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WO2020035853A1 - Procédé de préparation de base libre de lévodopamide purifiée - Google Patents

Procédé de préparation de base libre de lévodopamide purifiée Download PDF

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Publication number
WO2020035853A1
WO2020035853A1 PCT/IL2019/050888 IL2019050888W WO2020035853A1 WO 2020035853 A1 WO2020035853 A1 WO 2020035853A1 IL 2019050888 W IL2019050888 W IL 2019050888W WO 2020035853 A1 WO2020035853 A1 WO 2020035853A1
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WIPO (PCT)
Prior art keywords
dopamide
free base
salt
dopa
purified
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PCT/IL2019/050888
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English (en)
Inventor
Ronit Shaltiel-Karyo
Gil Mor
Alex Mainfeld
Elana Gazal
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Neuroderm Ltd
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Neuroderm Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates, in part, to processes of making L-dopamide free base, particularly but not exclusively, to processes for obtaining pharmaceutically acceptable L-dopamide free base.
  • Parkinson's disease is a degenerative condition characterized by reduced concentration of the neurotransmitter dopamine in the brain.
  • Levodopa L-dopa (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.
  • L-dopa The metabolic transformation of L-dopa to dopamine is catalyzed by the aromatic L-amino acid decarboxylase enzyme, a ubiquitous enzyme with particularly high concentrations in the intestinal mucosa, liver, brain, and brain capillaries. Due to the possibility of extracerebral metabolism of L-dopa, it is necessary to administer large doses of L-dopa leading to high extracerebral concentrations of dopamine that cause nausea in some patients (dopamine does not penetrate the blood brain barrier).
  • L-dopa is usually administered concurrently with oral administration of a L-dopa decarboxylase inhibitor, such as carbidopa or benserazide, which reduces by 60-80% the L-dopa dose required for a clinical response and, respectively, some of the side effects related, e.g., to conversion of levodopa to dopamine outside the brain, although not sufficiently.
  • a L-dopa decarboxylase inhibitor such as carbidopa or benserazide
  • Levodopa derivatives for example certain levodopa amide derivatives and ester derivatives are generally known in the art as prodrugs of levodopa. Derivatization of LD, e.g., amidation or esterification is used as a means to improve water solubility and/or stability of the drug.
  • LDA levodopa amide 2-amino-3-(3,4-dihydroxyphenyl) propanamide
  • LDA levodopa amide 2-amino-3-(3,4-dihydroxyphenyl) propanamide
  • Amides are known as much more stable molecules than esters and salts, and the hydrolysis rate of amides by amido peptidases is significantly reduced compared to the corresponding hydrolysis of ester or salts. Efficient processes for preparing pure L-dopamide and pharmaceutically acceptable salts thereof are desirable for providing Parkinson’s disease patients with more effective treatments.
  • the present disclosure provides, in part, a process of making (e.g., large-scale production) a purified pharmaceutically acceptable L-dopamide free base substantially free of L-dopa.
  • the processes of the present disclosure may not require, for example, intermediate steps of making crude and/or pure L-dopamide salt to remove L-dopa and/or a L-dopa salt from a pharmaceutically acceptable L-dopamide free base product.
  • the pure L-dopamide free base obtained by the disclosed process is useful for the preparation of drug substances and pharmaceutical compositions. This purified product may be, for example, in its crystalline form.
  • the present disclosure provides, in part, processes of producing, for example, large scale production, of a L-dopamide pharmaceutically acceptable free base.
  • the product obtained by the disclosed processes is, for example, a substantially purified pharmaceutically acceptable L-dopamide free base, optionally in its crystalline form.
  • L- dopamide free base LDA FB
  • LDA FB L- dopamide free base
  • Levodopa methyl ester (LD-OMe), and purified by precipitation (e.g., one or two subsequent precipitations) from a slightly basic solution.
  • the process provided herein circumvents the need to convert crude LDA FB to a crude L-dopamide salt followed by purifying the crude L-dopamide salt product by precipitation (e.g., one or two subsequent precipitations) from an acidic solution, and then neutralizing the purified L-dopamide salt so as to obtain pure LDA FB.
  • the disclosed process is substantially shorter than known process for making pure LDA FB and affords large-scale production of pharmaceutically acceptable L-dopamide free base.
  • L-dopamide is used herein interchangeably with the terms“LDA”,“L- dopamide free base”,“LDA free base” or, simply,“LDA FB”, all of which terms refer to the chemical compound, L-2-amino-3-(3,4-dihydroxyphenyl)propanamide, represented by:
  • Salts of L-dopamide for example, pharmaceutically acceptable salts or pharmaceutical salts are collectively and interchangeably referred to herein as“L-dopamide pharmaceutically acceptable salts”,“pharmaceutically acceptable L-dopa salts”,“LDA pharmaceutically acceptable salts”, pharmaceutically acceptable LDA salt or, simply,“LDA salts”.
  • Particular examples include, LDA HC1 salt, LDA lactate salt, LDA phosphate salt, LDA acetate salt, and the like.
  • L-dopamide is derived from levodopa, also interchangeably referred to herein as “L-dopa” or“LD”, or from a levodopa salt (LD salt).
  • LDA free base is useful as a prodrug of L-dopa.
  • L-dopa is represented by the formula:
  • L-dopa ester salt e.g., a hydrochloride salt
  • L-dopaester is represented by: wherein R is selected from a lower alkyl, lower alkenyl, lower alkynyl, aryl or heteroaryl;
  • the alcohol, R-OH, with which LD is reacted in step (a) of the disclosed process may be, for example, an alcohol of a lower alkyl, namely a straight or branched chain of 1 to 6 carbon atoms (herein“(Ci-C 6 )alkyl”); or an alcohol of a lower alkenyl or a lower alkynyl, namely a straight or branched chain of 2 to 6 carbon atoms having at least one carbon-carbon double bond or at least one carbon-carbon triple bond, respectively (herein“(C2-C6)alkenyl” and“(C2-C6)alkynyl”, respectively).
  • R-OH may be an alcohol of a saturated or partially saturated cyclic moiety of 3 to 6 carbon atoms.
  • R may be cyclopropyl, cyclobutyl, cyclohexyl, cyclobutenyl, cyclohexenyl and the like.
  • R may also be a cyclic non-saturated (i.e., aromatic moiety of 5-6 carbons (herein “aryl”) such as phenyl.
  • R may be a heterocyclic moiety of 5-6 carbons and at least one heteroatom such as N, S, O or P (herein“heteroaryl”).
  • heteroaryl any of the cyclic moieties, whether saturated, partially saturated or aromatic may be substituted by at least one substituent.
  • the alcohol R-OH may be an alcohol of a lower alkyl selected from methyl, ethyl, propyl (e.g., isopropyl), butyl (e.g., n-buthyl, ie/t-butyl, sec-buthyl), heptyl or hexyl.
  • a lower alkyl selected from methyl, ethyl, propyl (e.g., isopropyl), butyl (e.g., n-buthyl, ie/t-butyl, sec-buthyl), heptyl or hexyl.
  • the alcohol is methanol
  • the L-dopa ester obtained is LD methyl ester (LD-OMe).
  • Chlorination refers to replacement, in molecules bearing functional groups, such as alcohols, carboxylic acids, of an OH group with Cl by the use of a chlorination reagent, to thereby obtain the corresponding chlorides.
  • Carboxylic acid chlorides also termed acyl chlorides
  • Non- limiting examples of chlorination reagents useful for a process described herein include thionyl chloride (SOCl 2 ), oxalyl chloride (C2O2CI2), phosphoryl chloride (POCI3), phosphorus trichloride (PCI3), phosphorus pentachloride (PCI5), sulfuryl chloride (SO2CI2) and other chlorinating reagents commonly known in the art for chlorination.
  • the chlorinating reagent is thionyl chloride.
  • the acidic composition brought to contact with crude LDA FB in step (c) of the disclosed process comprises at least one antioxidant, namely, a substance which slows down or prevents the damage that can be caused to other substances by the effects of oxygen (i.e., oxidation).
  • antioxidants a substance which slows down or prevents the damage that can be caused to other substances by the effects of oxygen (i.e., oxidation).
  • the use of antioxidants in a contemplated process is based on the discovery that antioxidants prevent the oxidation of LDA FB which may cause the change in color of the pure product, e.g., into a brownish colored powder and/or a solution thereof.
  • Non-limiting examples of antioxidants include ascorbic acid (vitamin C) or a salt thereof (e.g., sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbyl palmitate, and ascorbyl stearate); cysteine or a cysteine derivative such as L-cysteine, N-acetyl cysteine (NAC), glutathione, a 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); butylate hydroxytoluene (BTH), butylated hydroxyanisole (BHA) and ubiquinol (coenzyme Q).
  • vitamin C ascorbic acid
  • a salt thereof e.g., sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbyl palmitate, and ascorbyl stearate
  • an acidic composition used in a disclosed process can include one, two, or more antioxidants such as ascorbic acid or a salt thereof, for example, sodium ascorbate, and cysteine or a cysteine derivative, for example, L-cysteine, NAC, glutathione, or a salt thereof.
  • antioxidants such as ascorbic acid or a salt thereof, for example, sodium ascorbate, and cysteine or a cysteine derivative, for example, L-cysteine, NAC, glutathione, or a salt thereof.
  • the amount of one antioxidant in the acidic composition may be in the range of from 0.01% to 2.5% by weight of total composition. For example, form about 0.01% to about 0.10%, from about 0.05% to about 0.10%, from about 0.10% to about 0.5%, from about 0.10% to about 0.30%, from about 0.20% to about 0.70%, from about 0.50% to about 1.00%, from about 0.90% to about 1.50%, from about 1.50% to about 2.00 or from about 1.90% to about 2.5%, by weight.
  • an acidic composition comprises about 0.2%, about 0.5% or about 1.0% of an antioxidant.
  • an acidic composition utilized in step (c) comprises NAC and L-ascorbic acid, each in the amount of 0.5% by weight of total composition.
  • step (b) of a disclosed process is aqueous ammonium hydroxide, for example, 25% ammonium hydroxide in water.
  • the ammonia is step (b) is ammonia in an organic solvent such as, but not limited to, methanol, tetrahydrofuran (THF), CH2CI2 and the like.
  • the crude, solid LDA FB is contacted and dissolved in aqueous composition comprising NAC and ascorbic acid, and an acid, preferably HC1, is added so as to obtain an acidic solution.
  • This acidic solution comprises LDA free base, LDA salts, for example, LDA HC1 salt, as well as small amounts of salts that may form by LDA and an acidic antioxidant, for example, LDA ascorbate and LDA acetyl cysteinic acid salt.
  • the acidic solution may further comprise L-dopa and L-dopa salt, for example, LD HC1 salt, LD ascorbate salt and/or LD acetyl cysteinic acid salt.
  • step (c) of a contemplated process is further demonstrated by performing the process in an oxygen free environment. Such conditions may be effected, for example, by keeping the reaction mixture constantly in a N2
  • the reaction vessel may be evacuated from time to time, for example after addition of a new reagent to the reaction mixture, and then the vacuum is release by purging gaseous N2 or Argon into the reaction vessel.
  • the reaction flask containing the acidic solution, in step (c) is evacuated to ⁇ 75 mBar and vacuum is than released with nitrogen.
  • This evacuation/N2 release process may repeat several times, for example 3, 4, 6 or 8 times during purification of LDA FB, and before the acid solution is mixed or contacted with the base solution.
  • the pH of the acidic solution is between about 1.3 and about 4.3. In exemplary embodiments, the pH is about 4.0 at 25°C.
  • the base composition with which the acidic solution is mixed in step (d) of a contemplated process may comprise one or more bases such as hydroxide bases (namely, substances that, in aqueous solution, release hydroxide (OH ) ions).
  • bases such as hydroxide bases
  • hydroxide bases include hydroxides of the alkali metals and the alkaline earth metals such as, but not limited to, sodium hydroxide (NaOH), potassium hydroxide (KOH), magnesium hydroxide (Mg(OH) 2 ), and calcium hydroxide (Ca(OH) 2 , or an organic molecules such as ammonium hydroxide (NH 4 OH).
  • the basic composition comprises the hydroxide base sodium hydroxide.
  • the pH of the basic solution may between about 8.0 to about 9.0.
  • the pH of the basic solution may between about 8.0 to about 9.0.
  • the pH of the basic solution is between about 8.20 to about 8.40.
  • about 8.20, about 8.25, about 8.30, about 8.35, or about 8.40 is between about 8.20 to about 8.40.
  • Embodiments described herein concern processes for making or producing LDA FB, optionally in its crystalline form, and processes for purification of crude LDA FB.
  • the LDA FB obtained by disclosed production and purification processes is a substantially pure product, for example, a substantially pure crystalline product.
  • the process does not include purification by
  • A“pure product”, as referred to herein, is a chemical entity or species produced or formed, e.g., in a chemical process or reaction, comprising, besides molecules of the principle compound, further amounts of molecules or atoms of various origins or types collectively termed herein“impurities”.
  • impurities include, for example, residual solvent molecules, degradation products, residual amounts of crystallization reagents, starting materials, optical isomers, salt forms, metal atoms, and polymorphs.
  • Voids in a crystalline product are also referred to herein as impurities.
  • Impurities can be incorporated into solid products, for example, crystals, in a number of ways. For example, surface impurities are left when residual mother liquor on the surface of the solid product evaporates, leaving behind any dissolved impurities. Inclusions of mother liquor may be formed in crystals, especially at high growth rates.
  • a pure product in the context of some embodiments described herein, is a chemical product obtained by any of the processes contemplated herein, for example, LDA free base also referred to herein as“active pharmaceutical ingredient” or“API”, produced or made by a disclosed process, for example, purification process, which contains, besides the principle API molecules, small amounts of impurities as defined herein, particularly, but not exclusively, remains of LDA salts, L-dopa and/or L-dopa salt, reaction solvent, anion and/or cations e.g., of salts or buffers used in the purification process.
  • a“small amount” of impurities is defined as a total amount of impurities which is less than 10% of total content or total composition of the product.
  • a pure product according to embodiments described herein is LDA, for example, crystalline LDA FB, containing less than 10% impurities as defined herein.
  • the amount of impurities in a product obtained from a contemplated purification process and/or production process may be less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 0.5% of total product.
  • a pure product obtained by a contemplated process may comprise residual amounts of L-dopa and/or a salt thereof in total amounts of from about from about 3% to about 5%, from about 5% to about 10%, or from about 8% to about 10%, of total product, and any ranges, subranges or individual values therebetween.
  • a pure pharmaceutically acceptable LDA free base may contain less than 10%, less than 8%, less than 5%, or less than 3%, by weight of LD or a LD salt.
  • A“substantially pure product”, as referred to herein, is a chemical product as defined herein comprising, besides molecules of API, trace amounts of impurities as defined herein.
  • A“trace amount”, as referred to herein, is a very small, a tiny or even scarcely detectable amount.
  • Impurities, including trace amounts of impurities are usually detected and optionally cleared using means known in the art, such as, but not limited to, chromatography techniques such as high-pressure liquid chromatography (HPLC), or gas chromatography (GC). Purity of a product may be further assessed using means such as nuclear magnetic resonance (NMR), infrared (IR) spectroscopy, mass spectroscopy (MS) and the like.
  • NMR nuclear magnetic resonance
  • IR infrared
  • MS mass spectroscopy
  • a substantially pure LDA FB in accordance with embodiments described herein, will typically contain trace amounts of impurities in a total amount which is less than 5.0% of total composition of the product.
  • the amount of impurities may be less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1.0%, less than 0.5%, less than 0.1%, less than 0.05%, or less than 0.01%, of total product.
  • a contemplated substantially pure LDA FB may comprise, for example, between 0.00% to about 0.03%, between 0.00% to about 0.01%, between about 0.01% to about 0.05%, between about 0.01% to about 1.00%, between about 0.05% to about 1.00%, between about 0.1% to about 1.0%, between about 0.03% to about 0.08%, between about 1.2% to about 2.0%, between about 2.0% to about 5.0%, or between about 3.5% to about 5.0%, by weight of impurities.
  • a substantially pure product is essentially devoid or free of any impurities.
  • a disclosed substantially pure LDA free base may have less than about 1.0%, less than about 0.5%, less than about 0.03% or less than about 0.01% levodopa and/or levodopa salt, assessed by, for example, by HPLC or any other known means.
  • Substantially pure LDA FB obtained by a contemplated process is also referred to herein as“pharmaceutically acceptable L-dopamide free base substantially free of L-dopa or a salt thereof’ or“LDA free base substantially free of L-dopa and/or L-dopa salt”.
  • the purity of a pharmaceutically acceptable pharmaceutical acceptable LDA free base may be above 80%. For example, above 87%, above 88%, above 90%, above 92%, above 94%, above 95%, above 96%, above 97%, above 98%, above 99%, or higher.
  • the purity of the purified LDA free base is above 98% or is above 99% by HPLC.
  • the term“by HPLC” as used herein refers to identification and quantification of a product (e.g., LDA free base or LDA salt) by HPLC.
  • the process reduces the content of LD and/or LD salt in the purified pharmaceutically acceptable LDA free base, such that the content of LD and/or LD salt in the purified LDA salt is less than about 0.5% by HPLC, for example, less than about 0.3% by HPLC.
  • Activated carbon also called activated charcoal, is charcoal that has been treated with oxygen to open up millions of tiny pores between the carbon atoms.
  • a contemplated process employs a carbon filtering method that uses a bed of activated carbon to remove contaminants and impurities. Each particle/granule of carbon provides a large surface area/pore structure, allowing contaminants the maximum possible exposure to the active sites within the filter media.
  • Activated carbon works via a process called adsorption, whereby pollutant molecules in the fluid to be treated are trapped inside the pore structure of the carbon substrate.
  • Active charcoal carbon filters are most effective at removing chlorine, sediments, and volatile organic compounds (VOCs).
  • Activated carbon is particularly useful is large-scale processes as described herein to purify reaction solutions containing unwanted impurities. The carbon may either be mixed with the solution then filtered off or immobilized in a filter.
  • the process provides at least about 1.0 gr of LDA FB, for example, purified pharmaceutically acceptable LDA free base, for example, in one batch.
  • a contemplated process provides at least about 10 gr, at least about 50 gr, at least about 100 gr, at least about 500 gr, at least 1 kg, at least 5 kg.
  • the amount of purified product obtained by a disclosed process may be between about 1.0 gr to about 50 gr, between about 50 gr to about 500 gr, between about 500 gr to about 1000 gr, between 800 gr to about 1500 gr, between 100 gr to about 2000 gr, between 1500 gr to about 3000 gr, between 2500 gr to about 4000 gr, or between 4000 gr to about 10 kg.
  • the amount of purified LDA FB in one batch may be in a range of from about 250 gr to about 550 gr, from about 500 gr to about 800 gr, from about 600 gr to about 900 gr, from about 750 gr to about 1000 gr, from about 850 gr to about 1200 gr, from about 1000 gr to about 1500 gr, from about 1200 gr to about 1700 gr, from about 1500 gr to about 2000 gr, from about 1800 gr to about 2300 gr, from about 2000 gr to about 2500 gr, from about 2200 gr to about 2600 gr, from about 2500 gr to about 3000 gr, from about 3000 gr to about 3700 gr, from about 3500 gr to about 4000 gr, from about 3800 gr to about 4500 gr, or from about 4000 gr to about 8000 gr, and even more, of LDA free base in one batch.
  • the present disclosure in an aspect thereof, provides a pure LDA free base, and substantially pure LDA free base, prepared or obtained by a process provided herein.
  • a pure product may be pharmaceutically acceptable and may form a drug substance.
  • compositions comprising it that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate.
  • preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.
  • drug substance is any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product, and that, when used in the production of a drug, becomes an active ingredient of the drug product, i.e., the active pharmaceutical ingredient (API).
  • active pharmaceutical ingredient Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or function of the body.
  • the drug substance depending on its purity, is mostly composed of the API or the‘naked’ drug without excipients.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable LDA free base obtained by a contemplated process described herein, and a pharmaceutically acceptable excipient.
  • the composition is a formulation for pharmaceutical administration and comprises a pharmaceutically acceptable carrier.
  • pharmaceutical composition refers to a formulation designed for medicinal utilization such as, but not limited to, therapeutic or diagnostic utilization.
  • “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.
  • a formulation may include one or more drug substances or active ingredients (APIs) 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-solid (e.g. gel, wax) or gas components.
  • the APIs are 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, tablets, linctus, ointment, infusion or injection.
  • a pharmaceutical composition is sometimes also referred to herein as “medicinal formulation”.
  • compositions for example aqueous formulations.
  • a contemplated pharmaceutical composition e.g., formulation
  • a suspension is a contemplated pharmaceutical composition.
  • active agent “active ingredient” and“active pharmaceutical ingredient (API)” as used herein are interchangeable, all of which refer to a compound, which is accountable for a desired biological or chemical effect.
  • the active agent may be one or more of LDA free base as defined herein, for example, a pure pharmaceutically acceptable LDA free base obtained by a contemplated process.
  • 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
  • Contemplated pharmaceutical compositions may include from 1% to about 25%, or more of a disclosed LDA free base obtained by a disclosed process.
  • a disclosed formulation may comprise, pure or substantially pure pharmaceutically acceptable LDA free base in amounts ranging 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, subranges 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 disclosed pharmaceutically acceptable LDA free base, obtained in their crystalline form.
  • a contemplated pharmaceutical composition may, optionally, further comprise one or more physiologically acceptable excipients and/or a physiologically acceptable carrier.
  • 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
  • compositions that are compatible with pharmaceutical administration.
  • Pharmaceutically acceptable excipients also encompass pharmaceutically acceptable carriers, namely, approved carriers or diluents that do not cause significant irritation to an organism and do 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. The use of such media and agents in combination with pharmaceutically active agents is well known in the art.
  • Excipients suitable for formulations described herein may comprise, for example, an enhancer (e.g., pyrrolidones, polyols, terpenes and the like) and/or a gelation agent (e.g., cellulose polymers, carbomer polymers and derivatives thereof), and/or a thickening agent (e.g., polysaccharides (agarose), polyacrylic polymers).
  • an enhancer e.g., pyrrolidones, polyols, terpenes and the like
  • a gelation agent e.g., cellulose polymers, carbomer polymers and derivatives thereof
  • a thickening agent e.g., polysaccharides (agarose), polyacrylic polymers.
  • Contemplated formulations described herein are useful in the treatment of diseases or disorders characterized by neurodegeneration and/or reduced levels of brain dopamine, for example, Parkinson’s disease.
  • 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 that may be useful in treating diseases or disorders characterized by neurodegeneration and/or reduced levels of brain dopamine include a decarboxylase inhibitor such as carbidopa, a carbidopa prodrug and/or a
  • pharmaceutically acceptable salt thereof e.g., the arginine-, histidine-, or lysine-salt of carbidopa; benserazide, a prodrug thereof or a pharmaceutically acceptable salt thereof; a catechol-O-methyl transferase (COMT) inhibitor; or a monoamine oxidase (MAO) (either MAO-A or MAO-B) inhibitor.
  • Particular COMT inhibitors include, without limiting, entacapone, tolcapone and opicapone; and particular MAO inhibitors can be selected from, e.g., moclobemide, rasagiline, selegiline, or safinamide.
  • adamantans e.g., amantadine
  • nicotinic receptor agonists e.g., nicotine, galantamine
  • dopamine receptor agonists e.g., apomorphine, rotigotine
  • a contemplated medicinal formulation comprises a pure pharmaceutically acceptable LDA free base and, e.g., a decarboxylase inhibitor (for example, carbidopa or a prodrug thereof), these main and secondary active ingredients, respectively, can be combined and formulated in the same formulation, namely, as a single unit dosage from or,
  • a plurality of dosage unit forms for example, two or more dosage unit forms, each comprising one or more of a first active agent, and/or a second active agent.
  • a disclosed pharmaceutical composition may often comprise one or more antioxidants, which can slow down the damage caused by oxidation.
  • Antioxidants are exemplified by 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, a 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 ste
  • antioxidants are exemplified by phenolic antioxidants such as di-tert-butyl methyl phenols, tert-butyl-methoxyphenols, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), polyphenols, tocopherols, ubiquinones (e.g., caffeic acid, tert- butylhydroquinone (TBHQ)), propyl gallate, flavonoid compounds, cinnamic acid
  • phenolic antioxidants such as di-tert-butyl methyl phenols, tert-butyl-methoxyphenols, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), polyphenols, tocopherols, ubiquinones (e.g., caffeic acid, tert- butylhydroquinone (TBHQ)), propyl gallate, flavonoid compounds, cinn
  • sulfite salts such as sodium hydrogen sulfite or sodium bisulfite (e.g. sodium metabisulfite).
  • a disclosed formulation can include one, two, or more antioxidants selected from 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, F-cysteine, NAC, glutathione, or a salt thereof.
  • 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, F-cysteine, NAC, glutathione, or a salt thereof.
  • the amount of one or more antioxidants in a contemplated formulation may be in the range of from about 0.01% to about 1% by weight. For example, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, or about 1.0%, by weight antioxidant.
  • Contemplated formulations may include 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
  • Contemplated formulations may contain 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 comprise a buffer.
  • buffers that may be used in accordance with described embodiments include, without limiting, 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.
  • a stable lyophilized powder comprising LDA FB obtained by any of the processes described herein.
  • Such a lyophilized powder can be reconstituted into a liquid formulation by addition of water with or without antioxidants, surfactants and other excipients.
  • 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.
  • these dosage unit forms can be formulated in different forms.
  • a first unit dosage form comprising, e.g. one or more pharmaceutical acceptable LDA FB
  • the second unit dosage form comprising, e.g., a decarboxylase inhibitor such as carbidopa, can be formulated as a solid formulation.
  • 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 administration.
  • the compositions may also be formulated for inhalation, or for direct absorption through mucous membrane tissues.
  • the pharmaceutical compositions disclosed are aqueous formulations particularly useful for subcutaneous administration e.g., via an infusion pump.
  • a contemplated formulation is designed for oral or buccal administration, 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 excipients selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • a contemplated formulation is designed for administration by inhalation and delivery, e.g., as an aerosol spray.
  • a contemplated formulation may be designed for rectal administration as suppositories or retention enemas.
  • 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.
  • contemplated formulations are designed for topical administration in the form of, for example limiting, lotions, suspensions, ointments gels, creams, drops, liquids, sprays emulsions and powders.
  • a contemplated formulation is designed for administration via a dermal patch suitable for transdermal or subcutaneous administration of an active agent.
  • a contemplated formulation is designed for parenteral administration, e.g., by bolus injection or continuous infusion.
  • Injectable formulations may be suspensions, solutions, e.g., aqueous solutions, or emulsions in oily or aqueous vehicles, and may contain excipients such as suspending, stabilizing, dispersing agents, substances which increase the viscosity of a suspension, and/or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient(s) may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • a pharmaceutical composition as disclosed herein is designed for a slow release of the pharmaceutically acceptable LDA free base, and therefore includes particles including the API and a slow release carrier (typically, a polymeric carrier). Slow release biodegradable carriers are well known in the art.
  • All compositions for any form of administration may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.
  • a contemplated composition or formulation comprising a disclosed API may be stable for at least 24 hours. For example, for at least 30 hours, at least 48 hours, at least 50 hours, at least 60 hours, at least 72 hours, at least 80 hours, at least 96 hours, at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 moth, at least 2 month, at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 1 year, at least 2 years and even more, at room temperature, 4 °C, or at -20 °C to -80 °C.
  • the pharmaceutical compositions can be administered over a defined time period, e.g., days, weeks, months, or years.
  • a contemplated pharmaceutical composition may have a“physiologically acceptable pH”, namely, a pH 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 l0°C to about 30°C. In exemplary embodiments, ambient temperature can be 25 °C.
  • a method of treatment of a subject inflicted with a neurological disease or disorder comprising
  • the neurological disease or disorder treatable 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, restless leg syndrome, Parkinson’s disease, secondary parkinsonism, Huntington’s disease, Parkinson’s like syndrome, progressive supranuclear palsy (PSP), Amyotrophic lateral sclerosis (ALS), Shy-Drager syndrome (also known as
  • MSA multiple system atrophy
  • AD Alzheimer’s disease
  • LBD Lewy body dementia
  • akinesia bradykinesia
  • hypokinesia conditions resulting from brain injury including carbon monoxide or manganese intoxication
  • conditions associated with a neurological a disorder including alcoholism, opiate addiction, and erectile dysfunction.
  • the neurological 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.
  • An effective amount or a therapeutically effective amount of a compound, i.e., an API, and/or a formulation comprising it is a quantity of API and/or formulation sufficient to achieve a desired effect in a subject being treated.
  • An effective amount of a compound or of a formulation comprising it can be administered in a single dose, or in several doses, for example daily, during a course of treatment.
  • the effective amount of the API will be dependent on the API applied, the subject being treated, the severity and type of the affliction, and the manner of administration of the compound.
  • the method comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable LDA free base obtained by any one of the processes described herein.
  • composition administered to a subject in need thereof may comprise from about 1% to about 25%, for example, form about 5% to about 20% of a pure pharmaceutically acceptable LDA free base obtained by the processes described herein.
  • administering as referred to herein is introduction of the API or a
  • 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
  • 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 the API and/or formulation comprising it into implantable devices or constructs, such as vascular stents or other reservoirs, which release the API over extended time intervals for sustained treatment effects.
  • Systemic administration includes any route of administration designed to distribute the API or a pharmaceutical composition or formulation comprising it widely throughout the body via the circulatory system.
  • systemic administration includes, but is not limited to, intra-arterial and intravenous administration, 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.
  • 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, e.g., a single 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.
  • a dosage e.g., a single dosage
  • a disclosed pharmaceutical composition may be administered, e.g., substantially continuously, at a rate of from 0.01 ml/hour/site to 0.6 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 subcutaneous or
  • intraduodenal administration of a disclosed pharmaceutical composition at a rate of, for example, 0.32 ml/hour/site or 1.0 ml/hour, respectively, 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 14 hours), and/or 0.08 ml/hour/site or 0.0 to 0.5 ml/hour, respectively, at rest or at night.
  • Substantially continuous administration can be achieved using a means such as transdermal patch or a pump device that continuously administers the formulation to a patient over time.
  • a pump for subcutaneous infusion or a transdermal patch may be operated at an average rate of from about 10 m 1/hour to about 1000 m 1/hour, 300 ⁇ 100 pl/hour, or 200 ⁇ 40 m 1/hour continuously for 24 hours; 440 ⁇ 200 m 1/hour or 200 ⁇ 50 m 1/hour continuously for 16 hours (during waking hours) and from 0 to about 80 m 1/hour or 0 to 200 m 1/hour for 8 hours (at night).
  • 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 pL/hour, or 1 ⁇ 0.5 pL/hour continuously for 24 hours; 1 ⁇ 0.5 m 1/hour continuously for 16 hours (during waking hours) and from 0 to about 0.5 m 1/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.
  • administration includes acute and immediate
  • administration such as inhalation or injection.
  • the formulation administered according to a contemplated method may comprise one or more pharmaceutically acceptable LDA free base obtained by a process described 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.
  • 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 method comprises co- administering to a patient in need thereof of at least two separate formulations, i.e., at least two dosage unit forms, a first formulation (or unit form) comprising one or more pure pharmaceutically acceptable LDA free base obtained by the processes described herein, and a second formulation comprising a decarboxylase inhibitor e.g., carbidopa, a prodrug thereof and/or a pharmaceutically acceptable salt thereof, and, optionally, one or more of a basic amino acid, an amino sugar, a COMT inhibitor, or a MAO inhibitor.
  • 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., pure pharmaceutically acceptable LDA free base obtained by the processes described herein
  • 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.
  • Two or more dosage unit forms may be administered to a subject at the same rate, or at different rates.
  • kits comprising a LDA free base obtained by a disclosed process, or a formulation comprising it as defined in any of the embodiments described herein and, optionally, instructions and means for administration of the active agents and/or the formulation to a subject in need thereof.
  • the kit comprises a first pharmaceutical composition comprising one or more pure pharmaceutically acceptable LDA free base obtained by the processes described 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 pure pharmaceutically acceptable LDA free base obtained by the processes described herein
  • a second pharmaceutical composition comprising one or more decarboxylase inhibitors or salts thereof
  • 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 optionally, instructions for co-administration of the pharmaceutical compositions.
  • kits are useful for treatment of a disease or disorder characterized by neurodegeneration and/or reduced levels of brain dopamine as described herein, for example Parkinson’s disease.
  • L-dopamide free base (LDA FB) was obtained from L-dopa (LD) and purified according to the process depicted in Scheme 1, using the following steps and ingredients.
  • reaction flask was evacuated to ⁇ 70 mBar, and vacuum was released with nitrogen to provide an oxygen-free atmosphere in the flask. This evacuation procedure was repeated two times more.
  • Aqueous ammonium hydroxide (25%) (1.38 kg, 4.5 volumes) was cooled to a temperature between -8 °C to -12 °C under nitrogen, and LD OMe HC1 salt (340 g, 1.37 mol) was added in 5 portions over approx. 50 minutes while keeping the temperature between -8 °C to -12 °C. The reaction mixture was stirred at this temperature range (-8 °C to -12 °C) for 20 hours (protected from light).
  • reaction flask and filter cake were washed with purified water (182 g, 1 volume).
  • the light yellow filtrate was polish filtered on GF/A paper (1.6 pm) to a clean 2 L 3 necked reaction flask, and the filter was washed with purified water (78 g).
  • the clear solution was evacuated to ⁇ 75 mBar and vacuum was released with nitrogen. This procedure was repeated two times more in order to maintain oxygen- free environment and prevent oxidation of LDA FB.

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Abstract

En partie, l'invention concerne des procédés de fabrication et de purification de base libre de L-Dopamide, telle qu'une base libre de L-dopamide pharmaceutiquement acceptable purifiée sensiblement exempte de L-dopa. De tels procédés sont utiles pour fournir de la L-dopamide pour le traitement de troubles neurodégénératifs tels que la maladie de Parkinson.
PCT/IL2019/050888 2018-08-15 2019-08-05 Procédé de préparation de base libre de lévodopamide purifiée Ceased WO2020035853A1 (fr)

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Citations (2)

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WO2019038638A1 (fr) * 2017-08-21 2019-02-28 Neuroderm Ltd Procédé de préparation d'amide de lévodopa purifié

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Publication number Priority date Publication date Assignee Title
US8048926B2 (en) * 2003-02-07 2011-11-01 Yissum Research Development Company Of The Hebrew University Of Jerusalem L-DOPA amide derivatives and uses thereof
WO2019038638A1 (fr) * 2017-08-21 2019-02-28 Neuroderm Ltd Procédé de préparation d'amide de lévodopa purifié

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ATLAS, DAPHNE: "DopAmide: Novel, Water Soluble, Slow Release 1 dihydroxyphenylalanine (1-DOPA) Precursor Moderates 1-DOPA Conversion to Dopamine and Generates a Sustained Level of Dopamine at Dopaminergic Neurons", CNS NEUROSCIENCE & THERAPEUTICS, vol. 22, no. 6, June 2016 (2016-06-01), pages 461 - 467, XP055352795 *
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