WO2019038639A1 - Base libre d'amide de lévodopa cristallin et procédés de fabrication et d'utilisation associés - Google Patents

Base libre d'amide de lévodopa cristallin et procédés de fabrication et d'utilisation associés Download PDF

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Publication number
WO2019038639A1
WO2019038639A1 PCT/IB2018/056127 IB2018056127W WO2019038639A1 WO 2019038639 A1 WO2019038639 A1 WO 2019038639A1 IB 2018056127 W IB2018056127 W IB 2018056127W WO 2019038639 A1 WO2019038639 A1 WO 2019038639A1
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Prior art keywords
acid
crystalline form
crystalline
less
dopamide
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PCT/IB2018/056127
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English (en)
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Oron Yacoby-Zeevi
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Neuroderm Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • 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
    • 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
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates, in part, to levodopa amide free base, particularly but not exclusively, pharmaceutically acceptable crystalline 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 water solubility and/or stability of the drug.
  • mixtures of various impure levodopa amide and 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.
  • Crystallization or polymorphism (i.e., the ability of a substance to crystallize in more than one crystal lattice arrangement), can influence many aspects of solid state properties of a drug substance.
  • a crystalline substance may differ considerably from an amorphous form, and different crystal modifications of a substance may differ considerably from one another in many respects including solubility, dissolution rate and/or bioavailability. Therefore, it can be advantageous to have a crystalline form of a therapeutic agent for certain formulations, e.g., formulations suitable for subcutaneous use.
  • the present disclosure provides a crystalline free base of levodopa amide (L-dopamide), i.e. a compound represented by:
  • a crystalline form of L-dopamide free base wherein the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2 ⁇ at about 19.7 and about 21.0. Such crystalline form may further have characteristic peaks in degrees 2 ⁇ at about 18.1, and about 28.9.
  • a crystalline form of L-dopamide free base wherein the crystalline form has a DSC thermogram with an endotherm having an onset at about 164 °C, and a peak at about 172.4°C.
  • Such a crystalline form may have less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than 1%, between about 0.01% and 10%, or between about 0.01% and 1%, in content, of a crystalline hydrochloric acid salt of L-dopamide, and/or less than about 1%, or less than about 0.5% levodopa and/or levodopa salt.
  • a crystalline L- dopamide wherein the crystalline form has less than about 0.3% levodopa and/or levodopa salt.
  • impurities may be analyzed by, e.g., HPLC.
  • the purity of the crystalline free base form is above 99% as determined by HPLC.
  • L-dopamide pharmaceutically acceptable salt formed from a process comprising reacting the disclosed free base crystalline form with an acid; thereby forming an acid salt of L-dopamide.
  • the acids which may form acid addition salts with LDA free base include, for example, hydrochloric acid, fumaric acid, lactic acid, phosphoric acid, sulfuric acid, and glucoheptanoic acid.
  • Contemplated herein is a pharmaceutical composition comprising the disclosed crystalline free base or salts formed therefrom, and a pharmaceutically acceptable excipient.
  • a drug substance is also contemplated herein, comprising e.g., at least a detectable amount of the crystalline LDA free base of the disclosure, and/or comprising substantially pure crystalline form of the L-levodopa amide of the disclosure.
  • all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.
  • Fig. 1 depicts the XRPD peaks pattern of crystalline L-dopamide freebase, obtained using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube and a Pixcel detector system. XRPD patterns were sorted and manipulated using HighScore Plus 2.2c software;
  • Fig. 2 is the ⁇ -NMR plot in intensity vs. ppm for crystalline L-dopamide freebase
  • Fig. 3 is a TG/DTA thermogram of crystalline L-dopamide free base analyzed in a temperature range from 25 °C to 300 °C at 10 °C per minute;
  • Fig. 4 is a DSC thermogram of crystalline L-dopamide free base analyzed in a temperature range from 30 °C to 300 °C at 10 °C per minute.
  • the present disclosure is directed, in part, to the discovery of a substantially pure crystalline form of L-dopamide free base. Such a form can be useful in making therapeutically acceptable salt forms of L-dopamide.
  • crystal refers to a solid material relating to, resembling or composed of crystals.
  • crystal refers to a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered, periodic microscopic structure, forming a crystal lattice that extends in all directions.
  • the three- dimensional structure of crystals is defined by regular, repeating planes of atoms that form a crystal lattice, as opposed to an amorphous solid.
  • a crystal structure may also be characterized by its unit cell, a basic repeating unit that defines the crystal structure, and contains the maximum symmetry that uniquely defines the crystal structure.
  • Crystallization is the process of forming a crystalline structure from a fluid or from materials dissolved in a fluid.
  • Polymorphism is the ability of a solid to exist in more than one crystal form.
  • a single fluid can solidify into many different possible forms termed "polymorphs" or "phases". It can form a single crystal, perhaps with various possible phases, stoichiome tries, impurities, defects, and habits. Or, it can form a polycrystal, with various possibilities for the size, arrangement, orientation, and phase of its grains.
  • the final form of the solid is determined by the conditions under which the fluid is being solidified, such as the chemistry of the fluid, the ambient pressure, the temperature, and the speed with which all these parameters are changing.
  • a crystalline substance may differ considerably from an amorphous form, and different crystal modifications of a substance, e.g. different polymorphs, may differ considerably from one another in many respects including solubility, dissolution rate and/or bioavailability.
  • Different crystalline forms or different crystallinity may further arise due to refinement of milling of an already formed crystals. Generally, it is difficult to predict whether or not a given compound will form various crystalline forms. It is even more difficult to predict the physical properties of these crystalline forms. Clear identification of different crystalline forms or different crystallinity is critical when developing pharmaceuticals because crystal polymorph and crystallinity influence medicinal effects and formulation stability.
  • a crystalline substance may be detected and characterized, for example, by its X-ray diffraction pattern.
  • a focused X-ray beam interacts with a plane of atoms in a crystal, part of the beam is refracted and scattered and part is diffracted.
  • the part of the X-ray that is not scattered passes through to the next layer (plane) of atoms, where again part of the X- ray is scattered and part passes through to the next layer.
  • This causes an overall diffraction pattern, similar to how a grating diffracts a beam of light.
  • the sample In order for an X-ray to diffract, the sample must be crystalline and the spacing between atom layers must be close to the radiation wavelength. X-rays are diffracted by each crystal differently, depending on what atoms make up the crystal lattice and how these atoms are arranged.
  • a powder X-ray diffractometer consists of an X-ray source, usually an X-ray tube, a sample stage, a detector and a way to vary angle ⁇ .
  • the X-ray is focused on the sample at some angle ⁇ , while the detector opposite the source reads the intensity of the X-ray it receives at angle 2 ⁇ away from the source path.
  • the incident angle is than increased over time while the detector angle always remains 2 ⁇ above the source path.
  • the diffraction peak position is recorded as the detector angle, 2 ⁇ .
  • data is collected at degree 2 ⁇ ranging from about 5° to about 70°, and these varying angles are preset in the X-ray diffraction scan.
  • An X-ray tube usually contains a metal target (e.g., Cu, Fe, Mo, Cr) which is bombarded by accelerated electrons that knock core electrons out of the metal. Electrons in the outer orbitals or higher levels of the metal drop down to fill the vacancies in the lower levels, emitting X-ray photons.
  • a metal target e.g., Cu, Fe, Mo, Cr
  • Electrons in the outer orbitals or higher levels of the metal drop down to fill the vacancies in the lower levels, emitting X-ray photons.
  • a characteristic radiation is thus obtained, composed of discrete peaks.
  • the energy (and wavelength) of the peaks depends solely on the metal used for the target.
  • These X-rays are collimated and directed onto the sample, which is ground to a fine powder (typically to produce particle sizes of less than 10 microns).
  • the diffracted X-ray signal is detected by the detector, processed and converted to a count rate. Changing the angle between the X-ray source, the sample, and the detector at a controlled rate between preset ⁇ limits generates an X-ray scan.
  • the diffraction peak pattern is a product of the unique crystal structure of a material.
  • the position and intensity of peaks in a diffraction pattern are determined by the crystal structure and serve as the crystal's "fingerprints".
  • the purity of a sample can be determined from its diffraction pattern, as well as the composition of any impurities present.
  • XRPD X-ray powder diffraction
  • the crystalline form of L-dopamide free base is provided herein.
  • the X-ray diffraction pattern of crystalline LDA free base was measured on X-ray diffractometer Panalytical Xpert Pro equipped with a Cu X-ray tube emitting K a radiation, and a Pixcel detector system, under the conditions specified in the Material and Methods section herein.
  • the crystalline form of LDA FB provided herein is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2 ⁇ at about 19.7 and about 21.0 and may have additional peaks in degrees 2 ⁇ at for example, about 18.1, and about 28.9.
  • Such a crystalline form may have a powder X-ray diffraction pattern substantially the same as depicted in Figure 1.
  • the X-ray diffraction peak pattern presented in Figure 1 is termed herein "LDA FB Pattern A" or "Pattern A”.
  • thermophysical properties of crystalline pharmaceuticals are influenced by temperature change, thus thermal analysis techniques are indispensable in understanding the thermophysical properties of crystalline pharmaceuticals.
  • Calorimetry is a technique for determining the quantity of heat that is either absorbed or released by a substance undergoing a physical or a chemical change, which alters the internal energy of the substance known as enthalpy, H.
  • the enthalpy of a crystalline substance decreases or lowered in an exothermic process such as crystallization decomposition, whereas endothermic processes such as evaporation, dehydration and melting increase the enthalpy.
  • Thermal analysis techniques are classified according to the property under study.
  • temperature changes of a process may be assessed by heating/cooling curves analysis; temperature differences of a process or reaction may be assessed by differential thermal analysis (DTA); the heat of a process may be assessed by calorimetry or differential scanning calorimetry (DSC); and mass changes may be assessed by thermogravimetry (TG) or thermogravimetric analysis (TGA).
  • DTA differential thermal analysis
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • DSC Differential scanning calorimetry
  • endothermic heat absorption
  • exothermic heat evolution
  • the difference in the amount of heat required to increase the temperature of a sample and a reference are measured as a function of temperature, while both the sample and reference are maintained at nearly the same temperature throughout the experiment.
  • the basic principle underlying this technique is that when the sample undergoes a physical transformation such as phase transitions, more or less heat will need to flow to it than to the reference to maintain both at the same temperature. Whether less or more heat must flow to the sample depends on whether the process is exothermic or endothermic.
  • differential scanning calorimeters are able to measure the amount of heat absorbed or released during such transitions.
  • the changes in heat flow allow the detection of transitions such as melts, phase changes, evaporation, dehydration and crystallization. In crystals, phase changes or polymorphs can be observed as well as the degree of purity.
  • the result of a DSC experiment is a curve of heat flux versus temperature or versus time, herein referred to as a "DSC thermogram". This curve can be used to calculate the enthalpy of a transition, ⁇ , by integrating the peak corresponding to a given transition. Often, a DSC thermogram of a contemplated crystalline may serve as an identifier or fingerprint of the crystalline. [0034] In an embodiment, the provided crystalline form of L-dopamide free base form has a DSC thermogram with an endotherm having an onset at about 164 °C, and a peak at about 172.4 °C, as shown in Figure 4.
  • a "substantially pure crystalline”, as referred to herein, is a crystalline comprising, besides molecules of the principle material or active pharmaceutical ingredient (API), further trace 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 of the API, metal atoms, and polymorphs.
  • Voids in the crystalline arrangement are also referred to herein as impurities.
  • Impurities can be incorporated into crystals in a number of ways. For example, surface impurities are left when residual mother liquor on the surface of the crystals evaporates, leaving behind any dissolved impurities. Inclusions of mother liquor may be formed in crystals, especially at high growth rates. Occlusions are voids formed between individual crystals, usually in agglomerates.
  • a "trace amount”, as referred to herein, is a very small, a tiny or even scarcely detectable amount. Impurities, including trace amounts of purities, are usually detected 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
  • purity of a disclosed LDA free base was determined using the HPLC system Agilent 1200 Series, under the conditions specified in the Materials and Methods section herein.
  • a contemplated substantially pure crystalline will typically contain trace amounts of impurities as defined herein in a total amount which is less than 5.0% of total composition of the crystalline.
  • 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 2.3%, 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%.
  • a contemplated substantially pure crystalline LDA FB may comprise between 0% to about 0.03%, between 0.00% to about 0.01%, between about 0.01% to about 5.0%, between about 0.01% to about 1.0%, between about 0.05% to about 1.0%, 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%, of impurities.
  • a substantially pure crystalline is essentially devoid or free of any impurities.
  • a disclosed substantially pure crystalline LDA free base may have some levodopa and/or levodopa salt impurities.
  • such a crystalline 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, wherein such levels can be characterized by HPLC.
  • a substantially pure crystalline LDA free base has about 0.3% levodopa and/or levodopa salt as measured by, e.g., HPLC.
  • a contemplated crystalline L-dopamide FB may be reacted with an acid or a base to form a pharmaceutically acceptable salt.
  • L-dopamine pharmaceutically acceptable salts are also provided herein.
  • An acid or base that forms a salt with LDA free base is termed herein "salt former".
  • the salt former may be, for example, HC1, acetic acid, ascorbic acid, L- aspartic acid, benzenesulfonic acid, benzoic acid, citric acid, fumaric acid, galactaric acid, gluceptic (glucoheptanoic), acid D-gluconic acid, D-glucuronic acid, L-glutamic acid, glutaric (pentanedioic) acid, glycolic (hydroxyacetic) acid, isethionic (2-hydroxy- ethanesulfonic) acid, L-lactic acid, lactobionic acid, L-maleic (but-2-enedioic) acid, L-malic acid, methanesulfonic acid, phosphoric acid (H3PO4), propionic (propanoic) acid, succinic (butanedioic) acid, sulfuric acid (H2SO4), L-tartaric acid and xinafoic (l-hydroxy-2- naphthoic) acid.
  • the salt former may also be a base such as, but not limited to, L-arginine and L-histidine.
  • Solvates e.g., hydrates
  • non-solvates e.g., anhydrates
  • crystalline forms of LDA free base or a salt thereof are also contemplated herein.
  • a LDA salt refers to any salt of an acidic or a basic group as described herein, which do not produce an adverse, allergic or other untoward reaction and is compatible with pharmaceutical administration.
  • a LDA salt may be, for example, a substantially pure salt containing trace amounts (e.g., 0 to about 3%) of LDA FB.
  • a disclosed crystalline LDA free base has less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than 1%, between about 0.01% and 10%, or between about 0.01% and 1%, in content, of crystalline salt of LDA, such as, but not limited to, crystalline LDA HC1 salt, crystalline LDA sulfate salt, crystalline LDA phosphate salt, crystalline LDA lactate salt, crystalline LDA maleate salt, crystalline LDA fumarate salt, and crystalline LDA gluceptic acid salt.
  • crystalline salt of LDA such as, but not limited to, crystalline LDA HC1 salt, crystalline LDA sulfate salt, crystalline LDA phosphate salt, crystalline LDA lactate salt, crystalline LDA maleate salt, crystalline LDA fumarate salt, and crystalline LDA gluceptic acid salt.
  • 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 L-dopamide free base of the disclosure, for example, in its crystalline form.
  • 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
  • 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, (namely, the API).
  • 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 substantially pure crystalline form of LDA FB of the disclosure, for example crystalline having X-ray powder diffraction peak pattern A substantially as shown in Figure 1.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable LDA free base as described herein, or a pharmaceutically acceptable salt thereof, 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 FB.
  • a disclosed formulation may comprise, pure or substantially pure crystalline pharmaceutically acceptable LDA FB 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 substantially pure crystalline form of LDA FB of the disclosure, for example, crystalline having X-ray powder diffraction peak pattern A substantially as shown in Figure 1.
  • 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 crystalline pharmaceutically acceptable LDA free base of the disclosure 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 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 free base of the disclosure.
  • 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.
  • the pharmaceutical composition comprises a plurality of dosage unit forms, for example two dosage unit forms, 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 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 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” as understood by a person of skill in the art refers to a temperature of from about 10°C to about 30°C. In exemplary embodiments, ambient temperature can be 25 °C.
  • 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 and/or a drug substance 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 FB or described herein.
  • composition administered to a subject in need thereof may comprise form about 5% to about 25% of a pure pharmaceutically acceptable LDA of a disclosed such as a substantially pure crystalline form of LDA FB of the disclosure, for example, crystalline having X-ray powder diffraction peak pattern A substantially as shown in Figure 1.
  • a pure pharmaceutically acceptable LDA of a disclosed such as a substantially pure crystalline form of LDA FB of the disclosure, for example, crystalline having X-ray powder diffraction peak pattern A substantially as shown in Figure 1.
  • 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 FB or a salt thereof of the disclosure 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 or a salts thereof of the present disclosure, 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., pharmaceutically acceptable LDA FB 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 a salt thereof of the present disclosure, 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 pharmaceutically acceptable LDA free base 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 second pharmaceutical composition comprising one or more decarboxylase inhibitors or salts thereof
  • a basic amino acid an amino sugar
  • a catechol-O- methyl transferase (COMT) inhibitor or a monoamine oxidase (MAO) inhibitor
  • instructions for co-administration of the pharmaceutical compositions 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.
  • XRPD analyses were performed using a Panalytical X'pert Pro diffractometer equipped with a Cu X-ray tube (Cu anode, wavelength 0.154 nm, max. 2.2 kW, 60 kV, long fine focus ceramic tube, type PW3373/00) and a Pixcel detector system. The isothermal samples were analysed in transmission mode and held between low density polyethylene films. The Almac default XRPD program was used (range 3 - 40 °2 ⁇ , step size 0.013°, counting time of 46 sec or 99 sec, depending on run time of -11 min or -22 min). XRPD patterns were sorted and manipulated using HighScore Plus 2.2c software.
  • DSC Differential scanning calorimetry
  • DSC Differential scanning calorimetry
  • the heaters automatically adapted to the temperature changes between the tested sample and the reference by supplying additional power.
  • the difference between the heat flow (or power applied) to the test sample and the reference was measured as a function of temperature and/or time.
  • the temperature program for the DSC analysis was designed such that the temperature increased linearly as a function of time.
  • the reference sample used had a well-defined heat capacity over the range of temperatures scanned, it was inert to the sample in the temperature range used, it did not exhibit any physical transitions in the temperature range used, and its melting point was sufficiently high.
  • Y axis may be a plot of heat capacity, Cp, of the test sample.
  • HDSC Hyper differential scanning calorimetry
  • HDSC Hyper differential scanning calorimetry
  • the measured value of T g depends, inter alia, on a crystal's thermal history and age, the water content in the crystal and on the rate of heating or cooling.
  • T g is roughly (0.67) Tm, the melting temperature of the crystalline material in degrees K.
  • HDSC uses scan rates (heating rates) that are much faster than conventional DSC (e.g., 100-500 °C/minute in heating as well as in cooling over a broad temperature range).
  • the rapid scan- rate can substantially enhance the sensitivity (by at least a factor of ten over most conventional DSC analyses), allowing small transitions such as the glass transition to be detected more readily and accurately.
  • Increased sensitivity of HDSC further enables the use of very low sample mass (ca. 1 mg) without any loss in detection of T g .
  • a PerkinElmer® diamond Differential Scanning Calorimeter was used for HDSC measurements.
  • the DSC was calibrated for temperature and heat flow with reference materials having transitions in the range of interest.
  • different cooling devices such as Intracooler or CryoFill (a liquid nitrogen device) were used.
  • thermogravimetric (TG) analysis Mass changes in a material as a function of temperature (or time) under a controlled atmosphere is known as thermogravimetric (TG) analysis, and its principal uses include measurement of a material's thermal stability and composition.
  • the changes that usually occur upon heating a sloid sample include melting, phase transition, sublimation, and decomposition.
  • Differential thermal analysis (DTA) is a thermal analysis method, in which the temperature of a sample is compared with that of an inert reference material during a programmed change of temperature. The temperature difference between the crystalline sample and the reference material ( ⁇ ) remains the same until a thermal event occurs, such as melting, decomposition or change in the crystal structure.
  • the HPLC method used to determine LDA free base purity is outlined in Table 1.
  • the retention time of L-dopamide was typically 6.3+0.1 min. Samples were dissolved in Diluent A.
  • Dynamic vapor sorption is a gravimetric technique that measures how quickly and how much of a solvent, for example water, is absorbed by a sample, for example, powdered crystalline material, by varying the vapor concentration, e.g., relative humidity (RH) surrounding the sample, and measuring the change in mass which this produces.
  • the DVS instrument used measures uptake and loss of moisture by flowing a carrier gas at a specified relative humidity (or partial pressure) over the sample (weigh between 1 mg and 4 g) suspending from the weighing mechanism of an ultra-sensitive recording microbalance, which is capable of measuring changes in sample mass lower than 1 part in 10 million.
  • the water sorption isotherms obtained from DVS measurements of crystalline L- dopamide free base show the equilibrium amount of vapor sorbed by the sample as a function of steady state relative humidity at a constant temperature.
  • the sample was exposed to a series of step changes in RH, for example, a cycle of 40 - 90 - 0 - 40 % RH change, and the mass change was monitored as a function of time.
  • the sample mass allowed to reach gravimetric equilibrium at each step change in RH before progressing to the next humidity level. Then, the equilibrium mass values at each RH step were used to generate the isotherm.
  • the hygroscopicity of the sample was determined according the European Pharmacopoeia Classification, setting the degree of hygroscopicity of a substance as ranging from non-hygroscopic to very hygroscopic based on the weight increases measured at 40-80% RH (25 °C). According to this classification: weight gain ⁇ 0.2 %, non-hygroscopic; weight gain >0.2 % and ⁇ 2 %, slightly hygroscopic; weight gain >2 % and ⁇ 15%, hygroscopic; weight gain >15%, very hygroscopic; and deliquescent - sufficient water was absorbed to form a liquid.
  • Methanol 135.0 kg was cooled to a temperature of from about -5 °C to about 10 °C under nitrogen.
  • Thionyl chloride (22.6 kg, 190.0 mol, 1.5 eq.) was added while keeping the temperature below -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. 40 L.
  • 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 pH 4 - 7 (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 HC1 salt of L-dopamide (compound 13) in 2-propanol.
  • the temperature of the mixture was then adjusted to 40 - 45 °C, and seeding was performed if needed.
  • 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 (13) (85%) as a white to off-white solid.
  • 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 13 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 compound 14 (74%) as a white to off-white solid.
  • Synthesis of 14 was also conducted on a scale of 10.7 mol of 11 following a procedure similar to that described above, and 14 was produced in 67.9% (overall yield from 11).
  • Synthesis of 15 was also conducted on a scale of 10.2 mol of 11 following a procedure similar to that described above, and 15 was produced in 59.8% (overall yield from 11).
  • LDA FB Crystalline L-dopamide free base
  • the XRPD pattern obtained for LDA FB is indicative of a crystalline material.
  • This unique X-ray diffraction peak pattern herein referred to as "Pattern A", is shown in Figure 1.
  • the XRPD peaks are listed in Table 2.
  • the XRPD peaks pattern of the crystalline LDA free base of the present disclosure is characterized, for example, by at least peaks No. 8 and No.10. Additional peaks which characterize the crystalline LDA FB of the disclosure include, for example, peaks Nos. 5, 27, 29 and 34. Table 2.
  • Hyper DSC was performed in order to generate amorphous material from fast cooling of molten L-dopamide and determine the temperature of glass transition (T g ) during the re-heat cycle. Glass transition is characterized by change in heat capacity (Cp). A transition from the disordered solid to a liquid appeared as a step (endothermic direction) in the thermogram taken from the second heating of a heat-cool-heat cycle, demonstrating the presence of a T g , observed at -131.5 °C (half height Cp value).
  • the hygroscopicity and the sorption properties of L-dopamide were determined using dynamic vapour sorption (DVS) as described in Materials and Methods.
  • the sample was cycled from 40-90-0-40 % RH at ambient temperature.
  • the isotherm showed the material exhibited slow uptake of moisture, with a negligible increase in weight from 40 % RH to 80 % RH of 0.04 %, indicating that the sample was non-hygroscopic, based on the European Pharmacopoeia classification, which sets that weight increase ⁇ 0.2 % from 40% RH to 80% RH at 25 °C accounts for a non-hygroscopic material.
  • Dynamic vapor sorption (DVS) revealed that L-dopamide was a non-hygroscopic material with weight change of - 0.04 % (w/w dry basis) occurring between 40-80 % RH.
  • XRPD analysis of post-DVS samples revealed no change in physical form.
  • L-dopamide free base was soluble at ambient temperature in water at -26 mg/mL and THF/H2O at -29 mg/mL at -26 - 29 °C. At elevated temperatures L-dopamide free base was soluble in IPA and IPA/H2O. L-dopamide FB was practically insoluble in most organic solvents.

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Abstract

L'invention concerne une base libre d'amide de lévodopa cristallin et son procédé de fabrication. En particulier, l'invention concerne une base libre de lévodopa cristallin sensiblement pur, appropriée pour la préparation de compositions pharmaceutiques destinées au traitement de maladies ou de troubles caractérisés par une neurodégénérescence et/ou des niveaux réduits de dopamine cérébrale, telles que la maladie de Parkinson.
PCT/IB2018/056127 2017-08-21 2018-08-15 Base libre d'amide de lévodopa cristallin et procédés de fabrication et d'utilisation associés WO2019038639A1 (fr)

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Cited By (5)

* 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
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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
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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