WO2019038638A1 - Procédé de préparation d'amide de lévodopa purifié - Google Patents

Procédé de préparation d'amide de lévodopa purifié Download PDF

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Publication number
WO2019038638A1
WO2019038638A1 PCT/IB2018/056126 IB2018056126W WO2019038638A1 WO 2019038638 A1 WO2019038638 A1 WO 2019038638A1 IB 2018056126 W IB2018056126 W IB 2018056126W WO 2019038638 A1 WO2019038638 A1 WO 2019038638A1
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Prior art keywords
dopamide
salt
dopa
purified
pharmaceutically acceptable
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PCT/IB2018/056126
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English (en)
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Oron Yacoby-Zeevi
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Neuroderm Ltd
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Publication of WO2019038638A1 publication Critical patent/WO2019038638A1/fr

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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
    • 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, in part, to processes of purification of a levodopa amide pharmaceutically acceptable salt, and processes of making a substantially purified pharmaceutically acceptable levodopa amide free base.
  • Parkinson's disease is a degenerative condition characterized by reduced concentration of the neurotransmitter dopamine in the brain.
  • Levodopa 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.
  • 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.
  • 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 levodopa amide derivatives and ester derivatives are known in the art as prodrugs of levodopa.
  • Derivatization of LD e.g., amidation or esterification is used as a means to improve solubility and/or stability of the drug.
  • L-dopamide impure levodopa amide
  • derivatives thereof and use thereof in formulations for treatment, e.g., of Parkinson's diseases, are disclosed, for example, in US 8,048,926 and WO 2017/090039.
  • Amides are known as much more stable molecules than esters and salts, and the hydrolysis rate of amides by amido peptidases is significantly reduced as compared with 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, processes of purification (e.g., large scale purification) of a L-dopamide pharmaceutically acceptable salt, processes of making a purified pharmaceutically acceptable L-dopamide free base substantially free of L-dopa, and processes of preparing a purified L-dopamide hydrochloride salt.
  • the processes of the present disclosure may not require, for example, chromatographic purification to remove L- dopa and/or a L-dopa salt from a pharmaceutically acceptable L-dopamide salt or L- dopamide free base.
  • the purified products obtained by any of the disclosed processes are useful for the preparation of drug substances and pharmaceutical compositions. These purified products may be, for example, in their crystalline form.
  • the present disclosure provides, in part, a process of purification, for example, large scale purification, of a L-dopamide pharmaceutically acceptable salt, and a process of preparing a substantially purified pharmaceutically acceptable L-dopamide free base.
  • L-dopamide free base that is substantially free of L-dopa may be obtained by purifying a crude L- dopamide salt product by precipitation (e.g., one or two subsequent precipitations) from an acidic solution at a certain pH, and then neutralizing the purified L-dopamide salt.
  • L- dopamide L-dopamide free base
  • LDA free base L-2-amino-3-(3,4-dihydroxyphenyl) propanamide
  • L-dopamide pharmaceutically acceptable salts 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”.
  • LDA HC1 salt LDA lactate salt
  • LDA phosphate salt LDA acetate salt
  • L-dopamide is derived from levodopa also interchangeably referred to herein as "L- dopa” or “LD”, or from a levodopa salt (LD salt).
  • LDA or LDA salt are useful as prodrugs of L-dopa.
  • L-dopa is represented by the formula:
  • Embodiments described herein concern processes for making or producing LDA FB and/or a LDA salt such as LDA HC1 salt, and processes for purification of crude LDA FB and/or a crude LDA salt, optionally in their crystalline form.
  • the LDA FB and/or LDA salts obtained by disclosed production and purification processes are substantially pure products, for example, substantially pure crystalline products.
  • 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 and/or a pharmaceutically acceptable LDA salt, collectively referred to herein as "active pharmaceutical ingredients" or "APIs", 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 FB or LDA salt product, for example, crystalline LDA FB and/or LDA HC1 salt, 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 3% to about 10%, from about 3% to about 10%, from about 3% to about 5%, 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 or a pure pharmaceutically acceptable LDA salt may contain less than 10%, less than 8%, less than 5%, or less than 3%, 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 or LDA salt, 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 5.0%, less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.3%, less than 2.0%, less than 1.8%, less than 1.5%, less than 1.2%, less than 1.0%, less than 0.8%, less than 0.5%, less than 0.3%, less than 0.2%, less than 0.15%, less than 0.1%, less than 0.05% or less than 0.01%, of total product.
  • a contemplated substantially pure LDA FB or LDA salt may comprise, for example, between 0.00% to about 0.03%, between 0.00% to about 0.01%, of impurities in total product or total substance.
  • a substantially pure product is essentially devoid or free of any impurities.
  • a disclosed substantially pure LDA free base or LDA salt 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, 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”.
  • Substantially pure LDA salt obtained by a contemplated process is also referred to herein as "pharmaceutically acceptable L-dopamide salt substantially free of L-dopa or a salt thereof or "LDA salt substantially free of L-dopa and/or L-dopa salt”.
  • a pharmaceutically acceptable LDA salt substantially free of L-dopa and/or a salt thereof is a substantially pure LDA HC1 salt.
  • the present disclosure in an aspect thereof, provides a process of purification of a crude L-dopamide salt.
  • a large-scale purification process is effective in providing, e.g., substantially pure L-dopamide pharmaceutically acceptable salt (LDA salt).
  • LDA salt substantially pure L-dopamide pharmaceutically acceptable salt
  • a process for purification of a crude LDA salt comprising the following steps:
  • a first crude LDA salt product comprising: a LDA salt, L-dopa (LD), and/or a L-dopa salt (LD salt);
  • the pH of the first and/or second acidic solution is between about 2.0 and about 3.0. In exemplary embodiments, the pH of the first and/or second acidic solution is from about 2.5 to about 2.7 at 25 °C.
  • the first and second acid are the same.
  • the first and second acid is hydrochloric acid (HC1).
  • the first or the second acid is HC1.
  • the purity of a pharmaceutically acceptable LDA salt and/or 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 salt is above 99% by HPLC.
  • HPLC refers to identification and quantification of a product (e.g., LDA free base or LDA salt) obtained by HPLC.
  • the described process reduces the content of LD and/or LD salt in the purified LDA pharmaceutically acceptable salt, 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.
  • Purification in accordance with processes described herein is mainly effected by crystallization, particularly repeating crystallization cycles, each time with a fresh crystallization medium.
  • the liquid reaction mixture Prior to crystallization, the liquid reaction mixture is often contacted with activated carbon.
  • 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 purified LDA salt is L-dopamide hydrochloride salt (LDA HC1 salt).
  • Also provided herein is a process of large scale purification of a L-dopamide pharmaceutically acceptable salt.
  • a large-scale process for the production of purified pharmaceutically acceptable L-dopamide salt comprises the following steps:
  • a crude L-dopamide salt product comprising: a L-dopamide salt, (LDA salt), L-dopa (LD), and/or a L-dopa salt (LD salt);
  • the purity of the purified LDA pharmaceutically acceptable salt is above 98% by HPLC.
  • the content of LD and/or a LD salt in the purified LDA pharmaceutically acceptable salt is less than about 1.0% by HPLC.
  • the purified LDA pharmaceutically acceptable salt is L- dopamide hydrochloride salt (LDA HC1 salt).
  • L-dopa ester hydrochloride salt (a) reacting L-dopa (LD) with a chlorinating reagent and an alcohol, R-OH, thereby obtaining a L-dopa ester hydrochloride salt, wherein the L-dopa ester (LD-OR) is a chemical compound, L-3,4-dihydroxy-phenylalanine methyl ester represented by:
  • R is selected from a lower alkyl, lower alkenyl, 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-C6)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., «-buthyl, teri-butyl, sec-buthyl), heptyl or hexyl.
  • a lower alkyl selected from methyl, ethyl, propyl (e.g., isopropyl), butyl (e,g., «-buthyl, teri-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 CI 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 (SOCk), gaseous HC1, osoxalyl chloride (C2O2CI2), phosphoryl chloride (POCI3), phosphorus trichloride (PCb), phosphorus pentachloride (PCI5), sulfuryl chloride (SO2CI2) and other chlorinating reagents commonly known in the art for chlorination.
  • the chlorinating reagent is thionyl chloride.
  • the chlorinating reagent is HC1 gas.
  • step (b) of a disclosed process is aqueous ammonium hydroxide, for example, from about 10% to about 40% aqueous ammonium hydroxide, or about 25% ammonium hydroxide in water.
  • the ammonia is step (b) is ammonia in, for example, methanol, tetrahydrofuran (THF), or CH2CI2.
  • the pH of the first and/or second acidic solution is between about 2.0 and about 3.0. In exemplary embodiments, the pH of the first and/or second acidic solution is from about 2.5 to about 2.7 at 25°C.
  • the purity of the purified LDA HC1 is above 99% by HPLC.
  • the process reduces the content of LD and/or LD HC1 in the purified LDA HC1 salt, such that the content of LD and/or LD HC1 in the purified LDA HC1 salt is less than about 0.5% by HPLC, for example, less than about 0.3% by HPLC.
  • LDA FB L-dopamide free base
  • the present disclosure provides a process for obtaining a pharmaceutically acceptable L-dopamide free base (LDA FB) substantially free of L-dopa.
  • LDA FB L-dopamide free base
  • Such a process is effective in providing, e.g., substantially pure LDA FB.
  • Purified LDA free base may be obtained by several routes.
  • LDA free base may be obtained from a purified LDA salt, for example, obtained as described herein by a contemplated process.
  • purified LDA FB e.g., substantially pure pharmaceutically acceptable LDA FB
  • LDA salt may be obtained by a process in which crude LDA salt is first produced from L-dopa (LD) by amidation, for example, by a contemplated process described herein, followed by purification, e.g., substantial purification of the LDA salt, for example by a contemplated purification process described herein. Then the purified LDA salt is converted to purified LDA free base ubder basic conditions.
  • LD L-dopa
  • Processes I, Process II and Process III Various exemplary process for obtaining or making LDA FB disclosed herein are designated herein Processes I, Process II and Process III.
  • a contemplated process for making a purified pharmaceutically acceptable LDA FB comprises the following steps:
  • the pH of the first and/or second acidic solution is between about 2.0 and about 3.0. In exemplary embodiments, the pH of the first and/or second acidic solution is between about 2.5 and about 2.7 at 25 °C.
  • the first and second acid are the same.
  • both the first and second acid are hydrochloric acid (HC1).
  • the first or second acid is HC1.
  • a contemplated process of making a purified pharmaceutically acceptable LDA FB substantially free of L-dopa comprises the following steps:
  • a contemplated process for making a purified pharmaceutically acceptable LDA FB comprises the following steps:
  • L-dopa ester hydrochloride salt (a) reacting L-dopa (LD) with a chlorinating reagent and an alcohol, R-OH, thereby obtaining a L-dopa ester hydrochloride salt, wherein the L-dopa ester (LD-OR) is the chemical compound, L-3,4-dihydroxy-phenylalanine methyl ester represented by:
  • R is selected from a lower alkyl, lower alkenyl, lower alkynyl, aryl or heteroaryl;
  • the alcohol R-HO, the chlorinating reagent and the ammonia are as defined herein.
  • the present disclosure provides a further process for making a purified pharmaceutically acceptable L-dopamide free base substantially free of L-dopa.
  • This process may be particularly suitable for large-scale production of purified pharmaceutically acceptable LDA FB.
  • This process resembles Process I herein, but instead of purifying LDA salt by 2 subsequent precipitations before contacting it with a base solution, LDA salt is precipitated only once from an acidic solution.
  • a crude L-dopamide salt product comprising: a L-dopamide salt (LDA salt), L-dopa (LD), and/or a L-dopa salt (LD salt);
  • LDA salt L-dopamide salt
  • LD L-dopa
  • LD salt L-dopa salt
  • the purity of the purified LDA pharmaceutically acceptable free base is above 98% by HPLC.
  • the content of L-dopa in the purified LDA pharmaceutically acceptable free base is less than about 1.0% by HPLC.
  • the process does not include purification by chromatography.
  • the pH of the first and/or second hydrochloric acid solution is between about 2.0 and about 3.0. In exemplary embodiments, the pH of the first and/or second hydrochloric acid solution is between about 2.5 and about 2.7 at 25 °C.
  • the base composition with which the purified LDA salt, e.g. LDA HC1 salt, is contacted for making a purified LDA free base 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 (namely, substances that, in aqueous solution, release hydroxide (OH " ) ions).
  • 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 9.1.
  • the pH of the basic solution is between about 8.20 to about 8.40.
  • the purity of the purified LDA FB is above 99% by HPLC.
  • a contemplated process for making pure LDA FB reduces the content of L-dopa and/or L-dopa salt in the purified pharmaceutically acceptable LDA FB, wherein the content of L-dopa and/or L-dopa salt in the purified LDA FB is less than about 0.5% by HPLC, for example, less than about 0.3% by HPLC.
  • a contemplated process may provide at least about 1.0 gr of purified product e.g., in one batch. In exemplary embodiments, 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, or 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 4000gr, or between 4000 gr to about 10 kg-
  • the amount of purified LDA salt and or 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 purified LDA salt in one batch.
  • a contemplated process is a large-scale process.
  • large scale process refers to a process that can produce a wide scope of product quantities, ranging, for example, from e.g., tens or hundreds of grams to kilograms and even to tons of product.
  • a large-scale process in the context of embodiments described herein, is a process that can produce purified LDA FB and/or purified LDA salt such as purified LDA HC1 salt, in amounts ranging, for example, from 100 gr to 5 kg, or from 1 kg to 10 kg per process cycle.
  • a large-scale process in some embodiments described herein is also a process that produces a purified product as defined herein in amounts ranging from, for example, 100 gr to 5 kg, or from 1 kg to 10 kg in a single batch.
  • the present disclosure in an aspect thereof, provides a purified LDA free base and/or a purified LDA salt, and substantially purified LDA free base and/or LDA salt, collectively referred to herein as "products" or “purified products”, prepared or obtained by any of the processes provided herein.
  • the contemplated purified product is a purified or substantially purified pharmaceutically acceptable salt of LDA obtained by a process described herein.
  • the pharmaceutically acceptable salt of LDA is L-dopamide hydrochloride salt (LDA HC1 salt).
  • the contemplated purified product is a purified or substantially purified pharmaceutically acceptable L-dopamine free base (LDA FB) prepared by a process disclosed herein.
  • LDA FB L-dopamine free base
  • salt refers to any salt of an acidic or a basic group that may be present in a compound of the present disclosure, which salt is compatible with pharmaceutical administration.
  • salts of the compounds of the present disclosure may be derived from inorganic or organic acids and bases.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, bitartrate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, flucoheptanoate, gentisinate, gluconate, glucaronate, glutamate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, isonicotinate, lac
  • the compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group such as in L-dopa.
  • the compound can exist as an acid addition salt, a zwitterion, or a base salt.
  • the purity of a contemplated purified or substantially purified pharmaceutically acceptable LDA salt and/or pharmaceutically acceptable LDA FB is above 99% by HPLC.
  • the content of L-dopa and/or a L-dopa salt in the purified or substantially purified pharmaceutically acceptable LDA salt and/or pharmaceutically acceptable LDA FB is less than about 0.5% or less than about 0.3% by HPLC.
  • the disclosure provides a drug substance comprising at least a detectable amount (e.g., an amount detectable within the limits of detection of a technique known to those of skill in the art, e.g., HPLC), of a contemplated product as defined herein obtained by a contemplated process of the disclosure.
  • a detectable amount e.g., an amount detectable within the limits of detection of a technique known to those of skill in the art, e.g., HPLC
  • a pure or purified product obtained by a contemplated process 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.
  • a drug substance comprises a pharmaceutically acceptable LDA free base and/or a pharmaceutically acceptable LDA salt obtained by a contemplated process described herein.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable LDA free base and/or a pharmaceutically acceptable LDA salt 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.
  • composition refers to a formulation designed for medicinal utilization such as, but not limited to, therapeutic or diagnostic utilization.
  • formulation 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.
  • 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”.
  • liquid pharmaceutical compositions for example aqueous formulations.
  • a contemplated pharmaceutical composition e.g., formulation
  • a suspension is a contemplated pharmaceutical composition.
  • active agent active ingredient
  • active pharmaceutical ingredient active pharmaceutical ingredient
  • 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 salt or LDA free base obtained by a disclosed process.
  • a disclosed formulation may comprise, pure or substantially pure pharmaceutically acceptable LDA salt or 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 salt or 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 preservatives, antioxidants, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration.
  • Pharmaceutically acceptable excipients, as used herein, 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.
  • Non- limiting examples of 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.
  • 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
  • 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).
  • a contemplated medicinal formulation comprises a pure pharmaceutically acceptable LDA salt or LDA free base and, e.g., a decarboxylase inhibitor (for example, carbidopa or a prodrug thereof)
  • these main and secondary active ingredients can be combined and formulated in the same formulation, namely, as a single unit dosage from or, alternatively, can be formulated in separate formulations, 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, and/or a second active agent.
  • a disclosed pharmaceutical composition may often comprise one or more antioxidants, namely, substances which slow down the damage that can be caused to other substances by the effects of oxygen (i.e., oxidation).
  • 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); and ubiquinol (coenzyme Q).
  • vitamin C ascorbic acid
  • a salt thereof e.g., sodium ascorbate, calcium ascorbate, potassium ascorbate, ascor
  • antioxidants are exemplified by phenolic antioxidants such as di-teri-butyl methyl phenols, teri-butyl-methoxyphenols, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), polyphenols, tocopherols, ubiquinones (e.g., caffeic acid, tert- butylhydroquinone (TBHQ)), propyl gallate, flavonoid compounds, cinnamic acid derivatives, coumarins, and sulfite salts such as sodium hydrogen sulfite or sodium bisulfite (e.g. sodium metabisulfite).
  • phenolic antioxidants such as di-teri-butyl methyl phenols, teri-butyl-methoxyphenols, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), polyphenols, tocopherols, ubiquinones (
  • 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, L-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, L-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 combination thereof.
  • Contemplated formulations may congtain 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 a LDA salt and/or LDA FB obtained by any of the processes described herein.
  • 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 salt and/or LDA FB, may be formulated as a liquid formulation
  • 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 salt or LDA free base, and therefore includes particles including the API 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.
  • 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 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 10°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 administrating to the subject an effective amount of a formulation described herein, thereby threating the subject.
  • 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 multiple system atrophy (MSA)), dystonia, Alzheimer's disease, Lewy body dementia (LBD), akinesia, bradykinesia, and hypokinesia; conditions resulting from brain injury including carbon monoxide or manganese intoxication; and 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 salt or LDA free base obtained by any one of the processes described herein.
  • a pharmaceutical composition comprising a pharmaceutically acceptable LDA salt or LDA free base obtained by any one of the processes described herein.
  • the composition administered to a subject in need thereof may comprise form about 5% to about 25% of a pure pharmaceutically acceptable LDA salt or LDA free base obtained by the processes described herein.
  • administering is introduction of the API or a pharmaceutical composition or formulation comprising it as defined 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 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 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 ⁇ to about 1000 ⁇ ⁇ , 300 ⁇ 100 ⁇ ⁇ , or 200 ⁇ 40 ⁇ continuously for 24 hours; 440 ⁇ 200 ⁇ or 200 ⁇ 50 ⁇ continuously for 16 hours (during waking hours) and from 0 to about 80 ⁇ or 0 to 200 ⁇ 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 ⁇ , or 1 ⁇ 0.5 ⁇ continuously for 24 hours; 1 ⁇ 0.5 ⁇ continuously for 16 hours (during waking hours) and from 0 to about 0.5 ⁇ 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 salt or 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 salts or 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 salts or 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 and/or LDA salt 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 salts or 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 coadministration of the pharmaceutical compositions.
  • a first pharmaceutical composition comprising one or more pure pharmaceutically acceptable LDA salts or LDA free base obtained by the processes described herein
  • 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,
  • a contemplated kit is 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 the scheme below, using the following steps and ingredients.
  • Methanol 135.0 kg was cooled to a temperature of from about -5 °C to about 0 °C under nitrogen.
  • Thionyl chloride (22.6 kg, 190.0 mol, 1.5 eq.) was added while keeping the temperature between -5 to 0 °C.
  • Levodopa (L-Dopa; compound 10) (25.0 kg, 126.8 mol) was added while maintaining the temperature within the range of from about -5 °C to about 10 °C. Then the temperature was adjusted to 20 - 25°C, and the mixture was stirred at this temperature for 12 - 24 hours until at least 95% conversion of 10 to compound 11 was achieved (as assessed by HPLC). The mixture was concentrated by distillation under reduced pressure to a volume of ca.
  • Aqueous ammonium hydroxide (25%) (81.0 kg) was cooled to a temperature in the range of from about -8 °C to about -12 °C under nitrogen, and compound 11 (3,4-dihydroxy- L-phenylalanine methyl ester hydrochloride; 15.0 kg, 60.6 mol) was added.
  • the reaction mixture was stirred at temperature in of from about -8 °C to -12 °C for 16 - 24 hours until minimum 99.0% conversion of compound 11 to compound 12 was achieved (assessed by HPLC).
  • the excess ammonium hydroxide was removed by azeotropic distillation with 2- propanol (164.0 kg) under reduced pressure.
  • Purified water (40.0 kg) was added to the distillation residue, and the pH of the resulting mixture was adjusted to pH 2.5 - 2.7 at 20 - 25 °C with addition of hydrochloric acid (37%) (-2.125 kg).
  • Activated carbon (1.410 kg) was added and the mixture was stirred for 30 - 60 minutes at 20 - 25 °C.
  • Celite (0.705 kg) was added and the mixture was then filtered on a pad of celite (1.50 kg). The filter cake was washed with purified water (12.4 kg).
  • 2-Propanol 143.5 kg was added to the filtrate and the pH was adjusted to pH 2.5-2.7 at 20-25 °C with addition of hydrochloric acid (37%) (-0.250 kg).
  • Azeotropic distillation with 2-propanol was performed under reduced pressure until a water content of 7.0 - 8.5% w/w (Karl Fischer (KF) titration) was achieved for the solution of crude compound 13 in 2-propanol.
  • the temperature of the mixture was then adjusted to 40 - 45 °C, and seeding was performed if needed.
  • KF Karl Fischer
  • seeding was performed if needed.
  • MTBE teri-Butyl methyl ether
  • teri-Butyl methyl ether (18.7 kg) was added.
  • the mixture was then cooled to 20 - 25 °C and stirred at this temperature for 1 - 2 hours.
  • teri-Butyl methyl ether (6.60 kg) was added over at least 1 hour and the mixture was stirred at 20 - 25 °C for 2 - 20 hours. The suspension was then cooled to 0 - 5 °C and stirred at this temperature for 2 - 6 hours. The solid was collected by filtration in two portions, and the filter cake was washed with cold (0 - 5 °C) 2-propanol (38.5 kg). The solid was dried in vacuum at 38 - 43 °C for at least 16 hours to afford 12.0 kg of crude L-2-amino-3-(3,4-dihydroxyphenyl)propanamide hydrochloride salt (LDA HC1 salt, compound 13) (85%) as a white to off-white solid.
  • LDA HC1 salt, compound 13 L-2-amino-3-(3,4-dihydroxyphenyl)propanamide hydrochloride salt
  • Azeotropic distillation with 2-propanol was performed under reduced pressure until a content of 7.0 - 8.5% w/w (KF titration) was achieved for the solution of LDA HC1 salt in 2-propanol.
  • the temperature of the mixture was adjusted to 40 - 45 °C and seeding was performed if needed.
  • teri-Butyl methyl ether (7.2 kg) was added and the mixture was stirred at 20 - 25 °C for 2 - 20 hours. The suspension was then cooled to 0-5 °C and stirred at this temperature for 2 - 6 hours.
  • the solid was collected by centrifugation, and the filter cake was washed with a cold (0 - 5 °C) mixture of 2-propanol (3.2 kg) and teri-butyl methyl ether (3.0 kg). If the content of L-dopa in a sample was ⁇ 0.50%, the solid was dried in vacuum at 38 - 43 °C for at least 38 hours, to afford 2.0 kg of pure LDA HC1 salt, compound 14 (74%) as a white to off-white solid.
  • L-dopa If the content of L-dopa was ⁇ 0.50%, the solid was dried in vacuum at 38 - 43 °C for at least 12 hours, to afford 5.3 kg of purified L- dopamide free base (LDA FB), compound 15 as a white to off-white solid.
  • LDA FB purified L- dopamide free base
  • Tables 2-4 depict experimental conditions and results for obtaining compounds 13-15.
  • Table 2 depicts experimental data of the amidation step, namely, production of crude LDA HCl salt (13) obtained from 4 different exemplary batches.
  • Table 3 depicts experimental data of the re-precipitation step, namely, production of purified LDA HCl salt (14) obtained from 2 exemplary batches.
  • Table 4 depicts experimental data of production of L-dopamide free base (15) obtained from 3 different exemplary batches. Batches 1 and 2 of Table 2 correspond to batches 1 and 2 of Table 3. Batches 2, 3, and 4 of Table 3 correspond to batches 2, 3, and 4 of Table 4.
  • RRT 1.55 N/A
  • RRT RRT 1.55 0.17%

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Abstract

La présente invention concerne en partie, des procédés de purification à grande échelle d'un sel pharmaceutiquement acceptable de L-dopamide et des procédés de fabrication d'un L-dopamide pharmaceutiquement acceptable purifié et de sels de L-dopamide pharmaceutiquement acceptables sensiblement exempts de L-dopa. De tels procédés sont utiles pour fournir de la L-dopamide destinée au traitement de troubles neurodégénératifs tels que la maladie de Parkinson.
PCT/IB2018/056126 2017-08-21 2018-08-15 Procédé de préparation d'amide de lévodopa purifié WO2019038638A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10624839B2 (en) 2014-03-13 2020-04-21 Neuroderm, Ltd. Dopa decarboxylase inhibitor compositions
US10813902B2 (en) 2014-03-13 2020-10-27 Neuroderm, Ltd. DOPA decarboxylase inhibitor compositions
WO2020035853A1 (fr) * 2018-08-15 2020-02-20 Neuroderm, Ltd. Procédé de préparation de base libre de lévodopamide purifiée
US11213502B1 (en) 2020-11-17 2022-01-04 Neuroderm, Ltd. Method for treatment of parkinson's disease
US11331293B1 (en) 2020-11-17 2022-05-17 Neuroderm, Ltd. Method for treatment of Parkinson's disease
US11458115B2 (en) 2020-11-17 2022-10-04 Neuroderm, Ltd. Method for treatment of Parkinson's disease
US11844754B2 (en) 2020-11-17 2023-12-19 Neuroderm, Ltd. Methods for treatment of Parkinson's disease

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