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WO2019038637A1 - Formes de sel cristallin d'amide de lévodopa et leurs procédés de fabrication et d'utilisation - Google Patents

Formes de sel cristallin d'amide de lévodopa et leurs procédés de fabrication et d'utilisation Download PDF

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WO2019038637A1
WO2019038637A1 PCT/IB2018/056125 IB2018056125W WO2019038637A1 WO 2019038637 A1 WO2019038637 A1 WO 2019038637A1 IB 2018056125 W IB2018056125 W IB 2018056125W WO 2019038637 A1 WO2019038637 A1 WO 2019038637A1
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acid
salt
crystalline form
compound
powder
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Oron Yacoby-Zeevi
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Neuroderm Ltd
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Neuroderm Ltd
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    • 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
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    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
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    • C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
    • C07C59/10—Polyhydroxy carboxylic acids
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    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
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    • C07C63/04—Monocyclic monocarboxylic acids
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    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
    • C07C65/11—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic with carboxyl groups on a condensed ring system containing two rings
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/62—Three oxygen atoms, e.g. ascorbic acid
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    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates, in part, to levodopa amide pharmaceutically acceptable salts, particularly but not exclusively, crystalline levodopa amide pharmaceutically acceptable salts.
  • 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 or derivatives thereof, particularly 2- amino-3-(3,4-dihydroxyphenyl) propanamide, 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
  • 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 pharmaceutically acceptable salt of levodopa amide (LDA) compound represented by:
  • Y is a solvent such as, but not limited to,
  • n is a fractional ur whole number between about 0. and about 3 inclusive; and X is a compound ox a counter ion that forms a salt, such as, but not limited to, HC1,
  • the present disclosure provides a pharmaceutically acceptable salt and/or solvate (e.g., hydrate) of levodopa amide (L-dopamide) (e.g., as shown above), wherein the salt is selected, for example, from die group consisting of hydrochloric acid, fumaric acid, lactate, phosphate, and sulfate salt.
  • the salt is selected, for example, from die group consisting of hydrochloric acid, fumaric acid, lactate, phosphate, and sulfate salt.
  • a hydrate of a hydrochloric acid salt of L-dopamidc or an anhydrous hydrochloric acid salt of L- dopamide is provided herein.
  • crystalline forms of pharmaceutically acceptable salts and/or solvates e.g., hydrates
  • crystalline form B a powder X-ray diffraction pattern having characteristic peaks in degrees 2 ⁇ at about 10.0 about 23.8 and about 31.5
  • the present disclosure provides a crystalline form of an anhydrous hydrochloric acid salt of L-dopamide, wherein the crystalline farm is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2 ⁇ at about 20.9, about 24.0, about 28.5 and about 30.5 (herein designated "crystalline form A").
  • the present disclosure also provides a crystalline form of a fumaratc salt of L- dopamide, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2 ⁇ at about 5.6, about 15.0, about 17.0 and about 24.8; and a crystalline form of a lactate salt of L-dopamide, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2 ⁇ at about 8.2, about 11.0. about 18 -5, about 20.0 and about 29.0.
  • a crystalline form of a phosphate salt of L-dopamide wherein the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2 ⁇ at about 11.0, about 18.6, at about 18.9 and about 2S.S.
  • the present disclosure also provides, for example, a crystalline form of a sulfate salt of L-dopamide, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2 ⁇ at about 16.5, about 23.5, about 2S.0, at about 29, and about 31.0.
  • Contemplated herein is a pharmaceutical composition comprising a disclosed salt, solvate and/or crystalline form of the disclosure, and a pharmaceutically acceptable excipient.
  • a drug substance comprising e.g., at least a detectable amount of the crystalline form of the salt of the disclosure, and/or comprising substantially pure crystalline form of a salt of the disclosure.
  • Fig. 1A is the X-ray powder diffraction (XRPD) peaks pattern of hydrated L- dopatnide HCI salt (Pattern B), obtained using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray cube and a Pixcel detector system. XRPD patterns were sorted and manipulated using HighScore Plus 2.2c software;
  • Fig. IB is the ⁇ -NMR plot in intensity vs. ppm of hydrated L-dopamide HCI salt having XRPD peak pattern designated Pattern B;
  • Fig. 2A is the XRPD peaks pattern of anhydrous L-dopamide HCI salt (Pattern A), obtained using the diffractometer specified in Fig. 1A;
  • Fig. 2B is the ⁇ -NMR plot in intensity vs. ppm of anhydrous L ⁇ dopa ⁇ lide HCI salt; having XRPD peak pattern designated Pattern A;
  • Fig. 3A is the XRPD peaks pattern of L-dopamide sulfate salt, obtained using the diffractometer specified in Fig. I A;
  • Fig. 3B is the 'H-NMR plot in intensity vs. ppm of L-dopanndc sulfate salt
  • Fig. 4A is the XRPD peaks pattern of L-dopamide lactate salt, obtained using the diffractometer specified in Fig. 1A;
  • Fig.4B is the ⁇ -NMR plot in intensity vs. ppm of L-dopamide lactate salt
  • Fig. 5A is the XRPD peaks partem of L-dopamide phosphate salt, obtained using the diffractometer specified in Fig. 1A;
  • Fig. SB is the ⁇ -NMR plot in intensity vs. ppm of L-dopamide phosphate salt
  • Fig. 6A is the XRPD peak pattern of L-dopamide fumarate salt, obtained using the diffractometer specified in Fig. 1A;
  • Fig. 6B is the 'H-NMR plot in intensity vs. ppm of L-dopamidc fumarate salt.
  • Fig. 7 is the XRPD peak pattern of L-dopamide gluceptic acid, obtained using the diffractometer specified in Fig. 1A.
  • the present disclosure in an aspect thereof, is directed to salts of levodopa amide derivatives and solvates thereof, which may serve as prodrug of levodopa, especially new crystalline forms thereof.
  • pharmaceutically acceptable salts of crystalline levodopa amide derivatives such as hydrochloric acid, fumarate, lactate, phosphate, and sulfate salts, or solvates thereof, for example, hydrates, are described herein.
  • a hydrate of a hydrochloric acid salt of a levodopa amide derivative and an anhydrous hydrochloric acid salt of levodopa amide derivative are contemplated herein.
  • Embodiments of the present disclosure concern salts of the levodopa amide compound propanamide, herein interchangeably referred to as “L-dopamide” or “LDA”.
  • L-dopamide salt and “LDA salt” are interchangeably used herein to denote a salt of 2-amino-3-(3,4-dihydroxyphenyl) propanamide.
  • Y is a solvent
  • n is a fractional or whole number between about 0 and about 3 inclusive; and X is a compound or a counter ion that forms a salt with LDA, for example, an L- dopamide acid addition salt.
  • X is further referred to herein as "salt former” or "acid salt former".
  • solvate refers to an aggregate or a complex that consists of a solute ion or molecule associated with one or more solvent molecules.
  • solvent molecules are water
  • the solvate is also referred to herein as "hydrate”.
  • a “non-solvate” or “non-solvated compound” is a solute ion or molecule substantially free of solvent molecules.
  • a solute substantially free of water molecule is referred to as "anhydrate”.
  • the indicator "m” represents the amount of solvent relative to LDA in the solvate, for example, the number of moles of solvent associated with 1 mole of LDA, or number of solvent molecules associated with one LDA molecule, or weight percent of the solvent remains in a LDA solvate.
  • a non-solvate is characterized with the indicator m being in the range of from 0.0 to about 0.1, or from 0.00 to about 0.01.
  • Y is selected from, for example, H2O, CH3CH2OH, CH3OH, isopropanol, acetonitrile, tetrahydrofuran (THF), and mixtures thereof, for example, THF/water (50:50 %v/v), THF/water (98:2 %v/v), or MeOH/THF/water.
  • the salt former X may be, for example, HQ, acetic acid, ascorbic acid, L-aspartic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, benzoic acid, p- toluenesulfonic acid, hippuric acid, formic 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, oxalic acid, phosphoric acid propionic (propanoic) acid, succinic (butanedioic) acid,
  • X is an acidic salt former, for example, selected from the group consisting of
  • Solvates e.g., hydrates
  • non-solvates e.g., anhydrates
  • crystalline forms of LDA are contemplated herein.
  • m is 0, in other embodiments m is about 1, in still other embodiments m is from about 1.2 to about 1.5, and in yet other embodiments m is about 1.6.
  • X may be HC1 and m is 0, or X may be HC1 and Y may be H2O and m is, for example, about 1.6.
  • the LDA salts contemplated herein may be pharmaceutically acceptable salts as defined herein, for example, hydrated or anhydrous pharmaceutically acceptable hydrochloric acid, fumaric acid, lactic acid, phosphoric acid, and sulfuric acid LDA salt.
  • a hydrochloric acid salt of L-dopamide or an anhydrous hydrochloric acid salt of L-dopamide is contemplated.
  • LDA salt and solvates thereof described herein may be crystalline or noncrystalline.
  • 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. The unit cells are stacked in three-dimensional space to form the crystal.
  • 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. The different polymorphs are usually referred to as different phases.
  • a single fluid can solidify into many different possible forms. It can form a single crystal, perhaps with various possible phases, stoichiometries, 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, i.e., different polymorphs may differ considerably from one another in many respects including solubility, dissolution rate and/or bioavailability. 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.
  • 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.
  • Described crystalline forms have X-ray powder diffraction (XRPD) pattern that may be obtained using Cu Ka radiation. Copper is the common target material for powder X-ray diffraction, with The term "about" in this context of XRPD means that there is an uncertainty in the measurements of the 2 ⁇ of ⁇ 0.S (expressed in 2 ⁇ ) or that there is an uncertainty in the measurements of the 2 ⁇ of ⁇ 0.2 (expressed in 2 ⁇ ).
  • Embodiments described herein provide a crystalline form of a pharmaceutically acceptable salt solvate of LDA, for example, a crystalline form of a hydrate of hydrochloric acid salt of LDA (hydrated LDA HC1 salt).
  • the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2 ⁇ at about 10.0, about 23.8 and about 31.S.
  • the crystalline form has a powder X-ray diffraction pattern substantially the same as depicted in Figure 1 A and/or the of Figure IB.
  • crystalline form A A crystalline characterized by or exhibiting peak Pattern A is designated herein "crystalline form A”.
  • a crystalline form of anhydrous hydrochloric acid salt of IDA is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2 ⁇ at about 20.9. about 24.0. about 28.S and about 30.5.
  • the crystalline form has a powder X-ray diffraction pattern substantially the same as depicted in Figure 2A and/or the ⁇ -NMR of Figure 2B.
  • Pattern B The X-ray diffraction peak pattern presented in Figure 1A is termed herein "Pattern B”.
  • a crystalline characterized by or exhibiting peak Pattern B is designated herein "crystalline form B”.
  • a crystalline form of a fumaric acid salt of LDA is provided, wherein the crystalline form of the fumarate salt of LDA is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2 ⁇ at about 5.6, about 15.0, about 17.0' and about 24.8.
  • the crystalline form has a powder X-ray diffraction pattern substantially the same as depicted in Figure 6A and/or the ⁇ -NMR of Figure 6B.
  • a crystalline form of a lactate salt of LDA is provided, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2 ⁇ at about 8.2 about 11.0, about 18.5, about 20.0 and about 29.0.
  • the crystalline form has a powder X-ray diffraction pattern substantially the same as depicted in Figure 4A and/or the ⁇ - ⁇ of Figure 4B.
  • a crystalline form of a phosphate salt of LDA is provided, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2 ⁇ at about 11.0, about 18.6, at about 18.9 and about 25.5.
  • the crystalline form has a powder X-ray diffraction pattern substantially the same as depicted in Figure 5A and/or the 1 H-NMR of Figure 5B.
  • a crystalline form of a sulfate salt of LDA is provided, wherein the crystalline form is characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 20 at about 16.5, about 23.5, about 25.0, at about 29, and about 31.0.
  • the crystalline form has a powder X-ray diffraction pattern substantially the same as depicted in Figure 3 A and/or the ' H-NMR of Figure 3B.
  • a disclosed crystalline form has less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 1%, between about 0.01% and 10%, or between about 0.01% and 1%, in content, of crystalline free base form of L-dopamide (herein designated "LDA FB").
  • LDA FB L-dopamide
  • Embodiments described herein concern LDA salt such as LDA HQ salt, optionally in their pure crystalline form.
  • the LDA salts 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, for example, a pharmaceutically acceptable LDA salt, also referred to herein as "active pharmaceutical ingredient" or " ⁇ ', produced or made by a disclosed process, for example, a crystallization process, which contains, besides the principle API molecules, small amounts of impurities as defined herein, particularly, but not exclusively, remains of L-dopamide free base, L-dopa and/or L-dopa salt, reaction solvent, anion and/or cations e.g., of salts or buffers used in the crystallization process.
  • a "small amount" of impurities is defined as a total amount of impurities which is less than 10% of total product, namely of total content or total composition of the product.
  • a pure product according to embodiments described herein is a pharmaceutically acceptable LDA salt product and/or a solvate thereof, for example, crystalline LDA HC1 salt, containing less than 10% of 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 pharmaceutically acceptable pharmaceutically acceptable LDA salt or a solvate thereof may comprise residual amounts of LDA free base, L-dopa (LD) and/or a L-dopa salt (LD salt) in total amounts of from about 1% to about 10%, for example, from about 1% to about 2%, from about 2% to about 4%, from about 3% to about 5%, from about 5% to about 10%, or from about 8% to about 10%, of total product, and any ranges, subranges or individual values therebetween.
  • LDA free base L-dopa
  • LD salt L-dopa salt
  • a pure pharmaceutically acceptable LDA salt for example, a hydrated LDA HC1 salt or an anhydrous LDA HQ salt, may contain less than less than 10%, less than 8%, less than 5%, or less than 3%, of LDA free base, LD and/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
  • purity of a disclosed LDA salt 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 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%, of the crystalline.
  • a contemplated substantially pure crystalline pharmaceutically acceptable LDA salt 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 salt may have some LD and/or LD 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% LD and/or LD salt, wherein such levels can be characterized by HPLC.
  • a substantially pure crystalline LDA salt has about 0.3% LD and/or LD salt by HPLC (namely assessed or detennined by HPLC).
  • a disclosed substantially pure crystalline LDA salt may have some L-dopamide 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% crystalline free base form of L-dopamide by HPLC.
  • a substantially pure crystalline LDA salt has from about 0.3% to about 2.5% crystalline free base form of L-dopamide.
  • Crystals of L-dopamide salts and/or hydrates may be obtained using any one or more crystallization techniques known in the art.
  • Non-limiting examples of commonly used techniques include solvent evaporation, slow cooling of the solution, solvent/non-solvent diffusion, vapour diffusion or vapour stress, sublimation, sonication, slurry formation, and the melt-cool technique.
  • the choice of technique may be dictated, for example, by the amount of sample, stability of the crystalline product and reagents availability.
  • Some of the crystallization techniques are further described and exemplified in Example 1 herein.
  • a contemplated crystalline LDA salt is obtained by the solvent evaporation technique, which is the simplest technique for air stable samples.
  • a near saturated solution is prepared in a suitable solvent.
  • the sample can then be left in a sample vial or a crystallization dish that has a perforated cap/cover, wherein the size of the perforations depends to some extent on the volatility of the sample.
  • the solvent is completely evaporated, the crystals may be collected.
  • a contemplated crystalline LDA salt is obtained by the slow cooling technique. This technique is suitable for less soluble solute-solvent systems where the boiling point of the solvent is in the range of 30 - 90 °C. A saturated solution is prepared where the solvent is heated to just below the boiling point for, e.g., an hour, and then allowed to cool, for example to room temperature. Solids formed after few days may then be collected.
  • a contemplated crystalline LDA salt is obtained by melt crystallization technique, also referred to herein as "melt-cool” technique.
  • melt crystallization technique also referred to herein as "melt-cool” technique.
  • This technique can be regarded as a special form of cooling crystallization process, the main difference being the absence of solvents, which implies that most melt crystallization processes are operated close to the melting point of the pure product.
  • the feed (initial product) for a melt crystallization process is an impure melt. Cooling this melt below the equilibrium temperature will typically result in the formation of a solid phase that is purer than the feed, while the impurities prefer to stay in the impure mother liquor.
  • a contemplated crystalline LDA salt is obtained by the solvent diffusion technique, particularly suitable for microgram quantities of sample that are air and/or solvent sensitive.
  • a solution is placed in a sample tube, then a second less dense solvent is carefully dripped down the side of the tube using either a pipette or a syringe to form a discreet layer. Crystals form at the boundary where the solvents slowly diffuse.
  • a contemplated crystalline LDA salt is obtained by sonication.
  • Sonication also known as sonocrystallization is the application of ultrasound insonation to initiate and enhance the crystallization process.
  • the main attributes of the sonocrystallization process are fast nucleation rate, promoting nucleation at low supersaturation levels, and yielding fine crystals with a narrow crystal size distribution.
  • salt refers to any salt of an acidic or a basic group that may be present in a compound of the present disclosure, which do not produce an adverse, allergic or other untoward reaction and 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 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 salt of the disclosure or a solvate thereof, 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
  • a contemplated L-dopamide salt of the disclosure or a solvate thereof, for example, in its crystalline form for example, in its crystalline form.
  • the term "drug substance”, as referred to herein, 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 an LDA salt of the disclosure, for example crystalline form A and/or crystalline form B as defined herein.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable LDA salt 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.
  • a formulation for pharmaceutical administration the APIs are combined or formulated together with one or more pharmaceutically and physiologically acceptable carriers, which can be administered to a subject (e.g., human or non-human subject) in a specific form, such as, but not limited to, tablets, linctus, ointment, infusion or injection.
  • a pharmaceutical composition is sometimes also referred to herein as "medicinal formulation”.
  • Some embodiments described herein pertain to liquid pharmaceutical compositions, for example aqueous formulations.
  • a contemplated pharmaceutical composition e.g., formulation
  • a suspension is a contemplated pharmaceutical composition.
  • active agent active agent
  • active ingredient active pharmaceutical ingredient
  • API 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.
  • a disclosed formulation may comprise, pure or substantially pure crystalline pharmaceutically acceptable LDA salt 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 LD A HC1 salt 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 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-tert-butyl methyl phenols, terr-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-tert-butyl methyl phenols, terr-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, galactos amine 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, e.g., medicinal formulation may comprise a buffer.
  • buffers examples 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 described herein.
  • Such a lyophilized powder can be reconstituted into a liquid formulation by addition of water with or without antioxidants, surfactants and other excipients.
  • a disclosed pharmaceutical composition may be formulated as a liquid, gel, cream, solid, film, emulsion, suspension, solution, lyophylisate or aerosol.
  • a contemplated pharmaceutical composition may be formulated as a liquid.
  • these dosage unit forms can be formulated in different forms.
  • a first unit dosage form comprising, e.g. one or more pharmaceutical acceptable LDA salt 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, 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.
  • All compositions for any form of administration may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.
  • a contemplated composition or formulation comprising a disclosed API may be stable for at least 24 hours. For example, for at least 30 hours, at least 48 hours, at least SO 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 2S°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 described herein.
  • composition administered to a subject in need thereof may comprise form about 5% to about 25% of a pure pharmaceutically acceptable LDA salt.
  • ''Administration 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, IS hours, 18 hours, 21 hours, 24 hours, 12 to 16 hours, 16 to 18 hours, 18 to 20 hours, or 20 to 24 hours.
  • a dosage e.g., a single dosage
  • a disclosed pharmaceutical composition may be administered, e.g., substantially continuously, at a rate of from 0.01 ml/hour/site to 0.6 ml/hour/site, e.g., from 0.08 ml/hour/site to 0.24 ml/hour/site.
  • Such rates may be constant throughout the day and night or varied according to patient's need, e.g., may reflect a patient resting or sleeping schedule and waking or higher activity level schedule.
  • a contemplated method may comprise subcutaneous or intraduodenal administration of a disclosed pharmaceutical composition at a rate of, for example, 0.32 ml/hour/site or 1.0 ml/hour, respectively, in the morning (e.g., for 2-4 hours before waking), 0.24 ml/hour/site during the daytime or activity time (e.g., for 10 to 14 hours), and/or 0.08 ml/hour/site or 0.0 to 0.S 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 uL/hour to about 1000 ⁇ /hour, 300 ⁇ 100 ⁇ L/hour, or 200 ⁇ 40 uL/hour continuously for 24 hours; 440 ⁇ 200 ⁇ -Jhour or 200 ⁇ 50 ⁇ L/hour continuously for 16 hours (during waking hours) and from 0 to about 80 ⁇ /hour or 0 to 200 uL/hour for 8 hours (at night).
  • substantially continuously administering a disclosed composition to a patient can be doubled or tripled by using more than one pump, patch, or infusion site.
  • substantially continuously administering using, e.g., a liquid composition can be at an average rate of 0.2-2 pL/hour, or 1 ⁇ 0.S pL/hour continuously for 24 hours; 1 ⁇ 0.S ⁇ continuously for 16 hours (during waking hours) and from 0 to about 0.S ⁇ -Jhour 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 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 salt, 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 described herein; (ii) a second pharmaceutical composition comprising one or more decarboxylase inhibitors or salts thereof; (iii) optionally, one or more of a basic amino acid, an amino sugar, a catechol- O-methyl transferase (COMT) inhibitor, or a monoamine oxidase (MAO) inhibitor; and (iv) optionally, instructions for co-administration of the pharmaceutical compositions.
  • a first pharmaceutical composition comprising one or more pure pharmaceutically acceptable LDA salts described herein
  • a second pharmaceutical composition comprising one or more decarboxylase inhibitors or salts thereof
  • optionally, one or more of a basic amino acid, an amino sugar, a catechol- O-methyl transferase (COMT) inhibitor, or a monoamine oxidase (MAO) inhibitor optionally, instructions for co-administration of the pharmaceutical compositions.
  • 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.
  • salt former An acid or base used for LDA salt formation is referred to herein as "salt former”.
  • test solvent water, typically ,10 uL
  • test solvent water, typically ,10 uL
  • IR infrared
  • Dissolution and precipitation events were recorded as the point of complete transmission of IR and the onset of turbidity by IR, respectively.
  • the solubility was estimated from these experiments based on the total solvent used to provide complete dissolution.
  • the solubility values for LDA and salts thereof were expressed as a range and rounded to the nearest whole number.
  • a solution of the salt former (-1 M, -100-102 ⁇ L, 1 mol. eq.) or neat salt former (1 mol. eq.) and LDA in THF/water (50:50 %v/v, 0.4 M, 253 ⁇ L ⁇ , 1 mol. eq.) were added to a clean HFLC vial and evaporated to dryness.
  • Methanol (2 volumes) was added to the solids and the mixtures were slurred for 5 days at 40 °C. Any solids present were collected by centrifugation, solvent was decanted and the solids were dried with thin strips of filter paper prior to analysis by XRPD.
  • methyl terf-butyl ether (MTBE) (4 volumes) was added and the mixture was stirred for 90 minutes at 40 °C (-400 rpm) before the heat was switched off. Any solids present were collected by centrifugation, solvent decanted and the solids were dried as described above prior to analysis by XRPD. Oils or waxes which were isolated were used for further experiments.
  • MTBE methyl terf-butyl ether
  • X-ray powder diffraction analyses were performed using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube and a Pixcel detector system The isothermal samples were analyzed 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).
  • X-ray powder diffraction patterns were sorted and manipulated using HighScore Plus 2.2c software.
  • Hi Thermogravimetric Analysis
  • Thermogravimetric analyses were carried out on a Mettler Toledo TGA/DSC1 STARe.
  • the calibration standards were indium and tin. Samples were placed in an aluminum sample pan, inserted into the TG furnace and accurately weighed. The heat flow signal was stabilized for one minute at 25 °C, prior to heating to 300 °C in a stream of nitrogen at a rate of 10°C/minute.
  • Microscopy analyses were carried out using an Olympus BX51 stereomicroscope with crossed-polarized light and a 1st order red compensator plate.
  • Photomicrographic images were captured using a ColorView IIIu digital camera and SynchronizIR basic V5.0 imaging software with objective lens magnification of xlO.
  • L-dopamide free base was a crystalline anhydrate containing residual EtOH (-0.1 mol. eq.).
  • EtOH -0.1 mol. eq.
  • Levodopa was contacted with a chlorinating mixture comprising n-propanol and thionyl chloride at a temperature of from about -S °C to about 0 °C so as to form L-dopa propyl ester.
  • Crude L-dopa propyl eater was precipitated form a basic solution (pH 8), then dissolved in a mixture of ethyl acetate and BTH and precipitated from this mixture.
  • L-dopa propyl ester was prepared in 28% aqueous ammonia, and precipitation of crude L-dopamide was effected from ethanol solution containing an antioxidant (e.g., 0.05%w/vBHT).
  • an antioxidant e.g., 0.05%w/vBHT.
  • the crude L-dopamde free base was purified by re-cyrstallization from ethanol solution containing an antioxidant (0.01 % L-ascorbyl palmitate) as a pale yellow solid.
  • L-dopamide salts were prepared as described in Materials and Methods. Most experiments were set up as 1:1 LDA:salt former molar ratio. Evaporation, slow cooling, sonication, slurry experiments, and vapour stress were the methods employed for solid salt formation. These methods are described in Material and Methods above.
  • the LDA salts were assessed using a number of properties; crystallinity, crystal habit, ease of manufacture, hygroscopicity, aqueous solubility, chemical stability, solvent content and polymorphic complexity. Some of the salt formers yielded oils, gels or solids composed of mixtures of FB and salt former.
  • Salt Pattern B Unique (novel) crystalline solids exhibiting XRPD peaks pattern, herein designated “Salt Pattern B”, were isolated from experiments with HQ (for example, using the slow evaporation, slurrying in water and sonication techniques).
  • the XRPD peaks of pattern of Salt Pattern B of L-dopamide HQ salt is shown in Fig. 1A, and the 'H-NMR plot of this crystalline salt is shown in Fig. IB.
  • Salt Pattern A Further unique crystalline HQ salts of LDA exhibiting XRPD peaks pattern herein designated "Salt Pattern A”, were isolated from experiments using other crystallization techniques, for example, the slurry technique.
  • the XRPD peaks pattern of Salt Pattern A of L-dopamide HQ salt is shown in Fig. 2A, and the 'H-NMR plot of this crystalline salt is depicted in Fig. 2B.
  • the LDA-phosphate salt was a crystalline anhydrate with assumed stoichiometry of 1:1 LDA:salt former.
  • the LDA fumarate salt was a crystalline EtOH solvate containing -1.2-1.5 mol. eq of EtOH.
  • L-dopamide lactate salt exhibiting Salt Pattern A XRPD peaks gained - 8% weight after stressing, however XRPD analysis showed no form change had occurred.

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Abstract

La présente invention concerne divers sels d'amide de lévodopa, et des formes cristallines associées, et des compositions pharmaceutiques comprenant les sels ou formes cristallines, qui sont utiles dans le traitement de maladies ou de troubles caractérisés par une neurodégénérescence et/ou des niveaux réduits de dopamine cérébrale comme la maladie de Parkinson.
PCT/IB2018/056125 2017-08-21 2018-08-15 Formes de sel cristallin d'amide de lévodopa et leurs procédés de fabrication et d'utilisation Ceased WO2019038637A1 (fr)

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Cited By (6)

* 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
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
US11844754B2 (en) 2020-11-17 2023-12-19 Neuroderm, Ltd. Methods for treatment of Parkinson's disease
US12161612B2 (en) 2023-04-14 2024-12-10 Neuroderm, Ltd. Methods and compositions for reducing symptoms of Parkinson's disease

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8048926B2 (en) 2003-02-07 2011-11-01 Yissum Research Development Company Of The Hebrew University Of Jerusalem L-DOPA amide derivatives and uses thereof
WO2017090039A2 (fr) 2015-11-24 2017-06-01 Neuroderm Ltd. Compositions pharmaceutiques comprenant un amide de lévodopa et ses utilisations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8048926B2 (en) 2003-02-07 2011-11-01 Yissum Research Development Company Of The Hebrew University Of Jerusalem L-DOPA amide derivatives and uses thereof
WO2017090039A2 (fr) 2015-11-24 2017-06-01 Neuroderm Ltd. Compositions pharmaceutiques comprenant un amide de lévodopa et ses utilisations

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ELDER DAVID P ET AL: "Use of pharmaceutical salts and cocrystals to address the issue of poor solubility", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 453, no. 1, 2010, pages 88 - 100, XP028675213, ISSN: 0378-5173, DOI: 10.1016/J.IJPHARM.2012.11.028 *
STEFFEN PAULEKUHN G ET AL: "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 50, no. 26, 27 December 2007 (2007-12-27), pages 6665 - 6672, XP002651069, ISSN: 0022-2623, [retrieved on 20071201], DOI: 10.1021/JM701032Y *
ZHOU T ET AL: "Design, synthesis and biological evaluation of l-dopa amide derivatives as potential prodrugs for the treatment of Parkinson's disease", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 45, no. 9, 1 September 2010 (2010-09-01), pages 4035 - 4042, XP027458833, ISSN: 0223-5234, [retrieved on 20100602], DOI: 10.1016/J.EJMECH.2010.05.062 *

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
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
US12161612B2 (en) 2023-04-14 2024-12-10 Neuroderm, Ltd. Methods and compositions for reducing symptoms of Parkinson's disease

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