WO2022190100A1 - Stabilized liquid compositions comprising a levodopa-tyrosine conjugate and uses thereof - Google Patents

Stabilized liquid compositions comprising a levodopa-tyrosine conjugate and uses thereof Download PDF

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Publication number
WO2022190100A1
WO2022190100A1 PCT/IL2022/050269 IL2022050269W WO2022190100A1 WO 2022190100 A1 WO2022190100 A1 WO 2022190100A1 IL 2022050269 W IL2022050269 W IL 2022050269W WO 2022190100 A1 WO2022190100 A1 WO 2022190100A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
liquid pharmaceutical
amino
composition according
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IL2022/050269
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English (en)
French (fr)
Inventor
Avital Laxer
Elana Gazal
Mazzi Dagan-Lion
Irena VAINSHTOK
Alaa TALHAMI
Alex MAINFIELD
Eduardo Zawoznik
Kenji Morokuma
Kazuki Nakayama
Eiji Yoshida
Akira Nakao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Neuroderm Ltd
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Neuroderm Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Neuroderm Ltd filed Critical Neuroderm Ltd
Priority to JP2023555193A priority Critical patent/JP2024509907A/ja
Priority to KR1020237033788A priority patent/KR20230155508A/ko
Priority to CA3211324A priority patent/CA3211324A1/en
Priority to CN202280019958.8A priority patent/CN116964069A/zh
Priority to US18/549,452 priority patent/US20240207410A1/en
Priority to EP22766532.0A priority patent/EP4305049A4/en
Priority to AU2022232759A priority patent/AU2022232759A1/en
Priority to BR112023018202A priority patent/BR112023018202A2/pt
Priority to IL305717A priority patent/IL305717A/en
Priority to MX2023010450A priority patent/MX2023010450A/es
Publication of WO2022190100A1 publication Critical patent/WO2022190100A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A61K38/063—Glutathione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
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    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a levodopa prodrug compound and its pharmaceutical use.
  • the present invention also is directed to stabilized compositions comprising a levodopa-tyrosine conjugate (LD-Tyr) and salts thereof, methods of preparing LD-Tyr compositions, and methods of using the same in, for example, the treatment of conditions characterized by neurodegeneration and/or reduced levels of dopamine in the brain, e.g., Parkinson's disease.
  • LD-Tyr levodopa-tyrosine conjugate
  • 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.
  • levodopa has remained the most effective therapy for the treatment of Parkinson’s disease.
  • levodopa The peripheral administration of levodopa is further complicated by the fact that only about 1-3% of the levodopa administered is able to enter the brain unaltered, wherein most of the levodopa is metabolized extracerebrally, predominantly by the decarboxylation of the levodopa to dopamine, which does not penetrate the blood brain barrier and therefore, is ineffective in treatment.
  • the metabolic transformation of levodopa to dopamine is catalyzed by the aromatic L- amino acid decarboxylase enzyme, an ubiquitous enzyme with particularly high concentrations in the intestinal mucosa, liver, brain and brain capillaries.
  • levodopa Due to the possibility of extracerebral metabolism of levodopa, it is necessary to administer large doses of levodopa, leading to high extracerebral concentrations of dopamine.
  • a peripheral dopamine decarboxylase (aromatic I .-amino acid decarboxylase) inhibitor such as carbidopa or benserazide, has been found to reduce the dosage requirements of levodopa and, respectively, some of the side effects; however, frequently, the obtained reduction is insufficient.
  • a method for administering a formulation containing levodopa with a pump continuously has been developed.
  • a method for continuous intestinal delivery of an L-dopa/carbidopa gel (known under the trade name DuoDopa® in Europe and Duopa® in the United States) is known, and treatment for Parkinson's disease has been performed using this method.
  • L-dopa/carbidopa gel known under the trade name DuoDopa® in Europe and Duopa® in the United States
  • Treatment for Parkinson's disease has been performed using this method.
  • An example of a less invasive delivery system is a method for subcutaneously administering a solution formulation with a pump.
  • Amino acids which contain both amino and carboxylic groups, are the basic unit of proteins. Generally, amino acids are known to play a major role in the body, being involved in tissue protein formation and enzyme hormone formation. Therefore, any deficiency in amino acids affects protein synthesis. Amino acids are also known to regulate processes related to gene expression and further, amino acids modulate the protein function involved in messenger RNA translation. Several amino acids, such as tyrosine, are synthesized in the human body, while others, known as essential amino acids, such as arginine and lysine, are consumed by diet. The lanthionine amino acid is a natural, but non-proteinogenic, diamino diacid, and is structurally related to the amino acid cysteine. Lanthionine has a central monosulfur moiety bound to two alanine residues (R/S configuration), allowing the possibility of different stereomeric forms of lanthionine.
  • Amino acids are ionized in aqueous solutions, wherein the pH of the solution affects the ionic species of the amino acid and determines whether the amino acid will be in the form of a zwitterion, cation or anion.
  • the permeability coefficients of the various compounds through the skin is dependent on their ionic form, wherein non-ionized species generally have higher permeability coefficients in comparison to ionized species and further, cations generally have higher permeability coefficients than anions.
  • U.S. Patent No. 3,803,120, U.S. Patent No. 4,035,507, U.S. Patent No. 5,686,423 and U.S. Patent Application No. 2002/099013 disclose certain levodopa amino acid and levodopa peptide conjugates; however, details regarding formulations are not provided therein, and when provided, only solid oral formulations are contemplated.
  • the theoretical option of preparing liquid compositions is briefly mentioned in U.S. Patent No. 3,803,120 (US ‘120, column 3, lines 49-53); however, no such compositions were prepared and moreover, it is erroneously disclosed that the conjugates are soluble (column 3, lines 65-66).
  • levodopa amino acid conjugates such as LD-Tyr
  • LD-Tyr has a propensity to form a diketopiperazine (DKP) impurity as shown in the scheme below.
  • DKP diketopiperazine
  • the present disclosure is intended to provide a novel compound that, by creating novel prodrug, has improved solubility and stability in solution compared to levodopa and allows the compound to be converted into levodopa in the body.
  • a levodopa prodrug compound represented by a general formula (I) or (III) has a high levodopa conversion efficiency and has a good solubility and stability in solution, and thus have accomplished the present invention.
  • the disclosure relates to levodopa amino acid complex represented by the following formula (I) or (III) or a pharmaceutically acceptable salt thereof:
  • R is an amino acid side chain that may be substituted
  • R 1 and R 2 may be the same or different, and are each independently a hydrogen atom, a C 1 -C 6 alkyl, a C 1 -C 6 alkanoyl, a phosphono, a sulfino, or a glycosyl that may be substituted, provided that R 1 and R 2 are not hydrogen atom at the same time;
  • R 3 and R 4 may be the same or different, and are each independently a hydrogen atom or a C 1 -C 6 alkyl
  • R 14 is a hydrogen or an alkyl, provided that following compounds are excluded;
  • the disclosure further relates to the levodopa amino acid complex according to the above (1) or a pharmaceutically acceptable salt thereof, wherein R3, R4 and R5 are hydrogen atoms,
  • R 1 and R 2 are the same or different, and are each a hydrogen atom, an acetyl or a phosphono, provided that R 1 and R 2 are not hydrogen atom at the same time.
  • the disclosure further relates to the levodopa amino acid complex according to the above (1) or (2) or a pharmaceutically acceptable salt thereof, wherein R3, R4 and R5 are hydrogen atoms,
  • R 1 is a hydrogen atom
  • R 2 is a phosphono
  • the disclosure further relates to the levodopa amino acid complex according to any one of the above embodiments, or a pharmaceutically acceptable salt thereof, wherein an amino acid of the amino acid side chain is a glutamic acid, valine, alanine, lysine, 3,4- dihydroxyphenylalanine or tyrosine.
  • the disclosure further relates to the levodopa amino acid complex selected from the group consisting of:
  • the disclosure further relates to a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising the levodopa amino acid complex according to any one of the above embodiments or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the disclosure further relates to therapeutic agent for a neurodegenerative disease and/or a disease or symptom caused by a decrease in dopamine concentration in the brain, the therapeutic agent comprising the levodopa amino acid complex according to any one of the above embodiments or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the neurodegenerative disease and/or the disease or symptom caused by a decrease in dopamine concentration in the brain is Parkinson's disease.
  • compositions comprising levodopa-tyrosine conjugates (LD-Tyr) or salts thereof (e.g., pharmaceutically acceptable salts thereof), for example, pharmaceutically acceptable compositions, for example, liquid pharmaceutical compositions, with improved stability.
  • LD-Tyr levodopa-tyrosine conjugates
  • salts thereof e.g., pharmaceutically acceptable salts thereof
  • pharmaceutically acceptable compositions for example, liquid pharmaceutical compositions, with improved stability.
  • methods of preparing such compositions are also disclosed. Also disclosed are methods of using compositions comprising LD-Tyr and pharmaceutically acceptable salts thereof, and compositions comprising the same in, for example, the treatment of conditions characterized by neurodegeneration and/or reduced levels of dopamine in the brain, e.g., Parkinson's disease.
  • a liquid pharmaceutical composition comprising: a levodopa-tyrosine (LD-Tyr) conjugate of the formula (II): an enantiomer, diastereomer, racemate, ion, zwitterion, pharmaceutically acceptable salt thereof, or any combination thereof; and a stabilizer.
  • LD-Tyr levodopa-tyrosine
  • a liquid pharmaceutical composition disclosed herein comprises between about 10 to about 45 % w/v, at least about 30 % w/v, or between about 30 to about 45 % w/v of the LD-Tyr, or an enantiomer, diastereomer, racemate, ion, zwitterion, pharmaceutically acceptable salt thereof, or any combination thereof.
  • the stabilizer is present in an amount of about 0.1 to about 30 % w/v.
  • the stabilizer comprises a base.
  • the base is selected from the group consisting of arginine, NaOH, NH 4 OH, tris(hydroxymethyl)aminomethane (TRIS), ethylendiamine, diethylamine, ethanolamine, diethanolamine, meglumine, and any combination thereof.
  • the base is selected from the group consisting of arginine, NH 4 OH, ethylendiamine, diethylamine, ethanolamine, diethanolamine, meglumine, and any combination thereof.
  • the base is selected from the group consisting of L-Arg, diethylamine, and a combination thereof.
  • the base is selected from the group consisting of L-Arg, ethanolamine, and a combination thereof.
  • the liquid pharmaceutical composition comprises between about 0.1 to about 30 % w/v of the base. In some embodiments, the liquid pharmaceutical composition comprises between about 1.5 to about 20 % w/v of the base.
  • a liquid pharmaceutical composition disclosed herein has a pH in the range of between about 5 to about 10 at about 25 °C. In some embodiments, a liquid pharmaceutical composition disclosed herein has a pH in the range of between about 8 to about 10. In some embodiments, a liquid pharmaceutical composition disclosed herein has a pH in the range of between about 8 to about 9.
  • a liquid pharmaceutical composition disclosed herein can include a free base of the compound of formula II and a counterion.
  • a liquid pharmaceutical composition disclosed herein can also include a decarboxylase inhibitor.
  • the decarboxylase inhibitor is carbidopa.
  • a liquid pharmaceutical composition disclosed herein can include between about 0.25 to about 2.0 % w/v of the decarboxylase inhibitor.
  • a liquid pharmaceutical composition described herein can further include an antioxidant or a combination of two or more antioxidants.
  • a liquid pharmaceutical composition described herein can include an antioxidant selected from the group consisting of ascorbic acid or a salt thereof, a cysteine, e.g., N-acetyl cysteine (NAC), a bisulfite or a salt thereof, glutathione, a tyrosinase inhibitor, a Cu 2+ chelator, and any combination thereof.
  • a liquid pharmaceutical composition described herein can include between about 0.05 to about 1.5 % w/v of an antioxidant or a combination of antioxidants.
  • the liquid pharmaceutical composition comprises a combination of ascorbic acid and NAC.
  • any of the aforementioned liquid pharmaceutical composition described herein can further include at least one of: a catechol-O-methyltransferase (COMT) inhibitor, a monoamine oxidase (MAO) inhibitor, a surfactant, a buffer, an acid, a base, a solvent, or any combination thereof.
  • the liquid pharmaceutical composition comprises between about 5.0 to about 40.0 % w/v of a buffer, base, or solvent.
  • a liquid pharmaceutical composition described herein can include a solvent, wherein the solvent may be N-methylpyrrolidone (NMP), tris(hydroxymethyl)aminomethane (tromethamine, TRIS), an ether such as tetrahydrofuran and 1,4-dioxane an amide, such as N,N-dimethylformamide and N- methylpyrrolidone, a nitrile, such as acetonitrile, a halogenated aliphatic hydrocarbon, such as chloroform and dichloromethane, an aromatic hydrocarbon, such as toluene or any combination thereof.
  • NMP N-methylpyrrolidone
  • TRIS tris(hydroxymethyl)aminomethane
  • TRIS tris(hydroxymethyl)aminomethane
  • an ether such as tetrahydrofuran and 1,4-dioxane
  • an amide such as N,N-dimethylformamide and N- methylpyrrolidone
  • a liquid pharmaceutical composition described herein can include a surfactant, wherein the surfactant is Tween-80.
  • a liquid pharmaceutical composition described herein can include a solvent and a surfactant, where the solvent is NMP and the surfactant is Tween-80.
  • the liquid pharmaceutical composition can include between about 0.1 to about 1.0 % w/v of the surfactant, for example, 0.1 to about 1.0 % w/v of Tween-80.
  • the liquid pharmaceutical composition can include between about 5.0 to about 40.0 % w/v of the solvent, for example, between about 5.0 to about 40.0 % w/v of NMP.
  • the solvent is TRIS.
  • the stabilizer includes polyethylene glycol.
  • the liquid pharmaceutical composition comprises less than about 1.5 % w/v LD-Tyr-diketopiperazine after two weeks at 2-8°C. In certain embodiments, the liquid pharmaceutical composition comprises less than about 0.8 % w/v LD-Tyr-diketopiperazine after two weeks at 2-8°C. In certain embodiments, the liquid pharmaceutical composition comprises less than about 5.0 % w/v LD-Tyr-diketopiperazine after two weeks at 25°C. In certain embodiments, the liquid pharmaceutical composition comprises no more than about 4 % w/v LD- Tyr-diketopiperazine after two weeks at 25 °C.
  • Also disclosed herein is a method of treating a neurodegenerative condition and/or a condition characterized by reduced levels of dopamine in the brain, wherein the method comprises administering a liquid pharmaceutical composition as described herein.
  • the method comprises administering a liquid pharmaceutical composition including LD-Tyr and a stabilizer.
  • a neurodegenerative condition and/or a condition characterized by reduced levels of dopamine in the brain, wherein the neurodegenerative condition is Parkinson’s disease.
  • the liquid pharmaceutical composition is administered concomitantly with an additional active ingredient.
  • the additional active ingredient is a decarboxylase inhibitor, a COMT inhibitor, a MAO inhibitor, or any combination thereof.
  • the liquid pharmaceutical composition is administered substantially continuously. In some embodiments, the liquid pharmaceutical composition is administered subcutaneously.
  • liquid pharmaceutical composition for use in treating a neurodegenerative condition and/or a condition characterized by reduced levels of dopamine in the brain.
  • a liquid pharmaceutical composition for use in treating a neurodegenerative condition and/or a condition characterized by reduced levels of dopamine in the brain, wherein the neurodegenerative condition is Parkinson’s disease.
  • the liquid pharmaceutical composition is administered concomitantly to the patient with an additional active ingredient, e.g., a decarboxylase inhibitor, a COMT inhibitor, a MAO inhibitor, and any combination thereof.
  • an additional active ingredient e.g., a decarboxylase inhibitor, a COMT inhibitor, a MAO inhibitor, and any combination thereof.
  • the liquid pharmaceutical composition is administered substantially continuously to the patient. According to further embodiments, the liquid pharmaceutical composition is administered subcutaneously.
  • Embodiments of the invention are further directed to a method of treating Parkinson’s disease in a patient in need thereof, comprising subcutaneously administering to the patient an effective amount of the liquid pharmaceutical formulation, as disclosed herein. Further embodiments of the invention are directed to uses of the liquid pharmaceutical formulation as disclosed herein for treating neurodegenerative conditions and/or conditions characterized by reduced levels of dopamine in the brain, such as Parkinson’s disease.
  • Also disclosed herein is a process for preparing a liquid pharmaceutical composition, wherein said process comprises providing a pharmaceutically acceptable salt of LD-Tyr; combining the pharmaceutically acceptable salt with at least one solvent thereby forming a solution, gel, cream, emulsion, or suspension; combining the solution, gel, cream, emulsion or suspension with a stabilizer; and adjusting the pH of the solution, gel, cream, emulsion, or suspension, to a physiologically acceptable pH value, thereby providing the liquid pharmaceutical composition.
  • a process for preparing a liquid pharmaceutical composition described herein includes providing a pharmaceutically acceptable salt of a LD-Tyr, an enantiomer, diastereomer, racemate, ion, zwitterion, pharmaceutically acceptable salt thereof, or any combination thereof.
  • the LD-Tyr compound of Formula (II) in a pharmaceutically acceptable salt form is mixed with at least one solvent and at least one stabilizer, thereby forming a solution.
  • the process includes a step of adjusting the pH that comprises adding a basic solution.
  • the process includes a step of adjusting the pH that comprises adding a basic solution, and the basic solution comprises NaOH. In some embodiments the process does not include heating.
  • Figure 1 is a graph depicting rate of LD-Tyr-diketopiperazine (LD-Tyr-DKP) formation over time at 2-8°C in LD-Tyr formulations comprising the indicated bases.
  • LD-Tyr-DKP LD-Tyr-diketopiperazine
  • Figure 2 is a graph depicting rate of LD-Tyr-diketopiperazine (LD-Tyr-DKP) formation over time at 25 °C in LD-Tyr formulations comprising the indicated bases.
  • LD-Tyr-DKP LD-Tyr-diketopiperazine
  • Figure 3 presents the KRBC/PL for LD-Tyr following incubation in rat blood.
  • Figure 4 presents the KRBC/PL for LD-Tyr following incubation in minipig blood.
  • Figure 5 presents the KRBC/PL for LD-Tyr following incubation in human blood.
  • Figure 6 presents the composite mean plasma LD-Tyr concentration vs. time profiles in domestic pigs following continuous subcutaneous infusion for 18 hours.
  • Figure 7 presents the composite mean plasma LD concentration vs. time profiles in domestic pigs following continuous subcutaneous infusion of LD-Tyr for 18 hours.
  • Figure 8 presents the composite mean plasma LD concentration vs. time profiles in domestic pigs following continuous subcutaneous infusion of high concentrations of LD-Tyr and 1% CD for 18 hours.
  • Figure 9 presents the composite mean plasma LD concentration vs. time profiles in domestic pigs following continuous subcutaneous infusion of high concentrations of LD-Tyr and 0.5% CD for 18 hours.
  • Figure 10 presents the composite mean plasma LD concentration vs. time profiles in domestic pigs following continuous subcutaneous infusion of LD-Tyr and varying amounts of CD for 18 hours.
  • Figure 11 presents the composite mean normalized LD plasma concentration-versus-time profiles in domestic pigs following an 18 hour continuous SC infusion of 30% LD-Tyr together with different CD concentrations.
  • Figure 12 presents the composite mean plasma LD concentration-versus-time profiles following different volumes bolus infusions and 2-hr continuous SC infusion of 30% LD-Tyr and 1% CD in domestic pigs.
  • Figure 13 shows the composite mean plasma LD-Tyr and LD concentration-versus-time profiles for the 2700 mg dosing regimen. PK parameters are also shown.
  • Figure 14 shows the composite mean plasma LD-Tyr and LD concentration-versus-time profiles for the 5400 mg dosing regimen. PK parameters are also shown.
  • Figure 15 shows the composite mean plasma LD concentration-versus-time profiles for the 2700 and 5400 mg dosing regimens.
  • the terms “treat,” “treatment,” “treating,” and the like are used herein to generally refer to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be therapeutic in terms of partially or completely curing a disease and/or adverse effect attributed to the disease.
  • treatment includes any treatment of a disease in a mammal, particularly a human, and includes: (a) inhibiting the disease, i.e., preventing the disease from increasing in severity or scope; (b) relieving the disease, i.e., causing partial or complete amelioration of the disease; or (c) preventing relapse of the disease, i.e., preventing the disease from returning to an active state following previous successful treatment of symptoms of the disease or treatment of the disease.
  • Preventing includes delaying the onset of clinical symptoms, complications, or biochemical indicia of the state, disorder, disease, or condition developing in a subject that may be afflicted with or predisposed to the state, disorder, disease, or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder, disease, or condition. “Preventing” includes prophylactically treating a state, disorder, disease, or condition in or developing in a subject, including prophylactically treating clinical symptoms, complications, or biochemical indicia of the state, disorder, disease, or condition in or developing in a subject.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” as used herein interchangeably refer to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration.
  • composition and “pharmaceutical formulation” as used herein refer to a composition or formulation comprising at least one biologically active compound, for example, a levodopa amino acid conjugate, or a pharmaceutically acceptable salt thereof, as disclosed herein, formulated together with one or more pharmaceutically acceptable excipients. It is noted that the terms “formulation” and “composition” are interchangeable unless specifically mentioned otherwise or unless a person skilled in the art would have understood otherwise.
  • pharmaceutically acceptable salt(s) refers to salts of acidic or basic groups that may be formed with the conjugates used in the compositions disclosed herein.
  • “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or non-human primates, and humans.
  • the mammal treated in the methods of the invention is a human suffering from neurodegenerative condition, such as Parkinson’s disease and/or a disease or symptom caused by a decrease in dopamine concentration in the brain.
  • stable refers to a state of a substance that does not or is difficult to decompose in a solution. Therefore, the term “stable” as used herein means that, for example, when a solution of the substance is prepared and a peak area ratio of the substance measured using an area percentage method of high performance liquid chromatography (HPLC) immediately after the preparation of the solution is compared to a peak area ratio of the substance after being left at 25 °C for about 1 day, a decrease in peak area ratio is not observed or the degree of the decrease in peak area ratio is low.
  • HPLC high performance liquid chromatography
  • stable refers to a substance that was physically stable after an indicated period of time, such that, upon visual view of the substance, e.g., formulation, under magnification of at least xl.75, no precipitants were visible.
  • stabilizer refers to a substance that prevents or slows precipitation or the development of impurities in a substance, e.g., a liquid pharmaceutical formulation.
  • stabilizer refers to any excipient that provides the liquid pharmaceutical composition with enhanced stability, e.g., physical and/or chemical stability.
  • the stabilizer may be, e.g., a solvent, buffer, base, acid, or any combination thereof and therefore, any excipient referred to herein, e.g., as a solvent, buffer, etc., may be considered a stabilizer as well.
  • liquid refers to any type of fluid, including gels, aqueous and non-aqueous compositions, and the like.
  • use in combination means administration of two or more active ingredients in combination, including administration of these active ingredients at the same time, either separately or in the same composition, and also includes administration of two or more active ingredients consecutively on the same day, and administration of the active ingredients separated from each other for a predetermined time period, and further includes administration of two or more active ingredients on different days.
  • composition refers to any type of combined administration of two or more active ingredients, including administration of those active ingredients at the same time, either in separate or the same composition, as well as administering the two or more active ingredients sequentially, consecutively, on the same day, with a predefined period of time separating the administration of the active ingredients from one another, and the like.
  • the period of time during which a composition is administered may be at least about six hours, about eight hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, three days, seven days, two weeks, a month, three months, six months, a year, two years, three years, five years, ten years, etc.
  • physiologically acceptable pH value refers to pH values in the range of between about 4.5 to about 10. It is further noted that when pH values are provided, including in the examples, the values may be in the range of about ⁇ 0.1 and/or ⁇ 10% of the listed value(s), such that if the measured pH is 8.1, the same formulation may be prepared to provide a pH of about 8.0 or 8.2. Such differences may be due to temperature changes, various measuring devices, etc.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof has a good conversion efficiency to levodopa and is useful as a prophylactic or therapeutic agent for a neurodegenerative disease and/or a disease or symptom caused by a decrease in dopamine concentration in the brain, for example, Parkinson's disease.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is highly soluble, and further, is highly stable in a solution and is easy to be handled in a solution state, and thus, is highly suitable for use in a form of a steady delivery system.
  • an alkyl refers to a linear or branched saturated hydrocarbon group having 1 - 6 carbon atoms (Ci 6 ).
  • a group having 1 - 4 carbon atoms (Ci 4) is preferable.
  • Specific examples thereof include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, i-pentyl, n-hexyl, and the like.
  • methyl is preferable.
  • An alkanoyl refers to a monovalent group in which the above-described alkyl is bonded to a carbonyl, and examples thereof include a linear or branched alkyl-CO- having 1 - 6 carbon atoms (Ci 6 ). Specific examples thereof include acetyl, propionyl, butyryl, pivaloyl, pentanoyl, hexanoyl, heptanoyle, and the like. In particular, acetyl is preferable.
  • An amino acid side chain refers to an amino acid side chain of a natural, synthetic, non- natural or non-protein-producing amino acid, and examples of the amino acid include arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, lanthionine, selenocysteine, pyrrolidine, ADDA amino acid ((2S, 3S, 4E, 6E, 8S, 9S)-3-amino-9-methoxy-2, 6, 8-trimethyl- 10-phenyldeca-4,6-dienoic acid), b-alanine, 4- aminobenzoic acid, g-aminobutyric acid, S-aminoethyl
  • the amino acid side chain in the present invention may be substituted, and examples thereof include -P(0)(0R 6 ) 2 (where R 6 is a hydrogen, an alkyl, or the like), a glucosyl group (such as [(2R, 3S, 4R, 5S, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]), a group that bonds to another adjacent group to form an alkylene group that may be substituted (examples of substituent groups include an alkyl group, an alkoxy group, and the like), and the like.
  • substituent groups include an alkyl group, an alkoxy group, and the like
  • substituted amino acid side chains include those in which a tyrosine side chain, a serine side chain, a threonine side chain, or an amino acid side chain having a hydroxy such as (3,4- dihydroxyphenyl)methyl is substituted, and specific examples thereof include phosphonooxymethyl, (4-phosphonooxyphenyl)methyl, [4-[(2S, 3R, 4S, 5S, 6R)-3,4,5- trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxyphenyl]methyl, (2,2-dimethyl- 1,3- benzodioxol-5-yl)methyl, (2-ethoxy-2-methyl-l,3-benzodioxol-5-yl)methyl, and the like.
  • monosaccharides that are the source of glycosyl include aldoses such as glucose (dextrose), ribose, erythrose, xylose, arabinose, mannose, and galactose, as well as ketoses such as ribulose, psicose, fructose, sorbose, and tagatose. These monosaccharides may be of d-form, 1-form or dl-form.
  • a monosaccharide in the present invention may be substituted, and examples of substituent groups include a carbonyl group, an acetylamino group, a sulfinooxy group, a phosphonooxy group, and the like.
  • substituent groups include a carbonyl group, an acetylamino group, a sulfinooxy group, a phosphonooxy group, and the like.
  • substituted monosaccharides include glucuronic acid, N-acetylglucos
  • the present invention includes as an embodiment a levodopa amino acid complex represented by the general formula (I) or (III) or a pharmaceutically acceptable salt thereof:
  • R is an amino acid side chain that may be substituted
  • R 1 and R 2 may be the same or different, and are each independently a hydrogen atom, a C 1 -C 6 alkyl, a C 1 -C 6 alkanoyl, a phosphono, a sulfino, or a glycosyl that may be substituted, provided that R 1 and R 2 are not hydrogen atom at the same time;
  • R 3 and R 4 may be the same or different, and are each independently a hydrogen atom or a C 1 -C 6 alkyl
  • stereoisomers optical isomers, and diastereomeric isomers
  • the compound (I) or (III) of the present invention includes any one of these stereoisomers and mixtures thereof.
  • the compound (I) or (III) of the present invention includes compounds labeled with isotopes (for example, 3H, 13C, 14C, 15N, 18F, 32P, 35S, 1251, and the like) and include deuterium converters.
  • the compound (I) or (III) of the present invention can be used for pharmaceutical purposes either in a free form or in a form of a pharmaceutically acceptable salt or a form of a co- crystal.
  • the pharmacologically acceptable salt of the compound (I) or (III) of the present invention include inorganic acid addition salts (such as salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like), organic acid addition salts (such as salts of methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartrate acid, succinic acid, mandelic acid, malic acid, pantothenic acid, methyl sulfuric acid, and the like), inorganic base addition
  • the compound (I) or (III) of the present invention or a pharmaceutically acceptable salt thereof can be orally or parenterally administered alone or as a pharmaceutical composition that contains the compound (I) or (III) or a pharmaceutically acceptable salt thereof and a pharmacologically acceptable carrier.
  • the pharmacologically acceptable carrier may be a carrier commonly used in the art, and examples thereof include diluents, binders (such as syrup, gum arabic, gelatin, sorbitol, tragacanth, and polyvinylpyrrolidone), excipients (such as lactose, sucrose, cornstarch, potassium phosphate, sorbitol, and glycine), lubricants (such as magnesium stearate, talc, polyethylene glycol, and silica), disintegrants (such as potassium starch), wetting agents (such as sodium lauryl sulfate), and the like.
  • binders such as syrup, gum arabic, gelatin, sorbitol, tragacanth, and polyvinylpyrrolidone
  • excipients such as lactose, sucrose, cornstarch, potassium phosphate, sorbitol, and glycine
  • lubricants such as magnesium stearate, talc, poly
  • a carrier commonly used in the art may be used, and examples thereof include aqueous solvents (such as water for injection, and purified water), isotonizing agents (such as sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borax, glucose, and propylene glycol), buffers (such as a phosphoric acid buffer, an acetic acid buffer, a boric acid buffer, a carbonic acid buffer, a citric acid buffer, a tris buffer, a glutamic acid buffer, and an epsilon aminocaproic acid buffer), preservatives (such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxy benzoate, chlorobutanol, benzyl alcohol, benzalconium chloride, sodium dehydroacetate, sodium edetate, boric acid, and borax), soothing agents (such as sodium chloride, potassium chloride, glycerin, manni
  • the liquid pharmaceutical composition can be produced by dissolving or dispersing the compound of the present invention described above in a solution to which these carriers are appropriately added.
  • Such pharmaceutically acceptable additives can be appropriately selected by a person skilled in the art according to a purpose, and a condition such as an additive amount can also be appropriately set. Further, when necessary, a solubilizing agent or the like may be used.
  • a dosage form of such a pharmaceutical composition is not particularly limited, and examples thereof include conventional pharmaceutical formulations such as tablets, granules, capsules, powders, injections, inhalants, and suppositories. In particular, liquid pharmaceutical compositions containing injections can be used.
  • the compound (I) or (III) of the present invention or a pharmaceutically acceptable salt thereof can be formulated in a form of a liquid pharmaceutical composition, for example, as a formulation applicable to all appropriate routes of administration by parenteral administration such as bolus administration, continuous administration or sustained administration.
  • a liquid pharmaceutical composition containing the compound of the present invention can be formulated for subcutaneous administration, transdermal administration, intradermal administration, transmucosal administration, intravenous administration, intraarterial administration, intramuscular administration, intraperitoneal administration, intratracheal administration, intrathecal administration, intraduodenal administration, intrapleural administration, intranasal administration, sublingual administration, buccal administration, buccal administration, intestinal administration, intraduodenal administration, rectal administration, intraocular administration or oral administration.
  • the composition can also be formulated for inhalation or direct absorption through mucosal tissues.
  • a dosage amount of the compound (I) or (III) of the present invention or a pharmaceutically acceptable salt thereof varies depending on an administration method, and age, body weight, condition and the like of a patient. However, when administered as a liquid pharmaceutical composition, it is usually 1 - 200 mg/kg per day.
  • the compound (I) or (III) of the present invention or a pharmaceutically acceptable salt thereof can be used alone or in combination with one or more other therapeutic agents, depending on the disease to be treated (for example, Parkinson's disease).
  • therapeutic agents for example, one or more agents selected from a group consisting of dopamine decarboxylase inhibitors (such as carbidopa and benserazide), catechol-O-methyltransferase (“COMT”) inhibitors (such as entacapone and tolcapone), and monoamine oxidase A (“MAO-A”) or monoamine oxidase B (“MAO-B”) inhibitors (such as moclobemide, rasagiline, selegiline and safinamide) can be used.
  • dopamine decarboxylase inhibitors such as carbidopa and benserazide
  • catechol-O-methyltransferase (“COMT”) inhibitors such as entacapone and tolcapone
  • MAO-A monoamine
  • the compound (I) or (III) of the present invention or a pharmaceutically acceptable salt thereof can be administered at the same time as the above-described therapeutic agents that can be used in combination, or can be administered separately. Further, when the compound of the present invention is used therapeutically together with the above-described therapeutic agents that can be used in combination, the compound of the present invention and the therapeutic agents can be administered in the same dosage form such as parenteral administration, and may be administered in different dosage forms such as parenteral administration for one and oral administration for the other.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be produced, for example, as follows.
  • the compound represented by the general formula [la] can be produced, for example, as follows.
  • the compound [a-1] and the compound [b-1] or the compound [b-2] are subjected to a condensation reaction to obtain the compound [c], and then, the compound [c] is subjected to phosphite esterification and oxidation, or is subjected to phosphate esterification, and thereby, the compound [f] is obtained.
  • the compound [f] can also be obtained by condensing the compound [e] and the compound [b-1] or the compound [b-2].
  • the compound [la] can be produced by subjecting the compound [f] thus obtained to deprotection or to hydrolysis and then deprotection.
  • the condensation between the compound [a- 1] and the compound [b-1] or a salt thereof or [b-2] can be carried out according to a conventional method in a suitable solvent in the presence or absence of a base, in the presence or absence of a condensing agent, and in the presence or absence of an activating agent.
  • a suitable solvent in the presence or absence of a base, in the presence or absence of a condensing agent, and in the presence or absence of an activating agent.
  • any solvent that does not affect the present reaction may be used.
  • Examples of the solvent include: ethers such as tetrahydrofuran and 1,4-dioxane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and dichlorome thane; aromatic hydrocarbons such as toluene; or a mixture of these compounds.
  • Examples of the base include triethylamine, diisopropylethylamine, l,8-diazabicyclo[5.4.0]undec- 7-ene, and the like.
  • Examples of the condensing agent include 0-(7-azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride, l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, and the like.
  • Examples of the activating agent include 1- hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), 4-dimethylaminopyridine and the like.
  • An amount of the compound [b-1] or [b-2] to be used can be 1.0 - 5.0 equivalents, preferably 1.0 - 2.0 equivalents, in molar ratio with respect to the compound [a-1].
  • An amount of the base to be used can be 1.0 - 5.0 equivalents, preferably 1.0 - 2.0 equivalents, in molar ratio with respect to the compound [a-1].
  • An amount of the condensing agent to be used can be 1.0 - 5.0 equivalents, preferably 1.0 - 2.5 equivalents, in molar ratio with respect to the compound [a-1].
  • An amount of the activating agent to be used can be 1.0 - 5.0 equivalents, preferably 1.0 - 2.5 equivalents, in molar ratio with respect to the compound [a-1].
  • the present reaction can be carried out at room temperature - under heating, for example, at room temperature - 80 °C, preferably at room temperature - 50 °C.
  • the condensation of the compound [c] and a phosphite esterifying agent can be carried out according to a conventional method in a suitable solvent in the presence of an activating agent.
  • the solvent any solvent that does not affect the present reaction may be used.
  • the solvent include: nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; or a mixture of these compounds.
  • An example of the phosphite esterifying agent is dibenzyl N,N-diisopropyl phosphoramidite.
  • An example of the activating agent is 1-tetrazole.
  • An amount of the phosphite esterifying agent to be used can be 1.0 - 5.0 equivalents, preferably 1.5 - 3.0 equivalents, in molar ratio with respect to the compound [c].
  • An amount of the activating agent to be used can be 1.0 - 5.0 equivalents, preferably 1.5 - 3.0 equivalents, in molar ratio with respect to the compound [c].
  • the present reaction can be carried out under ice-cooling - under heating, for example, at 0 °C - 80 °C, preferably at room temperature - 50 °C.
  • the oxidation of the compound [d] can be carried out according to a conventional method in a suitable solvent in the presence of an oxidizing agent.
  • a suitable solvent any solvent that does not affect the present reaction may be used.
  • the solvent include: nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; or a mixture of these compounds.
  • the oxidizing agent include a hydrogen peroxide solution, tert-butyl hydroperoxide, metachloroperbenzoic acid, and the like.
  • An amount of the oxidizing agent to be used can be 1.0 - 5.0 equivalents, preferably 1.5 - 3.0 equivalents, in molar ratio with respect to the compound [d].
  • the present reaction can be carried out under ice-cooling - under heating, for example, at 0 °C - 80 °C, preferably at room temperature - 50 °C.
  • the condensation of the compound [c] and a phosphate esterifying agent can be carried out according to a conventional method in a suitable solvent in the presence or absence of a base.
  • a suitable solvent any solvent that does not affect the present reaction may be used.
  • the solvent include: nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and dichloromethane; or a mixture of these compounds.
  • the phosphate esterifying agent include dibenzylphosphoryl chloride, tetrabenzyl pyrophosphate, and the like.
  • Examples of the base include: alkali metal alkoxides such as sodium t-butoxide and potassium t- butoxide; alkylamines such as triethylamine, diisopropylethylamine and 1,8- diazabicyclo[5.4.0]undec-7-ene; and the like.
  • alkali metal alkoxides such as sodium t-butoxide and potassium t- butoxide
  • alkylamines such as triethylamine, diisopropylethylamine and 1,8- diazabicyclo[5.4.0]undec-7-ene
  • An amount of the phosphate esterifying agent to be used can be 1.0 - 5.0 equivalents, preferably 1.5 - 3.0 equivalents, in molar ratio with respect to the compound [c].
  • An amount of the base to be used can be 1.0 - 5.0 equivalents, preferably 1.5 - 3.0 equivalents, in molar ratio with respect to the compound [c].
  • the present reaction can be carried out at room temperature - under heating, for example, at room temperature - 100 °C, preferably at room temperature - 70 °C.
  • the condensation of the compound [e] and the compound [b-1] or a salt thereof or [b-2] can be carried out in the same manner as the condensation of the compound [a- 1] and the compound [b-1] or a salt thereof or [b-2] in the general synthesis method (A).
  • the deprotection of the compound [f] can be carried out according to a conventional method by a treatment with a catalyst in a suitable solvent in a hydrogen atmosphere.
  • any solvent that does not affect the present reaction may be used.
  • the solvent include: ethers such as tetrahydrofuran and 1,4-dioxane; alcohols such as methanol, ethanol and isopropanol; water; or a mixture of these compounds; and the like.
  • Examples of the catalyst include palladium/carbon, and the like.
  • the present reaction can be carried out at room temperature - under heating, for example, at room temperature - 80 °C, preferably at room temperature - 50 °C.
  • the hydrolysis of the compound [g] can be carried out according to a conventional method in a suitable solvent in the presence of a base and water.
  • a suitable solvent any solvent that does not affect the present reaction may be used.
  • the solvent include: alcohols such as methanol, ethanol and isopropanol; ethers such as tetrahydrofuran, 1,4-dioxane and 1,2- dimethoxy ethane; water; or a mixture of these compounds; and the like.
  • the base include: alkali metal hydroxides such as sodium hydroxide and lithium hydroxide; and the like.
  • the present reaction can be carried out under ice-cooling - under heating, for example, at 0 °C - 50 °C, preferably at a room temperature.
  • An amount of the base to be used can be 1.0 - 10.0 equivalents, preferably 1.0 - 4.0 equivalents, with respect to the compound [g].
  • the compound represented by the general formula [lb] can be produced, for example, as follows.
  • the compound [a-2] and the compound [b-3] are subjected to a condensation reaction to obtain the compound [h], and then, the compound [h] is subjected to phosphite esterification and oxidation, or is subjected to phosphate esterification, and thereby, the compound [j] is obtained.
  • the compound [lb] can be produced by deprotecting the compound [j].
  • Step 2 The condensation of the compound [h] and a phosphite esterifying agent can be carried out in the same manner as the condensation of the compound [c] and a phosphite esterifying agent in the general synthesis method (A).
  • the oxidation of the compound [i] can be carried out in the same manner as the oxidation of the compound [d] in the general synthesis method (A).
  • the condensation of the compound [h] and a phosphate esterifying agent can be carried out in the same manner as the condensation of the compound [c] and a phosphate esterifying agent in the general synthesis method (A).
  • the deprotection of the compound [j] can be carried out in the same manner as the deprotection of the compound [f] in the general synthesis method (A).
  • the compound represented by the general formula [Ic] can be produced, for example, as follows.
  • the compound [a-3] and the compound [b-1] are subjected to a condensation reaction to obtain the compound [k], and then, the compound [k] is subjected to deprotection, and thereby, the compound [Ic] can be produced.
  • the condensation of the compound [a-3] and the compound [b-1] or a salt thereof can be carried out in the same manner as the condensation of the compound [a- 1 ] and the compound [b- 1] or a salt thereof in the general synthesis method (A).
  • Step 2 The deprotection of the compound [k] can be carried out in the same manner as the deprotection of the compound [f] in the general synthesis method (A).
  • the compound represented by the general formula [Id] can be produced, for example, as follows.
  • the compound [a-2] and the compound [b-1] are subjected to a condensation reaction to obtain the compound [1], and then, the compound [1] is subjected to deprotection, and thereby, the compound [Id] can be produced.
  • the condensation of the compound [a-2] and the compound [b-1] or a salt thereof can be carried out in the same manner as the condensation of the compound [a- 1 ] and the compound [b- 1] or a salt thereof in the general synthesis method (A).
  • the deprotection of the compound [1] can be carried out in the same manner as the deprotection of the compound [f] in the general synthesis method (A).
  • the starting compounds in the above methods can be produced in the same manner as in known methods and/or in methods described in Examples described later.
  • a compound of the present invention or a starting compound thereof produced as described above is isolated and purified in a free form thereof or as a salt thereof.
  • a salt can be produced by a commonly used salt preparation process. Isolation and purification can be carried out by applying conventional chemical procedures such as extraction, concentration, crystallization, filtration, recrystallization, and various types of chromatography.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof exists as optical isomers based on asymmetric carbon atoms, it can be separated into individual optical isomers by ordinary optical resolution means (for example, a fractional crystallization method, and a separation method using a chiral column). Further, an optical isomer can also be synthesized using an optically pure starting material. Further, an optical isomer can also be synthesized by stereoselectively performing each reaction using an asymmetric auxiliary group or an asymmetric catalyst.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is useful for prevention or treatment of a neurodegenerative disease and/or a disease or symptom caused by a decrease in dopamine concentration in the brain.
  • the compounds and the combination medicament of the present invention are useful for prevention or treatment of Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's disease-like syndrome, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), amyotrophic lateral sclerosis (AFS), Shy-Drager syndrome, dystonia, Alzheimer's disease, Fewy body dementias (FBD), akinesia, bradykinesia, and hypokinesia, and are preferably useful for prevention or treatment of Parkinson's disease.
  • the compound and a combination medicament of the present invention are useful for prevention or treatment of diseases or symptoms caused by a brain damage including carbon monoxide poisoning or manganese poisoning, or diseases or symptoms associated with neurological diseases or neurological disorders including alcoholism, drug addiction or erectile dysfunction.
  • Embodiments of the invention are directed to a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising a levodopa-tyrosine conjugate of the formula (II): an enantiomer, diastereomer, racemate, ion, zwitterion, pharmaceutically acceptable salt thereof, or any combination thereof, and a stabilizer.
  • the liquid pharmaceutical composition comprises an LD-Tyr compound in a pharmaceutically acceptable salt form.
  • the LD-Tyr salt is selected from a trifluoroacetic acid (TFA) salt, an HC1 salt, fumaric acid salt, lactate salt, maleic acid salt, gluceptic acid salt, phosphoric acid salt, sulfuric acid salt, HBr salt, nitric acid salt, acetic acid salt, propionic acid salt, hexanoic acid salt, cyclopentanepropionic acid salt, glycolic acid salt, pyruvic acid salt, lactic acid salt, hippuric acid salt, methanesulfonic acid salt, ascorbic acid salt, malonic acid salt, oxalic acid salt, maleic acid salt, tartaric acid salt, citric acid salt, succinic acid salt, benzoic acid salt, cinnamic acid salt, a sulfonic acid salt, lauryl sulfuric acid salt,
  • TFA trifluoroacetic acid
  • the liquid pharmaceutical composition of the invention may comprise between about 2.5 to about 70 % w/v of an LD-Tyr compound, an enantiomer, diastereomer, racemate, ion, zwitterion, pharmaceutically acceptable salt thereof, or any combination thereof, or any combination of two or more LD-Tyr enantiomers, diastereomers, racemates, ions, zwitterions, pharmaceutically acceptable salts thereof, or any combination thereof.
  • the liquid pharmaceutical composition comprises between about 2.5 to about 5 % w/v, between about 5 to about 10 % w/v, between about 10 to about 15 % w/v, between about 15 to about 20 % w/v, between about 20 to about 25 % w/v, between about 25 to about 30 % w/v, at least about 30%, between about 30 to about 35 % w/v, between about 35 to about 40 % w/v, between about 30 to about 45 % w/v, between about 30 to about 50 % w/v, between about 30 to about 55 % w/v, between about 30 to about 60 % w/v, between about 30 to about 65 % w/v, between about 30 to about 70 % w/v, between about 40 to about 45 % w/v, between about 45 to about 50 % w/v, between about 50 to about 55 % w/v, between about 55 to about 60 % w/v, between about 60 to about w/v,
  • a liquid formulation as described herein comprises a stabilizer that prevents or slows precipitation of the formulation and/or that prevents or slows the accumulation of impurities in the formulation.
  • LD-Tyr has a propensity to form a diketopiperazine (DKP) impurity as shown in the scheme below.
  • DKP diketopiperazine
  • a stabilizing agent as described herein is added to or is included in a liquid pharmaceutical composition and prevents diketopiperazine formation.
  • the liquid pharmaceutical composition comprises less than about 1.5 % w/v LD-Tyr-diketopiperazine (LD-Tyr DKP) after two weeks at 2-8°C.
  • the liquid pharmaceutical composition comprises less than about 0.8 % w/v LD- Tyr-diketopiperazine after two weeks at 2-8°C.
  • the liquid pharmaceutical composition can comprise less than about 0.8 % w/v, 0.7 % w/v, 0.6 % w/v, 0.5 % w/v, 0.4 % w/v, 0.3 % w/v, 0.2 % w/v or 0.1 % w/v LD-Tyr-diketopiperazine after two weeks at 2-8°C.
  • the liquid pharmaceutical composition comprises less than about 4.0 % w/v LD- Tyr-diketopiperazine after two weeks at 25°C.
  • the liquid pharmaceutical composition can comprise less than about 5.0 % w/v, 4.5 % w/v, 4.0 % w/v, 3.5 % w/v, 3.0 % w/v, 2.5 % w/v, 2.0 % w/v, 1.5 % w/v or 1.0 % w/v LD-Tyr-diketopiperazine after two weeks at 25 °C.
  • the liquid pharmaceutical composition comprises no more than about 4.0 % w/v LD-Tyr-diketopiperazine after two weeks at 25°C.
  • Methods for measuring DKP are known in the art and include, for example, high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS).
  • the liquid pharmaceutical composition comprises between about 0.1 % to about 30 % w/v of the stabilizer. In certain embodiments, the liquid pharmaceutical composition comprises between about 1.5 to about 20 % w/v of the stabilizer.
  • the liquid pharmaceutical composition can comprise between about 1.5 and about 5.0 %, about 1.5 and about 10.0 % w/v, about 1.5 and about 15.0 % w/v, about 1.5 and about 20.0 % w/v, about 1.5 and about 25.0 % w/v, about 3.0 and about 5.0 % w/v, about 3.0 and about 10.0 % w/v, about 3.0 and about 15.0 % w/v, about 3.0 and about 20.0 % w/v, about 3 and about 25.0 % w/v, about 3.0 and about 30.0 % w/v, about 5.0 and about 10.0 % w/v, about 5 and about 15.0 % w/v, about 5.0 and about 20.0 % w/v.
  • the stabilizer comprises a base.
  • a liquid pharmaceutical composition comprises a stabilizer and further comprises a base, e.g., in order to provide the composition with a pre-defined pH.
  • the base is selected from NaOH, NH 4 OH, Ca(OH) 2 , ammonium hydroxide, arginine, magnesium hydroxide, potassium hydroxide, meglumine, tromethamine (TRIS), triethylamine, ethylendiamine, diethylamine, ethanolamine, diisopropylethylamine, diazabicycloundecene or any combination thereof.
  • the liquid pharmaceutical compositions may comprise between about 0.1 to about 30.0 % w/v of a base.
  • the liquid pharmaceutical composition comprises between about 0.1 to about 1.0 % w/v, between about 1.0 to about 2.0 % w/v, between about 2.0 to about 3.0 % w/v, between about 3.0 to about 4.0 % w/v, between about 4.0 to about 5.0 % w/v, between about 5.0 to about 6.0 % w/v, between about 6.0 to about 7.0 % w/v, between about 8.0 to about 9.0 % w/v, between about 9.0 to about 10.0 % w/v, between about 10.0 to about 11.0 % w/v, between about 11.0 to about 12.0 % w/v, between about 12.0 to about 13.0 % w/v, between about 13.0 to about 14.0 % w/v, between about 14.0 to about 15.0 % w/v, between about 15.0 to about 16.0 %
  • the stabilizer comprises a base selected from the group consisting of arginine, NaOH, NH 4 OH, tris(hydroxymethyl)aminomethane (TRIS), ethylendiamine, diethylamine, ethanolamine, diethanolamine, meglumine, triethanolamine, and any combination thereof.
  • the base is selected from the group consisting of arginine, NH 4 OH, ethylendiamine, diethylamine, ethanolamine, diethanolamine, meglumine, and a combination thereof.
  • the base is selected from the group consisting of L-Arg, diethylamine, and a combination thereof.
  • the base is selected from the group consisting of L-Arg, ethanolamine, and a combination thereof.
  • the liquid pharmaceutical composition comprises between about 0.1 % to about 30.0 % w/v of the base. In certain embodiments, the liquid pharmaceutical composition comprises between about 1.5 % to about 20.0 % w/v of the base.
  • the liquid pharmaceutical composition can comprise between about 1.5 to about 5.0 % w/v, between about 1.5 to about 10.0 % w/v, between about 1.5 to about 15.0 % w/v, about 1.5 to about 20.0 % w/v, between about 1.5 to about 25.0% w/v, between about 3.0 to about 5.0 % w/v, about 3.0 to about 10.0 % w/v, between about 3.0 to about 15.0 % w/v, between about 3.0 and about 20.0 % w/v, about 3.0 to about 25.0 % w/v, between about 3.0 to about 30.0 % w/v, about 5.0 to about 10.0 % w/v, between about 5.0 to about 15.0 % w/v, between about 5.0 to about 20.0 % w/v, between about 5.0 to about 25.0 % w/v, between about 5.0 to about 30.0 % w/v, between about 7.0 to about 10.0 % w/v, between about
  • the liquid pharmaceutical composition comprises two, three, or four stabilizers in combination.
  • the liquid pharmaceutical composition comprises arginine and an additional base selected from the group consisting of NH 4 OH, ethylendiamine, diethylamine, ethanolamine, diethanolamine, meglumine.
  • each individual stabilizer is present in an amount as described above, or the combination of stabilizers is present in an amount as described above.
  • arginine is present in an amount of from about 7.0 to about 8.0 % w/v and the additional base is present in an amount of from about 3.0 to about 8.0 % w/v.
  • the formulation comprises about 7.0 to about 8.0 % (e.g., 7.2%) w/v L-Arg and about 3.0 to about 8.0 % (e.g., about 5.4 %) w/v diethylamine. In certain embodiments, the formulation comprises about 7.0 to about 8.0 % (e.g., 7.2 %) w/v L-Arg and about 2.0 to about 7.0 % (e.g., about 4.5%) w/v ethanolamine.
  • the stabilizer includes one or more of polyethylene glycol (e.g., PEG-300, PEG-400, PEG-600), propylene glycol, choline, sodium or ammonium ions, an amino acid (e.g., Lys or His), benzyl alcohol, ethanol, group IIA metal complexes (e.g., Ca 2+ salts such as CaCl 2 and Ca ascorbate), citric acid, lactic acid, or acetic acid, an electrophile (e.g., a Lewis acid such as Na + , K + , Ca2 + , boron compounds, Fe 3+ , Al 3+ , Cu 2+ and a-b unsaturated carbonyls such as maleic acid), phosphate buffer, Zn 2+ ions, a reducing sugar such as glucose, sodium acetate, hydroxypropyl beta cyclodextrin, soluble beta cyclodextrin a medium chain triglyceride such as
  • the liquid pharmaceutical compositions further comprises an acid, e.g., in order to provide a composition with a pre-defined pH.
  • the acid is selected from HC1, HBr, methanesulfonic acid, ascorbic acid, acetic acid, citric acid, or any combination thereof.
  • the liquid pharmaceutical compositions may comprise between about 0.1 to about 30.0 % w/v of an acid.
  • the liquid pharmaceutical composition comprises between about 0.1 to about 1.0 % w/v, between about 1.0 to about 2.0 % w/v, between about 2.0 to about 3.0 % w/v, between about 3.0 to about 4.0 % w/v, between about 4.0 to about 5.0 % w/v, between about 5.0 to about 6.0 % w/v, between about 6.0 to about 7.0 % w/v, between about 8.0 to about 9.0 % w/v, between about 9.0 to about 10.0 % w/v, between about 10.0 to about 11.0 % w/v, between about 11.0 to about 12.0 % w/v, between about 12.0 to about 13.0 % w/v, between about 13.0 to about 14.0 % w/v, between about 14.0 to about 15.0 % w/v, between about 15.0 to about 16.0 % w/v, between about 16.0 to about 17.0 % w/v, between about 17.0 to about
  • the pH of the liquid pharmaceutical composition of the invention may be between about 4.5 to about 10 at about 25°C. According to some embodiments, the pH of the liquid pharmaceutical compositions is between about 4.5 to about 5 at about 25 °C. According to some embodiments, the pH of the liquid pharmaceutical compositions is between about 5 to about 6 at about 25°C. According to some embodiments, the pH of the liquid pharmaceutical compositions is between about 6 to about 7 at about 25°C. According to some embodiments, the pH of the liquid pharmaceutical compositions is between about 7 to about 8 at about 25 °C. According to some embodiments, the pH of the liquid pharmaceutical compositions is between about 8 to about 9 at about 25 °C.
  • the pH of the liquid pharmaceutical compositions is between about 9 to about 10 at about 25°C. According to some embodiments, the pH of the liquid pharmaceutical compositions is between about 4.5 to about 5.5 at about 25 °C. According to some embodiments, the pH of the liquid pharmaceutical compositions is between about 5.5 to about 6.5 at about 25°C. According to some embodiments, the pH of the liquid pharmaceutical compositions is between about 6.5 to about 7.5 at about 25°C. According to some embodiments, the pH of the liquid pharmaceutical compositions is between about 7.5 to about 8.5 at about 25°C. According to some embodiments, the pH of the liquid pharmaceutical compositions is between about 8.5 to about 9.5 at about 25°C. According to some embodiments, the pH of the liquid pharmaceutical compositions is between about 9.5 to about 10 at about 25 °C.
  • the liquid pharmaceutical composition further comprises a decarboxylase inhibitor.
  • the decarboxylase inhibitor is selected from carbidopa, benserazide, methyldopa, 3',4',5,7-Tetrahydroxy-8- methoxyisoflavone, alpha-difluoromethyl-dopa, or any combination thereof.
  • the decarboxylase inhibitor is carbidopa.
  • the liquid pharmaceutical composition of the invention may comprise between about 0.25 to about 3.0 % w/v of a decarboxylase inhibitor, e.g., carbidopa.
  • the liquid pharmaceutical compositions comprises between about 0.25 to about 0.5 % w/v, between about 0.5 to about 0.75 % w/v, between about 0.75 to about 1.0 % w/v, between about 1.0 to about 1.25 % w/v, between about 1.25 to about 1.5 % w/v, between about 1.5 to about 1.75 % w/v, between about 1.75 to about 2.0 % w/v, between about 2.0 to about 2.25 % w/v, between about 2.25 to about 2.5 % w/v, between about 2.5 to about 2.75 % w/v, between about 2.75 to about 3.0 % w/v, between about 0.5 to about 1.0 % w/v, between about 1.0 to about 1.5 % w/v, between about 0.75 to about
  • the stabilizer comprises a buffer.
  • the liquid pharmaceutical composition comprises a stabilizer and further comprises a buffer.
  • the buffer is selected from citrate buffer, citric acid buffer, sodium acetate buffer, acetic acid buffer, tartaric acid buffer, phosphate buffer, succinic acid buffer, Tris buffer, glycine buffer, hydrochloric acid buffer, potassium hydrogen phthalate buffer, sodium buffer, sodium citrate tartrate buffer, sodium hydroxide buffer, sodium dihydrogen phosphate buffer, disodium hydrogen phosphate buffer, tromethamine (TRIS), or any combination thereof.
  • the liquid pharmaceutical compositions may comprise between about 0.1 to about 30.0 % w/v of a buffer.
  • the liquid pharmaceutical composition comprises between about 0.1 to about 1.0 % w/v, between about 1.0 to about 2.0 % w/v, between about 2.0 to about 3.0 % w/v, between about 3.0 to about 4.0 % w/v, between about 4.0 to about 5.0 % w/v, between about 5.0 to about 6.0 % w/v, between about 6.0 to about 7.0 % w/v, between about 8.0 to about 9.0 % w/v, between about 9.0 to about 10.0 % w/v, between about 10.0 to about 15.0 % w/v, between about 15.0 to about 20.0 % w/v, between about 20.0 to about 25.0 % w/v, between about 25.0 to about 30.0 % w/v of a buffer.
  • the liquid pharmaceutical composition further comprises an antioxidant.
  • the antioxidant is selected from ascorbic acid or a salt thereof, a cysteine, a bisulfite or a salt thereof, glutathione, a tyrosinase inhibitor, a bivalent cation, such as a Cu +2 chelator, butylated hydroxy toluene (BHT), beta hydroxy acid (BHA) tocopherol, gentisic acid, tocopherol, tocopherol derivative, such as tocopherol acetate or tocopherol succinate, thioglycerol, or any combination thereof.
  • the antioxidant is an ascorbic acid salt selected from sodium ascorbate, calcium ascorbate, potassium ascorbate, or any combination thereof.
  • the antioxidant is a cysteine selected from L-cysteine, N-acetyl cysteine (NAC) or any combination thereof.
  • the antioxidant is the bisulfite salt sodium metabisulfite.
  • the antioxidant is the tyrosinase inhibitor captopril.
  • the antioxidant is a Cu +2 chelator is selected from Na2-EDTA and Na2-EDTA-Ca, or any combination thereof.
  • the antioxidant is selected from methimazole, quercetin, arbutin, aloesin, N-acetylglucoseamine, retinoic acid, alpha-tocopheryl ferulate, Mg ascorbyl phosphate (MAP), substrate analogues, such as sodium benzoate, L- phenylalanine, dimercaptosuccinic acid, D-penicillamine, trientine-HCl, dimercaprol, clioquinol, sodium thiosulfate, triethylenetetramine, tetraethylenepentamine, curcumin, neocuproine, tannin, cuprizone, sulfite salts, such as sodium hydrogen sulfite or sodium metabisulfite, lipoic acid, CB4 (N-acetyl CysGlyProCys amide), CB3 (N-acetyl CysProCys amide), AD4 (N-acetyl
  • the liquid pharmaceutical compositions of the invention may comprise between about 0.05 to about 2.0 % w/v of an antioxidant or a combination of antioxidants.
  • the liquid pharmaceutical composition comprises between about 0.05 to about 0.1 % w/v, about 0.1 to about 0.2 % w/v, about 0.2 to about 0.3 % w/v, about 0.3 to about 0.4 % w/v, about 0.4 to about 0.5 % w/v, about 0.5 to about 0.6 % w/v, about 0.7 to about 0.8 % w/v, about 0.8 to about 0.9 % w/v, about 0.9 to about 1.0 % w/v, about 1.0 to about 1.1 % w/v, about 1.1 to about 1.2 % w/v, about 1.2 to about 1.3 % w/v, about 1.3 to about 1.4 % w/v, about 1.4 to about 1.5 % w/v, about 1.5 to about 1.6 % w
  • the liquid pharmaceutical composition comprises a combination of two antioxidants, wherein each antioxidant is present in an amount of between about 0% w/v and about 2% w/v and wherein the total amount of antioxidant is present in an amount of between about 0% w/v to about 2% w/v.
  • the liquid pharmaceutical composition comprises between about 0.05 to about 0.1 % w/v, about 0.1 to about 0.2 % w/v, about 0.2 to about 0.3 % w/v, about 0.3 to about 0.4 % w/v, about 0.4 to about 0.5 % w/v, about 0.5 to about 0.6 % w/v, about 0.7 to about 0.8 % w/v, about 0.8 to about 0.9 % w/v, about 0.9 to about 1.0 % w/v, about 1.0 to about 1.1 % w/v, about 1.1 to about 1.2 % w/v, about 1.2 to about 1.3 % w/v, about 1.3 to about 1.4 % w/v, about 1.4 to about 1.5 % w/v, about 1.5 to about 1.6 % w/v, about 1.6 to about 1.7 % w/v, about 1.7 to about 1.8 % w/v, about 1.8 to about 1.9
  • the first and second antioxidants comprise N-acetyl cysteine (NAC) and ascorbic acid or a salt thereof.
  • the liquid pharmaceutical composition comprises 0, about 0.25%, about 0.5%, about 0.75%, about 1%%, about 1.25%, about 1.5%, about 1.75%, or about 2% NAC and 0, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, or about 2% ascorbic acid or a salt thereof, wherein the liquid pharmaceutical compositions comprises no more than 2% of the combination of NAC and ascorbic acid or a salt thereof.
  • the liquid pharmaceutical composition comprises about 1% NAC and no ascorbic acid, about 1% NAC and about 1% ascorbic acid or a salt thereof, about 2% NAC and no ascorbic acid, or about 2% ascorbic acid or a salt thereof and no NAC.
  • the liquid pharmaceutical composition further comprises a catechol-O-methyltransferase (COMT) inhibitor.
  • the COMT inhibitor is selected from entacapone, tolcapone, opicapone or any combination thereof.
  • the liquid pharmaceutical composition comprises between about 0.1 to about 5.0 % w/v of a COMT inhibitor.
  • the liquid pharmaceutical composition comprises between about 0.1 to about 1.0 % w/v of a COMT inhibitor.
  • the liquid pharmaceutical composition comprises between about 1.0 to about 2.0 % w/v of a COMT inhibitor.
  • the liquid pharmaceutical composition comprises between about 2.0 to about 3.0 % w/v of a COMT inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 3.0 to about 4.0 % w/v of a COMT inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 4.0 to about 5.0 % w/v of a COMT inhibitor. According to some embodiments, the liquid pharmaceutical composition may be administered concomitantly with a COMT inhibitor.
  • the liquid pharmaceutical composition further comprises a monoamine oxidase (MAO) inhibitor.
  • the MAO inhibitor may be a MAO-A inhibitor or a MAO-B inhibitor.
  • the liquid pharmaceutical composition comprises between about 0.1 to about 5.0 % w/v of a MAO inhibitor.
  • the liquid pharmaceutical composition comprises between about 0.1 to about 1.0 % w/v of a MAO inhibitor.
  • the liquid pharmaceutical composition comprises between about 1.0 to about 2.0 % w/v of a MAO inhibitor.
  • the liquid pharmaceutical composition comprises between about 2.0 to about 3.0 % w/v of a MAO inhibitor.
  • the liquid pharmaceutical composition comprises between about 3.0 to about 4.0 % w/v of a MAO inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 4.0 to about 5.0 % w/v of a MAO inhibitor. According to some embodiments, the MAO inhibitor is selected from moclobemide, rasagiline, selegiline, safinamide, or any combination thereof. According to some embodiments, the liquid pharmaceutical composition may be administered concomitantly with a MAO inhibitor. [00169] According to some embodiments, the liquid pharmaceutical composition further comprises a surfactant.
  • the surfactant is selected from Tween- 80, Tween-60, Tween-40, Tween-20, Tween-65, Tween-85, Span 20, Span 40, Span 60, Span 80, Span 85, polyoxyl 35 castor oil (Cremophor EL), polyoxyethylene-660-hydroxystearate (macrogol 660), or Poloxamer 188 (Pluronic ® F-68), or any combination thereof.
  • the liquid pharmaceutical composition of the invention may include between about 0.1 to about 3.0 % w/v of a surfactant or combination of two or more surfactants.
  • the liquid pharmaceutical composition comprises between about 0.1 to about 0.2 % w/v, between about 0.2 to about 0.3 % w/v, between about 0.3 to about 0.4 % w/v, between about 0.4 to about 0.5 % w/v, between about 0.5 to about 0.6 % w/v, between about 0.6 to about 0.7 % w/v, between about 0.7 to about 0.8 % w/v, between about 0.8 to about 0.9 % w/v, between about 0.9 to about 1.0 % w/v, between about 1.0 to about 1.5 % w/v, , between about 1.5 to about 2.0 % w/v, between about 2.0 to about 2.5 % w/v, between about 2.5 to about 3.0 % w/v of a surfactant or combination of two or more surfactants.
  • the liquid pharmaceutical composition may further comprise an additional pharmaceutically acceptable excipient, such as N-methylpyrrolidone (NMP), polyvinylpyrrolidone (PVP), propylene glycol, a preservative, a pharmaceutically acceptable vehicle, a stabilizer, a dispersing agent, a suspending agent, an amino sugar, a calcium chelator, protease inhibitors, or any combination thereof.
  • NMP N-methylpyrrolidone
  • PVP polyvinylpyrrolidone
  • propylene glycol a preservative
  • a pharmaceutically acceptable vehicle such as a pharmaceutically acceptable vehicle, a stabilizer, a dispersing agent, a suspending agent, an amino sugar, a calcium chelator, protease inhibitors, or any combination thereof.
  • the liquid pharmaceutical composition of the invention may comprise between about 5.0 to about 80.0 % w/v or an additional pharmaceutically acceptable excipient, e.g., a solvent, a buffer or any other co-solvent
  • the liquid pharmaceutical composition of the invention comprises between about 5.0 to about 10.0 % w/v, between about 10.0 to about 15.0 % w/v, between about 15.0 to about 20.0 % w/v, between about 20.0 to about 25.0 % w/v, between about 25.0 to about 30.0 % w/v, between about 30.0 to about 35.0 % w/v, between about 35.0 to about 40.0 % w/v, between about 40.0 to about 45.0 % w/v, between about 45.0 to about 50.0 % w/v, between about 50.0 to about 55.0 % w/v, between about 55.0 to about 60.0 % w/v, between about 60.0 to about 65.0 % w/v, between about 65.0 to about 70.0 % w/v, between about 70.0 to about 75.0 % w/v, between about 75.0 to about 80.0 % w/v of a solvent, a buffer or any other co-
  • the liquid pharmaceutical compositions of the invention may be in the form of a solution, gel, cream, emulsion, or suspension.
  • the liquid pharmaceutical compositions of the invention may be dried to provide a solid, e.g., by lyophilization, wherein the dried material, e.g., the lyophilizate, may be constituted to provide a liquid composition, e.g., by the addition of a solvent, e.g., water.
  • Antioxidants, surfactants and the like may also be added when the dried composition is constituted.
  • the dried composition is reconstituted using a dedicated solution comprising, e.g., a solvent, an antioxidant, a surfactant and any other required excipients.
  • the liquid pharmaceutical composition of the invention is an aqueous composition.
  • the liquid pharmaceutical compositions of the invention may be formulated for any suitable route of administration, e.g., for parenteral administration, e.g., by bolus administration or continuous administration.
  • the liquid pharmaceutical composition of the invention may be formulated for subcutaneous, transdermal, intradermal, transmucosal, intravenous, intraarterial, intramuscular, intraperitoneal, intratracheal, intrathecal, intraduodenal, intrapleural, intranasal, sublingual, buccal, intestinal, intraduodenally, rectal, intraocular, or oral administration.
  • the compositions may also be formulated for inhalation, or for direct absorption through mucous membrane tissues.
  • Further embodiments of the invention are directed to a process for preparing a liquid pharmaceutical composition, wherein said process comprises: mixing a levodopa-tyrosine (LD-Tyr) conjugate of formula (II): in a pharmaceutically acceptable salt form with at least one solvent and/or stabilizer, thereby forming a solution, gel, cream, emulsion, or suspension; and adjusting the pH of the solution, gel, cream, emulsion, or suspension, to a physiologically acceptable pH value, thereby providing the liquid pharmaceutical composition.
  • LD-Tyr levodopa-tyrosine conjugate of formula (II): in a pharmaceutically acceptable salt form with at least one solvent and/or stabilizer, thereby forming a solution, gel, cream, emulsion, or suspension
  • adjusting the pH of the solution, gel, cream, emulsion, or suspension to a physiologically acceptable pH value, thereby providing the liquid pharmaceutical composition.
  • the process comprises mixing an LD-Tyr compound of Formula (II) in a pharmaceutically acceptable salt form with at least one stabilizer, thereby forming a solution.
  • the process comprises mixing an LD-Tyr compound of Formula (II) in a pharmaceutically acceptable solid salt form with at least one stabilizer.
  • the process of the invention includes further mixing the LD-Tyr compound of Formula (II) with any additional active pharmaceutical ingredients and/or pharmaceutically acceptable excipients, as detailed regarding the liquid pharmaceutical composition of the invention.
  • the mixing is performed without heating.
  • the mixing is performed at room temperature.
  • the process comprises mixing a salt form of an LD-Tyr with at least one solvent and/or stabilizer, wherein the salt is a TFA salt, an HC1 salt fumaric acid salt, lactate salt, maleic acid salt, gluceptic acid salt, phosphoric acid salt, sulfuric acid salt, HBr salt, nitric acid salt, acetic acid salt, propionic acid salt, hexanoic acid salt, cyclopentanepropionic acid salt, glycolic acid salt, pyruvic acid salt, lactic acid salt, hippuric acid salt, methanesulfonic acid salt, ascorbic acid salt, malonic acid salt, oxalic acid salt, maleic acid salt, tartaric acid salt, citric acid salt, succinic acid salt, benzoic acid salt, cinnamic acid salt, a sulfonic acid salt, lauryl sulfuric acid salt, gluconic acid salt, glutamic acid salt, hydroxyna
  • Some embodiments of the invention are directed to a liquid pharmaceutical composition in which the LD-Tyr compound, an enantiomer, diastereomer, racemate, ion, zwitterion, pharmaceutically acceptable salt thereof, or any combination thereof has a solubility of between about 100 to about 1000 mg/L at a physiologically acceptable pH.
  • the solubility of the LD-Tyr compound, an enantiomer, diastereomer, racemate, ion, zwitterion, pharmaceutically acceptable salt thereof, or any combination thereof is between about 100 to about 200 mg/L, between about 200 to about 300 mg/L, between about 300 to about 400 mg/L, between about 400 to about 500 mg/L, between about 500 to about 600 mg/L, between about 600 to about 700 mg/L, between about 700 to about 800 mg/L, between about 800 to about 900 mg/L, between about 900 to about 1000 mg/L, at a physiologically acceptable pH.
  • Further embodiments of the invention are directed to a method of treating neurodegenerative conditions and/or conditions characterized by reduced levels of dopamine in the brain, wherein the method comprises administering a liquid pharmaceutical composition, wherein the liquid pharmaceutical composition comprises a stabilizer and a levodopa-tyrosine (LD-Tyr) conjugate of formula (II): an enantiomer, diastereomer, racemate, ion, zwitterion, pharmaceutically acceptable salt thereof, or any combination thereof.
  • LD-Tyr levodopa-tyrosine
  • neurodegenerative conditions and/or conditions characterized by reduced levels of dopamine in the brain are selected from Parkinson’s disease, secondary parkinsonism, Huntington's disease, Parkinson’s like syndrome, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), Shy-Drager syndrome, dystonia, Alzheimer’s disease, Lewy body dementia (LBD), akinesia, bradykinesia, and hypokinesia, conditions resulting from brain injury, including carbon monoxide or manganese intoxication, conditions associated with a neurological disease or disorder, including alcoholism, opiate addiction, and erectile dysfunction.
  • the neurodegenerative condition and/or condition characterized by reduced levels of dopamine in the brain is Parkinson’s disease.
  • the method of the invention comprises administering the LD-Tyr compound of Formula (II), an enantiomer, diastereomer, racemate, ion, zwitterion, pharmaceutically acceptable salt thereof, or any combination thereof, or any combination of two or more LD-Tyr enantiomers, diastereomers, racemates, ions, zwitterions, pharmaceutically acceptable salts thereof, or any combination thereof, concomitantly with an additional active ingredient, such as a decarboxylase inhibitor, e.g., carbidopa, a COMT inhibitor, a MAO inhibitor, or any combination thereof.
  • a decarboxylase inhibitor e.g., carbidopa, a COMT inhibitor, a MAO inhibitor, or any combination thereof.
  • the LD-Tyr compound is administered together with a decarboxylase inhibitor, e.g., carbidopa, wherein the LD-Tyr compound and the decarboxylase inhibitor are administered in a single formulation.
  • a decarboxylase inhibitor e.g., carbidopa
  • the method of the invention comprises administering the liquid pharmaceutical composition substantially continuously.
  • the liquid pharmaceutical composition is administered subcutaneously.
  • the liquid pharmaceutical composition is administered subcutaneously via a designated pump device.
  • Embodiments of a designated pump may be, for example, any of the pump embodiments disclosed in US 62/529784, US 62/576362, PCT/IB2018/054962, US 16/027804, US 16/027710, US 16/351072, US 16/351076, US 16/351061, USD 29/655583, USD 29/655587, USD 29/655589, USD 29/655591, USD 29/655592, USD 29/655594, USD 29/655597, US 62/851903, and US 29/723714, all of which are incorporated herein by reference in their entirety.
  • the method of the invention comprises administering the liquid pharmaceutical composition at one site, two sites, or three or more sites, wherein the position of the sites may be changed at any appropriate, possibly pre-determined, intervals.
  • the administration via the same site, or the vicinity of that site may be only after a, possibly predefined, period of time.
  • the position of any one of the sites is changed after 12, 24, 36, 48, 60 or 72 hours.
  • the position of the site is changed after 4, 5, 6 or 7 days.
  • the position of the site is changed after two, three or four weeks.
  • the position of the site is changed when required or desired, e.g., according to subjective data received from the patient and/or according to objective data received, e.g., from sensors located at, or in the vicinity of, the injection site(s).
  • the administrated volume and/or the administration rate is identical in all or at least two of the sites. According to other embodiments, the administration rate and/or administrated volume differ from site to site. Each site may be controlled independently or otherwise, all sites may be controlled dependently on one another.
  • the method of the invention comprises subcutaneously administrating between about 1 to about 15 ml of the liquid pharmaceutical composition of the invention over the course of 24 hours.
  • the method of invention comprises subcutaneously administrating between about 1 to about 2, between about 2 to about 3, between about 3 to about 4, between about 4 to about 5, between about 5 to about 6, between about 6 to about 7, between about 7 to about 8, between about 8 to about 9, between about 9 to about 10, between about 10 to about 11, between about 11 to about 12, between about 12 to about 13, between about 13 to about 14, between about 14 to about 15 ml over the course of 24 hours.
  • the administration rate may be constant over the course of 24 hours or may change over the course of 24 hours.
  • the high activity/day hours may be, e.g., about 15, about 16, about 17, about 18 or about 19 hours, while the low activity night hours may be about 9, about 8, about 7, about 6 or about 5 hours, respectively.
  • the high activity/day rate is implemented for about 18 hours, while the low activity /night rate is implemented for about 6 hours.
  • the high activity/day rate is implemented for about 16 hours, while the low activity/night rate is implemented for about 8 hours.
  • the administration rate is constant over the course of 24 hours.
  • the liquid pharmaceutical formulation is administered for a certain period of time in each 24 hours, e.g., 8 hours a day, 9 hours a day, 10 hours a day, 11 hours a day, 12 hours a day, 13 hours a day, 14 hours a day, 15 hours a day , 16 hours a day, 17 hours a day, 18 hours a day, 19 hours a day, 20 hours a day, 21 hours a day, 22 hours a day, or 23 hours a day.
  • the number of hours of administration per day may be constant over the course of a certain number of days, e.g., 7 days, 14 days, 21 days, 28 days, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, or more.
  • the number of hours of administration per day may vary from day to day, according to the patient’s condition, aa caregiver’s or physician’s decision, input from sensors, and the like. It is further noted that while only whole hours are specifically mentioned, any parts of hours, days, months, etc., are possible for administration, e.g., 16.5 hours a day, 7.5 days, and the like.
  • the administration rate may be between about 0.01 mL/site/hour to about 1 mL/site/hour. According to some embodiments, the administration rate is between about 0.01-0.02 mL/site/hour. According to some embodiments, the administration rate is between about 0.02-0.03 mL/site/hour. According to some embodiments, the administration rate is between about 0.03-0.04 mL/site/hour. According to some embodiments, the administration rate is between about 0.04-0.05 mL/site/hour. According to some embodiments, the administration rate is between about 0.05-0.06 mL/site/hour. According to some embodiments, the administration rate is between about 0.06-0.07 mL/site/hour.
  • the administration rate is between about 0.07-0.08 mL/site/hour. According to some embodiments, the administration rate is between about 0.08-0.09 mL/site/hour. According to some embodiments, the administration rate is between about 0.09-0.1 mL/site/hour.
  • the administration rate is between about 0.1-0.15 mL/site/hour.
  • the administration rate is between about 0.15-0.2 mL/site/hour.
  • the administration rate is between about 0.2-0.25 mL/site/hour.
  • the administration rate is between about 0.25-0.3 mL/site/hour.
  • the administration rate is between about 0.3-0.35 mL/site/hour. According to some embodiments, the administration rate is between about 0.35-0.4 mL/site/hour.
  • the administration rate is between about 0.4-0.45 mL/site/hour.
  • the administration rate is between about 0.45-0.5 mL/site/hour.
  • the administration rate is between about 0.5-0.55 mL/site/hour.
  • the administration rate is between about 0.55-0.6 mL/site/hour.
  • the administration rate is between about 0.6-0.65 mL/site/hour.
  • the administration rate is between about 0.65-0.7 mL/site/hour.
  • the administration rate is between about 0.7-0.75 mL/site/hour.
  • the administration rate is between about 0.75-0.8 mL/site/hour.
  • the administration rate is between about 0.8-0.85 mL/site/hour.
  • the administration rate is between about 0.85-0.9 mL/site/hour.
  • the administration rate is between about 0.9-0.95 mL/site/hour.
  • the administration rate is between about 0.95-1.0 mL/site/hour.
  • the administration rate in the low activity/night hours is between about 0.01-0.15 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.01-0.02 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.02-0.03 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.03-0.04 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.04-0.05 mL/site/hour.
  • the administration rate in the low activity /night hours is between about 0.05-0.06 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.06-0.07 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.07-0.08 mL/site/hour. According to some embodiments, the administration rate in the low activity /night hours is between about 0.08-0.09 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.09-0.1 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.1-0.11 mL/site/hour.
  • the administration rate in the low activity /night hours is between about 0.11-0.12 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.12-0.13 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is between about 0.13-0.14 mL/site/hour. According to some embodiments, the administration rate in the low activity /night hours is between about 0.14-0.15 mL/site/hour. According to some embodiments, the administration rate in the low activity/night hours is about 0.04 mL/site/hour.
  • the administration rate in the high activity/day hours is between about 0.15-1.0 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.15-0.2 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.2-0.25 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.25-0.3 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.3-0.35 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.35-0.4 mL/site/hour.
  • the administration rate in the high activity/day hours is between about 0.4-0.45 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.45-0.5 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.5-0.55 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.55-0.6 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.6-0.65 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.65-0.7 mL/site/hour.
  • the administration rate in the high activity/day hours is between about 0.7-0.75 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.75-0.8 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.8-0.85 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.85-0.9 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.9-0.95 mL/site/hour. According to some embodiments, the administration rate in the high activity/day hours is between about 0.95-1.0 mL/site/hour.
  • the administration rate in the high activity/day hours is about 0.32 mL/site/hour.
  • the administrated volume and/or administration rate may be constant throughout the treatment, or may vary during different hours of the day, between different days, weeks or months of treatment, and the like.
  • the patient is monitored, e.g., independently, by a caretaker, or electronically, e.g., by sensors, possibly found in a dedicated device, e.g., a watch-like device, the administration pump, and the like.
  • the administration volume and/or rate are determined according to data received from such monitoring.
  • the bolus injection comprises between about 0.5 to about 2.0 mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 0.5 to about 0.75 mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 0.75 to about 1.0 mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 1.0 to about 1.25 mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 1.25 to about 1.5 mL/Kg of the liquid pharmaceutical composition.
  • the bolus injection comprises between about 1.5 to about 1.75 mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 1.75 to about 2.0 mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 0.75 to about 1.25 mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises about 1.0 mL/Kg of the liquid pharmaceutical composition.
  • the bolus subcutaneous injection may be administered at any time point in relation to any possible continuous subcutaneous administrations, e.g., prior to, during, or after the continuous administration.
  • the administered dose may be doubled, tripled or more, by using more than one pump, more than one injection site for each pump, and the like.
  • the liquid pharmaceutical compositions are administered for a defined period of time, e.g., days, weeks, months, or years. According to some embodiments, the liquid pharmaceutical compositions are administered endlessly, for the treatment of a chronic condition.
  • liquid pharmaceutical composition for use in the treatment of neurodegenerative conditions and/or conditions characterized by reduced levels of dopamine in the brain, wherein the liquid pharmaceutical composition comprises a stabilizer and a levodopa-tyrosine (LD-Tyr) conjugate of formula (II): an enantiomer, diastereomer, racemate, ion, zwitterion, pharmaceutically acceptable salt thereof, or any combination thereof.
  • LD-Tyr levodopa-tyrosine conjugate of formula (II): an enantiomer, diastereomer, racemate, ion, zwitterion, pharmaceutically acceptable salt thereof, or any combination thereof.
  • the liquid pharmaceutical composition is for use in the treatment of Parkinson’s disease, secondary parkinsonism, Huntington's disease, Parkinson’s like syndrome, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), Shy-Drager syndrome, dystonia, Alzheimer’s disease, Lewy body dementia (LBD), akinesia, bradykinesia, and hypokinesia, conditions resulting from brain injury, including carbon monoxide or manganese intoxication, conditions associated with a neurological disease or disorder, including alcoholism, opiate addiction, and erectile dysfunction. Certain embodiments of the invention are directed to the liquid pharmaceutical composition of the invention in the treatment of Parkinson’s disease.
  • composition for use according to the invention may include any of the additional materials, the amounts of any of the materials, as detailed herein regarding the embodiments of the composition of the invention. Further, the form, pH, and the like, of the compositions for use according to the invention may be as detailed herein regarding the embodiments of the composition of the invention. In addition, the composition of the invention may be used together with a COMT inhibitor, MAO inhibitor, or any other active ingredient, as detailed herein.
  • the levodopa prodrug compound and the stabilized formulations described herein are useful for the prevention or treatment of neurodegenerative diseases and/or diseases or symptoms caused by a decrease in dopamine concentration in the brain, such as Parkinson's disease and related symptoms. Therefore, the present invention has a high utility value in the pharmaceutical industry.
  • the reaction mixture was ice-cooled, a tert-butyl hydroperoxide decane solution (5.5 M) (0.18 mL) was added, and the mixture was stirred at room temperature for 1 hour.
  • the solvent of the reaction mixture was distilled away under reduced pressure, and then, toluene was added, and insoluble matter was removed with Phase-separator®.
  • 1,8-diazabicyclo[5.4.0]undec-7-ene (223 uL) and tetrabenzyl diphosphate (805 mg) were added to a mixuture of benzyl (2S)-3-(4-hydroxy-3-phenylmethoxyphenyl)-2-[[(2S)-4-methyl-2- (phenylmethoxycarbonylamino)pentanoyl]amino]propanoato (623 mg) and acetonitrile (5 mL) under ice cooling, and the temperature was gradually raised to room temperature, and the mixture was stirred for 21 hours.
  • (2S)-2-(benzyloxycarbonylamino) propanoic acid (1.02 g), 1-hydroxy-7- azabenzotriazole (HO At) (712 mg), 1-ethyl-x3y-(3-dimethylaminopropyl) carbodiimide hydrochloride (WSCI) (1.03 g), and N,N-diisopropylethylamine (0.750 mL) were added to a mixture of (2S)-2-amino-3-(4-hydroxy-3-phenylmethoxyphenyl) benzyl propanoate; hydrochloride (1.87 g) and N,N-dimethylformamide (18 mL), and the mixture was stirred at room temperature for 18 hours.
  • Acetic anhydride (0.291 mL) was added under ice-cooling to a mixture of (2S)-2-amino- 3-(3,4-dihydroxyphenyl) benzyl propanoate; hydrochloride (253 mg) and pyridine (1 mL), and the mixture was stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extraction with chloroform was performed. An organic layer was washed with a saturated solution of sodium chloride and was dried over sodium sulfate, and insoluble matter was filtered, and then, the solvent was distilled away under a reduced pressure.
  • N-(tert-butoxycarbonyl)-phosphonoglycine trimethyl ester (10 g) and 1 ,1,3,3- tetramethylguanidine (5 mL) were added under ice-cooling to a mixture of the compound A-1 (8.31 g) and dichlorome thane (90 mL), and the mixture was stirred at room temperature for 24 hours.
  • a saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, and extraction with ethyl acetate was performed.
  • An organic layer was passed through silica gel column chromatography (solvent: ethyl acetate), and the solvent of the filtrate was distilled away under a reduced pressure. The residue was suspended in ethanol, and a precipitated solid was collected by filtration and was dried under a reduced pressure, and the compound A-2 (10.7 g, yield: 79%) as a white powder was obtained.
  • (+)-l,2-bis((2S,5S)-2,5-diethylphosphorano)benzene(l,5-cyclooctadiene)rhodium(I) tetrafluoroborate ((S,S)-Et-DUPHOS-Rh) (144 mg) was added to a mixture of the compound A-2 (9.65 g) and tetrahydrofuran (80 mL), and the mixture was stirred under a pressurized hydrogen atmosphere (800 kPa) at 35 °C for 3 hours.
  • the residue was suspended in ethanol, and a precipitated solid was collected by filtration and was dried under a reduced pressure, and the compound A-3 (9.00 g, yield: 93%) as a white powder was obtained.
  • Conversion efficiency from a prodrug to levodopa was evaluated with a metabolic study using human hepatocytes.
  • a prodrug was incubated with human hepatocytes at 37 °C for 4 hours.
  • a part of the reaction solution was sampled at each predetermined time and mixed with an organic solvent to stop the reaction.
  • the reaction-stopped solution was centrifuged, and the obtained supernatant was analyzed using a liquid chromatography /tandem mass spectrometry method.
  • the conversion efficiency to levodopa was evaluated as a levodopa production amount after 4 hours of incubation.
  • Table 8 shows the levodopa production amounts of the compounds as some of the examples of the present invention.
  • a phosphate buffer solution at pH 7.4 was added to each of the compounds to dissolve the each of the compounds, and when necessary, a NaOH solution was added to adjust the pH of the mixture to prepare a solution of about 1 mg/mL. After storing this solution at 60 °C for about 1 day, HPLC purity (area percentage, %) was measured. The HPLC purity of the solution immediately after the preparation, or the HPLC purity of the compound, was subtracted from the HPLC purity after storage at 60 °C for about 1 day to obtain a HPLC purity difference.
  • Table 9- 2 shows the solution stabilities of the compounds of some of the examples of the present invention.
  • the compounds are expected to have high solubility at pH 6 - 8, and are considered to be particularly useful as a solution formulation.
  • a NaOH solution was added to LDP-Ala and stirred under room temperature to dissolve LDP-Ala.
  • Carbidopa and antioxidants N-acetylcysteine and ascorbic acid
  • Polysorbate 80 and a NaOH solution were added to make the formulation composition in Table 10-2, and the volume was adjusted with ultrapure water as appropriate.
  • the above solution was filtered through a 0.22 pm filter and filled into a vial while the headspace was replaced with nitrogen.
  • a KOH solution and Meglumine were added to LDP-Lys and stirred under room temperature to dissolve LDP-Lys.
  • Carbidopa and antioxidants N-acetylcysteine and ascorbic acid
  • Polysorbate 80 and a KOH solution were added to make the formulation composition in Table 10-3, and the volume was adjusted with ultrapure water as appropriate.
  • the above solution was filtered through a 0.22 pm filter and filled into a vial while the headspace was replaced with nitrogen.
  • a formulation comprising 300 mg/mL (30%) LD-tyrosine (LD-Tyr) and 7.5 mg/mL (0.75%) carbidopa was prepared with 5.5% L-Arginine and 11.5% Tris.
  • the formulation also included 0.5% ascorbic acid (Asc), 0.5% N-acetyl cysteine (NAC) and 0.3% Tween 80.
  • the formulation was stored at 2-8°C for the time indicated, and % recovery and % LD-Tyr-DKP formation (an impurity) were tested. Results are shown in Table 11. Percent recovery remained high over time. The DKP impurity accumulated over time.
  • LD-Tyr LD-tyrosine
  • Table 12 The solubility of the LD-tyrosine (LD-Tyr) was tested in various cosolvents, as indicated in Table 12.
  • the formulation was stored at 2-8°C or 25°C for the time indicated, and stability (as measured by the presence of precipitation) and % DKP formation (an impurity) were tested.
  • the formulation with propylene glycol was stable for at least up to 1 month at 2-8°C and at least up to 2 weeks at 25°C, and showed less DKP accumulation than the formulation comprising 5.5% L- Arginine and 11.5% Tris shown in Example 1.
  • the formulation with PEG 300 was unstable at 2-8°C and showed more DKP accumulation than the other formulations tested.
  • Formulations were prepared with 300 mg/mL LD-Tyr, 5 mg/mL (0.5%) NAC, 5 mg/mL (0.5%) ascorbic acid, 18.1% L-Arg, and the additive shown in Table 13.
  • PVP K17 stands for polyvinylpyrrolidone low molecular weight (PVP K17). All formulations were physically stable for at least two weeks at 2-8°C and 25°C. As shown in Table 13, none of the additives tested showed ability to inhibit or prevent DKP formation.
  • LD-Tyrosine was added in portions to an 0.8M solution of counter ion and antioxidants, while stirring.
  • the L-arginine formulation was heated while stirring, while the other formulations were not. pH was not adjusted. Solubility was confirmed following filtration by HPLC. Physical stability was measured after 2 weeks and 1 month of storage at 2-8°C or 25°C. As shown in Table 14, solubilizing LD-Tyrosine in ethanolamine, diethylamine, and ammonium hydroxide resulted in physical stability (no evidence of precipitation) at 2-8°C and at 25 °C up to at least one month. Solubility and stability were dependent upon the particular base used and not only upon pH.
  • DKP impurity
  • Formulations were prepared with 300 mg/mL LD-Tyr, 5 mg/mL (0.5%) NAC and 5 mg/mL (0.5%) ascorbic acid and either 17.2% Meglumine or 18.1% L-Arg. All formulations were physically stable for at least two weeks at 2-8°C and 25°C. As shown in Table 16, a lower level of DKP was observed when L-Arg was used relative to Meglumine.
  • Formulations were prepared with 300 mg/mL LD-Tyr, 5 mg/mL (0.5%) NAC and 5 mg/mL (0.5%) ascorbic acid and the combinations of bases indicated in Table 18. All formulations were physically stable for at least 70 days at 2-8°C.
  • Table 18 - Tris (Tromethamine) [00252] Formulations were prepared with 300 mg/mL LD-Tyr, 5 mg/mL (0.5%) NAC, 5 mg/mL (0.5%) ascorbic acid, 7.2% L-Arg, and either sodium hydroxide or ammonium hydroxide as indicated in Table 19. As shown in Table 19, formulations comprising sodium hydroxide demonstrated physical instability.
  • Table 22 presents additional 300 mg/mL (30%) LD-Tyrosine formulations prepared with L-Arginine and ethanolamine or diethylamine, as well as the antioxidants ascorbic acid (0.5%) and N-acetyl cysteine (NAC) (0.5%).
  • RB Blood/plasma ratio
  • KRBC/PL increased with the time of incubation for the two highest concentrations (150 and 2500 ng/mL), while for the lowest concentration (50 ng/mL), after reaching 1 at 15 and 30 minutes, the KRBC/PL declined to 0.0 (see Figure 4).
  • all KRBC/PL measured were below one, indicating no RBC binding (see Figure 5).
  • Formulations were prepared with 200 mg/mL LD-Tyr, 5 mg/mL (0.5%) NAC, 5 mg/mL (0.5%) ascorbic acid, 15.5% L-Arg, and the additives as shown in Table 24. As shown in Table 24, the tested additives were able to limit the DKP formation at 2-8°C; however, the amount of DKP at room temperature remained significant. It is further noted that the formulations comprising MgCh demonstrated relatively high viscosity. The solubility of the LD-Tyr was DMA>Ethanol>PEG 300, and the viscosity of the formulations was Ethanol ⁇ DMA ⁇ PEG 300.
  • LD resulting therefrom was determined following 18-hour continuous SC infusion to female domestic pigs. Each formulation was administered at one infusion site per animal using a Crono-
  • ND infusion pump Cane SpA Medical Technology, Rivoli, Italy
  • the objective of this study is to determine the pharmacokinetics (PK) of LD-Tyr following an 18-hr continuous subcutaneous (SC) administration in domestic pigs of a formulation comprising 30& LD-Tyr and ethanol.
  • Table 53 provides the LD-Tyr formulation tested in this study.
  • Figure 13 shows the composite mean plasma LD-Tyr and LD concentration-versus-time profiles for the 2700 mg dosing regimen. PK parameters are also shown.
  • Figure 14 shows the composite mean plasma LD-Tyr and LD concentration-versus-time profiles for the 5400 mg dosing regimen. PK parameters are also shown.
  • Figure 15 shows the composite mean plasma LD concentration-versus-time profiles for the 2700 and 5400 mg dosing regimens.
  • Table 54 provides a summary of PK results. The results presented in Figure 15, as well as in Table 54, show the dose proportionality of the LD-Tyr.

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EP4460289A4 (en) * 2022-01-03 2025-09-03 Neuroderm Ltd METHODS AND COMPOSITIONS FOR THE TREATMENT OF PARKINSON'S DISEASE
CN116850159A (zh) * 2023-07-12 2023-10-10 浙江同伍生物医药有限公司 一种盐酸左沙丁胺醇雾化吸入溶液组合物及其制备方法
CN116850159B (zh) * 2023-07-12 2025-08-22 浙江同伍生物医药有限公司 一种盐酸左沙丁胺醇雾化吸入溶液组合物及其制备方法

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