyl, propyl (e.g., n-propyl, isopropyl), and butyl (e.g., n-butyl, sec-butyl, isobutyl, tert-butyl); and R ⁶ is H. Alternatively, R ¹ and R ² are different and each independently is - P(0)(OH)2 or -R ⁵ -0-P(0)(OH)2, and R ⁵ and R ⁶ are each independently selected from ethyl, propyl (e.g., n-propyl, isopropyl), and butyl (e.g., n-butyl, sec -butyl, isobutyl and/or tert-butyl).

[096] For example, in a compound corresponding in structure to a compound of formula (II) or to a pharmaceutically acceptable salt thereof, of R ³ and R ⁴ are not the same and each independently is -P(0)(OH) ₂ or -R ⁵ -0-P(0)(OH) ₂ , R ⁵ is methyl and R ⁶ is methyl, ethyl, propyl or butyl. In an exemplary embodiment, R ⁶ is methyl. In a further exemplary embodiment, R ⁶ is ethyl. In further exemplary embodiments, R ⁶ is propyl such as n-propyl or isopropyl, or R ⁶ is butyl selected from n-butyl, sec-butyl, isobutyl and/or tert-butyl.

[097] In some embodiments, a contemplated formulation comprises a compound of the formula (IHi) corresponding in structure to:

(Ilh)

[098] Further exemplary embodiments, feature further combinations of R ⁵ and R ⁶ , wherein none of R ³ and R ⁴ is H, and R ³ and R ⁴ are different phosphoester groups as defined herein. For example, R ⁵ may be ethyl and R ⁶ may be methyl, ethyl, propyl or butyl; or R ⁵ may be propyl and R ⁶ may be methyl, ethyl, propyl or butyl; or R ⁵ may be butyl and R ⁶ may be methyl, ethyl, propyl or butyl.

[099] As used herein, the term "pharmaceutically acceptable salt", refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, or allergic response, and are commensurate with a reasonable benefit/risk ratio. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, fumaric, benzoic acid, cinnamic acid, a sulfonic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; and (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion such as lithium, sodium or potassium, an alkaline earth ion such as calcium or magnesium, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, and the like. [0100] Other pharmaceutically acceptable salts, include adipate, alginate, ascorbate, aspartate, benzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, digluconate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, laurate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, and valerate salts.

[0101] Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0102] Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. For example, S.M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1 -19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting a free base or free acid function with a suitable reagent. For example, a free base function can be reacted with a suitable acid.

[0103] Particular crystalline forms of the L-dopa prodrugs and carbidopa prodrugs described above are contemplated. Such crystalline forms include L-dopa 4' -monophosphate anhydrate (i), L-dopa 4'-monophosphate anhydrate (ii), L-dopa 3 '-monophosphate, L-dopa 3',4'-diphosphate trihydrate, carbidopa 4'-monophosphate trihydrate, carbidopa 4'-monophosphate dihydrate, carbidopa 4'-monophosphate dehydrate, carbidopa 3 '-monophosphate (i), carbidopa 3'- monophosphate (ii), and carbidopa 3', 4'-diphosphate sodium salt.

[0104] In some embodiments, the levodopa prodrug compound included in the pharmaceutical composition is levodopa 4' -monophosphate, levodopa 3 '-monophosphate, or a pharmaceutically acceptable salt thereof.

[0105] A disclosed formulation may comprise a carbidopa prodrug, for example a compound of formula (I), or a pharmaceutically acceptable salt thereof in an amount which is in a range of from about 0.01% to about 10% by weight. For example, from 0.01% to about 6.0%, from about 0.1% to about 1.0%, about 0.1% to about 5%, from about 0.1% to about 6.0%, from about 0.5% to about 6.0%, from about 0.5% to about 8.0%, from about 0.5% to about 1.0%, from about 0.6% to about 4.0%, from about 0.6% to about 5.0%, from about 0.8% to about 3%, from about 1.0% to about 2.0%, from about 1.0% to about 3.0%, from about 1.0% about to 4.0%, from about 1.0% to about 5.0%, from about 1.2% to 3.0%, from about 1.2% to about 4%, from about 2.5% to about 3.5%, from about 3% to about 5.0%, from about 3.0% to about 7.0%, from about 5.0% to about 10.0%, from about 5.0% to about 7.0%, or from about 7.0% to about 10.0% by weight, and any amounts therebetween, of a carbidopa a prodrug.

[0106] In exemplary embodiments, a contemplated formulation may comprise about 0.01%, about 0.1%, about 0.25%, about 0.50%, about 0.75%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 2%, about 2.5%, about 3.0%, about 3.3% about 3.5%, about 4%, about 4.5%, about 5.0%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, or about 10.0% carbidopa prodrug for example a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0107] A disclosed formulation may comprise levodopa or a levodopa prodrug thereof, for example a compound of formula (II) or a pharmaceutically acceptable salt thereof, in varying amounts, for example, in an amount which is in a range of from about 1% to about 20% by weight. For example, from about 2% to about 8%, from about 2% to about 16%, from about 4% to about 7%, from about 8% to about 20%, from about 8% to about 16%, from about 10% to about 14%, or from about 11% to about 14%, from about 11% to about 15% or from about 12% to about 14% by weight, and any amounts therebetween, of levodopa or a levodopa prodrug thereof and/or a pharmaceutically salt thereof.

[0108] In exemplary embodiments, a contemplated formulation may comprise about 5%, about 6%, about 12% or about 13.2% by weight levodopa and/or a prodrug thereof or a pharmaceutically acceptable salt thereof.

[0109] Any of the active agents as defined herein may undergo oxidation and/or degradation resulting in release of various degradants. For example, hydrazine may result from oxidative degradation of a carbidopa prodrug such as a carbidopa phosphoester. Hydrazine, is a carcinogen, thus, it is important to reduce the release of hydrazine into the pharmaceutical compositions.

[01 10] As used herein, the term "antioxidant" refers to a substance which slows down the damage that can be caused to other substances by the effects of oxygen. In other words, an antioxidant inhibits the oxidation of other molecules. Antioxidants include two different groups of substances: industrial chemicals which are added to products to prevent oxidation, and natural chemicals found in foods and body tissue. Non-limiting examples of antioxidants include ascorbic acid (vitamin C) or a salt thereof (e.g., sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbyl palmitate, and ascorbyl stearate); cysteine or a cysteine derivative such as L-cysteine, N- acetyl cysteine (NAC), glutathione, thiol precursor such as L-2-oxo-4-thiazolidine carboxylic acid (OTC), diacetylcysteine, S-methyl-N-acetylcysteine amide, acetyl derivatives of S-methyl-N- acetylcysteine methylhydrazide, S-methylcysteine morpholineamide, and S-methyl-N- acetylcysteine morpholineamide, or a salt thereof; lipoic acid; uric acid; carotenes; a-tocopherol (vitamin E); and ubiquinol (coenzyme Q).

[01 1 1 ] Further antioxidants contemplated herein are phenolic antioxidants such as di-tert- butyl methyl phenols, tert-butyl-methoxyphenols, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), polyphenols, tocopherols, ubiquinones (e.g., caffeic acid, tertiarybutylhydroxyquinone (TBHQ)), propyl gallate (PG), flavonoid compounds, cinnamic acid derivatives, coumarins, and others.

[0112] Other contemplated antioxidants that may form part of a disclosed formulation include sulfite salts such as sodium hydrogen sulfite or sodium bisulfite (e.g. sodium metabisulfite).

[0113] Ascorbic acid is a monosaccharide oxidation -reduction (redox) catalyst found in both animals and plants. Ascorbic acid acts as an oxygen scavenger to reduce molecular oxygen.

[0114] Thiol containing compounds such as cysteine, NAC, glutathione and thiol precursors such as OTC have several potential antioxidant effects. These agents can directly scavenge radicals via hydrogen donation from their SH group, resulting in formation of a thiyl (S) radical. [01 15] Formulations including at least two antioxidants (e.g., one of them being L-cysteine or NAC) can result in substantially lower levels of hydrazine, as compared to formulations with fewer antioxidants. For example, when two antioxidants are included in the formulation they may be ascorbic acid and L-cysteine, or ascorbic acid and NAC, or sodium ascorbate and L-cysteine, or sodium ascorbate and NAC. Such formulations can, e.g., reduce formation of undesired degradation products and/or provide substantially stable formulations.

[01 161 Oxidation of carbidopa prodrugs may further occur in the body, for example, by tyrosinase, and may produce 3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid and 6,7-dihydroxy- 3-methylcinnoline. The catechol (di-hydroxy phenyl) moiety can oxidize to an o-quinone.

[0117] Tyrosinase, a copper-containing enzyme, is involved in the conversion of an o- diphenol (or a di-hydroxy phenyl moiety) to the corresponding o-quinone.

[0118] Disclosed formulations may include active agents such as a carbidopa prodrug, levodopa and/or levodopa prodrug and/or pharmaceutically acceptable salts thereof and any combination thereof, and further include one or more agents that inhibit the formation of oxidation products as well as other degradants after the prodrugs are administered into the body. Such agents may be e.g., antioxidants, tyrosinase inhibitors and/or Cu ⁺⁺ chelators.

[0119] Tyrosinase inhibitors contemplated herein include, but not limited to, captopril, methimazole, quercetin, arbutin, aloesin, N-acetylglucoseamine, retinoic acid, a-tocopheryl, ferulate, Mg ascorbyl phosphate (MAP), substrate analogues (e.g., sodium benzoate, L- phenylalanine) and/or Cu ⁺⁺ chelators.

[0120] None-limiting examples of Cu ⁺⁺ chelators include, Na ₂ -EDTA, Na ₂ -EDTA-Ca, DMSA (succimer), D-penicillamine (DPA), trientine-HCl, dimercaprol, clioquinol, sodium thiosulfate, TETA, TEPA, curcumin, neocuproine, tannin, and/or cuprizone.

[0121] In some embodiments, a contemplated pharmaceutical composition comprises a carbidopa prodrug compound of the formula (I) as defined herein, for example, one or more compounds of formulae (la), (lb), (Ic), (Id), (Ie), (If), (Ig) and/ or (Ih), as defined herein, at least one antioxidant. [0122] In some embodiments, a contemplated pharmaceutical composition comprises a levodopa prodrug compound of the formula (II) as defined herein, for example, one or more compounds of formulae (Ila), (lib), (lie), (lid), (He), (Ilf), (Ilg) and/ or (Ilh), as defined herein, at least one antioxidant.

[0123] In some embodiments, a contemplated pharmaceutical composition comprises a carbidopa prodrug compound of the formula (I), herein also referred to as a "first active agent", and a levodopa and/or levodopa prodrug compound of the formula (II) herein also referred to as a "second active agent", at least one antioxidant. For example, a contemplated formulation may comprise any combination of a carbidopa prodrug of formula (I) which may be, for example, one or more compounds of formulae (la), (lb), (Ic), (Id), (Ie), (If), (Ig) and/or (Ih), or a pharmaceutically acceptable salt thereof, as defined herein (a first active agent), and a levodopa prodrug of formula (II) which may be, for example, one or more compounds of formulae (Ila), (lib), (lie), (lid), (He), (Ilf), (Ilg) and/or (Ilh), or a pharmaceutically acceptable salt thereof, as defined herein (a second active agent).

[0124] Disclosed formulations can include one, two, or more antioxidants. For example, a disclosed formulation can include one, two, or more of an agent selected from the group consisting of ascorbic acid or a salt thereof, for example, sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbyl palmitate, and ascorbyl stearate, particularly sodium ascorbate, and cysteine or a cysteine derivative, for example, L-cysteine, NAC, glutathione, diacetylcystine, S-methyl-N- acetylcysteine amide, acetyl derivatives of S-methyl-N-acetylcysteine methylhydrazide, S- methylcysteine morpholineamide, and S-methyl-N-acetylcysteine morpholineamide, or a salt thereof.

[0125] In an exemplary embodiment, a disclosed formulation may include ascorbic acid, or a salt thereof.

[0126] Contemplated formulation that comprise ascorbic acid or a salt thereof (e.g., sodium ascorbate), may include from about 0.1% to about 10% by weight, or more ascorbic acid (or salt thereof). For example, from about 0.1% to about 2.0%, from about 0.1% to about 1.0%, from about 0.1% to about 5%, about 0.2% by weight to about 1.0%, from about 0.2% to about 1.5%, from about 0.2% to about 2.0%, from about 0.2% to about 2.5%, from about 0.2% to about 5%, from about 0.3% to about 1.2%, from about 0.4% to about 1.0%, from about 0.4% to about 1.3%, from about 0.4% to about 2.0%, from about 0.4% to about 3.0%, from about 0.8% to about 1.3%, from about 1% to about 2.5%, from about 1.0% to about 3.0%, from about 1.0% to about 5.0%, from about 1% to about 10.0%, from about 2.0% to about 5.0%, from about 3.0% to about 5.0%, from about 3.0% to about 7.0%, from about 5.0% to about 7.0%, from about 5.0% to about 10.0%, from about 7.0% to about 10.0%, or from about 3.0% to about 10.0% by weight ascorbic acid or salt thereof such as sodium ascorbate.

[0127] In exemplary embodiments, a disclosed formulation may include, for example, about 0.01%, about 0.1%, about 0.25%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.3%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, or about 10.0% by weight sodium ascorbate or ascorbic acid.

[0128] In some embodiments, disclosed formulations may include a bisulfite, e.g., sodium bisulfite or other sulfite salts, e.g., sodium hydrogen sulfite or sodium metabisulfite.

[0129] In some embodiments, a disclosed formulation may comprise L-cysteine or a pharmaceutically acceptable salt thereof, N-acetylcysteine (NAC) or a pharmaceutically acceptable salt thereof, glutathione or a pharmaceutically acceptable salt thereof, diacetylcysteine or a pharmaceutically acceptable salt thereof, or sodium bisulfite.

[0130] Contemplated pharmaceutical compositions may comprise from about 0.001% to about 5% by weight, or more, L-cysteine. For example, in some embodiments a disclosed pharmaceutical composition includes from about 0.01% to about 1%, from about 0.1% to about 0.6% or from about 0.3% to about 0.5% by weight L-cysteine or a pharmaceutically acceptable salt thereof. [013 1 ] In exemplary embodiments, a disclosed pharmaceutical composition includes about 0.3%, about 0.4% or about 0.5% by weight L-cysteine or a pharmaceutically acceptable salt thereof.

[0132] Contemplated pharmaceutical compositions may include NAC at varying concentrations in a range of, for example, from about 0.001% to about 5%, or more. In exemplary embodiments, a disclosed pharmaceutical composition includes from about 0.01% to about 1% by weight NAC.

[0133] In exemplary embodiments, a disclosed pharmaceutical composition includes about 0.1%, about 0.2%, about 0.3%, about 0.4% or about 0.5% by weight NAC or a pharmaceutically acceptable salt thereof.

[0134] Contemplated pharmaceutical compositions may include sodium bisulfite at varying concentrations ranging, for example, from about 0.01% to about 2%, or more. In exemplary embodiments a disclosed pharmaceutical composition includes from about 0.075% to about 0.75% by weight sodium bisulfite or a pharmaceutically acceptable salt thereof.

[0135] In exemplary embodiments, a disclosed pharmaceutical composition includes about 0.1 % by weight sodium bisulfite.

[0136] Contemplated pharmaceutical compositions may include glutathione at varying concentrations ranging, for example, from about 0.001% to about 5.0% by weight, or more. For example, in some embodiments a disclosed pharmaceutical composition includes from about 0.1% to about 1.0% by weight glutathione or a pharmaceutically acceptable salt thereof.

[0137] Contemplated pharmaceutical compositions may include diacetylcysteine or a pharmaceutically acceptable salt thereof at varying concentrations ranging, for example, from about 0.001% to about 5.0% by weight, or more. For example, in some embodiments a disclosed pharmaceutical composition includes, from about 0.01% to about 1.0% by weight diacetylcysteine or a pharmaceutically acceptable salt thereof. [0138] Contemplated formulation may comprise, for example, NAC, L-cysteine, diacetylcystine, and/or glutathione, and/or a pharmaceutically acceptable salt thereof.

[0139] For example, a disclosed pharmaceutical composition may include: from about 0.001% to about 5.0%, from about 0.01% to about 1.0%, from about 0.1% to about 0.6%, about 0.3% or about 0.4% by weight L-cysteine or a pharmaceutically acceptable salt thereof such as L- cysteine hydrochloride; from about 0.001% to about 5.0%, from about 0.01% to about 1.0%, about 0.1%, about 0.2%, about 0.3%, or about 0.4% by weight NAC; from about 0.01% to about 2.0%, from about 0.075% to about 0.75%, or about 0.1% by weight sodium bisulfite; from about 0.001% to about 5.0%, or from about 0.1 % to about 1.0% by weight glutathione; and/or from about 0.001 % to about 5.0%, or from about 0.01% to about 1% by weight diacetylcysteine or a pharmaceutically acceptable salt thereof.

[0140] In exemplary embodiments, a formulation includes from about 0.001% to about 5%, from about 0.01% to about 5%, from about 0.1% to about 5%, from about 0.001% to about 1%, from about 0.01% to about 1%, or from about 0.1% to about 1% by weight of a compound selected from the group consisting of NAC, L-cysteine, diacetylcystine, and/or glutathione, or a pharmaceutically acceptable salt thereof.

[0141 ] For example, a disclosed formulation can include from about 0.01% to about 5%, e.g., from about 0.05% to about 1%, from 0.1% to about 0.6%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, or about 0.5% by weight of NAC and/or L-cysteine.

[0142] In some embodiments, a contemplated formulation may comprise a fist antioxidant which is ascorbic acid or a salt thereof, and a second antioxidant which is L-cysteine and/or a cysteine derivative, or a pharmaceutically acceptable salt thereof such as cysteine hydrochloride, NAC, or sodium bisulfite.

[0143] In an exemplary embodiment, a disclosed formulation may include ascorbic acid, or salt thereof, and a cysteine derivative.

[0144] Exemplary embodiments contemplate a pharmaceutical composition comprising ascorbic acid and L-cysteine, sodium ascorbate and NAC, ascorbic acid and NAC, sodium ascorbate and L-cysteine, ascorbic acid and diacetylcystine, sodium ascorbate and diacetylcystine, ascorbic acid and glutathione, or sodium ascorbate and glutathione.

[0145] For example, a disclosed formulation can include ascorbic acid (or a salt thereof) and a cysteine derivative such as L-cysteine, NAC and/or diacetylcystine. In an exemplary embodiment, a disclosed formulation includes from about 0.1% to about 10% ascorbic acid (or salt thereof), and from about 0.001% to about 5%, or from about 0.001% to about 1% by weight L-cysteine and/or NAC and/or diacetylcystine and/or glutathione.

[0146] A contemplated formulation may comprise:

(a) any combination of one or more active agents selected from a carbidopa prodrug of formula (I), levodopa, a levodopa prodrug of formula (II), and/or pharmaceutically acceptable salts thereof;

(b) a first antioxidant that is ascorbic acid or a pharmaceutically acceptable salt thereof;

(c) a second antioxidant; and

(d) a pharmaceutically acceptable carrier,

wherein, in some embodiments, the formulation has less than about 5 μg/ml (5 ppm) of hydrazine, as determined by a gas chromatography-mass spectrometry (GC-MS) method, and/or less than 5% or less than 1% by weight of a degradant, as calculated relative to the initial amount of carbidopa prodrug.

[0147] For example, provided herein are formulations that include a carbidopa prodrug thereof, for example, a compound of formula (I) herein, or one or more of the compounds of formulae (la), (lb), (Ic), (Id), (Ie), (If), (Ig) and/or (Ih), as defined herein, or a pharmaceutically acceptable salt thereof, having less than 0.1 μg/ml (0.1 ppm) or less than 0.5 μg/ml (0.5 ppm) by weight hydrazine, as determined by GC-MS, and/or less than 5% or less than 1% by weight of a degradant, as calculated relative to the initial amount of carbidopa prodrug.

[0148] The term "degradant", as referred to herein, is the product of the process of degradation, namely, the breakdown of an organic compound. The degradation process may be, for example, a chemical, physical or a biological, for example, enzymatic, process. In the context of embodiments described herein, "degradants" encompass the breakdown products of ingredients of a contemplated formulation, before and/or after administration or use thereof.

[0149] A degradant may be a desired component such as the main active agent or a secondary active agent. In that respect, a degradant may be a drug obtained or released after degradation or breakdown of a corresponding prodrug compound.

[0150] A degradant may also feature an undesired consequence e.g., of a chemical breakdown process of a compound, for example, an active agent or a prodrug form thereof. Undesired degradants, for example in a formulation, may be the consequence of lack of stability of one or more ingredients of the formulation, for example due to certain conditions provided to the formulation (e.g., pH, temperature, solvent, atmosphere, cross-reactivity and the like). Formulations may comprise various degradants.

[0151] In some embodiments, a degradant is hydrazine (H2N-NH2). Hydrazine is the product of an oxidative degradation of compounds comprising the -HN-NH2 moiety such as carbidopa and/or a prodrug thereof, for example, a compound of formula (I).

[0152] For the formulations disclosed herein, an upper limit of the amount of hydrazine is set. For example, an upper limit in the amount of hydrazine accumulated as a function of time and temperature. For example, in disclosed pharmaceutical composition the maximum level of hydrazine is less than about 10 μg/ml (10 ppm) or less than about 1 μg/ml (1 ppm) 1-48 hours, 1- 30 days, 1-12 months, or 1-3 years, at a temperature in a range of about -20°C to about 25°C.

[0153] Contemplated pharmaceutical compositions may have less than about 10 μg/ml (10 ppm), less than about 9 μg/ml (9 ppm), less than about 8 μg/ml (8 ppm), less than about 7 μg/ml (7 ppm), less than about 6 μg/ml (6 ppm), less than about 5 μg/ml (5 ppm), less than about 4 μg/ml (4 ppm), less than about 3 μg/ml (3 ppm), less than about 2 μg/ml (2 ppm), or less than about 1 μg/ml (1 ppm) of hydrazine, after storage for periods of 1-24 hours, 1-30 days, 1-12 months, or 1- 3 years, at a temperature in a range of from about -20°C to about 25 °C, from about -20°C to about 0°C, from about 0°C to about 25°C, from about 2°C to about 8°C, from about 0°C to about 10°C, or from about 10°C to about 25°C, or at a temperature of about -20°C, -15°C, -10°C, -5°C, 0°C, 1°C, 2°C, 3°C, 4°C, 0°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 15°C, 17°C, 20°C, 22°C, or 25°C. The hydrazine level in a formulation may be determined using methods well known in the art, for example by a GC-MS method as disclosed in the Examples section herein.

[0154] In an embodiment, the pharmaceutical composition includes less than 1 μg/ml (1 ppm) of hydrazine after 7 days storage at a temperature of 25 °C.

[0155] In some embodiments, a disclosed pharmaceutical composition may have less than about 1 μg/ml (1 ppm), less than about 0.5 μg/ml (0.5 ppm), or less than about 0.1 μg/ml (0.1 ppm) of hydrazine, as determined by a GC-MS method.

[0156] In some embodiments, a disclosed pharmaceutical composition has from about 0.1 μg/ml (0.1 ppm) to about 1.0 μg/ml (1.0 ppm), from about 1.0 μg/ml (1.0 ppm) to about 5.0 μg/ml (5.0 ppm), from about 3.0 μg/ml (3.0 ppm) to about 5.0 μg/ml (5.0 ppm), from about 5.0 μg/ml (5.0 ppm) to about 7.0 μg/ml (7.0 ppm), from about 1.0 μg/ml (1.0 ppm) to about 10.0 μg/ml (10.0 ppm), from about 7.0 μg/ml (7.0 ppm) to about 10 μg/ml (10.0 ppm), or from about 5.0 μg/ml to about 10.0 μg/ml (from about 5.0 ppm to about 10.0 ppm) of hydrazine.

[0157] In some embodiments, a contemplated pharmaceutical composition comprises a degradant which is a compound of the formula (III) represented by the structural formula:

(HI), or a pharmaceutically acceptable salt thereof, wherein

R ¹ and R ² and are each independently selected from the group consisting of H, -P(0)(OH) ₂ , and -R ⁵ -0-P(0)(OH) ₂ ;

R ³ is H or a Ci-C ₄ -alkyl R ⁵ is a Ci-C ₆ -alkyl; and

R ⁶ is H or a Ci-C4-alkyl or a C3-C6 cycloalkyl.

[0158] In some embodiments, at least one of R ¹ , R ² , R ³ , and R ⁶ in the degradant is not hydrogen. For example, R ¹ and/or R ² is -P(0)(OH) ₂ or -R ⁵ -0-P(0)(OH) ₂ .

[0159] In some embodiments, R ¹ , R ² and R ⁶ in the degradant are hydrogens, and R ³ is hydrogen or alkyl.

[0160] In an embodiment, the degradant is the compound 3,4-dihydroxyphenyl-2-methyl propionic acid.

[0161] Contemplated formulations may have less than about 5.0% by weight of a degradant, for example a degradant of formula (III) herein, as calculated, for example, relative to the amount of a carbidopa prodrug of formula (I). For example, the amount of a degradant may be less than 4.0%, less than 3.0%, less than 2.0%, less than 1.0%, less than 0.5%, less than 0.3%, less than 0.2%, less than 0.1% or less than 0.05% by weigh relative to the amount of a carbidopa prodrug.

[0162] Contemplated pharmaceutical compositions may include one or more of excipients selected from basic compounds such as arginine, a glucose amine such as meglumine, a pharmaceutically acceptable salt thereof or any combination thereof in varying amounts, to facilitate stabilization and solubilization of the active agents. Arginine and meglumine may form salts with levodopa thereby increasing their stability in the formulation.

[0163] In some embodiments, a disclosed pharmaceutical composition includes arginine.

[0164] In some embodiments, a disclosed pharmaceutical composition includes meglumine.

[0165] In some embodiments, a disclosed pharmaceutical composition includes arginine and meglumine.

[0166] The pharmaceutical composition may include arginine, meglumine, or a combination thereof in a range of from about 0% to about 42% by weight. For example, from about 0% to about 3%, from about 0.1% to about 40%, from about 1% to about 10%, from about 2% to about 7%, from about 12% to about 18%, from about 10% to about 20%, from about 10% to about 25%, from about 2% to about 40%, from about 12% to about 36%, or from about 15.2% to about 32%, from about 30% to about 38%, from about 32% to about 40%, or from about 25% to about 40% by weight, arginine, meglumine, or a combination thereof.

[0167] In exemplary embodiments, a contemplated formulation may comprise about 3.2%, about 3.4%, about 3.6%, about 3.7%, or about 4.6%, about 12.8%, about 14.8%, about 15.2%, about 15.5%, about 18.5%, about 32% or about 36% by weight arginine and/or meglumine and/or a salt thereof. For example, a disclosed formulation may not include arginine and/or meglumine at all, or include 32% arginine, 32% meglumine, 36% arginine, or 36% meglumine.

[0168] Contemplated pharmaceutical compositions may include a surfactant, for example, polysorbate 20, 40, 60 and/or 80. For example, polysorbate 80 (Tween® 80) may be present in varying amounts, ranging, for example, from about 0.01% to about 5%, from about 0.1% to about 0.5%, or about 0.3% by weight of polysorbate 80 or another surfactant.

[0169] Disclosed formulations can have a pH that is pharmaceutically acceptable for subcutaneous administration, e.g., a pH of about 7 to about 10, for example, about 9.1 to about 9.8, for example, 9.2 to 9.6, at 25 °C.

[0170] The carbidopa prodrugs and/or levodopa prodrugs disclosed herein (and their pharmaceutically acceptable salts) can be combined and formulated in the same pharmaceutical composition, namely, as a single unit dosage from, or can be present in separate pharmaceutical compositions, namely a plurality of dosage unit forms, for example, two or more dosage unit form, each comprising one or more of a first active agent (e.g., a compound corresponding in structure to a compound of formula (I)), and/or a second active agent (e.g., a compound corresponding in structure to a compound of formula (II)). For example, a formulation disclosed herein can comprise a first unit dosage form with a carbidopa prodrug and a second unit dosage form with a L-dopa prodrug. Alternatively, a formulation can comprise a carbidopa prodrug and L-dopa prodrug in the same pharmaceutical composition. [ 0171 ] A formulation of any of the above embodiments may be in a form selected from the group consisting of liquid, gel, cream, solid, film, emulsion, suspension, solution, and aerosol (e.g., a liquid formulation).

Exemplary formulations

[0172] Exemplary embodiments disclosed herein pertain to formulations comprising various combinations of a first active agent, a second active agent, a first antioxidant, a second antioxidant, and various excipients and other components as defined herein. These formulations have improved resistance to oxidative degradation (e.g., have minimal amounts of a degradation species, for example, hydrazine), and are significantly stable.

[0173] In an embodiment, a disclosed formulation comprises levodopa or a prodrug thereof such as a compound of formula (II), from about 0.1 % to about 6% by weight of a carbidopa prodrug such as a compound of formula (I), and at least at least one antioxidant.

[0174] In an embodiment, a disclosed formulation comprises form about 8% to about 16% (e.g., from about 11% to about 15%, or from about 12% to about 14%) by weight levodopa or a prodrug thereof such as a compound of formula (II), or a pharmaceutically acceptable salt thereof; from about 1% to about 4% by weight of a carbidopa prodrug such as compound of formula (I), or a pharmaceutically acceptable salt thereof; and at least one antioxidant.

[0175] Any of the formulations above may comprise one or more antioxidants selected from: ascorbic acid or a salt thereof in amounts ranging from about 0.1% to about 10% by weight; NAC in amounts ranging from about 0.01% to about 3% by weight; L-cysteine in amounts ranging from about 0.01% to about 1 % by weight; glutathione in amounts ranging from about 0.001% to about 1% by weight; and/or diacetylcystine or a salt thereof in amounts ranging from about 0.001% to about 1 % by weight.

[0176] In an embodiment, a disclosed formulation comprises:

(a) a carbidopa prodrug such as a compound of formula (I), or a pharmaceutically acceptable salt thereof, in an amount within a range, for example, of from about 0.1% to about

10% by weight (e.g., from about 0.1% to about 6%, from about 0.1 % to about 4%, from about 0.6% to about 1.4 %, from about 1.2% to about 4%, about 0.75%, about 1.4%, about 3%, or about 3.3% by weight);

(b) ascorbic acid or a salt thereof in an amount within a range, for example, of from about 0.1% to 10% (e.g., from about 0.3% to about 2%, from about 0.4% to about 0.6%, from about 0.4% to about 1%, from about 1.0% to about 1.3%, about 0.5%, about 1.2%, or about 1.3%) by weight; and

(c) one or more antioxidants such as: (i) L-cysteine or a pharmaceutically acceptable salt thereof in an amount within a range, for example, of from about 0.001% to about 5%, or from about 0.01% to about 1% (e.g., from about 0.1% to about 0.6%, from about 0.1% to about 1%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, or about 0.8%); (ii) NAC in an amount within a range, for example, of from about 0.001% to about 5%, or from about 0.01% to about 3% (e.g., from about 0.1% to about 0.6%, from about 0.1% to about 1%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, or about 0.8%); and, optionally, (iii) glutathione and/or diacetylcystine or a salt thereof.

[0177] In an embodiment, a disclosed pharmaceutical composition comprises form about 0.1% to about 10% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, from about 0.1% to about 10% by weight ascorbic acid or a pharmaceutically acceptable salt thereof, and either from about 0.001 % to about 5% by weight L-cysteine or a pharmaceutically acceptable salt thereof, from about 0.001% to about 5% by weight NAC, or from about 0.01% to about 2% by weight sodium bisulfite.

[0178] In exemplary embodiments, the pharmaceutical composition comprises from about 0.5% to about 6.0% or from about 1.0% to about 4.0% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof; from about 0.2% to about 2.0% or from about 0.4% to about 1.3% by weight ascorbic acid or a pharmaceutically acceptable salt thereof; from about 0.01% to about 1.0% or from about 0.1% to about 0.6% by weight of L-cysteine or a pharmaceutically acceptable salt thereof; and either from about 0.01% to about 3.0% or from about 0.1% to about 2% by weight NAC or from about 0.075% to about 0.75% by weight sodium bisulfite. [0179] In an embodiment, a disclosed pharmaceutical composition comprises about 12% by weight of levodopa and/or a levodopa prodrug such as a compound of formula (II) or a pharmaceutically acceptable salt thereof, about 3% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, about 1.2% by weight sodium ascorbate, and about 0.3% by weight L-cysteine or cysteine hydrochloride.

[0180] In an embodiment, a disclosed pharmaceutical composition comprises about 13.2% by weight of levodopa and/or a levodopa prodrug (e.g., compound of formula (II)) or a pharmaceutically acceptable salt thereof, about 3.3% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, about 1.3% by weight sodium ascorbate, and about 0.3% by weight L-cysteine or cysteine hydrochloride.

[0181 ] In an embodiment, a disclosed pharmaceutical composition comprises about 12% by weight of levodopa and/or a levodopa prodrug (e.g., compound of formula (II)), or a pharmaceutically acceptable salt thereof, about 3% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, about 1.2% by weight sodium ascorbate, and about 0.3% by weight NAC.

[0182] In an embodiment, a disclosed pharmaceutical composition comprises from about 2% to about 16% by weight of levodopa and/or a levodopa prodrug (e.g., compound of formula (II)), or a pharmaceutically acceptable salt thereof, about 1.2% to about 3% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, from about 1.0% to about 1.3% by weight sodium ascorbate, and about 0.3% by weight L-cysteine or NAC.

[0183] In an embodiment, a disclosed pharmaceutical composition comprises about 6.0% by weight of levodopa and/or a levodopa prodrug (e.g., compound of formula (II)), or a pharmaceutically acceptable salt thereof, about 1.4% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, about 0.5% by weight ascorbic acid, about 0.4% by weight L-cysteine, and about 0.3% by weight polysorbate 80.

[0184] In an embodiment, a disclosed pharmaceutical composition comprises about 6.0% by weight of levodopa and/or a levodopa prodrug (e.g., compound of formula (II)), or a pharmaceutically acceptable salt thereof, about 0.75% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, about 0.5% by weight ascorbic acid, about 0.4% by weight L-cysteine, and about 0.3% by weight polysorbate 80.

[0185] In an embodiment, a disclosed pharmaceutical composition comprises about 6.0% by weight levodopa and/or a levodopa prodrug (e.g., compound of formula (II)), or a pharmaceutically acceptable salt or an ester thereof, about 0.75% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, about 0.5% by weight ascorbic acid, about 0.5% by weight NAC, and about 0.3% by weight polysorbate 80.

[0186] In any one of the embodiments described above, the formulation may have less than about 1.0 g ml (1.0 ppm), less than about 0.75 μg/ml (0.75 ppm), less than about 0.5 μg/ml (0.5 ppm), less than about 0.25 μg/ml (0.25 ppm), less than about 0.1 μg/ml (0.1 ppm), or less than about 0.05 μg/ml (0.05 ppm) of hydrazine, e.g., as determined by a gas chromatography-mass spectrometry (GC-MS) method. In particular embodiments, the formulation has less than about 0.1 μg/ml (0.1 ppm) or less than about 0.05 μg/ml (0.05 ppm) of hydrazine, or from about 0.1 μg/ml to about 0.5 μg/ml (from about 0.1 to about 0.5 ppm) of hydrazine.

[0187] A contemplated formulation may further include levodopa, a levodopa prodrug, for example, a compound of formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, a disclosed formulation comprises less than 4% (e.g., less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.05%, or less than 0.01%) by weight of levodopa and/or a levodopa prodrug or a pharmaceutically acceptable salt thereof. In some embodiments, a disclosed formulation does not include a levodopa prodrug, or a pharmaceutically acceptable salt thereof.

[0188] In some embodiments, the pharmaceutical composition includes: from about 0.1% to about 10% by weight of the compound of formula (I); from about 0.1% to about 10% by weight, ascorbic acid or a pharmaceutically acceptable salt thereof; from about 0.001% to about 5% by weight L-cysteine or a pharmaceutically acceptable salt thereof, from about 0.001% to about 5% by weight NAC, or about 0.01% to about 2% by weight sodium bisulfite; from about 1% to about 20% by weight levodopa and/or a levodopa prodrug, or a pharmaceutically acceptable salt or an ester thereof; optionally, from 0% to about 42% by weight arginine, meglumine, or a combination thereof; and, optionally from about 0.01% to about 5% by weight polysorbate 80. In such embodiments, the composition comprises less than about 10 μg/ml (10 ppm), less than about 5 μg/ml (5 ppm), or less than about 1 μg/ml (1 ppm) hydrazine.

[0189] In an embodiment, a disclosed pharmaceutical composition may comprise: from about 0.5% to about 6%, from about 1% to about 4%, about 0.75%, about 1.4%, about 3%, or about 3.3% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof; from about 0.2% to about 2%, from about 0.4% to about 1.3%, about 0.5%, about 1.2%, or about 1.3% by weight ascorbic acid or a pharmaceutically acceptable salt thereof; from about 0.01% to about 1% or from about 0.1% to about 0.6% by weight L-cysteine or a pharmaceutically acceptable salt thereof; and either from about 0.01% to about 3% or from about 0.1% to about 2% by weight NAC, or from about 0.075% to about 0.75% by weight sodium bisulfite; from about 2% to about 16%, about 4%, about 6%, about 12%, or about 13.2% by weight levodopa, a levodopa prodrug, or a pharmaceutically acceptable salt thereof; optionally, from 0% to about 40%, from about 12% to about 36%, or from about 15.2% to about 32% by weight arginine, meglumine, or a combination thereof; and, optionally, from about 0.1% to about 0.5% or about 0.3% by weight polysorbate 80.

[0190] In an embodiment, a disclosed formulation comprises: from about 2% to about 8% by weight of levodopa and/or a levodopa prodrug such as a compound of formula (II); from about 0.1% to about 3% by weight of carbidopa prodrug such as a compound of formula (I); from 0% to about 25% by weight arginine; from about 0.1% to about 10% (e.g., from about 0.3% to about 2%) by weight ascorbic acid or salts thereof; and from about 0.001% to about 5% by weight of one of L-cysteine or a salt thereof, NAC, glutathione or diacetylcysteine or a salt thereof.

[0191 ] In an embodiment, a disclosed formulation comprises: from about 8% to about 16% by weight of levodopa and/or a levodopa prodrug such as a compound of formula (II); form about 1% to about 4% by weight of carbidopa prodrug such as a compound of formula (I); optionally, from 0% to about 40% by weight of a component selected from the group consisting of arginine, meglumine, and a combination thereof; from about 0.1% to about 10% by weight ascorbic acid or a salt thereof; and from about 0.001% to about 1 % by weight of one of L-cysteine or a salt thereof, NAC, glutathione or diacetylcysteine or a salt thereof.

[0192] Exemplary formulations (i)-(ix) are described in following Tables (i)-(ix):

Table (i). Exemplary formulation (i)

Table (Hi). Exemplary formulation (Hi)

Table (vi). Exemplary formulation (vi)

Table (viii). Exemplary formulation (viii)

Table (ix). Exemplary formulation (ix)

[0193] Any one of the formulations described above may be in a liquid form.

[0194] In an embodiment, a liquid formulation is disclosed comprising form about 4% to about 8% (e.g., about 6%) by weight of levodopa and/or a levodopa prodrug, for example, a compound of formula (II) or a pharmaceutically acceptable salt thereof; from about 0.1% to about 1.5% (e.g., from about 0.6% to about 1.4%, about 0.75%, or about 1.4%) by weight of a carbidopa prodrug thereof, for example a compound of formula (I) or a pharmaceutically acceptable salt thereof; optionally, from 0% to about 20% (e.g., 0%, from about 10% to about 16%, about 15.2%, or about 15.6%) by weight arginine; and from about 0.1% to about 1.5% (e.g., from about 0.4 to about 1%, from about 0.4% to about 0.6%, or about 0.5%) by weight ascorbic acid or a salt thereof; and, optionally, from about 0.1% to about 0.7% (e.g., about 0.4% or about 0.5%) by weight of L- cysteine or NAC, wherein the formulation, for example, after 1 day at 25°C, or after 30 days at 25°C or after 180 days at 25°C, has less than about 7.0 μg/ml (7.0 ppm), less than about 6.0 μg/ml (6.0 ppm), less than about 0.5 μg/ml (0.5 ppm), or less than about 0.2 μg/ml (0.2 ppm) hydrazine, as determined, by GC-MS.

[0195] In an exemplary embodiment, a disclosed formulation, for example, a liquid formulation, includes (a) from about 0.4% to about 3% or from about 0.4 to about 2% by weight ascorbic acid or a salt thereof; and (b) from about 0.1% to about 3% by weight of L-cysteine or NAC. In accordance with this embodiment, the formulation may further include from about 0.1% to about 0.5% (e.g., about 0.3%) by weight Tween®-80.

[0196] In an embodiment, a liquid formulation is disclosed comprising form about 8% to about 16% (e.g., from about 12% to about 15%, about 12%, or about 13.2%) by weight of a levodopa and/or a levodopa prodrug, for example, a compound of formula (II) or a pharmaceutically acceptable salt thereof; from about 1% to about 4% (e.g., about 3.0% or about 3.3%) by weight of carbidopa prodrug, for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof; optionally, from about 0% to about 42% (e.g., 0%, from about 32% to about 42%, about 32%, or about 36%) by weight of arginine, meglumine, or a combination thereof; from about 0.1% to about 1.5% (e.g., from about 1.0% to about 1.4%, about 1.2%, or about 1.3%) by weight ascorbic acid or a salt thereof (e.g., sodium ascorbate); and from about 0.1% to about 1% (e.g., about 0.1% to about 0.5%, about 0.3%, or about 0.5%) by weight of L-cysteine or a salt thereof (e.g., cysteine HCl), or NAC. wherein the formulation, after, for example, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 20, 24 or 48 hours; 1, 2, 3, 5, 7, 10, 14, 21, 28, or 30 days; 1, 2, 3, 4, 6, 9, or 12 months; or 1, 1.5, 2, 2.5, or 3 years at 25°C, has less than about 1.0 μg/ml (1.0 ppm), less than about 0.75 μg/ml (0.75 ppm), less than about 0.5 μg/ml (0.5 ppm), less than about 0.2 μg/ml (0.2 ppm), less than about 0.1 μg/ml or (0.1 ppm) hydrazine as determined by GC-MS.

[01971 Contemplated pharmaceutical compositions may have varying pH values or pH values that fall within a pH range. In some embodiments a disclosed pharmaceutical composition has a pH of from about 9.1 to about 10.0, from about 7.0 to about 10.0, from about 8.0 to about 10.0, from about 8.0 to about 9.0, from about 9.0 to about 9.5, from about 9.5 to about 10.0, from about 9.1 to about 9.3, from about 9.3 to about 9.6, from about 9.5 to about 9.7, or a pH from about 9.7 to about 10.0.

[0198] In exemplary embodiments, a pharmaceutical composition may have a pH of about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.1, about 9.2, about 9.3, about 9.4, about 9.5, about 9.6, about 9.7, about 9.8, about 9.9, about 10.0, or about 11.0. [0199] For example, a contemplated formulation may comprise, for example, a carbidopa prodrug or a pharmaceutically acceptable salt thereof, one or toe antioxidants and, optionally, a surfactant, and the pH of the formulation may be within the range of from about 9.1 to about 10.0 or from about 9.6 to about 9.8.

[0200] Any of the formulation described herein may further comprise other active agents. A non-limiting example is catechol-O-methyl transferase (COMT) inhibitor, such as tolcapone or entacapone, or a pharmaceutically acceptable salt thereof.

[0201] Contemplated pharmaceutical formulations may be formulated in different media. For example, in embodiments of the invention, a pharmaceutical composition may be formulated as a liquid, a gel, a cream, a solid, a film, an emulsion, a suspension, a solution, a lyophilisate, or an aerosol.

Preparation of pharmaceutical compositions

[0202] Formulations comprising a carbidopa prodrug such as a compound of formula (I), or a pharmaceutically acceptable salt thereof, one or more antioxidants, and, optionally further comprising levodopa and/or a levodopa prodrug such as a compound of formula (II), or a pharmaceutically acceptable salt thereof, may be prepared by mixing these ingredients, each in its powdered form, to form a powder mixture. Water can be added to the mixture to dissolve the mixture. Specific methods of preparation are described in the Examples below.

[0203] A procedure wherein the ingredients of the formulation are first mixed together as powders and then a solution is formed by the addition of water, may result in a more stable solution, as compared to a preparation that includes a stepwise preparation of individual water solutions of the ingredients and later combination thereof.

[0204] In some embodiments, N ₂ may be provided to the stirred suspension or solution.

[0205] Disclosed formulations may be sterilized, e.g., by using 0.2 μπι filters such as filters with nylon or PVDF membranes. Methods of Treatment

[0206] In an aspect of the disclosure, provided herein is a method of treatment of a subject inflicted with neurological disease or disorder, the method comprising administrating to the subject an effective amount of a formulation comprising a carbidopa prodrug or a pharmaceutically acceptable salt thereof and optionally further comprising levodopa and/or a levodopa prodrug or a pharmaceutically acceptable salt thereof, thereby threating the subject.

[0207] The method of treatment provided herein comprises the administration of a provided formulation as described herein, optionally in a liquid form.

[0208] In some embodiments, the formulation administered comprises a compound of formula (I) and/or a compound of formula (II) as described herein.

[0209] The neurological disease or disorder being treated by a contemplated method may be a neurological disorder such as a disorder associated with reduced dopamine or loss of dopaminergic neurons, or a movement disorder. Such diseases and disorders include, for example, neurological or movement disorders including restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Shy-Drager syndrome, and conditions resulting from brain injury including carbon monoxide or manganese intoxication.

[0210] In an exemplary embodiment, the disease to be treated is Parkinson's disease.

[021 1] Treating a disease, as referred to herein, means ameliorating, inhibiting the progression of, delaying worsening of, and even completely preventing the development of a disease, for example inhibiting the development of neurological manifestations in a person who has neurological disease or disorder. Treatment refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or a pathological condition after it has begun to develop. In particular examples, however, treatment is similar to prevention, except that instead of complete inhibition, the development, progression or relapse of the disease is inhibited or slowed.

[0212] "Administration" as referred to herein is introduction of the formulation described herein into a subject by a chosen route. Administration of the active compound or pharmaceutical composition can be by any route known to one of skill in the art, and as appropriate for the particular condition and location under treatment. Administration can be local or systemic. Examples of local administration include, but are not limited to, topical administration, subcutaneous administration, intramuscular administration, intrathecal administration, intrapericardial administration, intra-ocular administration, topical ophthalmic administration, or administration to the nasal mucosa or lungs by inhalational administration. In addition, local administration includes routes of administration typically used for systemic administration, for example by directing intravascular administration to the arterial supply for a particular organ. Thus, in particular embodiments, local administration includes intra-arterial administration, subcutaneous administration, intraduodenally administration, and intravenous administration when such administration is targeted to the vasculature supplying a particular organ. Local administration also includes the incorporation of active compounds and agents into implantable devices or constructs, such as vascular stents or other reservoirs, which release the active agents and compounds over extended time intervals for sustained treatment effects.

[0213] Systemic administration includes any route of administration designed to distribute an active compound or composition widely throughout the body via the circulatory system. Thus, systemic administration includes, but is not limited to, intra-arterial and intravenous administration. Systemic administration also includes, but is not limited to, topical administration, subcutaneous administration, intraduodenally administration, intramuscular administration, or administration by inhalation, when such administration is directed at absorption and distribution throughout the body by the circulatory system.

[0214] An effective amount of a compound, for example, of a compound of formula (I) or a compound of formula (II), is a quantity of compound sufficient to achieve a desired effect in a subject being treated. An effective amount of a compound can be administered in a single dose, or in several doses, for example daily, during a course of treatment. However, the effective amount of the compound will be dependent on the compound applied, the subject being treated, the severity and type of the affliction, and the manner of administration of the compound. [ 0215] Contemplated formulations may be administered to a patient in need thereof via one or more routes such as, but not limited to, parenteral routes selected from subcutaneous, transdermal, intradermal, intratracheal, intraocular, intramuscular, intraarterial, intraduodenally or intravenous.

[0216] In some embodiments, the formulations as described herein are administered continuously, for example by a designated pump. Alternatively, or additionally, formulations may be administered non-continuously, e.g., as bolus, injection, or eye drops.

[0217] In some embodiments, a provided formulation is administered subcutaneously and substantially continuously.

[0218] By "substantially continuous" administration is meant that a dose of the formulation being administered is not administered as a bolus, e.g., a pill taken orally or a bolus injection. For example, substantially continuous administration can involve administration of a dosage at over a period of at least 10 minutes, 30 minutes, 1 hour, 2 hours, 4, hours, 6 hours, 8 hours, 12 hours, 15 hours, 18 hours, 21 hours, or 24 hours to administer a single dose. Substantially continuous administration can be achieved using a transdermal patch or a pump device that continuously administers the formulation to a patient over time.

[0219] In some embodiments, administration include acute and immediate administration such as inhalation or injection.

[0220] In some embodiments, compositions comprising e.g., levodopa or a compound of formula (II) and/or a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g. a disclosed liquid composition) may be administered at a rate of from about 0.16 ml/hour/site to about 0.24 ml/hour/site, or, e.g., from about 0.01 ml/hour/site to about 0.4 ml/hour/site. Such rates may be constant throughout the day and night or varied according to patient's need, for example, may reflect a patient resting or sleeping schedule and waking or higher activity level schedule.

[0221] For example, liquid compositions such as those disclosed herein (e.g., including a compound of formula (I) and/or levodopa and/or a compound of formula (II) or a pharmaceutically acceptable salt thereof) may be administered at a rate of about 0.32 ml/hour/site in the morning (e.g., for about 2-4 hours before waking), about 0.24 ml/hour/site during the daytime or activity time (e.g., for about 10 to about 12 hours), and/or about 0.08 ml/hour/site at rest or at night.

[0222] In some embodiment, liquid composition such as those disclosed herein may be administered, e.g., intraduodenally, at a rate of about 1.0 ml/hour during the daytime or activity time (e.g., for about 2-3 hours before waking and for about 10 to about 12 hours thereafter), and 0 to about 0.5 ml hour at rest or at night.

[0223] In an embodiment, liquid compositions such as disclosed herein (e.g., comprising levodopa and/or a compound of formula (II) and/or a compound of formula (I) or a pharmaceutically acceptable salt thereof), may be administered at a rate of about 1.25 ml/hour (e.g., about 1.25 ± 0.5 ml/hour during the daytime or activity time (e.g., for about 2-3 hours before or after waking and for about 10 to about 14 hours thereafter), and 0 to about 0.5 ml/hour (e.g. about 0.5 ± 0.25 ml hour) at rest or night.

[0224] In further embodiments, such compositions may be administered at a rate of about 0.1 to about 1000 μΐ/hour/site; or at a volume of about 2 to about 10 ml/24 hour/site, preferably about 4 to about 6 ml/24 hour/site; or at a dose of about 80 to about 800 mg of levodopa and/or a levodopa prodrug (e.g., a compound of formula (II) or a pharmaceutically acceptable salt thereof)/day and about 20 to about 200 mg of a carbidopa prodrug (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof)/day; or at a rate of about 240 to about 360 mg of levodopa and/or a levodopa prodrug and about 60 to about 90 mg of a carbidopa prodrug/day/site.

[0225] Contemplated administration, following the disclosed methods, typically can be carried out over a defined time period, usually weeks, months, or years, by any of the administration routes and means defined herein.

[0226] In an embodiment, substantially continuously administering using, e.g., a liquid formulation can be via a pump for subcutaneous infusion (insulin pump) at an average rate of about 10-1000 μΐ/hour (e.g., 10-250 μΐ/hour), about 300 ± 100 μΐ/hour, or about 200 ± 40 μΐ/hour continuously for 24 hours; about 440 ± 200 μΐ/hour or about 200 ± 50 μΐ/hour continuously for 16 hours (during waking hours), and at night (e.g., for 8 hours), about 0 to 80 μΐ/hour or 0 to 200 μΐ hour. Substantially continuously administering the formulation into a patient can be doubled or tripled by using more than one pump or site of infusion. In an embodiment, substantially continuously administering using, e.g., a liquid formulation can be at an average rate of about 0.2- 2 μΐ/hour, or about 1 ± 0.5 μΐ/hour continuously for 24 hours; about 1.0 ± 0.5 μΐ hour continuously for 16 hours (during waking hours) and at night (e.g., for 8 hours), about 0 to 0.5 μΐ/hour via a pump or transdermal patch, or combination of delivery devices that are suitable for, e.g., subcutaneous, intravenous, intrathecal, and/or via the duodenum.

Kits, Devices, and Articles

[0227] Contemplated herein, is a patch suitable for transdermal or subcutaneous administration of an active agent in a formulation as disclosed herein, for example, including levodopa or a levodopa prodrug such as a compound of formula (II) or a pharmaceutically acceptable salt thereof; and/or carbidopa prodrug such as a compound of formula (I) or a pharmaceutically acceptable salt thereof. Such patches can have one or more compartments that can have the same or different formulations, for example, one compartment can have a disclosed formulation and another compartment a different disclosed formulation, or a different active agent. A dermal patch refers to any device that is capable of delivering one or more of the active agents contained in a disclosed formulation, through the skin or mucous membrane, into a patient.

[0228] In some embodiments, disclosed liquid formulations (e.g., comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and optionally a compound of formula (II) or a pharmaceutically acceptable salt thereof thereof), can be provided in, e.g., a pre-filled cartridge or vial suitable for use by a patient or physician.

[0229] For example, provided herein is a kit comprising a prefilled cartridge wherein a disclosed liquid formulation is disposed within the cartridge (e.g., a pre-filled cartridge having a single dose of a disclosed formulation or a dose suitable for a single or multiple administration to a patient, and optionally instructions for use). For example, provided herein is a container, vial, pre-filled syringe or the like that can include about 1-10 ml of a disclosed formulation. For example, a contemplated kit can include one, two, or more pre-filled vials, containers or syringes having an amount of a disclosed liquid formulation suitable for filling a syringe pump or patch pump, e.g., a vial, container, or syringe having about 1-6 ml, 2-5 ml, 1-2 ml, or 4-10 ml of a disclosed formulation.

[0230] The invention also contemplates kits that include formulations disclosed herein, taking advantage of an increased stability of the disclosed formulations. These kits can include a supply of a formulation sufficient for at least 1, 2, 3, 4, or 5 days; 1, 2, 3 or 4 weeks; 1, 2, 3, 4, 6, or 9 months; or 1 or 1.5 years of administration to a patient, which can be packaged, for example, into suitable dosage (e.g., unit dosage) formulations. These kits can optionally include instructions for their use. A kit for daily use for example, can include one, two or more containers or vials of a disclosed formulation, an infusion set, and a disposable delivery unit (e.g. syringe).

[0231 ] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0232] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.

EXAMPLES

Materials and Methods

[0233] Various L-dopa monophosphoester, L-dopa diphosphoesters, carbidopa monophosphoester and carbidopa diphosphosphoesters may be obtained as described, for example, in U.S. Patent No. 9,446,059, incorporated herein by reference as if fully described herein. Determination of hydrazine by GC-MS

[0234] The determination of hydrazine was carried out by derivatization of hydrazine with acetone-d6, to form the derivative (CD3)2C=N-N=C(CD3)2.

The reagents with the described quality for analyses listed in following Table

Table 1. Reagents

All ingredients were purchased from Sigma-Aldrich; water deionized were purchased from Millipore, Milli Q.

[0236] The reference materials with described quality listed in following Table 2 were used (all were purchased from Sigma-Aldrich) :

Table 2. Reagents

[0237] The equipment or equipment of equivalent performance listed in following Table 3 were used:

Table 3. Equipment

[0238] (a) Solutions. The following solutions were prepared: (i) internal standard stock solution (ISTD) was prepared by dissolving 10 μΐ of toluene-dB (density 0.87 g/ml) in 1 -methyl- 2-pyrrolidone to obtain a 870 μg/ml toluene-dB solution; (ii) reagent solution was prepared by mi ing: 125 ml of l-methyl-2-pyrrolidone, 25 ml of cyclobexane, 1.25 ml of formic acid. 1 .25 ml of acetone-d6, and 10 μΐ of ISTD, and agitating to mix the phases. Toluene-dB concentration: 0.06 μg/ml; (iii) NaOH solution was prepared by diluting 2.5 ml of sodium hydroxide solution 50% in 100 ml water deionized; (iv) EDTA solution was prepared by dissolving and diluting to volume 0. 1 g of ethylenediamine tetra acetic acid disodium salt dihydrate ( EDTA ) with water deionized.

[0239] (b) Reference solutions. The following reference stock solutions were prepared:

Reference stock solution 1 (RSS 1) was prepared by dissolving 20 mg to 25 mg of hydrazine sulfate with EDTA solution by agitating overhead at approx. 40 rpm for 20 to 30 min, and then diluting to volume with EDTA solution. Concentration of hydrazine: 277 μg/ml;

Reference stock solution 2 (RSS2) was prepared by diluting 900 μΐ of reference stock solution 1 (RSS1 ) with EDTA solution. Concentration of hydrazine: 24.9 u /ml: and Reference stock solution 3 (RSS3) was prepared by diluting 400 μΐ RSS2 with EDTA solution. Concentration of hydrazine: 1.0 .ug/ml.

[0240] (c) Comparison solutions. Six comparison solutions (CS 1-CS6)) listed in Table 4 were prepared by adding various volumes of RSS3 to 5000 μΐ of the reagent, shortly agitating to mix the phases, and leaving the solutions for derivatization for 10 min. Derivatization was ended by addition of 2 ml of sodium hydroxide solution, mixing for phase separation, and centrifugation. The clear upper phase was separated and analyze by GC-MS.

Table 4. Comparison solutions

[0241] (d) Blank solution. A blank solution was prepared by mixing 5000 μΐ of reagent solution with 100 μΐ of EDTA and solution and agitating shortly to mix the phases. The solution was left for derivatization for 10 min. Derivatization was ended by addition of 2 ml of sodium hydroxide solution, mixing for phase separation, and centrifugation. The clear upper phase was separated and analyze by GC-MS. Seven blank solutions were prepared and remained stable for at least 12 hours when stored at room temperature.

[0242] (e) Test solutions. An exemplary test solution was prepared in duplicates, by mixing 100 μΐ of a test formulation with 5000 μΐ of reagent solution, agitating shortly to mix the phases, and leaving the solutions for derivatization for 8 min. Derivatization was ended by addition of 2 ml of sodium hydroxide solution, agitating shortly, and mixing for phase separation. The test solutions was centrifuged (3000 rpm for 5 min), and the clear upper phase was separated and analyze by GC-MS. The test solutions remained stable for at least 12 hours when stored at room temperature.

[0243] (f) Chromatography was conducted as well known in the art, adhering to equipment- specific components and operating instructions (e.g., injection mode: split, 1: 10; injector temp 200°C; injection volume 3 μΐ; carrier gas: helium; flow rate: constant flow, 1.5 ml/min; GC routine: 10 min). The order of injection: a blank solution, CS1-CS6, CS3 (performance control every 10 injections), blank solution and test solution.

[0244] (g) Mass spectroscopy was conducted as well known in the art, adhering to equipment-specific components and operating instructions (e.g., Electron Ionization (EI+), 70 eV; Temperature: ion source 230°C, transfer line 240°C). The detection mode of analyte mass was selective ion monitoring (SIM), as indicated in Table 5:

Table 5. MS Detection mode

[0245] (h) Data analysis. The peak area ratios of hydrazine derivative/toluene-dB in the chromatogram of calibration solutions CS 1-CS6 were calculated, and the calibration function was determined by regression calculations (calibration function: linear, not forced through origin; correlation coefficient (r) 0.99). The peak area ratio of hydrazine derivative/toluene-dB in chromatograms of the test solutions was determined, and the concentration of hydrazine derivative (in ppm or μ /ml) was calculated against the calibration function. Results are disclosed as means (in ppm or mg/ml) of duplicate preparations.

EXAMPLE 1

Formulation Preparation Procedure

[0246] Formulations comprising a compound of formula (I) (FI) and/or a compound of formula (II) (FII) were prepared using the powder mixing method, as follows: powders of the FII, and/or FI, ascorbic acid (or sodium ascorbate) and, optionally sodium bisulfite (Na-Bis) and N- acetylcysteine (NAC) were weighed, mixed together and water was added.

EXAMPLE 2

Hydrazine levels in carbidopa phosphoester and levodopa phosphoester formulations

[0247] Stability of formulations with phosphate esters of carbidopa (CD-p) and/or phosphate esters of levodopa (LD-p) was assessed. Formulations were prepared using the all powders mixing method as described in Example 1 above. Formulations with 4-levodopa monophosphate and/or 4-carbidopa monophosphate and one or two antioxidants were tested. Briefly: powdered CD-p and/or LD-p were mixed with powders of one or more of the antioxidants ascorbic acid, NAC and/or Na-Bis, and water was added. The solutions were mixed to reach solubility. The pH was measured and adjusted as needed. The final solutions were filtered (Nylon syringe filter 0.22 μπι) and divided into vials. Gaseous nitrogen was purged during preparation of formulations 1-4 (Fl- F4).

[0248] Six formulations (F1-F6) were prepared for two separate sets of measurements. In the first set, formulation F1-F4 did not contain LD-p, were prepared in N ₂ atmosphere and kept at RT for up to 48 hours; in the second set, formulationsF5, F6 contained LD-p, were prepared without N ₂ and kept at RT. The formulations and the relative amounts of ingredients are indicated in Tables 6. Table 6. Formulations F1-F6

[0249] The effect of antioxidant(s) presence in the formulations on the level of hydrazine was assessed for formulations F1-F6. The determination of hydrazine was carried out by hydrazine derivatization using acetone-d6, and evaluation of hydrazine derivative by gas chromatography- mass spectrometry (GC-MS) as described in Materials and Methods. Hydrazine release was assessed at T=0, and then following 24 h (T=24) and 48 h (T=48). Hydrazine levels (expressed in μg/ml or ppm; ^g/ml = 1 ppm) in the tested formulations of the three sets of measurement are depicted in Tables 7 and 8.

Table 7. Hydrazine levels ^ /ml or ppm) in formulations F1-F4

Table 8. Hydrazine levels (μ^ηιΐ or ppm) in formulations F5-F6

[0250] As seen in Table 7 and Fig. 1, formulation with CD-p and two antioxidants (F3) presented lower levels of hydrazine as compared to formulations without antioxidants (Fl).

[0251 ] As seen in Table 8 and Fig. 2, formulations with CD-p and LD-p comprising two antioxidants (F6) presented lower levels of hydrazine as compared to formulations without antioxidants (F5. Addition of at least two antioxidants to CD-p formulations seem to incredibly increase the carbidopa phosphoester stability in terms of hydrazine release.

[0252] Moreover, formulations F7 and F8 containing both CD-p and LD-p were prepared with increasing concentrations of ascorbic acid and NAC, without N ₂ , and kept at -20°C. Formulation F7 comprised 1.36% by weight of CD-p, 5.64% by weight LD-p, 1% by weight ascorbic acid, and 1% by weight NAC. Formulation F8 comprised 1.36% by weight of CD-p, 5.64% by weight LD-p, 1.5% by weight ascorbic acid, and 1.5% by weight NAC. These formulations presented lower level of hydrazine as compared to formulations without antioxidants. Increased amounts of two antioxidants was manifested in decreased hydrazine release (results not shown).

EQUIVALENTS

[0253] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0254] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention.