WO2020178810A1 - Compositions pharmaceutiques comprenant des dérivés d'amide de lévodopa et leurs utilisations - Google Patents

Compositions pharmaceutiques comprenant des dérivés d'amide de lévodopa et leurs utilisations Download PDF

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WO2020178810A1
WO2020178810A1 PCT/IL2020/050202 IL2020050202W WO2020178810A1 WO 2020178810 A1 WO2020178810 A1 WO 2020178810A1 IL 2020050202 W IL2020050202 W IL 2020050202W WO 2020178810 A1 WO2020178810 A1 WO 2020178810A1
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acid
formulation
lda
derivative
disease
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Eduardo Zawoznik
Alex Mainfeld
Einat SELA
Elena GAZAL
Ronit Shaltiel-Karyo
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Neuroderm Ltd
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Neuroderm Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A61K31/175—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine having the group, >N—C(O)—N=N— or, e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the present invention relates, at least in part, to formulations comprising a levodopa amide derivative, particularly, but not exclusively, pharmaceutical formulations, and use thereof.
  • Parkinson's disease is a degenerative condition characterized by reduced
  • Levodopa (hereon designated L- dopa or LD), 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 actually enters the brain unaltered, the remainder being metabolized extracerebrally, predominantly by decarboxylation, to dopamine, which does not penetrate the blood brain barrier.
  • the metabolic transformation of levodopa to dopamine is catalyzed by the aromatic I, -amino acid decarboxylase enzyme, a ubiquitous enzyme with particularly high concentrations in the intestinal mucosa, liver, brain and brain capillaries.
  • L-dopa as a means to improve water solubility and/or stability has been described in the art.
  • US 8,048,926 and WO 2017/090039 disclose L-dopa amide derivatives and/or pharmaceutical compositions comprising them, for use in the treatment of, e.g., Parkinson's disease.
  • a formulation comprising an acid and at least one levodopa a ide (LDA) derivative of the general formula I:
  • R' each independently, is H, (Ci-C 6 )alkyl, (C2-C6)alkenyl, cycloalkyl, aryl, or heteroaryl bonded through a ring carbon;
  • R" is a saturated or unsaturated hydrocarbon chain having at least 10 carbon atoms.
  • the formulation disclosed comprises a monovalent acid and the molar ratio of the at least one LDA derivative to the acid is from about 1 :0.10 to about 1 :0.89, for example, from about 1.00:0.60 to about 1.00:0.89.
  • the formulation disclosed comprises a divalent or trivalent acid, and the molar ratio of the at least one LDA derivative to the acid is from about 1.00:0.20 to about 1.00:1.15, excluding molar ratios of 1.00:0.50 and 1.00:0.33, when the pH is from about 6.0 to about 7.0.
  • the amount of at least one LDA derivative in a disclosed formulation may be from about 5% to about 25%, or from about 5% to about 20% by weight, for example, from about 10% to about 25%, or from about 10% to about 20%, or about 15% by weight of at least one LDA derivative;
  • the pH of a disclosed formulation may be from about 2.0 to about 11.0 at 25 °C, for example, from about 5.0 to about 7.5, from about 6.0 to about 9.5, from about 7.1 to about 9.5 or from about 6.0 to about 7.0. Any of the formulations disclosed herein is stable for at least 24 hours at room temperature.
  • An LDA derivative in a disclosed formulation may be, for example, the compound 2- amino-3-(3,4-dihydroxyphenyl) propanamide, an enantiomer, and/or a racemate thereof.
  • the acid in a disclosed formulation may be one or more of an organic acid such as, but not limited to, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, hippuric acid, maleic acid, malic acid, fumaric acid, tartaric acid, benzoic acid, acetic acid, citric acid, ascorbic acid, lactic acid, lactobionic acid, gluconic acid, galactaric acid, gluceptic (glucoheptanoic) acid, D-glucuronic acid, glutaric (pentanedioic) acid, glycolic (hydroxyacetic) acid, isethionic (2-hydroxy-ethanesulfonic) acid, formic acid, propionic (propanoic) acid, succinic (butanedioic) acid, oxalic acid, xinafoic (l-hydroxy-2-naphthoic
  • a disclosed formulation comprises one or more organic solvents, for example, N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMA), tetrahydrofuran (THF), ethanol, isopropanol, propylene glycol (PG), tetraglycol, transcutol and polyethylene glycol (PEG) (e.g., PEG 400).
  • NMP N-methyl-2-pyrrolidone
  • DMSO dimethyl sulfoxide
  • DMA dimethyl acetamide
  • THF tetrahydrofuran
  • ethanol isopropanol
  • PG propylene glycol
  • tetraglycol tetraglycol
  • transcutol and polyethylene glycol (PEG) (e.g., PEG 400).
  • PEG polyethylene glycol
  • the formulation is a pharmaceutical composition intended for medicinal application.
  • a disclosed formulation and/or pharmaceutical composition may further comprise one or more of:
  • a decarboxylase inhibitor for example, carbidopa, benserazide, a salt thereof, or a combination thereof;
  • the basic amino acid may be, for example, arginine, histidine, lysine, or a combination thereof
  • the amino sugar may be, for example, meglumine, D-glucosamine, sialic acid, N-acetylglucosamine, galactosamine, or a combination thereof;
  • a buffer such as citrate buffer, acetate buffer, sodium acetate buffer, tartrate 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, borate buffer, carbonate buffer or a mixture thereof;
  • At least one antioxidant for example, ascorbic acid or a salt thereof, L-cysteine, a cysteine derivative such as N-acetyl cysteine (NAC), bisulfite or a salt thereof, glutathione, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tocopherol, gentisic acid, or any combination thereof;
  • ascorbic acid or a salt thereof L-cysteine
  • a cysteine derivative such as N-acetyl cysteine (NAC), bisulfite or a salt thereof, glutathione, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tocopherol, gentisic acid, or any combination thereof
  • NAC N-acetyl cysteine
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • tocopherol gentisic acid, or any
  • a catechol-O-methyl transferase (COMT) inhibitor or a monoamine oxidase (MAO) inhibitor.
  • the COMT inhibitor may be entacapone, tolcapone, or opicapone
  • the MAO inhibitor may be moclobemide, rasagiline, selegiline, or safinamide;
  • a surfactant such as Tween®-80.
  • a disclosed pharmaceutical composition may comprise carbidopa as the decarboxylase inhibitor, optionally along with the basic amino acid arginine and/or the amino sugar meglumine.
  • the molar ratio of a LDA derivative to the decarboxylase inhibitor may be from about 1:1 to about 100:1, from about 2: 1 to about 60:1, from about 4:1 to about 40:1, or from about 10:1 to about 40:1.
  • compositions disclosed herein are useful for treatment of diseases or disorders characterized by neurodegeneration and/or reduced levels of brain dopamine, for example, Parkinson's disease.
  • a method of treatment for treatment of disorders characterized by neurodegeneration and/or reduced levels of brain dopamine, the method comprising administering to a patient in need thereof a therapeutically effective amount of a disclosed pharmaceutical composition, thereby treating the patient.
  • the present disclosure further provides a method for treatment of a disease or disorder characterized by neurodegeneration and/or reduced levels of brain dopamine, comprising co-administering to a patient in need thereof a first pharmaceutical composition comprising a LDA derivative and an acid; and a second pharmaceutical composition comprising a decarboxylase inhibitor or a salt thereof, and optionally at least one of a basic amino acid such as arginine, an amino sugar, catechol-O-methyl transferase (COMT) inhibitor, or a monoamine oxidase (MAO) inhibitor, thereby treating the patient.
  • a basic amino acid such as arginine
  • an amino sugar catechol-O-methyl transferase (COMT) inhibitor
  • MAO monoamine oxidase
  • the diseases and disorders treatable by a disclosed method include, for example, neurological or movement diseases or disorders selected from restless leg syndrome, 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 disease (LBD), akinesia, bradykinesia, and hypokinesia; conditions resulting from brain injury including carbon monoxide or manganese intoxication; and conditions associated with a neurological disease or disorder including alcoholism, opiate addiction, and erectile dysfunction.
  • the disease is Parkinson's disease.
  • the disclosure further relates, in an aspect thereof, to a kit comprising (i) a first pharmaceutical comprising at least one LDA derivative and an acid as defined herein; (ii) a second pharmaceutical composition comprising one or more of a decarboxylase inhibitor or a salt thereof, a basic amino acid, an amino sugar, a catechol-O-methyl transferase (COMT) inhibitor, and/or a monoamine oxidase (MAO) inhibitor; and (iii) optionally, instructions for co administration of the pharmaceutical compositions.
  • a contemplated kit may be used in treatment of a disease or disorder characterized by neurodegeneration and/or reduced levels of brain dopamine, for example, Parkinson's disease.
  • DETAILED DESCRIPTION DETAILED DESCRIPTION
  • the disclosure relates, at least in part, to formulations comprising a levodopa amide (LDA) derivative and particularly, but not exclusively, to pharmaceutical compositions comprising a LDA derivative and use thereof for treating diseases and disorders characterized by neurodegeneration and/or reduced levels of brain dopamine, more particularly a neurological or movement disorder such as Parkinson's disease.
  • LDA levodopa amide
  • Levodopa amide derivatives particularly when used in a pharmaceutical composition, may be referred to as prodrugs or precursors of levodopa.
  • prodrug refers to an inactive substance that is converted to a drug within the body.
  • a prodrug may itself be biologically inactive and circulate harmlessly until activated by some metabolic process or a clinically relevant event in the body, by the action of, for example, enzymes or other chemicals, so as to produce an active therapeutic drug.
  • Prodrug approaches include chemical modifications of drugs to improve, e.g., stability, permeability and/or bioavailability, in the circulation system and/or in the target cell and tissues, while minimally affecting the pharmacokinetic profile of the drug.
  • a prodrug may feature modification of the charge and lipophilicity of a drug in favor of blood brain barrier (BBB) permeability.
  • Chemical modifications to produce prodrugs include, for example, esterification (i.e. reacting a carboxylic group -COOH in the drug with an alcohol ROH to form an ester -COOR and water), amidation (i.e.
  • Additional prodrugs may be, for example, phosphoesters, carbamates or imines forms of the active drug, and the like.
  • Levodopa amides prodrugs when administered to a subject, for example a human subject, are hydrolyzed in vivo by ami do peptidase so as to afford release of levodopa (LD) in the periphery (and may be even in the brain). Conversion of LD to dopamine is therefore moderated, and a sustained level of dopamine at dopaminergic neurons is generated (Atlas et al., CNS Neuroscience & Therapeutics, 22: 461-467, 2016). The release profile of LD may enable the administration of lower doses of levodopa amide derivatives to thereby produce clinically meaningful effects with reduced adverse side effects and prolonged treatment period.
  • LD levodopa
  • Levodopa is relatively rapidly metabolized to dopamine, thus, for example, in medicinal applications, LD is optionally co-administrated/co-formulated with a decarboxylase inhibitor and/or a COMT inhibitor so as to improve the pharmacokinetics of LD.
  • Levodopa a ide derivatives contemplated in a disclosed formulation are described, for example, in U.S. Patent Application No. 8,048,926, International Application Publication No. WO 2017/09003 and Zhou et al. (Eur. J. Med. Chem. 45:4035-4042, 2010), the content of which is incorporated herein by reference.
  • a contemplated formulation may comprise one or more levodopa a ide derivatives presented by the general formula I:
  • R' each independently, is H, (Ci-C 6 )alkyl, (C2-C6)alkenyl, cycloalkyl, aryl, or heteroaryl bonded through a ring carbon;
  • R" is a saturated or unsaturated hydrocarbon chain having at least 10 carbon atoms.
  • alkyl as used herein means a straight or branched saturated hydrocarbon group having 1-6 carbon atoms and includes, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isoamyl, 2,2-dimethylpropyl, n-hexyl, and the like.
  • Exemplary alkyl groups are (Ci-C3)alkyl groups such as methyl and ethyl.
  • the alkyl group may be unsubstituted or substituted.
  • the alkyl is substituted with amino group.
  • the substituted alkyl is (Ci-C3)alkyl-NH2
  • alkenyl and alkynyl as used herein mean straight and branched hydrocarbon radicals having 2-6 carbon atoms and one or more double or triple bonds, respectively, and include ethenyl, propenyl, 3-buten-l-yl, 2-ethenylbutyl, and the like, and propynyl, 2-butyn-l-yl, 3-pentyn-l-yl, 3-hexynyl, and the like.
  • Some exemplary embodiments feature C2-C3 alkenyl and alkynyl radicals, particularly C2 alkenyl and alkynyl.
  • cycloalkyl as used herein means a cyclic or bicyclic hydrocarbyl group having 3-10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, bicyclo[3.2. l]octyl, bicyclo[2.2.1]heptyl, and the like.
  • Some exemplary embodiments feature (C5-Cio)cycloalkyls, particulalry (C5-C7)cycloalkyls.
  • the cycloalkyl group may be unsubstituted or substituted.
  • aryl denotes an aromatic carbocyclic group having 6-14 carbon atoms consisting of a single ring or multiple rings either condensed or linked by a covalent bond such as, but not limited to, phenyl, naphthyl, phenanthryl, and biphenyl.
  • the aryl group may be unsubstituted or substituted.
  • heteroaryl refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having one or more heteroatoms selected from nitrogen, oxygen and sulfur, and a completely conjugated pi-electron system.
  • heteroaryl groups include pyrrole, furane, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine.
  • LDA derivatives encompassed by general formula I include compounds in which R1-R6 are as are listed in Table 1 below:
  • the evodopa amide derivative is the compound 2-amino-3- (3,4-dihydroxyphenyl)propanamide, also termed herein“levodopa amide free base” (LDA FB).
  • LDA FB 2-amino-3-(3,4- dihydroxyphenyl) propanamide
  • the LDA derivative is an acid addition salt of 2-amino-3-(3,4- dihydroxyphenyl) propanamide, for example, HC1 salt, fumaric acid salt, lactate salt, maleic acid salt, gluceptic acid salt, phosphoric acid salt, sulfuric acid, and the like.
  • a formulation comprising a levodopa amide compound and an acid selected from a monovalent, divalent, and/or trivalent acid, and, optionally, a pharmaceutically acceptable carrier.
  • the term“formulation”, as used herein, refers to any mixture of different components or ingredients prepared in a certain way, i.e., according to a particular formula, and used for a specific purpose such as, but not limited to, medicinal, agricultural, veterinarian, horticulture, environmental or applied in a chemical process.
  • a formulation may include one or more active ingredients combined or formulated together with, for example, one or more carriers, excipients, stabilizers and the like.
  • the formulation may comprise solid and/or non-solid, e.g., liquid, gel, semi -sol id (e.g. gel, wax) or gas components.
  • pharmaceutical composition refers to a formulation designed for medicinal utilization such as, but not limited to, therapeutic or diagnostic utilization, comprising one or more biologically and/or chemically active agents, combined or formulated together with one or more pharmaceutically and physiologically acceptable carriers, which can be administered to a subject (e.g., human or non-human subject) in a specific form, such as, but not limited to, a tablet, linctus, ointment, infusion or injection.
  • a pharmaceutical composition is sometimes also referred to herein as“medicinal formulation”.
  • liquid pharmaceutical compositions for example aqueous pharmaceutical compositions.
  • a contemplated LDA derivative formulation e.g., a pharmaceutical formulation is a suspension.
  • the active agent may be at least one of the levodopa amide compounds as defined herein.
  • the active agent may be a levodopa amide derivative, for example, as represented by formula I herein or a pharmaceutically acceptable salt thereof, carbidopa, a carbidopa prodrug or a pharmaceutically acceptable slat thereof, and the biological desired effect is treatment, amelioration, prevention, mitigation and/or curing of a central nervous system (CNS) disease or disorder such as Parkinson’s disease.
  • CNS central nervous system
  • the terms“pharmaceutically acceptable”,“pharmacologically acceptable” and“physiologically acceptable” are interchangeable and mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. These terms include formulations, molecular entities, and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by, e.g., the U.S. Food and Drug Administration (FDA) agency, and the European Medicines Agency (EMA).
  • FDA U.S. Food and Drug Administration
  • EMA European Medicines Agency
  • physiologically suitable carrier refers to an approved carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of a possible active agent.
  • Physiologically suitable carriers in liquid medicinal formulations may be, for example, solvents or dispersion media.
  • formulation comprising a LDA derivative and one or more acids selected from a monovalent, divalent or a trivalent acid.
  • the formulation may be, for example, an aqueous formulation, and the acid may serve, for example, as a counter ion of the basic LDA derivative, thereby facilitating solubilization thereof.
  • the amount of LDA derivative in a contemplated formulation may be in the range of from about 1% to about 25%, for example, from about 5% to about 20%, from about 1% to about 5%, from about 3% to about 8%, from about 5% to about 10%, from about 5% to about 15%, from about 8% to about 15%, from about 5% to about 20%, from about 10% to about 15%, from about 10% to about 20%, from about 12% to about 18%, from about 15% to about 20%, from about 5% to about 25%, from about 17% to about 23%, or from about 20% to about 25%, and any ranges, sub ranges and individual values therebetween.
  • a contemplated formulation comprises from about 5% to about 20%, from about 10% to about 25%, about 5%, about 10%, about 15% or about 25% by weight of a levodopa amide derivative.
  • a formulation described herein may comprise an organic solvent.
  • One or more organic solvents may be used in a contemplated formulation, for example, for solubilizing the LDA derivative.
  • Formulation comprising organic solvent(s) may comprise lower amount of acids than would be otherwise required to solubilize the LDA derivative.
  • Non-limiting examples of organic solvents suitable for the purpose of embodiments described herein include: methanol, N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), dimethyl acetamide (DMA), tetrahydrofuran (THF), ethanol, isopropanol, propylene glycol (PG), glycerin, tetraglycol, transcutol, and polyethylene glycol (PEG), dioxane and dimethyl form amide (DMF).
  • the amount of the organic solvent in a contemplated formulation may range from 0 to about 99.9%, for example, from about 0% to about 5%, from about 0% to about 10%, from about 5% to about 15%, from about 10% to about 15%, from about 13% to about 20%, from about 15% to about 25%, from about 20% to about 25%, from about 25% to about 35%, from about 30% to about 50%, from about 35% to about 65%, from about 40% to about 50%, from about 40% to about 60%, from about 50% to about 65%, from about 60% to about 65%, from about 63% to about 70%, from about 65% to about 75%, from about 70% to about 80%, from about 75% to about 85%, from about 80% to about 95%, or from about 90% to about 99%, and any ranges and subranges therebetween.
  • a contemplated formulation may contain about 1%, about 2%, about 5%, about 10%, about 15%, about 20%, about 40%, about 60%, about 80% organic solvent, for example, NMP or DMSO.
  • a described formulation is a LDA derivative-containing liquid formulation, for example an aqueous formulation containing one or more LDA derivatives, having a pH of from about 2 to about 11 at 25°C, for example, a pH of from about 2.0 to about 9.0, from about 6.0 to about 11.0, from about 2.0 to about 3.5, from about 2.5 to about 4.3, from about 3.0 to about 4.5, from about 3.3 to about 5.5, from about 4.0 to about 5.5, from about 5.0 to about 7.5, from about 5.2 to about 7.5, from about 5.5 to about 5.8, from about 6.0 to about
  • a pH of from about 2 to about 11 at 25°C for example, a pH of from about 2.0 to about 9.0, from about 6.0 to about 11.0, from about 2.0 to about 3.5, from about 2.5 to about 4.3, from about 3.0 to about 4.5, from about 3.3 to about 5.5, from about 4.0 to about 5.5, from about 5.0 to about 7.5, from about 5.2 to about 7.5, from about 5.5 to
  • a pharmaceutical composition for example, aqueous, having a pH of from about 2.0 to about 9.0, from about 6.0 to about 11.0, from about 6.5 to about 7.5, from about 6.6 to about 7.1, from about 6.7 to about 7.0, from about 7.1 to about 9.5, from about 7.1 to about 8.5, or from about 6.5 to about 8.0 at 25°C, the composition comprising one or more acids and from about 1% to about 30%, or from about 5% to about 20%, by weight of a levodopa amide derivative.
  • the molar ratio of the LDA derivative and a one or more acids in a contemplated formulation may be from about 1.0:0.1 to about 1.0:2.0 or more.
  • the molar ratio LDA:acid may be from about 1.0:0.1 to about 1.0:0.89, from about 1.0:0.1 to about 1.0:0.5, from about 1.0:0.2 to about 1.0:0.5, from about 1.0:0.3 to about 1.0:0.6, from about 1.0:0.4 to about 1.0:0.6, from about 1.0:0.2 to about 1.0:0.7, from about 1.0:0.5 to about 1 :0.8, from about 1.0:0.5 to about 1.0:1.0, from about 1.0:0.05 to about 1.00: 1.15, from about 1.0:0.6 to about 1.0:0.8, from about 1.0:0.7 to about 1.0:0.87, from about 1.0:0.6 to about 1.0:0.89, from about 1.0:0.8 to about 1.0:0.9, from about 1.0:0.8 to about 1.0: 1.0, from about 1.0:0.9 to about 1.0: 1.1, from about 1.0:0.95 to about 1.0: 1.2, from about 1.0:1.0 to about 1.0: 1.2, from about 1.0: 1.5 to about 1.0
  • the ratio term“LDA:acid”, as used herein, encompasses the molar ratio of a LDA derivative and one particular acid present in the formulation, for example, a monovalent, divalent or trivalent acid, as well as the molar ratio of one or more LDA derivatives and one, two, three, four or more acids (e.g., all acids) present in the formulation.
  • the acid in a formulation may be an organic acid, an inorganic acid, or any combination thereof.
  • the acid may serve as a counter ion for solubilizing one or more LDA derivatives present in the formulation.
  • suitable organic acids include, without being limited to, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hippuric acid, maleic acid, malic acid, fumaric acid, tartaric acid, benzoic acid, acetic acid, citric acid, ascorbic acid, lactic acid, lactobionic acid, gluconic acid, galactaric acid, gluceptic (glucoheptanoic) acid, D-glucuronic acid, glutaric (pentanedioic) acid, glycolic (hydroxyacetic) acid, isethionic (2-hydroxy-ethanesulfonic) acid, formic acid, propionic (propanoic) acid, succin
  • a disclosed pharmaceutical composition comprises hydrochloric acid, succinic acid, glutamic acid, citric acid, tartaric acid and/or acetic acid as a counter ion.
  • the acid is a monovalent acid, for example, acetic acid, ascorbic acid, lactic acid (unspecified form), gluconic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, boric acid, butyric acid, caprylic acid, deoxycholic acid, diatrizoic acid, erythorbic acid, formic acid, gentisic acid ethanolamine, lactobionic acid, levulinic acid, hydrochloric acid, hydrobromic acid, hippuric acid, gluceptic acid, glucuronic acid, glycolic acid, isethionic acid, isostearic acid,
  • acetic acid for example, ascorbic acid, lactic acid (unspecified form), gluconic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluen
  • methylboronic acid myristic acid, nitric acid, oleic acid, palmitic acid, propionic acid, sorbic acid, stearic acid, undecylenic acid, xinafoic acid and carbonic acid.
  • the molar ratio of a LDA derivative and monovalent acid may be, for example, from about 1.0:0.10 to about 1.0: 1.00, from about 1.00:0.10 to about 1.00:0.89, from about 1.0:0.30 to about 1.0:0.90, from about 1.0:0.40 to about 1.0:0.80, from about 1.0:0.50 to about 1.0:0.70, about 1.0:0.50, about 1.0:0.75, about 1.0:0.80, about 1.0:0.85, about 1.0:0.89, about 1.0:1.10, about 1.0: 1.70, about 1.0: 1.80, about 1.0:1.90, about 1.0:2.00, or about 1.0:>2.0.
  • the acid is a divalent acid, for example, adipic acid, maleic acid, malic acid, fumaric acid, tartaric acid, galactaric acid, glutaric acid, oxalic acid, succinic acid, glutamic acid, glutamic acid hydrochloride, aspartic acid, phosphoric acid sebacic acid and sulfuric acid.
  • adipic acid maleic acid, malic acid, fumaric acid, tartaric acid, galactaric acid, glutaric acid, oxalic acid, succinic acid, glutamic acid, glutamic acid hydrochloride, aspartic acid, phosphoric acid sebacic acid and sulfuric acid.
  • the molar ratio of a LDA derivative and divalent acid may be, for example, about 1.0:0.4, about 1.0:0.75, about 1.0:0.8, about 1.0:0.85, about 1.0: 1.1, about 1.0:1.7, about 1.0: 1.8, about 1.0:1.9, about 1.0:2.0, or about 1.0:>2.0.
  • the acid is a trivalent acid, for example, citric acid, fatty acid glycerides, and hydrogenated tallow acid
  • the molar ratio of a LDA derivative and trivalent acid may be, for example, about 1.0:0.4, about 1.0:0.5, about 1.0:0.75, about 1.0:0.8, about 1.0:0.85, about 1.0: 1.1, about 1.0: 1.7, about 1.0: 1.8, about 1.0:1.9, about 1.0:2.0, or about 1.0:>2.0.
  • a contemplated formulation may have a pH of from about 2.0 to about 9.0, from about 7.1 to about 8.5, from about 6.7 to about 7.1, from about 6.0 to about 9.5, or from about 6.5 to about 8.0 at 25 °C, the formulation may comprise a monovalent acid, and from about 1% to about 30%, or from about 5% to about 20%, by weight of a LDA compound, wherein the composition is stable for at least 24 hours at room temperature.
  • a contemplated formulation may have a pH of from about 4.0 to about 11.0, from about 6.5 to about 7.5, from about 6.6 to about 7.1, from about 6.7 to about 7.0, or from about 7.1 to about 9.5 at 25 °C, the composition may comprise a divalent or trivalent acid, and from about 1% to about 30%, or from about 5% to about 20%, by weight of a LDA derivative, wherein the molar ratio of the LDA compound to the acid is from about 1 :0.1 to about 1: 1.2, but excluding molar ratios of 1 :0.50 and 1 :0.33 when the pH is from about 6.0 to about 7.0, wherein the composition is stable for at least 24 hours at room temperature.
  • a formulation for example a contemplated pharmaceutical composition, may comprise a pharmaceutically acceptable salt, e.g., an acid addition salt of a levodopa amide compound.
  • a pharmaceutically acceptable salt e.g., an acid addition salt of a levodopa amide compound.
  • the term“pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, or allergic response, and are commensurate with a reasonable benefit/risk ratio.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, hippuric acid, methanesulfonic acid, ascorbic acid, malonic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, fumaric, benzoic acid, cinnamic acid, a sulfonic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mu conic acid, and the like; and (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, digluconate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, laurate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, and valerate salts
  • a contemplated formulation may be stable for at least 24 hours.
  • Exemplary formulations may be stable for at least 24, for at least 48, for at least 72, for at least 96 hours, for at least 1, 2 or 3 weeks, or for at least 1, 2 or 3 months, and even for at least 1 year, at room temperature or at -20 to -80°C.
  • a disclosed formulation may have an acid, for example a monovalent, divalent or trivalent acid, and at least one LDA derivative represented by the general formula I:
  • R' each independently, is H, (Ci-C 6 )alkyl, (C2-C6)alkenyl, cycloalkyl, aryl, or heteroaryl bonded through a ring carbon;
  • R" is a saturated or unsaturated hydrocarbon chain having at least 10 carbon atoms.
  • a contemplated formulation for example a medicinal formulation, may comprise an acid and a LDA compound of formula I herein, a salt thereof (e.g., a pharmaceutically acceptable slat), an enantiomer, diastereomer, and/or racemate thereof, wherein:
  • Rl, R2, R3 and R4 each is H
  • a contemplated pharmaceutical composition may comprise a LDA derivative of formula I herein, a pharmaceutically acceptable salt thereof, an enantiomer, diastereomer, and/or racemate thereof, wherein R5 and R6 each independently is (Ci-C3)alkyl, for example, methyl or ethyl, or H. In alternative exemplary embodiments, R5 and R6 each is H.
  • a contemplated formulation comprises the compound 2-amino-3-(3,4-dihydroxyphenyl) propanamide (levodopa amide free base) represented by the structural formula:
  • a described pharmaceutical composition may further comprise a decarboxylase inhibitor or a prodrug thereof, added to the formulation in order to inhibit an undesired enzymatic decarboxylation of levodopa to dopamine outside the central nervous system (CNS).
  • the decarboxylase inhibitor may be, for example, carbidopa, benserazide, a prodrug thereof (e.g., an ester of a carbidopa), or a salt thereof, e.g., the arginine-, histidine-, or lysine-salt of carbidopa or of a prodrug thereof.
  • the molar ratio of a LDA derivative to a decarboxylase inhibitor may be from about 1 : 1 to about 100: 1, from about 2: 1 to about 60: 1, from about 5:1 to about 40: 1, or from about 10:1 to about 40: 1.
  • molar ratio of a LDA derivative to a decarboxylase inhibitor is, for example, 4: 1, 8:1 or 23: 1.
  • any one of the formulations contemplated herein may include, besides one or more LDA derivatives and optionally a decarboxylase inhibitor which may be regarded as the prime active agents, at least one ingredient selected from a secondary active agent, a stabilizer to e.g., provide stabilization to the active agent(s) and optionally protect it against breakdown (e.g., hydrolysis) before it reaches its end target, a buffering agent to maintain a desired pH of the formulation, physiologically suitable carriers, and/or excipients such as diluents, lubricants, glidants, disintegrants, preservatives, flavors, bulking agents (e.g. mannitol), antioxidants (e.g., ascorbic acid or sodium bisulfite), local anesthetics and combinations thereof.
  • a stabilizer to e.g., provide stabilization to the active agent(s) and optionally protect it against breakdown (e.g., hydrolysis) before it reaches its end target
  • a disclosed pharmaceutical composition may comprise one or more LDA derivatives, one or more acids, a decarboxylase inhibitor (or a prodrug thereof) and, optionally, either one of, or at least one of, a basic amino acid or an amino sugar.
  • the basic amino acid and/or the amino sugar may be added to a disclosed formulation so as to help is solubilizing the decarboxylase inhibitor.
  • the basic amino acid may be, for example, arginine, histidine, or lysine.
  • the amino sugar may be, for example, meglumine, D-glucosamine, sialic acid, N-acetylglucosamine, galactosamine or a combination thereof.
  • a contemplated pharmaceutical composition may further comprise a buffer.
  • buffers that may be used in accordance with described embodiments include, without being limited to, citrate buffer, acetate buffer, sodium acetate buffer, tartrate buffer, phosphate buffer, borate buffer, carbonate 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, or a mixture thereof.
  • any of the active agents as defined herein may undergo oxidation and/or degradation resulting in release of various degradants.
  • hydrazine may result from oxidative degradation of carbidopa or a prodrug thereof.
  • Hydrazine is a carcinogen, thus, it is important to reduce the release of hydrazine into the pharmaceutical compositions.
  • Disclosed formulations may include active agents such as one or more LDA derivatives, carbidopa, a carbidopa prodrug, and/or pharmaceutically acceptable salts thereof and any combination thereof, and further include one or more agents that inhibit the formation of oxidation products as well as the formation of other degradants after the prodrugs are administered into the body.
  • agents may be e.g., antioxidants, tyrosinase inhibitors and/or Cu 2+ chelators.
  • antioxidant refers to a substance which slows down the damage that can be caused to other substances by the effects of oxygen. In other words, an antioxidant inhibits the oxidation of other molecules. Antioxidants include two different groups of substances: industrial chemicals which are added to products to prevent oxidation, and natural chemicals found in foods and body tissue.
  • antioxidants include ascorbic acid (vitamin C) or a salt thereof (e.g., sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbyl palmitate, and ascorbyl stearate); cysteine or a cysteine derivative such as L- cysteine, N-acetyl cysteine (NAC), glutathione, thiol precursor such as L-2-oxo-4-thiazolidine carboxylic acid (OTC), or a salt thereof; lipoic acid; uric acid; carotenes; a-tocopherol (vitamin E); and ubiquinol (coenzyme Q).
  • vitamin C ascorbic acid
  • a salt thereof e.g., sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbyl palmitate, and ascorbyl stearate
  • cysteine or a cysteine derivative such as L- cysteine, N-acetyl cysteine (NAC), gluta
  • antioxidants contemplated herein are phenolic antioxidants such as di -tert- butyl methyl phenols, icri-butyl-mcthoxy phenols, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), polyphenols, tocopherols, ubiquinones (e.g., caffeic acid, tert- butylhydroquinone (TBHQ)), propyl gallate, flavonoid compounds, cinnamic acid derivatives, coumarins, and others.
  • phenolic antioxidants such as di -tert- butyl methyl phenols, icri-butyl-mcthoxy phenols, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), polyphenols, tocopherols, ubiquinones (e.g., caffeic acid, tert- butylhydroquinone (TBHQ)),
  • Ascorbic acid is a monosaccharide oxidation-reduction (redox) catalyst found in both animals and plants. Ascorbic acid acts as an oxygen scavenger to reduce molecular oxygen.
  • redox oxidation-reduction
  • Thiol containing compounds such as cysteine, NAC, glutathione and thiol precursors such as OTC have several potential antioxidant effects. These agents can directly scavenge radicals via hydrogen donation from their SH group, resulting in formation of a thiyl (S) radical.
  • Disclosed formulations can include one, two, or more antioxidants.
  • a disclosed formulation can include one, two, or more of an agent selected from the group consisting of ascorbic acid or a salt thereof, for example, sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbyl palmitate, and ascorbyl stearate, particularly sodium ascorbate, and cysteine or a cysteine derivative, for example, L-cysteine, NAC, glutathione, or a salt thereof.
  • an agent selected from the group consisting of ascorbic acid or a salt thereof for example, sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbyl palmitate, and ascorbyl stearate, particularly sodium ascorbate, and cysteine or a cysteine derivative, for example, L-cysteine, NAC, glutathione, or a salt thereof.
  • a disclosed formulation may include ascorbic acid, or a salt thereof.
  • Contemplated formulation that comprise ascorbic acid or a salt thereof may include from about 0.01% to about 1.0% by weight, or more, ascorbic acid (or salt thereof).
  • ascorbic acid or salt thereof
  • Contemplated formulation that comprise ascorbic acid or a salt thereof may include from about 0.01% to about 1.0% by weight, or more, ascorbic acid (or salt thereof).
  • ascorbic acid or salt thereof
  • from about 0.01% to about 0.05% from about 0.03% to about 0.1%, from about 0.1% to about 0.2%, from about 0.1% to about 0.3%, from about 0.2% to about 0.35%, from about 0.2% to about 0.5%, from about 0.3% to about 0.45%, from about 0.4% to about 0.6%, from about 0.5% to about 0.65%, from about 0.5% to about 0.8%, from about 0.6% to about 0.9%, or from about 0.7% to about 0.95%, or from about 0.8% to about 1.0%, by weight ascorbic acid or salt thereof such as sodium ascorbate.
  • a disclosed formulation may include, for example, about 0.01%, about 0.10%, about 0.25%, about 0.40%, about 0.50%, about 0.60%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95%, or about 1.00%, by weight sodium ascorbate or ascorbic acid as antioxidant.
  • a disclosed formulation may comprise L-cysteine or a pharmaceutically acceptable salt thereof, NAC or a pharmaceutically acceptable salt thereof, glutathione or a pharmaceutically acceptable salt thereof, and/or sodium bisulfite or a pharmaceutically acceptable salt thereof.
  • disclosed formulations may include a bisulfite, e.g., sodium bisulfite or other sulfite salts, e.g., sodium hydrogen sulfite or sodium metabisulfite.
  • a bisulfite e.g., sodium bisulfite or other sulfite salts, e.g., sodium hydrogen sulfite or sodium metabisulfite.
  • Contemplated pharmaceutical compositions may comprise from about 0.001% to about 1.0% by weight, or more, L-cysteine.
  • a disclosed pharmaceutical composition includes from about 0.01% to about 1.00%, from about 0.1% to about 0.6% or from about 0.3% to about 0.5% by weight L-cysteine or a pharmaceutically acceptable salt thereof.
  • a disclosed pharmaceutical composition includes about 0.3%, about 0.4% or about 0.5% by weight L-cysteine or a pharmaceutically acceptable salt thereof.
  • Contemplated pharmaceutical compositions may include NAC at varying concentrations in a range of, for example, from about 0.001% to about 1.0%, or more.
  • a disclosed pharmaceutical composition comprises from about 0.01% to about 0.5% by weight NAC.
  • a disclosed pharmaceutical composition includes about 0.1%, about 0.2%, about 0.3%, about 0.4% or about 0.5% by weight NAC or a pharmaceutically acceptable salt thereof.
  • Contemplated pharmaceutical compositions may include sodium bisulfite at varying concentrations ranging, for example, from about 0.01% to about 1.0%, or more.
  • a disclosed pharmaceutical composition includes from about 0.075% to about 0.75% by weight sodium bisulfite or a pharmaceutically acceptable salt thereof.
  • a disclosed pharmaceutical composition includes about 0.1 % by weight sodium bisulfite.
  • Contemplated pharmaceutical compositions may include glutathione at varying concentrations ranging, for example, from about 0.001% to about 1.0% by weight, or more.
  • a disclosed pharmaceutical composition includes from about 0.1% to about 0.7% by weight glutathione or a pharmaceutically acceptable salt thereof.
  • Contemplated formulation may comprise, for example, NAC, L-cysteine, glutathione, and/or a pharmaceutically acceptable salt thereof.
  • a disclosed pharmaceutical composition may include: from about 0.001% to about 0.5%, from about 0.010% to about 1.0%, from about 0.1 % to about 0.6%, about 0.3% or about 0.4% by weight L-cysteine or a pharmaceutically acceptable salt thereof such as L-cysteine hydrochloride; from about 0.001% to about 0.5%, from about 0.01% to about 1.0%, about 0.1%, about 0.2%, about 0.3%, or about 0.4% by weight NAC; from about 0.01% to about 1.0%, from about 0.075% to about 0.75%, or about 0.1% by weight sodium bisulfite; and/or from about 0.001% to about 0.5%, or from about 0.1 % to about 1.0% by weight glutathione.
  • a formulation includes from about 0.001% to about 1.0%, from about 0.01% to about 1.0%, from about 0.1% to about 0.5%, or from about 0.1% to about 1% by weight of a compound selected from the group consisting of NAC, L-cysteine, glutathione, and/or a pharmaceutically acceptable salt thereof.
  • a disclosed formulation can include from about 0.01% to about 1.0%, e.g., from about 0.05% to about 0.3%, from 0.2% to about 0.6%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, or about 0.5% by weight of NAC and/or L-cysteine.
  • Formulations including at least two antioxidants can result in substantially lower levels of oxidation products, for example, hydrazine, as compared to formulations with fewer antioxidants.
  • two antioxidants when included in the formulation, they may be ascorbic acid and L-cysteine, or ascorbic acid and NAC, or sodium ascorbate and L-cysteine, or sodium ascorbate and NAC.
  • a contemplated formulation may comprise a first antioxidant which is ascorbic acid or a salt thereof, and a second antioxidant which is L-cysteine and/or a cysteine derivative, or a pharmaceutically acceptable salt thereof such as cysteine hydrochloride, NAC, sodium bisulfite, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tocopherol or gentisic acid.
  • a first antioxidant which is ascorbic acid or a salt thereof
  • a second antioxidant which is L-cysteine and/or a cysteine derivative, or a pharmaceutically acceptable salt thereof such as cysteine hydrochloride, NAC, sodium bisulfite, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tocopherol or gentisic acid.
  • Exemplary embodiments contemplate a pharmaceutical composition comprising ascorbic acid and L-cysteine, sodium ascorbate and NAC, ascorbic acid and NAC, sodium ascorbate and L-cysteine, ascorbic acid and glutathione, or sodium ascorbate and glutathione.
  • a disclosed formulation may include ascorbic acid, or salt thereof, and a cysteine derivative.
  • Oxidation of carbidopa or a prodrug thereof may further occur in the body, for example, by tyrosinase, a copper-containing enzyme, which is involved in the conversion of an o-diphenol (or a di-hydroxy phenyl) moiety to the corresponding o-quinone.
  • Tyrosinase inhibitors contemplated herein include, but not limited to, captopril, methimazole, quercetin, arbutin, aloesin, N-acetylglucoseamine, retinoic acid, a-tocopheryl, ferulate, Mg ascorbyl phosphate (MAP), substrate analogues (e.g., sodium benzoate, L- phenylalanine) and/or Cu 2+ chelators.
  • captopril methimazole
  • quercetin arbutin
  • aloesin N-acetylglucoseamine
  • retinoic acid retinoic acid
  • a-tocopheryl ferulate
  • substrate analogues e.g., sodium benzoate, L- phenylalanine
  • Cu 2+ chelators e.g., Cu 2+ chelators.
  • Non-limiting examples of Cu 2+ chelators include, Na2-EDTA, Na2-EDTA-Ca, DMSA (succimer), D-penicillamine (DPA), trientine-HCl, dimercaprol, clioquinol, sodium thiosulfate, triethylenetetr amine (TETA), tetraethylenepentamine (TEPA), curcumin, neocuproine, tannin, and/or cuprizone.
  • Contemplated pharmaceutical compositions may include a surfactant.
  • surfactants include polysorbate 20, 40, 60 and/or 80, (Tween®-20, Tween®-40, Tween®-60 and Tween®-80, respectively), Span 20, Span 40, Span 60, Span 80, Span 85, polyoxyl 35 castor oil (Cremophor EL), polyoxyethylene-660-hydroxystearate (macrogol 660), triton or Poloxamer 188 (Pluronic® F-68).
  • polysorbate 80 may be present in varying amounts, ranging, for example, from about 0.01% to about 5.0%, from about 0.1% to about 0.5%, or about 0.3% by weight of polysorbate 80 or another surfactant.
  • a contemplated pharmaceutical composition may, optionally, further comprise one or more excipients.
  • excipient refers to an inert substance added to a pharmaceutical composition (formulation) to further facilitate process and administration of the active ingredients.
  • “Pharmaceutically acceptable excipients”, as used herein, encompass preservatives, antioxidants, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents in combination with pharmaceutically active agents is well known in the art. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, terpens and polyethylene glycols.
  • Excipients suitable for formulations described herein may comprise, for example, an enhancer and/or a gelation agent and/or a thickening agent.
  • Contemplated enhancers include pyrrolidones such as N-methyl-2-pyrrolidone (NMP) or polyvinyl alcohol (PVP), polyols, terpenes (nonaromatic compounds found in essential oils, which may be extracted from flowers, fruits, and other natural products), glycerol, lauroglycol, propylene glycol, diethylene glycol monoethyl ether, and/or propylene glycol monocaprylate.
  • NMP N-methyl-2-pyrrolidone
  • PVP polyvinyl alcohol
  • polyols polyols
  • terpenes nonaromatic compounds found in essential oils, which may be extracted from flowers, fruits, and other natural products
  • glycerol lauroglycol
  • propylene glycol diethylene glycol monoethyl ether
  • Contemplated thickening agents include cellulose polymers such as hydroxypropyl cellulose, and/or carbomer polymers and derivatives, e.g., polysaccharides (agarose) polyacrylic polymers, poloxamers, and mixtures thereof.
  • cellulose polymers such as hydroxypropyl cellulose, and/or carbomer polymers and derivatives, e.g., polysaccharides (agarose) polyacrylic polymers, poloxamers, and mixtures thereof.
  • terpenes such as, but not limited to, d- limonene, dipentene (d/l-limonene), a-pinene, g-terpinene, b-mircene, p-cimene, a-pinene, a- phellandrene, citronellol, geraniale (citrale), nerol, beta-carotene, menthol, geraniol, farnesol, phytol, their homologs, derivatives, enantiomers, isomers including constitutional isomers, stereoisomerisms, regioisomers, and geometric isomers, and any combinations thereof.
  • terpenes such as, but not limited to, d- limonene, dipentene (d/l-limonene), a-pinene, g-terpinene, b-mircene, p-cimene, a-pinene,
  • ethanolamines e.g., monoethanolamine, diethanolamine, triethanolamine, phenyl ethanolamine, acetyl ethanolamine, or benzoyl ethanolamine.
  • a disclosed pharmaceutical composition may further comprise one or more active agents, herein termed“secondary active agents” which may be added to the formulation so as to support, enhance, intensify, promote or strengthen the biological activity of the main or prime active agent(s). Additionally or alternatively, the secondary active compounds may provide supplemental or additional therapeutic functions.
  • a secondary active agent include a catechol-O-methyl transferase (COMT) inhibitor, or a monoamine oxidase (MAO) (either MAO-A or MAO-B) inhibitor.
  • COMT inhibitors include, without limiting, entacapone, tolcapone and opicapone; and particular MAO inhibitors can be selected from, e.g., moclobemide, rasagiline, selegiline, or safinamide.
  • Further secondary active agents may be exemplified by adamantans (e.g., amantadine), nicotinic receptor agonists (e.g., nicotine, galantamine), dopamine receptor agonists (e.g., apomorphine, rotigotine).
  • adamantans e.g., amantadine
  • nicotinic receptor agonists e.g., nicotine, galantamine
  • dopamine receptor agonists e.g., apomorphine, rotigotine
  • a contemplated medicinal formulation comprises a LDA derivative and a decarboxylase inhibitor
  • these main active agents can be combined and formulated in the same pharmaceutical composition, namely, as a single unit dosage from or, alternatively, can be present in separate pharmaceutical compositions, namely a plurality of dosage unit forms, for example, two or more dosage unit forms, each comprising one or more of a first active agent (e.g., a LDA derivative, for example a compound corresponding in structure to a compound of formula I), and/or a second active agent (e.g., a decarboxylase inhibitors, for example carbidopa or a prodrug thereof).
  • a first active agent e.g., a LDA derivative, for example a compound corresponding in structure to a compound of formula I
  • a second active agent e.g., a decarboxylase inhibitors, for example carbidopa or a prodrug thereof.
  • a medicinal formulation disclosed herein can comprise a first unit dosage form comprising one or more LDA derivatives (e.g., a derivative of formula I and/or a pharmaceutically acceptable salt thereof) and an acid (e.g., a monovalent, divalent or trivalent acid), and a second unit dosage form comprising one or more decarboxylase inhibitors (e.g., carbidopa, a prodrug thereof and/or a pharmaceutically acceptable salt thereof).
  • LDA derivatives e.g., a derivative of formula I and/or a pharmaceutically acceptable salt thereof
  • an acid e.g., a monovalent, divalent or trivalent acid
  • decarboxylase inhibitors e.g., carbidopa, a prodrug thereof and/or a pharmaceutically acceptable salt thereof.
  • a formulation can comprise a L-dopa prodrug such as one or more LDA derivatives and a decarboxylase inhibitor such as carbidopa, a prodrug thereof and/or a pharmaceutically acceptable salt thereof in the same pharmaceutical composition.
  • a disclosed pharmaceutical composition may be formulated as a liquid, gel, cream, solid, film, emulsion, suspension, solution, lyophylisate or aerosol.
  • a contemplated pharmaceutical composition may be formulated as a liquid.
  • the pharmaceutical compositions comprise a plurality of dosage unit forms, for example two dosage unit forms, they can be formulated in different forms.
  • a first unit dosage form comprising, e.g. one or more LDA derivatives and acid
  • the second unit dosage form comprising, e.g., carbidopa
  • compositions may be formulated for any suitable route of administration, e.g., for subcutaneous, transdermal, intradermal, transmucosal, intravenous, intraarterial, intramuscular, intraperitoneal, intratracheal, intrathecal, intraduodenal, intrapleural, intranasal, sublingual, buccal, intestinal, intraduodenally, rectal, intraocular, or oral
  • compositions may also be formulated for inhalation, or for direct absorption through mucous membrane tissues.
  • the pharmaceutical composition comprises a plurality of dosage unit forms, for example two dosage unit forms, they can be administered in different routes.
  • a first unit dosage form comprising e.g., a LDA derivative and acid may administered subcutaneously as a liquid formulation
  • a second unit dosage form comprising e.g., carbidopa, can be administered orally as a pill.
  • compositions disclosed are aqueous, liquid formulations particularly useful for subcutaneous administration e.g., via in infusion pump.
  • a contemplated formulation is designed for oral
  • compositions in accordance with such embodiments, may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and may be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like. Such compositions may further comprise one or more ingredients selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredients in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets. These excipients may be, e.g., inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate;
  • granulating and disintegrating agents e.g., corn starch or alginic acid; binding agents, e.g., starch, gelatin or acacia; and lubricating agents, e.g., magnesium stearate, stearic acid, or talc.
  • the tablets may be either uncoated or coated utilizing known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated using the techniques described in the U.S. Patent Nos. 4,256,108, 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for control release.
  • the oral compositions may also be in the form of oil-in-water emulsions.
  • a composition in the form of a capsule for oral administration may be prepared by filling the suitable gelatin capsule with dry LDA derivative, for example, one or more LDA derivatives of the general formula I herein, and a filler such as methylcellulose or sodium carboxymethyl cellulose, and, optionally, coating the capsule with enteric coating.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, PVP, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions for oral administration include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and optionally stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • compositions are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the active agent and a suitable powder base such as lactose or starch.
  • compositions described herein may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative.
  • the compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active ingredients in water-soluble form. Additionally, suspensions of the active ingredients may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient(s) may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile, pyrogen-free water
  • compositions for rectal administration may be prepared as suppositories or retention enemas, using for example conventional suppository bases such as cocoa butter or other glycerides.
  • Contemplated pharmaceutical compositions may also be formulated for local administration, such as a depot preparation. Such long acting formulations may be administered by implantation, e.g., subcutaneously or intramuscularly, or by intramuscular injection.
  • the composition may be formulated, e.g., with suitable polymeric or hydrophobic materials, e.g., as an emulsion in an acceptable oil, or ion exchange resins, or as sparingly soluble derivatives such as sparingly soluble salts.
  • Formulations for topical administration may include, without limiting, lotions, suspensions, ointments gels, creams, drops, liquids, sprays emulsions and powders.
  • a disclosed composition in the form of gel for topical administration may be prepared by adding sodium metabisulfite, enhancers, e.g., lauroglycol, Capryol 90, and a gelation agent such as hydroxypropyl cellulose, e.g., Klucel HFC or MF grades, or poly( acrylic) acid, polymethyacrylate (e.g., Carbopol 934P pH 5-6 with or without about 1-5% Eudragit RL-100), to an aqueous solution of a LDA derivative, e.g., one or more LDA derivatives of the general formula I.
  • a LDA derivative e.g., one or more LDA derivatives of the general formula I.
  • a composition in the form of gel may be prepared by combining a LDA derivative, tolcapone, arginine in water, and propylene glycol containing enhancers gelled with hydroxypropyl cellulose, e.g., Klucel HFX.
  • Contemplated herein, in part, is a dermal patch suitable for transdermal or subcutaneous administration of an active agent that comprises a composition as disclosed herein.
  • a pharmaceutical composition as disclosed herein is designed for a slow release of the LDA derivative, and therefore includes particles including said compound and a slow release carrier (typically, a polymeric carrier).
  • a slow release carrier typically, a polymeric carrier.
  • Slow release biodegradable carriers are well known in the art. These are materials that may form particles that may capture therein an active compound(s) and slowly degrade/dissolve under a suitable environment (e.g., aqueous, acidic, basic, etc.), and thereby degrade/dissolve in body fluids and release the active compound(s) therein.
  • the particles can be, e.g., nanoparticles, i.e., in the range of, e.g., from about 1 to about 500 nm, from about 50 to about 200 nm, or from about 100 nm, in diameter.
  • a stable lyophilized powder comprising a LDA derivative, e.g., one or more LDA derivatives of the general formula I, a pharmaceutically acceptable salt thereof, an enantiomer, diastereomer, or racemate thereof.
  • a lyophilized powder can be reconstituted into a liquid formulation by addition of water with or without antioxidants, surfactants and other excipients.
  • compositions disclosed herein are useful for treatment of diseases or disorders characterized by neurodegeneration and/or reduced levels of brain dopamine.
  • physiologically acceptable pH is understood to mean a pH of, e.g., a formulation or composition that facilitates administration of the formulation or composition to a patient without significant adverse effects, e.g., a pH of about 4 to about 9.8 (for example, about 4 ⁇ 0.3 to about 9.5 ⁇ 0.3).
  • Ambient temperature refers to a temperature of from about 10°C to about 30°C. In exemplary embodiments, ambient temperature can be 25 °C.
  • Percentages disclosed herein are by weight unless indicated otherwise.
  • a method of treatment of a subject inflicted with a neurological disease or disorder comprising administrating to the subject an effective amount of a formulation described herein, thereby threating the subject.
  • the method comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a levodopa amide derivative, for example one or more LDA derivatives represented by formula I as defined herein, and a monovalent, divalent and/or trivalent acid, wherein the molar ratios of the LDA derivative and the monovalent, divalent or trivalent acid are as defined herein.
  • a pharmaceutical composition comprising a levodopa amide derivative, for example one or more LDA derivatives represented by formula I as defined herein, and a monovalent, divalent and/or trivalent acid, wherein the molar ratios of the LDA derivative and the monovalent, divalent or trivalent acid are as defined herein.
  • the composition administered to a subject in need thereof may comprise form about 5% to about 25% of a LDA derivative of formula I, and a monovalent acid such as, but not limited to, HC1, and the molar ratio of the LDA compound to the acid may be from about 1.00:0.80 to about 1.00:0.89.
  • the composition administered to a subject in need thereof may comprise form about 5% to about 25% of a LDA derivative of formula I, and a divalent or trivalent acid such as, but not limited to, tartaric acid, citric acid, or glutamic acid, and the molar ratio of the LDA compound to the acid is, e.g., from about 1.00:0.30 to about 1.00:0.55.
  • a divalent or trivalent acid such as, but not limited to, tartaric acid, citric acid, or glutamic acid
  • the molar ratio of the LDA compound to the acid is, e.g., from about 1.00:0.30 to about 1.00:0.55.
  • the formulation administered according to a contemplated method may comprise one or more LDA derivatives as defined herein as a first active agent, and at least one decarboxylase inhibitor as a second active agent, for example carbidopa, a carbidopa prodrug and/or a pharmaceutically acceptable salt thereof, and a monovalent, divalent and/or trivalent acid, wherein the molar ratios of the LDA derivative(s) and the monovalent, divalent and/or trivalent acid are as defined herein.
  • Such a formulation may further comprise one or more of a basic amino acid, an amino sugar, a catechol-O-methyl transferase (COMT) inhibitor, or a monoamine oxidase (MAO) inhibitor, as defined herein.
  • the molar ratio of the LDA derivative to the decarboxylase inhibitor may be from about 1 :1 to about 100: 1, for example, from about 2: 1 to about 60: 1, from about 4:1 to about 40:1 , or from about 10: 1 to about 40:1.
  • the molar ratio LDA derivative: decarboxylase inhibitor is 4: 1, 8: 1 or 23:1.
  • the formulation administered according to a contemplated method may comprise a LDA derivative, for example, one or more LDA derivatives of formula I, and at least one COMT inhibitor such as entacapone, tolcapone, or opicapone, and, optionally, and/or MAO inhibitor such as moclobemide, rasagiline, selegiline, or safinamide, and a monovalent, divalent and/or trivalent acid, wherein the molar ratios of the LDA derivative(s) and the monovalent, divalent or trivalent acid are as defined herein.
  • a LDA derivative for example, one or more LDA derivatives of formula I
  • COMT inhibitor such as entacapone, tolcapone, or opicapone
  • MAO inhibitor such as moclobemide, rasagiline, selegiline, or safinamide
  • a monovalent, divalent and/or trivalent acid wherein the molar ratios of the LDA derivative(s) and the monovalent, divalent or
  • the method comprises co-administering to a patient in need thereof at least two separate pharmaceutical compositions, the first pharmaceutical composition comprising one or more LDA derivatives as defined herein, and a monovalent, divalent and/or trivalent acid, wherein the molar ratios of the LDA derivative(s) and the monovalent, divalent and/or trivalent acid are as defined herein; and a second pharmaceutical composition comprising a decarboxylase inhibitor or a salt thereof, and, optionally, one or more of a basic amino acid, an amino sugar, a COMT inhibitor, or a MAO inhibitor.
  • a contemplated method may comprise administration of a second pharmaceutical composition comprising carbidopa, a carbidopa prodrug and/or a
  • a pharmaceutically acceptable salt thereof as the decarboxylase inhibitor optionally together with a basic amino acid such as arginine, an amino sugar such as meglumine, a COMT inhibitor such as entacapone, tolcapone or opicapone, and/or a MAO inhibitor such as moclobemide, rasagiline, selegiline or safinamide.
  • a basic amino acid such as arginine
  • an amino sugar such as meglumine
  • COMT inhibitor such as entacapone, tolcapone or opicapone
  • MAO inhibitor such as moclobemide, rasagiline, selegiline or safinamide.
  • the first pharmaceutical composition is essentially devoid of a decarboxylase inhibitor, and may, optionally, be devoid of a COMT inhibitor and/or a MAO inhibitor.
  • a pharmaceutical composition administered in a contemplated method may optionally be in a liquid form.
  • the neurological disease or disorder being treated by a contemplated method may be a neurological disorder such as a disorder associated with reduced dopamine or loss of dopaminergic neurons, or a movement disorder.
  • diseases and disorders include, for example: neurological or movement disorders including restless leg syndrome, Parkinson’s disease, secondary parkinsonism, Huntington’s disease, Parkinson’s like syndrome, PSP, MSA, ALS, Shy-Drager syndrome, dystonia, Alzheimer’s disease, LBD, akinesia, bradykinesia, and hypokinesia; conditions resulting from brain injury including carbon monoxide or manganese intoxication; and conditions associated with a neurological disease or disorder including alcoholism, opiate addiction, and erectile dysfunction.
  • the disease is Parkinson’s disease.
  • Treating a disease means ameliorating, inhibiting the progression of, delaying worsening of, and even completely preventing the development of a disease, for example inhibiting the development of neurological manifestations in a person who has neurological disease or disorder.
  • Treatment refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or a pathological condition after it has begun to develop. In particular examples, however, treatment is similar to prevention, except that instead of complete inhibition, the development, progression or relapse of the disease is inhibited or slowed.
  • administering is introduction of the pharmaceutical composition described herein into a subject by a chosen route.
  • Administration of the active compound or pharmaceutical composition can be by any route known to one of skill in the art, and as appropriate for the particular condition and location under treatment.
  • Administration can be local or systemic. Examples of local administration include, but are not limited to, topical administration, subcutaneous administration, intramuscular administration, intrathecal administration, intrapericardial administration, intra-ocular administration, topical ophthalmic administration, or administration to the nasal mucosa or lungs by inhalational administration.
  • local administration includes routes of administration typically used for systemic administration, for example by directing intravascular administration to the arterial supply for a particular organ.
  • local administration includes intra-arterial administration, subcutaneous administration, intraduodenally administration, and intravenous administration when such administration is targeted to the vasculature supplying a particular organ.
  • Local administration also includes the incorporation of active compounds and agents into implantable devices or constructs, such as vascular stents or other reservoirs, which release the active agents and compounds over extended time intervals for sustained treatment effects.
  • Systemic administration includes any route of administration designed to distribute an active compound or composition widely throughout the body via the circulatory system.
  • systemic administration includes, but is not limited to, intra-arterial and intravenous administration.
  • Systemic administration also includes, but is not limited to, topical
  • administration subcutaneous administration, intraduodenally administration, intramuscular administration, or administration by inhalation, when such administration is directed at absorption and distribution throughout the body by the circulatory system.
  • An effective amount of a compound for example, of a compound of formula I herein or a pharmaceutically acceptable salt thereof, or of a decarboxylase inhibitor, e.g., carbidopa or a prodrug thereof, is a quantity of compound sufficient to achieve a desired effect in a subject being treated.
  • An effective amount of a compound can be administered in a single dose, or in several doses, for example daily, during a course of treatment. However, the effective amount of the compound will be dependent on the compound applied, the subject being treated, the severity and type of the affliction, and the manner of administration of the compound.
  • a disclosed pharmaceutical composition may be administered to a patient in need thereof via one or more routes such as, but not limited to, parenteral routes selected from subcutaneous, transdermal, intradermal, intratracheal, intraocular, intramuscular, intraarterial, intraduodenally or intravenous.
  • parenteral routes selected from subcutaneous, transdermal, intradermal, intratracheal, intraocular, intramuscular, intraarterial, intraduodenally or intravenous.
  • the pharmaceutical compositions are administered continuously, for example by a designated pump.
  • formulations may be administered non-continuously, e.g., as bolus, injection, a pill taken orally or eye drops.
  • a disclosed method features subcutaneous and substantially continuous administration of a disclosed pharmaceutical.
  • substantially continuous administration is meant that a dose of the formulation being administered is not administered as a bolus, e.g., a pill taken orally or a bolus injection, but rather that a single dose of the composition is being administered to a patient or individual over a particular predetermined period of time.
  • substantially continuous administration can involve administration of a dosage at over a period of at least 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, 12 to 16 hours, 16 to 18 hours, 18 to 20 hours, or 20 to 24 hours, to administer a single dose.
  • Substantially continuous administration can be achieved using a transdermal patch or a pump device that continuously administers the formulation to a patient over time.
  • administration includes acute and immediate administration such as inhalation or injection.
  • a disclosed aqueous pharmaceutical composition may be administered, e.g., subcutaneously, at a rate of from 0.01 ml/hour/site to 0.4 ml/hour/site, e.g., from 0.08 ml/hour/site to 0.24 ml/hour/site.
  • Such rates may be constant throughout the day and night or varied according to patient’s need, e.g., may reflect a patient resting or sleeping schedule and waking or higher activity level schedule.
  • a contemplated method may comprise administration of a disclosed pharmaceutical composition at a rate of, for example, 0.32 ml/hour/site in the morning (e.g., for 2-4 hours before waking), 0.24 ml/hour/site during the daytime or activity time (e.g., for 10 to 12 hours), and/or 0.08 ml/hour/site at rest or at night.
  • subcutaneous administration may be effected at a rate of 1.25 ml/hour during the daytime or activity time (e.g., for 2-3 hours before or after waking and for 10 to 14 hours thereafter), and 0 to 0.05 ml/hour (e.g., 0.05+0.005 ml/hour) at rest or night.
  • a contemplated method may comprise intraduodenal administration of a disclosed composition, at a rate of, for example, 1.0 ml/hour during the daytime or activity time (e.g., for 2-3 hours before waking and for 10 to 12 hours thereafter), and from 0.0 to 0.5 ml/hour at rest or at night.
  • a subject in need thereof is being treated with at least two separate formulations, i.e., at least two dosage unit forms, for example, a first formulation comprising, e.g., a levodopa amide compound and/or a pharmaceutically acceptable salt thereof, and an acid, and a second formulation comprising, for example, a decarboxylase inhibitor, e.g., carbidopa, a prodrug thereof and/or a pharmaceutically acceptable salt thereof.
  • the at least two dosage unit forms may be administered simultaneously, or sequentially at a predetermined time interval.
  • Two or more dosage unit forms may be administered to a subject by the same route of administration or, alternatively, by different routes of administration.
  • a first dosage form e.g., a LDA derivative formulation
  • a second unit dosage form e.g., a carbidopa formulation
  • a particular dosage form may be administered by two or more different routes, for example, both subcutaneously and orally either simultaneously of subsequently.
  • a first composition may be administered parenterally, intravenously, subcutaneously, intraduodenally, rectally, intrathecally, sublingually, intradermally, intranasally, or intramuscularly; and a second composition may be administered parenterally, intravenously, subcutaneously, transdermally, rectally, intrathecally, sublingually, intradermally, intranasally, intramuscularly, or orally.
  • Two or more dosage unit forms may be administered to a subject at the same rate, or at different rates.
  • administration e.g., subcutaneous administration, of a first formulation containing one or more LDA derivatives and an acid, in accordance with a contemplated method, may be effected at a rate of 0.1 to 1000 m ⁇ /hour/site; or at a volume of from about 2 to about 10 ml/24 hour/site, for example, from about 4 to about 6 ml/24 hour/site; or at a dose of from about 80 to about 800 mg LDA/day, and a second formulation containing e.g., carbidopa (a prodrug thereof or a pharmaceutically acceptable salt thereof), may be administered at a dose of from about 20 to 200 mg carbidopa/day; or the first formulation may be administered at a rate of from about 240 to about 360 mg LDA derivative, and the second formulation may be administered at a rate of from about 60 to about 90 mg carbidopa/day
  • the LDA derivative being administered in accordance with a contemplated method is the levodopa amide free base compound.
  • composition may be substantially continuously administered, e.g., using a pump for subcutaneous infusion at an average rate of 10-1000 m ⁇ /hour (e.g., 10-250 pl/hour), 300 ⁇ 100 m ⁇ /hour, or 200 ⁇ 40 m ⁇ /hour continuously for 24 hours; 440 ⁇ 200 m ⁇ /hour or 200 ⁇ 50 m ⁇ /hour continuously for 16 hours (during waking hours) and from 0 to about 80 m ⁇ /hour or 0 to 200 m ⁇ /hour for 8 hours (at night); or using a transdermal patch.
  • substantially continuously administering a disclosed composition to a patient can be doubled or tripled by using more than one pump, patch, or infusion site.
  • substantially continuously administering using, e.g., a liquid composition can be at an average rate of 0.2-2 m ⁇ /hour, or 1 ⁇ 0.5 m ⁇ /hour continuously for 24 hours; 1 ⁇ 0.5 m ⁇ /hour continuously for 16 hours (during waking hours) and from 0 to about 0.5 m ⁇ /hour for 8 hours (at night), via a pump, transdermal patch, or a combination of delivery devices that are suitable for, e.g., subcutaneous, intravenous, intrathecal, and/or intraduodenal administration.
  • kits comprising a pharmaceutical composition as defined in any of the embodiments described herein and, optionally, instructions and means for administration of the pharmaceutical composition to subject in need thereof.
  • the kit comprises a formulation comprising one or more LDA derivatives as defined herein, and an acid selected from a monovalent, divalent and/or trivalent acid, wherein the molar ratios of the one or more LDA derivatives and the acid are as defined herein.
  • the kit comprises a first pharmaceutical composition comprising one or more LDA derivatives or salts thereof, and an acid selected from a monovalent, divalent and/or trivalent acid, wherein the molar ratios of the LDA derivative(s) and the acid are as defined herein; (ii) a second pharmaceutical composition comprising one or more decarboxylase inhibitors or salts thereof; (iii) optionally, one or more of a basic amino acid, an amino sugar, a catechol-O-methyl transferase (COMT) inhibitor, or a monoamine oxidase (MAO) inhibitor; and (iv) optionally, instructions for co-administration of the pharmaceutical compositions.
  • a first pharmaceutical composition comprising one or more LDA derivatives or salts thereof, and an acid selected from a monovalent, divalent and/or trivalent acid, wherein the molar ratios of the LDA derivative(s) and the acid are as defined herein; (ii) a second pharmaceutical composition comprising one or more decarboxylase inhibitors or
  • a contemplated kit is useful for treatment of a disease or disorder characterized by neurodegeneration and/or reduced levels of brain dopamine, for example Parkinson’s disease.
  • Example 1 Compositions comprising levodopa amide and a monovalent acid
  • LDA FB Levodopa amide free base
  • the counter ion can be an acid which may be organic or inorganic acid.
  • compositions comprising LDA FB at various concentrations and an organic or inorganic monovalent acid were prepared using the minimal amount of acid required to obtain complete dissolution of LDA FB.
  • compositions comprising HCl as the monovalent acid.
  • compositions comprising LDA FB and the monovalent acid HCl
  • compositions comprising ascorbic acid as the monovalent acid.
  • compositions comprising methanesulfonic acid as the monovalent acid.
  • Vials with suspensions of 5%, 10% and 20% (w/w) LDA FB in water were prepared as described in (i) above. Then, methanesulfonic acid was added to the vials so as to obtain molar ratios LDA FB: methanesulfonic acid of 1.00:0.20, 1.00:0.50, 1.00:0.75, 1.00:0.80, 1.00:0.85 and 1.00:0.89. No heating was applied, and pH was measured only in the clear solutions. The resulting appearances of the LDA FB solutions are depicted in Table 4.
  • Example 2 Compositions comprising LDA FB and a divalent acid
  • a divalent acid is expected to be as twice effective in dissolving levodopa amide free base as a monovalent acid, namely, the expected molar ratio of LDA FB:divalent acid is 1.0:0.5.
  • Compositions comprising LDA FB at various concentrations and an organic or inorganic divalent acid were prepared using the minimal amount of acid required to obtain complete dissolution of LDA FB.
  • compositions comprising tartaric acid as the divalent acid.
  • Vials with suspensions of 5%, 10% and 20% (w/w) LDA FB in water were prepared as described in Example l(i) above. Then, tartaric acid (in its solid form) was added to the vials until clear solutions were obtained. No heating was applied, and pH was measured only in the clear solutions. The resulting appearances of the LDA FB solutions are depicted in Table 5.
  • compositions comprising glutamic acid as the divalent acid.
  • Glutamic acid is an amino acid which has two carboxyl groups and is expected to act as a divalent acid that would dissolve LDA derivatives, particularly LDA FB, in a molar ratio LDA:glutamic acid of 1.0:0.5.
  • Vials with suspensions of 20% (w/w) LDA FB in water were prepared as described in Example l(i) above. Then, glutamic acid (in its solid form) was added to the vials until clear solutions were obtained. No heating was applied, and pH was measured only in the clear solutions. The appearances of the resulting LDA FB solutions are depicted in Table 6.
  • compositions with molar ratio acid/LDA ⁇ 1.0 were stable for at least 24 hours.
  • Vials with suspensions of 5%, 10% and 20% (w/w) LDA FB in water were prepared as described in Example l(i) above. Then, liquid sulfuric acid was added to the vials. No heating was applied, and pH was measured only in the clear solutions. The resulting LDA FB solutions are depicted in Table 7. Table 7. Compositions with IT) A FB and sulfuric acid
  • compositions with molar ratio acid/LDA FB > 0.40 were stable for at least 24 hours.
  • Example 3 Compositions comprising LDA FB and a trivalent acid
  • a trivalent acid is expected to be three times as effective in dissolving levodopa amide free base in comparison to a monovalent acid, namely, the expected molar ratio of LDA FB: trivalent acid is 1.00:0.33.
  • Compositions comprising LDA FB at various concentrations and the organic trivalent citric acid were prepared using the minimal amount of acid required to obtain complete dissolution of LDA FB.
  • compositions comprising citric acid as the trivalent acid.
  • Vials with suspensions of 5%, 10%, 20%, 30% and 35% (w/w) LDA FB in water were prepared as described in Example l(i) above. Then, citric acid (in its solid form) was added to the vials until clear solutions were obtained. No heating was applied, and pH was measured in clear solutions only. The resulting appearances of the LDA FB solutions are depicted in Table 8. Table 8. Compositions with LDA LDA FB and citric acid
  • molar ratio LDA FB:citric acid was 1.0:0.3 for low LDA FB concentration of 5% (w/w) as well as for higher concentration of 10% and 20% LDA FB. This molar ratio was lower than the expected molar ration of 0.33.
  • increasing LDA FB concentration to 30% and 35% (w/w) necessitated higher concentrations of citric acid and, moreover, higher LDA FB:citric acid molar ratios in order to completely dissolve LDA FB and converting the free base into its citrate salt.
  • Compositions with up to 20% LDA FB and molar ratio citric acid/LDA FB of 0.30 were stable for at least 24 hours.
  • Vials with suspensions of 5%, 10%, 20% and 30% (w/w) LDA FB in water were prepared as described in Example l(i) above. Then, predetermined amounts of liquid ortho phosphoric acid (85%) were added to the vials until clear solutions were obtained. No heating was applied, and pH was measured in clear solutions only. The resulting LDA FB solutions are depicted in Table 9.
  • compositions with molar ratio phosphoric acid/LDA FB > 0.45 were stable for at least 24 hours.
  • Example 4 Formulations comprising levodopa amide free base, HC1, ascorbic acid and N-acetyl cysteine (NAC)
  • Formulations with increasing concentrations of LDA FB and HC1 as the counter ion were prepared, further comprising ascorbic acid and N-acetyl cysteine (NAC) as antioxidants.
  • Tween® 80 solution was added to the compositions while purging with N2.
  • the preparations were stirred continuously for -15 minutes, and then transferred into volumetric flasks and completed to volume (100 ml) with water.
  • the pH was set to be in the range of 6.4-7.0.
  • Example 5 Compositions with levodopa amide free base, a monovalent acid and an organic co-solvent
  • Example 6 Compositions comprising levodopa amide free base, various acids and carbidopa
  • Formulations with carbidopa (CD; MW 226.2), FB and HC1 as the counter-ion were prepared.
  • Ascorbic acid and N-acetyl cysteine (NAC) were added as antioxidants.
  • arginine was added in order to solubilize the acidic CD.
  • Pre -prepared Tween® 80 solution was added to the formulations while purging with N2. The preparations were stirred continuously for -15 minutes, and then transferred into volumetric flasks and completed to volume (100 ml) with water. The pH was set to be in the range of 6.4-7.0.

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Abstract

L'invention concerne des formulations comprenant un dérivé d'amide de lévodopa et un acide monovalent, divalent et/ou trivalent, qui sont stables pendant au moins 24 heures à température ambiante.
PCT/IL2020/050202 2019-03-04 2020-02-24 Compositions pharmaceutiques comprenant des dérivés d'amide de lévodopa et leurs utilisations Ceased WO2020178810A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115494231A (zh) * 2022-09-02 2022-12-20 武汉三鹰生物技术有限公司 一种蛋白酶抑制剂混合物及其制备方法与应用
EP4305049A4 (fr) * 2021-03-10 2025-09-10 Neuroderm Ltd Compositions liquides stabilisées comprenant un conjugué de lévodopa-tyrosine et leurs utilisations

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015136538A1 (fr) * 2014-03-13 2015-09-17 Neuroderm Ltd Compositions d'inhibiteurs de dopa-décarboxylase
US20160106765A1 (en) * 2014-10-21 2016-04-21 Abbvie Inc. Carbidopa and L-Dopa Prodrugs and Methods of Use
WO2017090039A2 (fr) * 2015-11-24 2017-06-01 Neuroderm Ltd. Compositions pharmaceutiques comprenant un amide de lévodopa et ses utilisations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015136538A1 (fr) * 2014-03-13 2015-09-17 Neuroderm Ltd Compositions d'inhibiteurs de dopa-décarboxylase
US20160106765A1 (en) * 2014-10-21 2016-04-21 Abbvie Inc. Carbidopa and L-Dopa Prodrugs and Methods of Use
WO2017090039A2 (fr) * 2015-11-24 2017-06-01 Neuroderm Ltd. Compositions pharmaceutiques comprenant un amide de lévodopa et ses utilisations

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4305049A4 (fr) * 2021-03-10 2025-09-10 Neuroderm Ltd Compositions liquides stabilisées comprenant un conjugué de lévodopa-tyrosine et leurs utilisations
CN115494231A (zh) * 2022-09-02 2022-12-20 武汉三鹰生物技术有限公司 一种蛋白酶抑制剂混合物及其制备方法与应用

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