Pharmaceutical compositions comprising a tartrate salt of n-[2-(3-fluoro-5-methane-sulfonylphenoxy) ethyl] (propyl)amine

Abstract

Pharmaceutical compositions comprising tartrate salts of medopredane and methods for making the pharmaceutical compositions are provided. The pharmaceutical composition is useful in the treatment of diseases such as L-DOPA induced dyskinesia.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480051310.8 (22) Application Date 2024.08.06 (30) Priority Data 2312055.3 2023.08.07 GB (85) PCT International Application Entering National Phase Date 2026.02.04 (86) PCT International Application Application Data PCT / EP2024 / 072281 2024.08.06 (87) PCT International Application Publication Data WO2025 / 032103 EN 2025.02.13 (71) Applicant: Ireland 790 AG Address: Gothenburg, Sweden (72) Inventors: Thibault Dupont, Klas Soneson, Anne Petit, Laurent Bertock, Marie Delport, Didier Kubiak (74) Patent Agency: Beijing Sanju Sunshine Intellectual Property Agency Co., Ltd. 11250 Patent Attorney: Qin Jie (51) Int.Cl. A61K 9 / 16 (2006.01) (54) Invention Title: Pharmaceutical Composition Containing Tartrate of N-[2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine (57) Abstract: A pharmaceutical composition containing tartrate of levodopa and a method for manufacturing the pharmaceutical composition are provided. The pharmaceutical composition can be used to treat diseases such as L-DOPA-induced movement disorders. Claims (5 pages), Description (29 pages), Drawings (6 pages), CN 121620362 A 2026.03.06 CN 1 21 62 03 62 A 1. A pharmaceutical composition comprising: a solid particulate crystalline hemitartaric acid salt of ledoperidine, wherein the hemitartaric acid salt of ledoperidine is a combination of ledoperidine and tartaric acid in a molar ratio of 1:0.5; wherein the hemitartaric acid salt has a particle size distribution in which D90 < 350 μm and / or D50 < 150 μm; a diluent; a disintegrant; a lubricant; and optionally a flow aid. 2. The pharmaceutical composition according to claim 1, wherein D90 < 300 μm, < 290 μm, < 280 μm, < 270 μm or < 260 μm; and / or D50 < 140 μm, < 120 μm, 100 μm or < 80 μm. 3. The pharmaceutical composition according to claim 1 or 2, wherein D90 < 300 μm. 4. The pharmaceutical composition according to any of the preceding claims, wherein the tartaric acid is L-(+)-tartaric acid and / or D-(-)-tartaric acid. 5. The pharmaceutical composition according to any of the preceding claims, wherein the tartaric acid is L-(+)-tartaric acid.6. The pharmaceutical composition according to any one of claims 1 to 4, wherein the tartaric acid is D-(-)-tartaric acid. 7. The pharmaceutical composition according to any one of the preceding claims, wherein the solid particulate crystalline hemitartarate of ledopetan is characterized in that its XRP diffraction pattern includes a peak at 13.0 2θ and optionally at least one, at least two, at least three, or four additional peaks selected from the group consisting of: 12.4 2θ, 14.4 2θ, 21.1 2θ, and 24.4 2θ. 8. The pharmaceutical composition according to any one of the preceding claims, wherein the solid particulate crystalline hemitartarate of ledopetan is characterized in that its XRP diffraction pattern includes peaks at 12.4 2θ, 13.0 2θ, 14.4 2θ, 21.1 2θ, and 24.4 2θ and optionally at least one additional peak selected from the group consisting of: 19.62 2θ and 21.44 2θ. 9. The pharmaceutical composition according to any one of the preceding claims, wherein the solid particulate crystalline hemitartarate of ledoperamide is characterized in that its XRP diffraction pattern corresponds to FIG. 1. 10. The pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises 3 wt% to 20 wt% of solid particulate crystalline ledoperamide hemitartarate on a dry solids basis. 11. The pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises: about 3 wt% to about 20 wt% of solid particulate crystalline ledoperamide hemitartarate, 75 wt% to 95 wt% of a diluent, 1 wt% to 5 wt% of a disintegrant, 0.1 wt% to 1.0 wt% of a lubricant, and 0.1 wt% to 1.5 wt% of a flow aid, all on a dry solids basis.12. The pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises: (i) 3 wt% to 5 wt% of solid particulate crystalline ledopetan hemitartarate, 90 wt% to 93 wt% of diluent, 3 wt% of disintegrant, 0.5 wt% of lubricant, and 1 wt% of flow aid, all on a dry solids basis; (ii) 7 wt% to 9 wt% of solid particulate crystalline ledopetan hemitartarate, 86 wt% to 89 wt% of diluent, 3 wt% of disintegrant, 0.5 wt% of lubricant, and 1 wt% of flow aid, all on a dry solids basis; (iii) 11 wt% to 13 wt% of solid particulate crystalline ledopetan hemitartarate, 82 wt% to 85 wt% of diluent, 3 wt% of disintegrant, 0.5 wt% of lubricant, and 1 wt% of flow aid, all on a dry solids basis. (iv) wt% of a diluent, 3 wt% of a disintegrant, 0.5 wt% of a lubricant, and 1 wt% of a flow aid, all on a dry solids basis; or (iv) 5 wt% to 17.5 wt% of solid particulate crystalline ledopertan hemitartarate, 78 wt% to 80 wt% of a diluent, 3 wt% of a disintegrant, 0.5 wt% of a lubricant, and 1 wt% of a flow aid, all on a dry solids basis. 13. The pharmaceutical composition according to any one of the preceding claims, wherein the diluent comprises a carbohydrate, a pharmaceutically acceptable synthetic polymer, an inorganic diluent, or a mixture thereof.14. The pharmaceutical composition according to any one of the preceding claims, wherein: the diluent comprises cellulose, carboxymethyl cellulose, alginate, starch, glucose binder, dextrin, maltodextrin, one or more sugars, one or more sugar alcohols, vinylpyrrolidone-vinyl acetate copolymer, calcium carbonate, calcium phosphate, calcium sulfate, kaolin, magnesium carbonate, magnesium oxide, sodium chloride, or any mixture thereof; the disintegrant comprises alginic acid, calcium alginate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, powdered cellulose, chitosan, colloidal silica, croscarmellose sodium, croscarmellose, docusate sodium, guar gum, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, polacolin potassium, povidone, sodium alginate, sodium glycolate starch, starch, pregelatinized starch, or any mixture thereof; The lubricant comprises calcium stearate, magnesium stearate, zinc stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitate stearate, leucine, medium-chain triglycerides, mineral oil, light mineral oil, myristic acid, palmitic acid, polyethylene glycol, polyoxyethylene stearate, potassium benzoate, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearoyl fumarate, stearic acid, talc, hydrogenated vegetable oil, sucrose fatty acid esters, or any mixture thereof; and if present, the flow aid comprises tricalcium phosphate, powdered cellulose, colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, starch, talc, or any mixture thereof. 15. The pharmaceutical composition according to any one of the preceding claims, wherein the diluent is pregelatinized starch, the disintegrant is sodium glycolate starch, the flow aid is colloidal silica, and / or the lubricant is magnesium stearate. 16. The pharmaceutical composition according to any one of the preceding claims, wherein the solid particulate crystalline hemitartaric acid salt is provided in an amount corresponding to about 2 mg to about 10 mg of the free base of ledoperamide. 17. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is formulated for immediate release. 18. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is formulated for oral administration. 19. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is encapsulated. 20. A solid particulate crystalline hemitartaric acid salt of ledoperamide, characterized in that it has a particle size distribution of D90 < 350 μm or < 300 μm and / or D50 < 150 μm.21. The solid granular crystalline hemitartaric acid salt of ledopastatine according to claim 20, wherein D90 < 300 μm, < 290 μm, < 280 μm, < 270 μm or < 260 μm, and / or D50 < 140 μm, < 120 μm, 100 μm or < 80 μm. 22. The solid granular crystalline hemitartaric acid salt of ledopastatine according to claim 20 or 21, wherein D90 < 300 μm. 23. The solid granular crystalline hemitartaric acid salt of ledopastatine according to any one of claims 20 to 22, wherein the tartaric acid is L-(+)-tartaric acid and / or D-(-)-tartaric acid. 24. The solid granular crystalline hemitartaric acid salt of ledopastatine according to any one of claims 20 to 23, wherein the tartaric acid is L-(+)-tartaric acid. 25. The solid granular crystalline hemitartaric acid salt of ledopastatine according to any one of claims 20 to 23, wherein the tartaric acid is D-(-)-tartaric acid. 26. The solid granular crystalline hemitartaric acid salt of ledopastatine according to any one of claims 20 to 25, characterized in that the XRP diffraction pattern includes a peak at 13.0 2θ and optionally at least one, at least two, at least three, or four additional peaks selected from the group consisting of: 12.4 2θ, 14.4 2θ, 21.1 2θ, and 24.4 2θ. 27. The solid granular crystalline hemitartaric acid salt of ledopastatine according to any one of claims 20 to 26, characterized in that the XRP diffraction pattern includes peaks at 12.4 2θ, 13.0 2θ, 14.4 2θ, 21.1 2θ, and 24.4 2θ and optionally at least one additional peak selected from the group consisting of: 19.62 2θ and 21.44 2θ. 28. The solid granular crystalline hemitaritate of medopetan according to any one of claims 20 to 27, characterized in that the XRP diffraction pattern corresponds to Figure 1.29. A method for preparing a pharmaceutical composition according to any one of claims 1 to 19, the method comprising: a) weighing and sieving a solid particulate crystalline ledopetan hemitartarate as defined in any one of claims 1 to 28, a diluent, a disintegrant, and optionally a flow aid; b) blending the solid particulate crystalline ledopetan hemitartarate with about one-third of the total amount of the diluent to form a first premixed composition, and optionally sieving the first premixed composition; c) preparing a second premixed composition comprising about one-third of the total amount of the diluent, optionally wherein preparing the second premixed composition comprises blending about one-third of the diluent with the flow aid; and optionally sieving the second premix; d) blending the first and second premixed compositions with a disintegrant and about one-third of the total amount of the diluent to form a first dry mixture, and optionally sieving the first dry mixture; e) Weighing and sieving the lubricant, and blending the lubricant with the first dry blend composition, optionally with any additional excipients, flavoring agents, sweeteners and / or coloring agents, to form a final blend composition; and f) optionally compressing the final blend composition or filling the final blend composition into capsules.30. The method of claim 29, wherein the method comprises: a) weighing and sieving the solid particulate crystalline ledopetan, diluent, disintegrant, and flow aid as defined in any one of claims 1 to 28; b) blending the solid particulate crystalline ledopetan hemitartaric acid salt with about one-third of the total amount of diluent to form a first premixed composition, and sieving the first premixed composition; c) preparing a second premixed composition comprising about one-third of the total amount of diluent, wherein preparing the second premixed composition comprises blending about one-third of the diluent with the flow aid; and sieving the second premixed composition; d) blending the first and second premixed compositions with the disintegrant and about one-third of the total amount of diluent to form a first dry mix, wherein preparing the first dry mix comprises: i. adding the first premixed composition to the second premixed composition in a mixer tank; ii. adding the disintegrant to the first and second premixed compositions in the mixer tank; iii. iv. Add approximately one-third of the total amount of diluent to the first and second premixed compositions and disintegrant in the mixer tank; and iv. Blend the first and second premixed compositions, disintegrant, and diluent in the mixer tank; and sieve the first dry blend composition; e) Weigh and sieve the lubricant and blend the lubricant with the first dry blend composition, optionally with any additional excipients, flavoring agents, sweeteners, and / or coloring agents, to form a final blend composition; and f) Optionally compress the final blend composition to form a compressed composition such as a tablet or fill the final blend composition into capsules such as hard capsules or soft capsules. 31. The method according to claim 29 or claim 30, wherein the blending in step (b) is performed for about 1 minute to about 15 minutes; the blending in step (c) is performed for about 1 minute to about 15 minutes; the blending in step (d) is performed for about 15 minutes to about 45 minutes; and / or the blending in step (e) is performed for about 1 minute to about 15 minutes. 32. The method according to any one of claims 29 to 31, wherein the blending in steps (b), (c), (d) and / or (e) is performed at a speed of about 10 rpm to about 20 rpm. 33. The method according to any one of claims 29 to 32, wherein the diluent, the disintegrant, the lubricant, and / or the flow aid are as defined in any one of claims 13 to 15. 34. The method according to any one of claims 29 to 33, wherein the solid crystalline medopetan hemitartaric acid salt is ground prior to step (a).35. A pharmaceutical composition obtained by any one of claims 29 to 34, or obtainable by any one of claims 29 to 34. 36. The pharmaceutical composition according to any one of claims 1 to 19 or 35, for the treatment and / or prevention of diseases, disorders and / or conditions selected from: psychosis, schizophrenia, schizophrenia-like disorders, bipolar disorder, psychotic disorders, drug-induced psychotic disorders, mood disorders, anxiety disorders, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Tourette syndrome, brain injury, sleep disorders, sexual dysfunction, eating disorders, obesity, headache, pain in a condition characterized by increased muscle tone, Parkinson's disease, Parkinson's syndrome, movement disorders, L-DOPA-induced movement disorders, tardive dyskinesia, dystonia, tic and tremor dementia, Huntington's disease, drug-induced movement disorders, restless legs, narcolepsy, Alzheimer's disease and disorders associated with Alzheimer's disease. 37. The pharmaceutical composition of claim 36, wherein the disease, disorder, and / or condition is schizophrenia, L-DOPA-induced movement disorder, and / or Huntington's disease. 38. The pharmaceutical composition of claim 36 or 37, wherein the pharmaceutical composition is administered at a dose of 2 mg to 10 mg, such as 2.5 mg, 5.0 mg, or 7.5 mg, optionally wherein the composition is administered once, twice, or more than twice daily. 39. A method for treating and / or preventing diseases, disorders, and / or conditions selected from: psychosis, schizophrenia, schizophrenia-like disorders, bipolar disorder, psychotic disorders, drug-induced psychotic disorders, mood disorders, anxiety disorders, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorders, ADHD, cerebral palsy, Tourette syndrome, brain injury, sleep disorders, sexual dysfunction, eating disorders, obesity, headache, pain in a condition characterized by increased muscle tone, Parkinson's disease, Parkinson's syndrome, movement disorders, L-DOPA-induced movement disorders, tardive dyskinesia, dystonia, tic and tremor dementia, Huntington's disease, drug-induced movement disorders, restless legs, narcolepsy, Alzheimer's disease, and Alzheimer's disease-related disorders, wherein said method comprises administering a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 19 or 35 to a subject in need, such as a person. 40. The method of claim 39, wherein the disease, disorder and / or condition is schizophrenia, L-DOPA-induced motor disorder and / or Huntington's disease.41. The method according to claim 39 or 40, wherein the therapeutically effective amount is 2 mg to 10 mg, such as 2.5 mg, 5.0 mg or 7.5 mg, optionally wherein the composition is administered once, twice or more daily. 42. Use of the pharmaceutical composition according to any one of claims 1 to 19 or 35 in the manufacture of a medicament for treating diseases, disorders and / or conditions selected from: psychosis, schizophrenia, schizophrenia-like disorders, bipolar disorder, psychotic disorders, drug-induced psychotic disorders, mood disorders, anxiety disorders, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Tourette syndrome, brain injury, sleep disorders, sexual dysfunction, eating disorders, obesity, headache, pain in a condition characterized by increased muscle tone, Parkinson's disease, Parkinson's syndrome, movement disorders, L-DOPA-induced movement disorders, tardive dyskinesia, dystonia, tic and tremor dementia, Huntington's disease, drug-induced movement disorders, restless legs, narcolepsy, Alzheimer's disease and disorders associated with Alzheimer's disease. 43. The use according to claim 42, wherein the disease, disorder, and / or condition is schizophrenia, L-DOPA-induced movement disorder, and / or Huntington's disease. 44. The use according to claim 42 or 43, wherein the pharmaceutical composition is administered at a dose of 2 mg to 10 mg, such as 2.5 mg, 5.0 mg, or 7.5 mg, optionally wherein the composition is administered once, twice, or more than twice daily. Claims 5 / 5 Page 6 CN 121620362 A Pharmaceutical composition comprising N-[2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine tartrate

[0001] This disclosure relates to pharmaceutical compositions comprising dosage forms such as tablets or capsules, comprising mesdopetam monotartrate or hemitartrate. This disclosure also provides methods for manufacturing said compositions and the use of said compositions in therapy. Background Art

[0002] Any enumeration or discussion of previously disclosed literature in this specification should not necessarily be construed as an admission that such literature is part of the prior art or common general knowledge.

[0003] Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting more than one million people in the European Union (EU) and North America. It is estimated that within five years of starting standard dopamine replacement therapy, approximately 50% of patients with PD will develop on-phase involuntary movements (i.e., so-called L-DOPA-induced dyskinesia (LID)) in response to their medical treatment. LID is often a key complication limiting further dose increases in dopaminergic therapy.Furthermore, treatment-induced psychotic symptoms may also develop over time in a significant proportion of patients. Options for treating and preventing such long-term complications are limited.

[0004] Madopertan ([2-(3-fluoro-5-methanesulfonylphenoxy)-ethyl](propyl)amine; IRL-790 and / or IPN60170; CAS 1403894-72-3) is one of a class of compounds described in WO 2012 / 143337 that are modulators of dopaminergic and N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission in the cortex and basal ganglia. Such compounds can be used to treat diseases that respond to regulation of dopaminergic and glutamatergic function in the central nervous system, and can be used to treat, for example, Parkinson's disease, movement disorders, and L-DOPA-induced movement disorders. Ledopertan has the following structure in its free base form:

[0005] Preclinical studies in experimental animals have shown that ledopertan helps alleviate adverse reactions such as LID without affecting the basic efficacy of the anti-Parkinson's disease drug. Preclinical pharmacology of ledopertan as a novel dopamine transport modulator for the treatment of motor and psychiatric complications of Parkinson's disease was disclosed in J. Pharmacol. Exp. Ther. 374:113-125, July 2020. Ledopertan was found to reduce adverse involuntary movements (AIM) in a dose-dependent manner, and this reduction in involuntary movements was not achieved at the expense of any impairment of the motor function of L-DOPA itself, which was captured as a rotational response to L-DOPA.

[0006] Salts of ledopertan and related compounds are described in WO 2020 / 239568 and have been investigated in a recently completed Phase IIb study. Pharmaceutical compositions containing ledoperamide and their use in treatment methods are described in WO 2022 / 101227.

[0007] Pharmaceutical formulations of ledoperamide are needed, such as formulations providing doses required for therapeutic use. Such forms also require a cost-effective and reliable method of manufacture to meet acceptance and regulatory parameters. Summary of the Invention

[0008] One object of this disclosure is to provide ledoperamide monotartrate or hemitartrate in a form suitable for pharmaceutical compositions such as pharmaceutical compositions that allow for dose uniformity. Furthermore, one object of this disclosure is to provide aspects and / or advantages not provided by the technology known to date.

[0009] In one aspect, this disclosure provides pharmaceutical compositions comprising ledoperamide monotartrate or hemitartrate, a diluent, a disintegrant, a lubricant, and optionally a flow aid.

[0010] On the other hand, this disclosure provides solid particulate medopetan monotartrate or hemitartrate (e.g. hemitartrate, such as L-hemitartrate) having a particle size distribution in which D90 < 350 μm or < 300 μm (e.g. < 290 μm, < 280 μm, < 270 μm or < 260 μm) and / or D50 < 150 μm (e.g. < 140 μm, < 120 μm, 100 μm or < 180 μm).

[0011] On the other hand, this disclosure provides a method for preparing a pharmaceutical composition comprising ledopertan monotartrate or hemitartrate, the method comprising: (a) weighing and sieving ledopertan monotartrate or hemitartrate, a diluent, a disintegrant, and optionally a flow aid; (b) blending ledopertan monotartrate or hemitartrate with about one-third of the total amount of diluent to form a first premix composition, and optionally sieving the first premix composition; (c) preparing a second premix composition comprising about one-third of the total amount of diluent, optionally wherein preparing the second premix composition comprises blending about one-third of the diluent with a flow aid; and optionally sieving the second premix; (d) blending the first and second premix compositions with a disintegrant and about one-third of the total amount of diluent to form a first dry mix composition, and optionally sieving the first dry mix composition; (e) Weighing and sieving the lubricant and blending it with a first dry-mix composition, optionally with any additional excipients, flavoring agents, sweeteners and / or coloring agents, to form a final blend composition; and (f) optionally compressing the final blend composition (e.g., to form tablets) or filling the final blend composition into capsules (e.g., hard capsules or soft capsules).

[0012] On the other hand, this disclosure provides pharmaceutical compositions prepared by the methods described herein or any embodiments thereof, or which may be prepared by the methods described herein or any embodiments thereof.

[0013] On the other hand, a treatment method is provided comprising administering a therapeutically effective amount of ledopertan monotartrate or hemitartrate to a subject in need, wherein ledopertan monotartrate or hemitartrate is administered in a pharmaceutical composition disclosed herein. In a related aspect, this disclosure provides the use of ledopertan monotartrate or hemitartrate in the manufacture of a medicament, wherein the medicament is a pharmaceutical composition disclosed herein. In another related aspect, this disclosure provides the use of the pharmaceutical compositions disclosed herein in the manufacture of a medicament. In a further related aspect, this disclosure provides pharmaceutical compositions as disclosed herein for therapeutic purposes.

[0014] This disclosure also provides pharmaceutical compositions described herein or ledopetan monotartrate or hemitartrate described herein for the treatment and / or prevention of diseases, disorders and / or conditions selected from: psychosis, schizophrenia, schizophrenia-like disorders, bipolar disorder, psychotic disorders, drug-induced psychotic disorders, mood disorders, anxiety disorders, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Tourette syndrome, brain injury, sleep disorders, sexual dysfunction, eating disorders, obesity, headache, pain in conditions characterized by increased muscle tone, Parkinson's disease, Parkinson's syndrome, movement disorders, L-DOPA-induced movement disorders, tardive dyskinesia, dystonia, tic and tremor dementia, Huntington's disease, drug-induced movement disorders, restless legs, narcolepsy, Alzheimer's disease and disorders associated with Alzheimer's disease.

[0015] This disclosure also provides the use of the pharmaceutical compositions described herein or the ledopetan monotartrate or hemitartrate described herein in the manufacture of a medicament for the treatment and / or prevention of diseases, disorders and / or conditions selected from: psychosis, schizophrenia, schizophrenia-like disorders, bipolar disorder, psychotic disorders, drug-induced psychotic disorders, mood disorders, anxiety disorders, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Tourette syndrome, brain injury, sleep disorders, sexual dysfunction, eating disorders, obesity, headache, pain in a condition characterized by increased muscle tone, Parkinson's disease, Parkinson's syndrome, movement disorders, L-DOPA-induced movement disorders, tardive dyskinesia, dystonia, tic and tremor dementia, Huntington's disease, drug-induced movement disorders, restless legs, narcolepsy, Alzheimer's disease and disorders associated with Alzheimer's disease.

[0016] This disclosure also provides methods for treating and / or preventing diseases, disorders and / or conditions selected from: psychosis, schizophrenia, schizophrenia-like disorders, bipolar disorder, psychotic disorders, drug-induced psychotic disorders, mood disorders, anxiety disorders, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorders, ADHD, cerebral palsy, Tourette syndrome, brain injury, sleep disorders, sexual dysfunction, eating disorders, obesity, headache, pain in a condition characterized by increased muscle tone, Parkinson's disease, Parkinson's syndrome, movement disorders, L-DOPA-induced movement disorders, tardive dyskinesia, dystonia, tic and tremor dementia, Huntington's disease, drug-induced movement disorders, restless legs, narcolepsy, Alzheimer's disease and Alzheimer's disease-related disorders, wherein the method comprises administering to a subject in need, such as a human, a therapeutically effective amount of the pharmaceutical composition described herein or the levodopa monotartrate or hemitartrate described herein.

[0017] Figure 1 shows the XRP diffraction pattern of levodopatan L-hemitartaric acid. XRPD data were collected on a Bruker D8 Advance (2005) instrument. Radiation: copper Kα, λ = 1.54180 Å, Kβ filter 0.020 mm nickel foil, anode voltage: 40 kV, anode current: 40 mA, detector: LynxEye (1D position sensitive), slits 0.6 mm and 8 mm, step size 0.02, scan rate 0.2 s / step, interval (2θ) (3–35) in a 2θ scale.

[0018] Figure 2 depicts an example of the method described herein. In Figure 2, IPN60170 represents levodopatan L-hemitartaric acid.

[0019] Figure 3 depicts the particle size distribution of levodopatan L-hemitartaric acid when ground according to different parameters. Figure 3A shows the density distribution, and Figure 3B shows the cumulative distribution. Particle size distribution was determined by wet laser diffraction in silicone oil at a concentration of 10 mg / mL. Triangles represent particles of levodopa-L-hemitartaric acid, which were ground at 6000 rpm using a conical mill with a 610 μm mesh. Circles represent particles of levodopa-L-hemitartaric acid, which were ground at 6000 rpm using a conical mill with a 279 μm mesh. Squares represent particles of levodopa-L-hemitartaric acid, which were ground at 6000 rpm using a conical mill with a 457 μm mesh.

[0020] Figure 4 shows SEM micrographs of levodopa-L-hemitartaric acid before and after grinding with a mortar and pestle. Figure 4A shows SEM micrographs of levodopa-L-hemitartaric acid before grinding at two different magnifications. Crystals with a so-called "bundle" structure are visible. Figure 4B shows SEM micrographs after the size was reduced using a mortar and pestle.The particle size is significantly reduced, with sizes ranging from tens of micrometers. Some larger particles of about 30 to 40 micrometers can be observed. The morphology of the ground particles is irregular, with a plate-like surface. Specification 3 / 29 pages 9 CN 121620362 A Detailed Description

[0021] Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Although any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, exemplary methods, apparatus, and materials are described hereafter. All technical and patent publications referenced herein are incorporated herein by reference in their entirety. Nothing herein should be construed as an admission that the invention is not entitled to the prior art prior to this disclosure.

[0022] Madopertan, also known as IRL-790 and IPN60170, has CAS Registry No. 1403894-72-3 and IUPAC name N-[2-(3-fluoro-5-methylsulfonyl-phenoxy)ethyl]propane-1-amine. The term "madopertan free base" as used herein refers to the compound itself. Unless otherwise stated, "madopertan" as used herein without any further limitation includes madopertan free base or madopertan monotartrate or hemitartrate. Therefore, unless otherwise specified, the term "madopertan" means madopertan in its free base form or its monotartrate or hemitartrate.

[0023] All numerical names, such as pH, temperature, time, concentration, molecular weight, etc. (including ranges), are approximate values ​​varying (+) or (-) in increments of, for example, 0.1 or 1.0, where appropriate. When a numerical name is preceded by the term "about," this is used to indicate a general level of variability. For example, a numerical name for a given value "about" may vary by ±10% of said value; alternatively, the variation may be ±5%, ±2%, or ±1% of that value.

[0024] To avoid doubt, any disclosure of a numerical range, such as "up to X," is intended to include the upper limit of the numerical value X. Thus, a disclosure of "up to 60 mg" includes 60 mg. Similarly, any disclosure of a numerical range is also intended to include the lower limit of the numerical value, such as "A to" or "at least A." Thus, a disclosure of, for example, "5 mg to 50 mg" or "at least 5 mg" includes 5 mg.

[0025] As used herein, when the amount of substance is described as a % (w / w), unless otherwise stated, this is intended to refer to "weight %" (also expressed as %wt, wt%, %w / w, w / w%, %(w / w), (w / w)%, etc.).

[0026] As used in the specification and claims, the singular forms “a / an” and “the” include the plural objects unless explicitly stated otherwise in the context. For example, the term “diluent” includes a variety of diluents, including mixtures thereof. Unless specifically stated or obvious from the context, the term “or” as used herein should be understood as inclusive. The term “comprising” as used herein refers to the phrase “including but not limited to” and is used interchangeably with that phrase.

[0027] As used herein, the term “comprising” is intended to mean that a composition and method includes the described elements but does not exclude other elements. When used to define compositions and methods, “consisting substantially of” should mean excluding other elements that are of any significance to the purposes described. Thus, a composition consisting substantially of the elements defined herein will not exclude trace contaminants and pharmaceutically acceptable carriers, such as phosphate-buffered saline, preservatives, etc., in methods of separation and purification. "Comprising" should mean excluding other ingredients beyond trace elements and a large number of method steps for administering the composition of this disclosure or for producing the composition or achieving the desired result. Embodiments defined by each of these transitional terms are within the scope of this disclosure. The term "comprising" is used herein to cover and disclose corresponding statements in which the term "comprising" is replaced by "substantially consisting of" or "consisting of".

[0028] "Subject", "individual" or "patient" are used interchangeably herein and refer to vertebrates, such as mammals. Mammals include, but are not limited to, rodents, farm animals, locomotives, pets and primates; for example, rats, rats, rabbits, apes, cattle, sheep, pigs, dogs, cats, horses and humans. In a particular embodiment, the mammal is a human.

[0029] "Administer" herein is defined as a manner in which the agent or a composition containing the agent is delivered to a subject in a manner that results in contact with the subject's body (e.g., within the subject's body). Such administration can be carried out via any route, including but not limited to oral, transdermal, transmucosal (e.g., via vaginal, rectal, or oral mucosa), by injection (e.g., subcutaneous, intravenous, parenteral, intraperitoneal, or into the central nervous system), or by inhalation (e.g., oral or nasal). Administration can also involve providing a substance or composition to a part of the subject's body surface, such as by topical application to the skin. Of course, pharmaceutical formulations are given in a form suitable for each route of administration.

[0030] “Treatment” of a disease includes: (1) preventing the disease, even if the clinical symptoms of the disease do not develop in patients who may be susceptible to the disease but have not yet experienced or exhibited symptoms of the disease; (2) suppressing the disease, i.e., preventing or reducing the development of the disease or its clinical symptoms; and / or (3) alleviating the disease, even if the disease or its clinical symptoms subside.

[0031] When referring to the term “treatment”, the term “suffering” means a patient or individual who has been diagnosed with or is susceptible to the disease. Patients may also be referred to as “at risk of suffering from the disease” because of a family history of the disease or because of the presence of a gene mutation associated with the disease. Patients at risk of the disease have not yet developed all or part of the characteristic pathology of the disease.

[0032] An “effective amount” or “therapeutic effective amount” is an amount sufficient to achieve a beneficial or desired outcome. An effective amount may be administered, applied, or administered in a single or multiple doses. Such delivery depends on many variables, including the time period for which a single dose unit is used, the bioavailability of the therapeutic agent, the route of administration, etc. However, it is understood that the specific dose level of the therapeutic agents disclosed herein for any particular subject depends on a variety of factors, including, for example, the activity of the specific compound used, the subject's age, weight, general health condition, sex and diet, time of administration, excretion rate, drug combination, severity of the specific condition being treated, and form of administration. Generally, therapeutic doses can be titrated to optimize safety and efficacy. Typically, dose-response relationships tested in vitro and / or in vivo can initially provide useful guidance for the appropriate dose administered to the patient. Generally, it is desirable that the amount of compound administered effectively achieves serum levels commensurate with the effective concentrations found in vitro. The determination of these parameters is well known to those skilled in the art. These considerations, as well as effective formulations and administration procedures, are well known in the art and are described in standard textbooks. Consistent with this definition, as used herein, the term "therapeuticly effective amount" is an amount sufficient to treat (e.g., improve) one or more symptoms associated with a condition. The total daily dose may be administered as a single dose or in divided doses and may fall outside the typical range given herein, depending on the physician's judgment.

[0033] Unless otherwise stated, the amount of the active compound used for administration (whether as a free base or as a salt) refers to or is based on the amount of the compound in the form of a free base. Therefore, unless otherwise stated, when referring to doses of ledopertan, these doses are calculated in terms of the amount of ledopertan free base, making the actual mass of ledopertan salt larger. For example, a 5 mg dose of ledopertan free base corresponds to approximately 6.36 mg of ledopertan hemitarite.

[0034] As used herein, the phrase “in treatment or prevention” (such as in the phrase “in treatment or prevention of pain”) is intended to be equivalent to the phrase “in a method of treatment or prevention” (such as in the phrase “in a method of treatment or prevention of pain”).

[0035] When referring to methods of treating and / or preventing diseases using levodopa or pharmaceutically acceptable salts of it, such as its monotartrate or hemitartrate salts, these statements should be understood to include each of the following: (i) levodopa or pharmaceutically acceptable salts of it, such as its monotartrate or hemitartrate salts, for the treatment and / or prevention of said diseases; or levodopa or pharmaceutically acceptable salts of it, such as its monotartrate or hemitartrate salts, for the treatment and / or prevention of said diseases; (ii) the use of levodopa or pharmaceutically acceptable salts of it, such as its monotartrate or hemitartrate salts, in said methods of treating and / or preventing diseases; or the use of levodopa or pharmaceutically acceptable salts of it in the treatment and / or prevention of said diseases; and (iii) the use of levodopa or pharmaceutically acceptable salts of it, such as its monotartrate or hemitartrate salts, in the manufacture of medicaments for the treatment and / or prevention of said diseases.

[0036] As used herein, the term “pharmaceuticalally acceptable excipient” encompasses any standard pharmaceutical excipient, including diluents and carriers, to enable the formulation of levodopatan in its free base form or pharmaceutically acceptable salt form (e.g., tartrates, such as hemi-tartrates, including L-hemi-tartrates, as described on page 5 / 29 of the specification, CN 121620362 A) for use in pharmaceutical formulations. Pharmaceutically acceptable excipients can be, for example, as described in Remington's Pharmaceutical Sciences (20th edition, Mack Publishing Co. 2000). Such excipients include carriers, such as phosphate-buffered saline solutions, water and emulsions, such as oil / water or water / oil emulsions, and various types of wetting agents. Pharmaceutical compositions may also include stabilizers, preservatives, adjuvants, fillers, binders, lubricants, etc.

[0037] Suitable forms of ledoperamide include free base forms, including its amorphous solid dispersions, pharmaceutically acceptable salt forms such as monotartrates or hemitartrates, including its crystalline forms, and pharmaceutically acceptable eutectic forms. Unless otherwise stated, the term "pharmaceutically acceptable salt" includes acid addition salts formed between ledoperamide and any pharmaceutically acceptable acid (e.g., Brønsted acid) in any molar ratio permitted by the acid structure. For example, basic compounds can be provided as pharmaceutically acceptable acid addition salts with acids such as HCl. Pharmaceutically acceptable salts of ledoperamide can be synthesized by conventional chemical methods from free base compounds containing a basic moiety by mixing or reacting with a suitable acid. Typically, such salts can be prepared by, for example, mixing the free base form of these compounds with a stoichiometric amount of a suitable acid in water or in an organic solvent or in a mixture of both; generally, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.Methods for forming salts are also known in the art (see, for example, Berge et al., J Pharm Sci. (1977) 66:1–19). As used herein, the term “pharmaceutical acceptable” when used in conjunction with a salt refers to a salt of a currently disclosed compound that can be administered without producing any significant undesirable biological effects or any harmful interactions with any other component of a pharmaceutical composition that may contain that salt. Examples of pharmaceutically acceptable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc., and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, tartaric acid, fumaric acid, maleic acid, malic acid, etc. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propynates, oxalates, malonates, succinates, octanoates, sebates, fumarates, maleates, butyn-1,4-dicitates, hexyn-1,6-dicitates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates (e.g., monotartrates or hemitartrates), methanesulfonates, propanesulfonates. Naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate, etc. In particular, pharmaceutically acceptable salts may be tartaric acid.

[0038] In some embodiments, the salt is a crystalline solid (e.g., salt crystals). In embodiments, the crystalline salt form of ledopetan is a crystalline hemitartaric acid salt, disclosed, for example, in WO 2020 / 239568 (the contents of which are incorporated herein by reference in their entirety), with particular reference to page 9, line 25 through page 10, line 9, and Figure 1 of that document.

[0039] Isotopically labeled compounds are also within the scope of this disclosure. As used herein, "isotopically labeled compound" means ledopetan as described herein, including its pharmaceutical salts, wherein one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds (including salts) disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. For example, one or more hydrogen atoms in medopetan can be substituted with deuterium.

[0040] All references, patents, patent applications, scientific literature, and other printed publications mentioned or cited herein are hereby incorporated in their entirety by reference.

[0041] Those skilled in the art will understand that various changes and modifications can be made to the preferred embodiments of the invention, and that the specification, page 6 / 29, CN 121620362 A, does not depart from the spirit of the invention. All such changes are intended to fall within the scope of the invention.

[0042] Pharmaceutical Compositions In one aspect, this disclosure provides pharmaceutical compositions comprising levodopatan or its tartrate salts, such as monotartrate or hemitartrate salts of levodopatan, a diluent, a disintegrant, a lubricant, and optionally a flow aid.

[0043] Suitable diluents include carbohydrates (e.g., sugars and polysaccharides), pharmaceutically acceptable synthetic polymers, inorganic diluents, and mixtures thereof.

[0044] Suitable carbohydrates include cellulose (e.g., microcrystalline cellulose (such as silicified microcrystalline cellulose), powdered cellulose, or cellulose acetate), carboxymethyl cellulose (e.g., calcium carboxymethyl cellulose), alginate (e.g., sodium alginate or ammonium alginate), starch (e.g., pregelatinized starch, such as Starch 1500®), glucose binders, dextrin, maltodextrin, sugars (e.g., glucose, fructose, lactose (such as lactose monohydrate or spray-dried lactose), maltose, trehalose, or sucrose (such as compressible sugar or powdered sugar)), sugar alcohols (e.g., erythritol, isomaltitol, lactitol, maltitol, mannitol, sorbitol, or xylitol) and mixtures thereof.

[0045] Suitable pharmaceutically acceptable synthetic polymers include povidones (such as crospovidone) and vinylpyrrolidone-vinyl acetate copolymers (such as Kollidon® VA64).

[0046] Suitable inorganic diluents include calcium carbonate, calcium phosphate (e.g., anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate (calcium phosphate dihydrate), or tricalcium phosphate), calcium sulfate, kaolin, magnesium carbonate, magnesium oxide, sodium chloride, and mixtures thereof.

[0047] In some embodiments, the diluent may comprise, consist substantially of, or consist of: carbohydrates or mixtures of carbohydrates, such as those disclosed above.

[0048] In some embodiments, the diluent may comprise, consist substantially of, or consist of: pharmaceutically acceptable synthetic polymers or mixtures of pharmaceutically acceptable synthetic polymers, such as those disclosed above.

[0049] In some embodiments, the diluent may comprise, consist substantially of, or consist of: inorganic diluents or mixtures of inorganic diluents, such as those disclosed above.

[0050] In some embodiments, the diluent may comprise, consist substantially of, or consist of: a mixture of at least one carbohydrate and at least one inorganic diluent, such as those disclosed above.

[0051] In some embodiments, the diluent may comprise, consist substantially of, or consist of: a mixture of at least one carbohydrate and at least one pharmaceutically acceptable synthetic polymer, such as those disclosed above.

[0052] In some embodiments, the diluent may comprise, consist substantially of, or consist of: a mixture of at least one pharmaceutically acceptable synthetic polymer and at least one inorganic diluent, such as those disclosed above.

[0053] In some embodiments, the diluent is selected from cellulose (e.g., microcrystalline cellulose (such as silicified microcrystalline cellulose), powdered cellulose or cellulose acetate), carboxymethyl cellulose (e.g., calcium carboxymethyl cellulose), glucose binder, dextrin, glucose, erythritol, fructose, isomaltitol, lactitol, lactose (e.g., lactose monohydrate or spray-dried lactose), maltitol, maltodextrin, maltose, mannitol, povidone, alginate (e.g., sodium alginate or ammonium alginate), sorbitol, starch (e.g., pregelatinized starch), sucrose, compressible sugar, powdered sugar, trehalose, xylitol, calcium carbonate, calcium phosphate (e.g., anhydrous dicalcium phosphate, dicalcium phosphate dihydrate (calcium phosphate dihydrate) or tricalcium phosphate), calcium sulfate, kaolin, magnesium carbonate, magnesium oxide, sodium chloride, and mixtures thereof.

[0054] In some embodiments, the diluent is selected from cellulose (e.g., microcrystalline cellulose (such as silicified microcrystalline cellulose), powdered cellulose or cellulose acetate), carboxymethyl cellulose (e.g., calcium carboxymethyl cellulose), alginate (e.g., sodium alginate or ammonium alginate), starch (e.g., pregelatinized starch), glucose binders, dextrin, maltodextrin, and mixtures thereof.

[0055] In some embodiments, the diluent comprises pregelatinized starch, is substantially composed of pregelatinized starch, or is composed of pregelatinized starch.

[0056] Suitable disintegrants include alginate, calcium alginate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, powdered cellulose, chitosan, colloidal silica, croscarmellose sodium, croscarmellose, docusate sodium, guar gum, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, polacolin potassium, povidone, sodium alginate, sodium glycolate starch, starch, pregelatinized starch, and mixtures thereof.

[0057] In some embodiments, the disintegrant comprises sodium glycolate starch, is substantially composed of sodium glycolate starch, or is composed of sodium glycolate starch.

[0058] Suitable lubricants include calcium stearate, magnesium stearate, zinc stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitate stearate, leucine, medium-chain triglycerides, mineral oil, light mineral oil, myristic acid, palmitic acid, polyethylene glycol, polyoxyethylene stearate, potassium benzoate, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearoyl fumarate, stearic acid, talc, hydrogenated vegetable oil, sucrose fatty acid esters, and mixtures thereof.

[0059] In some embodiments, the lubricant comprises magnesium stearate, is substantially composed of magnesium stearate, or is composed of magnesium stearate.

[0060] In embodiments containing a flow aid, suitable flow aids include tricalcium phosphate, powdered cellulose, colloidal silica (e.g., Aerosil® 200), magnesium oxide, magnesium silicate, magnesium trisilicate, starch, talc, and mixtures thereof. When the flow aid contains magnesium silicate, it is preferably used in combination with silica.

[0061] In some embodiments, the flow aid contains colloidal silica, is substantially composed of colloidal silica, or is composed of colloidal silica.

[0062] In principle, some components can act as two or more of diluents, disintegrants, lubricants, and / or flow aids. As non-limiting examples, crospovidone, microcrystalline cellulose, calcium carboxymethyl cellulose, and powdered cellulose can each be used as a diluent or disintegrant; tricalcium phosphate and magnesium oxide can be used as diluents or flow aids; colloidal silica can be used as a disintegrant or flow aid; talc can be used as a lubricant or flow aid; and sodium chloride can be used as a diluent or lubricant. In such cases, the function performed by the individual components is generally affected by the amount of each component present. For example, microcrystalline cellulose can act as a diluent when present in an amount of 20% to 90% of the composition, and as a disintegrant when present in an amount of 15% or less. When any given component can have more than one function, the appropriate amount (e.g., concentration range, such as % (e.g., wt%)) to achieve the given function is known to those skilled in the art and can be found, for example, in standard manuals and reference works, such as Handbook of Pharmaceutical Excipients, 5th Edition, Pharmaceutical Press (London / Chicago), 2006, edited by RC Rowe, PJ Sheskey, and SCOwen. For example, lubricants and gliding agents are typically used in amounts from about 0.1% to about 2% by weight, disintegrants are typically used in amounts up to about 10% by weight, and diluents are typically used in amounts greater than 20% by weight.Therefore, in embodiments containing any such component having more than one use, any given such component is typically present only as a diluent, disintegrant, flow aid, or lubricant, the function of which depends, for example, on the amount of such component present and the properties of any other components combined with it. Those skilled in the art can appropriately select the amount and properties of the components in the formulations disclosed herein to achieve the desired function. In this document, the terms formulation and composition are used interchangeably. Thus, for example, if microcrystalline cellulose is present as a diluent, a non-microcrystalline cellulose disintegrant will also be present in an appropriate amount.

[0063] In embodiments of the compositions disclosed herein, the diluent comprises pregelatinized starch, the disintegrant comprises sodium glycolate starch (see specification page 8 / 29, 14 CN 121620362 A), the flow aid comprises colloidal silica, and the lubricant comprises magnesium stearate. In embodiments of the compositions disclosed herein, the diluent is substantially composed of pregelatinized starch, the disintegrant is substantially composed of sodium glycolate starch, the flow aid is substantially composed of colloidal silica, and the lubricant is substantially composed of magnesium stearate. In embodiments of the compositions disclosed herein, the diluent comprises pregelatinized starch, the disintegrant comprises sodium glycolate starch, the flow aid comprises colloidal silica, and the lubricant comprises magnesium stearate.

[0064] In embodiments, the composition comprises about 3 wt% to about 20 wt% of levodopa or its tartrate salt, such as its monotartrate or hemitartrate, based on dry solids. In embodiments, the composition comprises about 3 wt% to about 18 wt%, or about 3 wt% to about 14 wt% of levodopa or its tartrate salt, such as its monotartrate or hemitartrate, such as about 3 wt% to about 13 wt%, about 3 wt% to about 5 wt%, about 7 wt% to about 9 wt%, about 11 wt% to about 13 wt%, or about 15 wt% to about 17 wt%, for example about 4 wt%, about 8 wt%, about 13 wt%, or about 17 wt%, based on dry solids.

[0065] In an embodiment, the composition comprises about 75 wt% to about 95 wt% of a diluent based on dry solids, such as about 75 wt% to about 92 wt%, about 80 wt% to about 92 wt%, about 80 wt% to about 88 wt%, or about 82 wt% to about 87 wt%, for example about 91 wt%, about 87 wt%, about 83 wt%, or about 79 wt%.

[0066] In an embodiment, the composition comprises about 1 wt% to about 5 wt% of a disintegrant based on dry solids, such as about 2 wt% to about 4 wt% or about 3 wt% to about 4 wt%, for example about 3 wt%.

[0067] In an embodiment, the composition comprises about 0.1 wt% to about 1.0 wt% of a lubricant, such as about 0.2 wt% to about 0.8 wt%, about 0.3 wt% to about 0.7 wt%, about 0.4 wt% to about 0.6 wt%, or about 0.3 wt% to about 0.5 wt%, for example, about 0.5 wt%.

[0068] In an embodiment, the composition comprises about 0.1 wt% to about 1.5 wt% of a flow aid, such as about 0.5 wt% to about 1.5 wt%, about 0.8 wt% to about 1.3 wt%, about 0.9 wt% to about 1.1 wt%, or about 1.0 wt% to about 1.1 wt%, for example, about 1 wt%, such as about 1.0 wt%.

[0069] In an embodiment, the composition comprises about 3 wt% of a disintegrant, about 1 wt% of a flow aid, and about 0.5 wt% of a lubricant, all on a dry solids basis.

[0070] In an embodiment, the composition comprises about 3 wt% to about 20 wt% of a levodopa or its tartrate salts, such as monotartrate or hemitartrate, about 75 wt% to about 95 wt% of a diluent, about 1 wt% to about 5 wt% of a disintegrant, about 0.1 wt% to about 1.0 wt% of a lubricant, and about 0.1 wt% to about 1.5 wt% of a flow aid, all on a dry solids basis. In a preferred embodiment, the diluent is pregelatinized starch, the disintegrant is sodium glycolate starch, the flow aid is colloidal silica, and / or the lubricant is magnesium stearate.

[0071] In an embodiment, the composition comprises about 3 wt% to about 20 wt% of ledopatan or its tartrate salts, such as monotartrate or hemitartrate salts, about 75 wt% to about 95 wt% of a diluent, about 3 wt% of a disintegrant, about 0.5 wt% of a lubricant, and about 1 wt% of a flow aid (e.g., about 1.0 wt%), all on a dry solids basis. In a preferred embodiment, the diluent is pregelatinized starch, the disintegrant is sodium glycolate starch, the flow aid is colloidal silica, and / or the lubricant is magnesium stearate.

[0072] In an embodiment, the composition comprises about 3 wt% to about 5 wt% (e.g., about 4 wt%) of ledopatan or its tartrate salts such as monotartrate or hemitartrate, about 90 wt% to about 93 wt% (e.g., about 90.5 wt% to about 92.5 wt% such as about 91 wt%) of a diluent, about 3 wt% of a disintegrant, about 0.5 wt% of a lubricant, and about 1 wt% (e.g., about 1.0 wt%) of a flow aid, all on a dry solids basis.In a preferred embodiment, the diluent is pregelatinized starch, the disintegrant is sodium glycolate starch, the flow aid is colloidal silica, and / or the lubricant is magnesium stearate. Specification 9 / 29 pages 15 CN 121620362 A

[0073] In an embodiment, the composition comprises about 7 wt% to about 9 wt% (e.g., about 8 wt%, such as about 8.5 wt%) of levodopa or its tartrate salts, such as its monotartrate or hemitartrate salts, about 86 wt% to about 89 wt% (e.g., about 86.5 wt% to about 88.5 wt%, such as about 87 wt%) of diluent, about 3 wt% of disintegrant, about 0.5 wt% of lubricant, and about 1 wt% (e.g., about 1.0 wt%) of flow aid, all on a dry solids basis. In a preferred embodiment, the diluent is pregelatinized starch, the disintegrant is sodium glycolate starch, the flow aid is colloidal silica, and / or the lubricant is magnesium stearate.

[0074] In an embodiment, the composition comprises about 11 wt% to about 13 wt% (e.g., about 12 wt% to about 13 wt%, such as about 12.7 wt%) of levodopa or its tartrate salts such as its monotartrate or hemitartrate salts, about 82 wt% to about 85 wt% (e.g., about 82.5 wt% to about 84.5 wt%, such as about 82.8 wt%) of diluent, about 3 wt% of disintegrant, about 0.5 wt% of lubricant, and about 1 wt% (e.g., about 1.0 wt%) of flow aid, all on a dry solids basis. In a preferred embodiment, the diluent is pregelatinized starch, the disintegrant is sodium glycolate starch, the flow aid is colloidal silica, and / or the lubricant is magnesium stearate.

[0075] In an embodiment, the composition comprises about 15.5 wt% to about 17.5 wt% (e.g., about 16 wt% to about 17.5 wt%, such as about 17.0 wt%) of levodopa or its tartrate salts such as its monotartrate or hemitartrate salts, about 78 wt% to about 80 wt% (e.g., about 78.5 wt% to about 79.5 wt%, such as about 78.5 wt%) of diluent, about 3 wt% of disintegrant, about 0.5 wt% of lubricant, and about 1 wt% (e.g., about 1.0 wt%) of flow aid, all on a dry solids basis. In a preferred embodiment, the diluent is pregelatinized starch, the disintegrant is sodium glycolate starch, the flow aid is colloidal silica, and / or the lubricant is magnesium stearate.

[0076] It will be apparent to those skilled in the art that in all embodiments of the compositions disclosed herein, the total wt% of the components, calculated on a dry solids basis, does not exceed 100%.Therefore, those skilled in the art will understand that the amounts of the identified individual components can be appropriately varied (e.g., within the identified wt%) so as not to exceed 100%. For example, those skilled in the art can first determine the wt% of each of levodopatan or its pharmaceutically acceptable salts such as its monotartrate or hemitartrate, diluents, disintegrants, lubricants, and (if present) gliding agents, and then balance the equilibrium by accordingly selecting the amount of diluent (i.e., reaching a maximum amount not exceeding 100 wt% when all components of the composition are added together).

[0077] The compositions disclosed herein may further comprise one or more additional pharmaceutically acceptable excipients, flavoring agents, sweeteners, and / or coloring agents, provided that the sum of all components (i.e., the total amount of levodopatan or its tartrates such as its monotartrate or hemitartrate, diluents, disintegrants, lubricants, gliding agents (if present), and diluents, and any additional pharmaceutically acceptable excipients, flavoring agents, sweeteners, and / or coloring agents) does not exceed 100 wt%. In some embodiments, the colorant may be used to make the product appearance uniform and / or protect any photosensitive components. Suitable colorants include all pigments, dyes, and lakes approved by the U.S. Food and Drug Administration (e.g., FD&C colorants), including but not limited to FD&C Yellow #6, FD&C Blue #1, FD&C Red #3, black iron oxide, red iron oxide, titanium dioxide, or any combination thereof. For capsules, the colorant may be included within the capsule shell, within the capsule filler, or both.

[0078] In embodiments of the compositions disclosed herein, ledopetan or its tartrate salts, such as its monotartrate or hemitartrate salts, are provided in amounts corresponding to about 2 mg to about 10 mg of ledopetan free base, such as about 2 mg to about 8 mg, about 2.5 mg to about 5.0 mg, about 2.5 mg to about 7.5 mg, about 2.5 mg to about 10.0 mg, or about 5.0 mg to about 10.0 mg or about 5.0 mg to about 7.5 mg of ledopetan free base.

[0079] In embodiments of the compositions disclosed herein, ledopetan or its tartrate salts, such as its monotartrate or hemitartrate salts, are provided in an amount corresponding to about 2.5 mg of ledopetan free base (e.g., about 3.2 mg of ledopetan hemitartrate, such as ledopetan L-hemitartrate, such as 3.18 mg). Specification 10 / 29 pages 16 CN 121620362 A

[0080] In embodiments of the compositions disclosed herein, ledopetan or its tartrate salts, such as its hemitartrate salts, are provided in an amount corresponding to about 5.0 mg of ledopetan free base (e.g., about 6.4 mg of ledopetan hemitartrate, such as ledopetan L-hemitartrate, such as 6.36 mg).

[0081] In embodiments of the compositions disclosed herein, ledopetan or its tartrate salts, such as its monotartrate salts or hemitartrate salts, are provided in amounts corresponding to about 7.5 mg of ledopetan free base (e.g., about 9.5 mg of ledopetan hemitartrate, such as ledopetan L-hemitartrate, such as 9.54 mg).

[0082] In embodiments of the compositions disclosed herein, ledopetan or its tartrate salts, such as its monotartrate salts or hemitartrate salts, are provided in amounts corresponding to about 10.0 mg of ledopetan free base (e.g., about 12.7 mg of ledopetan hemitartrate, such as ledopetan L-hemitartrate, such as 12.72 mg).

[0083] Ledopetan can form pharmaceutically acceptable salts with pharmaceutically acceptable acids such as tartaric acid. Examples of pharmaceutically acceptable acids include those identified in the “Definitions” section above. In embodiments, ledopetan may be present in the form of tartrate salts. Because tartaric acid has two carboxylic acid groups, it can form salts with tartrate (the conjugate base of tartaric acid) in varying molar ratios. For example, a salt in which the molar ratio of tartrate to tartrate is approximately 1:1 can be called a monotartrate, and a salt in which the molar ratio of tartrate to tartrate is approximately 1:2 (or equivalently, a molar ratio of tartrate to tartrate is approximately 1:0.5) can be called hemitartrate tartrate (also known as tartrate 1 / 2-tartrate). Unless otherwise stated, the term "tartrate" as used herein encompasses all possible stoichiometry, i.e., molar ratios, including 1:1 and hemitartrate. Similarly, other dicarboxylic acids such as, for example, fumaric acid, succinic acid, maleic acid, and malic acid can also form more than one stoichiometry with tartrate.

[0084] It should be understood that the chemical structure of medopetan monotartrate (i.e., a salt in which the molar ratio of medopetan to tartaric acid is 1:1) can be described as follows:

[0085] Furthermore, it should be understood that the chemical structure of medopetan hemitartrate (i.e., a salt in which the molar ratio of medopetan to tartaric acid is 1:0.5) can be described as follows:

[0086] Furthermore, those skilled in the art will understand that one or both of the acidic protons of tartaric acid that form part of the medopetan monotartrate or hemitartrate may be attached to or shared between the nitrogen atom of medopetan and tartaric acid, and this is covered in the chemical structures described herein. For example, the hemitartaric acid salt of medopetan can be represented as follows, wherein one of the acidic protons of tartaric acid is attached to the nitrogen of medopetan: Specification 11 / 29 page 17 CN 121620362 A

[0087] Tartrate salts can exist in various stereoisomeric forms.Tartaric acid has three stereoisomers: L-(+)-tartaric acid (also simply L-tartaric acid or dextrorotatory tartaric acid) and its enantiomers, levorotatory tartaric acid or D-(-)-tartaric acid (also known as D-tartaric acid), as well as the achiral form, meso-tartaric acid. The L or D designation does not indicate the acid's ability to rotate the plane of polarized light. Any stereoisomer of tartaric acid can be used to prepare medopetan salts, including medopetan hemi-tartaric acid. For example, the salt can be formed from only one stereoisomer or a combination thereof. Therefore, tartrates (e.g., hemi-tartaric acid) can be selected from D-tartaric acid, L-tartaric acid, meso-tartaric acid, or racemic D,L-tartaric acid. In specific embodiments, the tartrate (e.g., hemi-tartaric acid) is L-tartaric acid. "L-tartaric acid" refers to a tartrate (e.g., hemi-tartaric acid) formed from L-tartaric acid. Racemic D,L-tartrate means that both D-tartrate and L-tartrate are used in the preparation of the salt. The amount of D-tartrate in racemic D,L-tartrate may be greater than, equal to or less than the amount of L-tartrate present.

[0088] When the stereochemical is named (e.g., L-(+)-tartaric acid) or described by structure, the named or described stereoisomer has a purity of at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight relative to other stereoisomers. When a single enantiomer is named or described by structure (e.g., in L-(+)-tartaric acid), the described or named enantiomer has an optical purity of at least 80%, 90%, 99% or 99.9% by weight. The percentage of optical purity by weight is the ratio of the weight of the enantiomer to the weight of the enantiomer plus the weight of its optical isomer. "Raceous mixture" or "racemic mixture" means a compound of two enantiomers in equimolar amounts, wherein such a mixture does not exhibit optical activity; that is, it does not rotate the plane of polarization.

[0089] In embodiments of the compositions disclosed herein, ledopetan is provided as a tartrate (e.g., 1:1 tartrate or hemi-tartrate). In some embodiments, ledopetan is provided as an L-tartrate, such as mono-L-tartrate or as an L-hemi-tartrate (1 / 2 L-tartrate). In other embodiments, ledopetan is provided as a D-tartrate, such as mono-D-tartrate or hemi-D-tartrate (1 / 2 D-tartrate). In certain embodiments, the tartrate of levodopatan (e.g., 1:1 tartrate or hemi-tartrate, such as 1:1 L-tartrate or L-hemi-tartrate) is provided in amounts corresponding to about 2 mg to about 10 mg of free base or about 2 mg to about 8 mg of free base (e.g., about 2.5 mg, about 5.0 mg, about 7.5 mg, or about 10.0 mg of free base).Therefore, for example, when ledopetan is provided as a hemitartaric acid salt (e.g., L-hemitartaric acid salt), it can be provided in amounts of about 2.5 mg to about 12.7 mg of hemitartaric acid salt, such as about 3.2 mg, about 6.4 mg, about 9.5 mg, or about 12.7 mg, which correspond to about 2.5 mg, about 5.0 mg, about 7.5 mg, and about 10.0 mg of free base, respectively. For example, the compositions disclosed herein may contain amounts of 3.18, 6.36, 9.54, or 12.72 mg of ledopetan hemitartaric acid.

[0090] The compositions disclosed herein may be provided in the form of bulk solids (such as powders), for example, bulk solids for dosage form formulation. Alternatively, the compositions disclosed herein may be provided as finished dosage forms, such as oral dosage forms, like capsules (e.g., soft capsules or hard capsules) or tablets (e.g., chewable tablets, orally disintegrating tablets, dispersible tablets, or classic tablets or capsules), optionally wherein said finished dosage form comprises about 2 mg to about 10 mg of levodopatan (measured as an equivalent amount of free base), such as about 2 mg to about 8 mg, such as about 2.5 mg, about 5.0 mg, about 7.5 mg, or about 10.0 mg of levodopatan (measured as an equivalent amount of free base).

[0091] Tablets may be round, square, rectangular, spherical, oval, flattened, ovoid, or any other suitable shape, including capsule-shaped (i.e., capsules). Tablets may optionally be scored for easy cutting and may optionally be engraved.

[0092] In examples, the compositions described herein may be formulated for immediate release.

[0093] In examples, the compositions described herein may be formulated for oral administration.

[0094] In embodiments, the composition is encapsulated, i.e., provided as a capsule (e.g., a capsule for oral administration), such as a soft capsule or a hard (“hard-shell”) capsule. Soft capsules include soft gelatin capsules or modified starch capsules. Hard capsules include hard gelatin capsules or HPMC (hydroxypropyl methylcellulose) capsules. Specification 12 / 29 pages 18 CN 121620362 A

[0095] Hard-shell capsules are two-piece gel encapsulations of solid material. The capsule shell consists of two halves, an outer half and an inner half, which, when joined and sealed, form a secure outer shell for containing solid material therein. The active pharmaceutical ingredient, i.e., ledopatan or its monotartrate or hemitartrate, may be contained within the capsule as a powder or in the form of one or more granules or pellets. Such granules or pellets may be manufactured by any suitable means, including crushing.

[0096] When packaged as an active pharmaceutical ingredient (API), the compositions of this disclosure are generally provided in the form of a powder (fine or coarse powder) and packaged in sterile containers, such as bags or drums.

[0097] In a particular embodiment, the composition comprises about 4 wt% (e.g., 4.24 wt%) of ledopertan hemitartarate (e.g., ledopertan L-hemitartaric acid), about 91 wt% (e.g., 91.26 wt%) of a diluent, about 3 wt% (e.g., 3.00 wt%) of a disintegrant, about 0.5 wt% (e.g., 0.50 wt%) of a lubricant, and about 1 wt% (e.g., 1.00 wt%) of a flow aid, all on a dry solids basis, wherein the diluent is pregelatinized starch, the disintegrant is sodium glycolate starch, the flow aid is colloidal silica, and / or the lubricant is magnesium stearate. Optionally, the composition is encapsulated, for example, in an HPMC capsule.

[0098] In embodiments of the compositions disclosed herein, ledopetan or a pharmaceutically acceptable salt thereof (e.g., hemitartaric acid salts, such as L-hemitartaric acid salts) may be provided in the form of hydrates, solvates, and / or polymorphs (such as anhydrous polymorphs). In embodiments, ledopetan or a pharmaceutically acceptable salt thereof (e.g., hemitartaric acid salts, such as L-hemitartaric acid salts), including any hydrates, solvates, and / or polymorphs (such as anhydrous polymorphs), may be provided in solid crystalline form or solid amorphous form.

[0099] In certain embodiments, at least a certain weight percentage of ledopetan or a pharmaceutically acceptable salt thereof (e.g., hemitartaric acid salts, such as L-hemitartaric acid salts) is crystalline. Specific weight percentages include 70%, 72%, 75%, 77%, 80%, 82%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or percentages between 70% and 100%. Crystalline ledopetan or its pharmaceutically acceptable salts (e.g., hemitartaric acid salts, such as L-hemitartaric acid salts) can be monocrystalline crystals or mixtures of different monocrystalline crystals. Monocrystalline crystal means that ledopetan or its pharmaceutically acceptable salts (e.g., hemitartaric acid salts, such as L-hemitartaric acid salts) are a single crystal or multiple crystals, wherein each crystal has the same crystal form. Therefore, in another specific embodiment, at least a specific weight percentage of ledopetan or its pharmaceutically acceptable salts (e.g., hemitartaric acid salts, such as L-hemitartaric acid salts) is a monocrystalline form. Specific weight percentages include 70%, 72%, 75%, 77%, 80%, 82%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or percentages between 70% and 100%.When a specific weight percentage of ledopetan or a pharmaceutically acceptable salt thereof (e.g., hemitartaric acid salt, such as L-hemitartaric acid salt) is a monocrystalline form, the remainder is a combination of one or more other crystalline forms (excluding monocrystalline forms) of amorphous ledopetan or a pharmaceutically acceptable salt thereof (e.g., hemitartaric acid salt, such as L-hemitartaric acid salt) and / or ledopetan or a pharmaceutically acceptable salt thereof (e.g., hemitartaric acid salt, such as L-hemitartaric acid salt). When crystalline ledopetan or a pharmaceutically acceptable salt thereof (e.g., hemitartaric acid salt, such as L-hemitartaric acid salt) is defined as a specific percentage of a particular crystalline form, the remainder consists of an amorphous form and / or crystalline forms other than the specified one or more particular crystalline forms. Examples of monocrystalline forms include ledopetan hemitartaric acid salts (such as L-hemitartaric acid salts), characterized by one or more XRPD properties as described below.

[0100] In embodiments of the compositions disclosed herein, ledopetan is provided in the form of solid crystalline ledopetan hemitartaric acid salts (e.g., L-hemitartaric acid salt). In embodiments, the crystalline ledopetan hemitartarate (e.g., L-hemitartarate) may be in solid crystalline form, characterized in that the XRP diffraction pattern includes a peak at about 13.0 2θ (such as 13.02 2θ) and optionally at least one, at least two, at least three or four additional peaks selected from: about 12.4 2θ (such as about 12.43 2θ), about 14.4 2θ (such as about 14.40 2θ), about 21.1 2θ (such as about 21.10 2θ), about 24.4 2θ (such as about 24.36 2θ, page 13 / 29 of the specification, CN 121620362 A). In embodiments, the solid crystalline form of ledopetan hemitartarate (e.g., L-hemitartarate) is characterized by an XRP diffraction pattern including peaks at about 12.4 2θ, about 13.0 2θ, about 14.4 2θ, about 21.1 2θ, about 24.4 2θ, and optionally at least one additional peak selected from the group consisting of about 18.1 2θ and about 19.9 2θ. For example, the XRP diffraction pattern may include peaks at about 12.43 2θ, about 13.02 2θ, about 14.40 2θ, about 18.07 2θ, about 19.92 2θ, about 21.10 2θ, about 24.36 2θ, and optionally at least one additional peak selected from the group consisting of about 19.62 2θ and about 21.44 2θ. In the embodiments, the solid crystalline form of medopetan hemitartaric acid (e.g., L-hemitartaric acid salt) is characterized by an XRP diffraction pattern corresponding to Figure 1. In the embodiments, XRP diffraction patterns are collected using Cu Kα radiation, for example, λ = 1.54180 Å. In the embodiments, the peak angle 2θ is given an accuracy of ±0.02° 2θ.

[0101] In embodiments of the compositions disclosed herein, ledoperamide or a pharmaceutically acceptable salt thereof (e.g., a hemitartaric acid salt, such as L-hemitartaric acid salt), including any hydrate, solvate, and / or polymorph (such as anhydrous polymorph), and including any solid crystalline or solid amorphous form thereof, such as any solid crystalline form as defined above, may have a particle size distribution in which D90 < 350 μm or < 300 μm (e.g., < 290 μm, < 280 μm, < 270 μm, or < 260 μm) and / or D50 < 150 μm (e.g., < 140 μm, < 120 μm, 100 μm, or < 180 μm). In embodiments, D10 < 15 μm, for example < 10 μm. In some embodiments, D90 < 300 μm (e.g., <290 μm, <280 μm, <270 μm, or <260 μm), D50 < 150 μm (e.g., <140 μm, <120 μm, <100 μm, or <80 μm), and D10 < 15 μm, for example, <10 μm. In some embodiments, D90 < 250 μm (e.g., <240 μm, <230 μm, or <220 μm) and / or D50 < 120 μm (e.g., <100 μm, <80 μm, or <75 μm). In some embodiments, D90 < 250 μm (e.g., <240 μm, <230 μm, or <220 μm) and D50 < 120 μm (e.g., <100 μm, <80 μm, or <75 μm). In some embodiments, D90 < 250 μm (e.g., <240 μm, <230 μm, or <220 μm), D50 < 120 μm (e.g., <100 μm, <80 μm, or <75 μm), and D10 < 15 μm, e.g., <10 μm. In some embodiments, the particle size distribution can be determined by laser diffraction, e.g., wet laser diffraction (wet dispersion), for example, at a concentration of 10 mg / ml in silicone oil.

[0102] In a related aspect, this disclosure provides solid particles of ledopetan or a pharmaceutically acceptable salt thereof (e.g., a hemitartaric acid salt, such as L-hemitartaric acid salt) having a particle size distribution in which D90 < 350 μm or < 300 μm (e.g., < 290 μm, < 280 μm, < 270 μm or < 260 μm) and / or D50 < 150 μm (e.g., < 140 μm, < 120 μm, 100 μm or < 180 μm). In examples, D10 < 15 μm, for example < 10 μm.In some embodiments, D90 < 300 μm (e.g., <290 μm, <280 μm, <270 μm, or <260 μm), D50 < 150 μm (e.g., <140 μm, <120 μm, <100 μm, or <80 μm), and D10 < 15 μm, for example, <10 μm. In some embodiments, D90 < 250 μm (e.g., <240 μm, <230 μm, or <220 μm) and / or D50 < 120 μm (e.g., <100 μm, <80 μm, or <75 μm). In some embodiments, D90 < 250 μm (e.g., <240 μm, <230 μm, or <220 μm) and D50 < 120 μm (e.g., <100 μm, <80 μm, or <75 μm). In some embodiments, D90 < 250 μm (e.g., <240 μm, <230 μm, or <220 μm), D50 < 120 μm (e.g., <100 μm, <80 μm, or <75 μm), and D10 < 15 μm, e.g., <10 μm.

[0103] In embodiments, the particle size distribution can be determined by laser diffraction, e.g., wet laser diffraction (wet dispersion), e.g., at a concentration of 10 mg / ml in silicone oil.

[0104] In embodiments, solid particles of ledopetan are provided in the form of solid crystalline ledopetan hemitarite (e.g., L-hemitarite), e.g., having XRPD characteristics as defined above.

[0105] It should be understood that the D value associated with the particle size distribution is a percentile value. For example, D90 may refer to a particle size below which particles account for 90% of the total particles. Similarly, D50 can refer to a particle size in which particles smaller than this size comprise 50% of the total particles, and D10 can refer to a particle size in which particles smaller than this size comprise 10% of the total particles. It should be understood that D values ​​can be indicated by uppercase or lowercase letters, such that “D” and “d” are used interchangeably. For example, D90 can be represented as d90, and vice versa. Particle size distribution can be cumulative and / or volume-based, as described on page 14 / 29 of the specification, 20 CN 121620362 A. Furthermore, particle size can refer to the diameter of spherical particles or the equivalent diameter of non-spherical particles. In the latter case, the equivalent diameter value can be obtained using shape factor analysis, etc.

[0106] Surprisingly, it has been found that the particle size distribution of the monotartrate and hemitartrate salts of ledopetan described herein allows for a uniform distribution (such as homogeneous distribution) of the aforementioned salts (i.e., APIs) in compositions (such as pharmaceutical compositions). This is particularly advantageous for pharmaceutical compositions in which the API is present in low doses, such as doses of about 2 mg to about 10 mg of levodopatan as described herein (measured in equivalent amounts of free base), where accurate dose uniformity is known to be challenging.

[0107] Not wishing to be bound by theory, the inventors believe that the irregular morphology of such granular crystalline metopetan hemitartaric acid with a plate-like surface is particularly suitable for ensuring the uniform distribution of such particles in the composition (e.g., those disclosed herein), for example, due to the minimization and / or improved distribution of particle agglomeration within diluents (such as pregelatinized starch).

[0108] Method for preparing a pharmaceutical composition In one aspect, this disclosure provides a method for preparing a pharmaceutical composition comprising ledopertan monotartrate or hemitartrate as described herein, the method comprising: (a) weighing and sieving ledopertan monotartrate or hemitartrate, a diluent, a disintegrant, and optionally a flow aid; (b) blending ledopertan monotartrate or hemitartrate with about one-third of the total amount of the diluent to form a first premixed composition, and optionally sieving the first premixed composition; (c) preparing a second premixed composition comprising about one-third of the total amount of the diluent, optionally wherein preparing the second premixed composition comprises blending about one-third of the diluent with a flow aid; and optionally sieving the second premix; (d) blending the first and second premixed compositions with a disintegrant and about one-third of the total amount of the diluent to form a first dry mix, and optionally sieving the first dry mix; (e) Weighing and sieving the lubricant and blending it with the first dry blend composition, optionally with any additional excipients, flavoring agents, sweeteners and / or coloring agents, to form a final blend composition; and (f) optionally compressing the final blend composition (e.g., to form tablets) or filling the final blend composition into capsules (e.g., hard capsules or soft capsules).

[0109] In an embodiment, the blending in steps (b), (c) and / or (d) is carried out in a mixer tank.

[0110] In an embodiment, the blending in step (d) includes adding the first premix composition to a second premix composition in the mixer tank (i.e., wherein the second premix composition is present in the mixer tank before the introduction of the first premix composition); introducing a disintegrant into the mixer tank after the first premix composition; and introducing approximately one-third of the total amount of diluent into the mixer tank after the introduction of the disintegrant.

[0111] In an embodiment, the blending in step (b) is performed for about 1 minute to about 15 minutes, for example, about 2 minutes to about 10 minutes, or about 4 minutes to about 8 minutes. In an embodiment, the blending in step (b) is performed for about 6 minutes. In an embodiment, the blending in step (b) is performed at a speed of about 10 rpm to about 20 rpm, for example, about 15 rpm. In a particular embodiment, the blending in step (b) is performed at about 15 rpm for about 6 minutes. In some embodiments, the first premixed composition is sieved after blending in step (b).In an embodiment, after blending in step (b), the first premixed composition is sieved through a sieve with a mesh size of about 600 μm.

[0112] In an embodiment, the blending in step (c) is carried out for about 1 minute to about 15 minutes, for example, about 2 minutes to about 10 minutes, or about 3 minutes to about 8 minutes. In an embodiment, the blending in step (c) is carried out for about 5 minutes. In an embodiment, the blending in step (c) is carried out at a speed of about 10 rpm to about 20 rpm, for example, about 15 rpm. In the specification of a specific embodiment, page 15 / 29 of CN 121620362 A, the blending in step (c) is carried out at about 15 rpm for about 5 minutes. In some embodiments, after blending in step (c), the second premixed composition is sieved. In an embodiment, after blending in step (c), the second premixed composition is sieved through a sieve with a mesh size of about 600 μm.

[0113] In an embodiment, the blending in step (d) is performed for approximately 15 minutes to approximately 45 minutes, for example, approximately 20 minutes to approximately 40 minutes, or approximately 25 minutes to approximately 35 minutes. In an embodiment, the blending in step (d) is performed for approximately 30 minutes. In an embodiment, the blending in step (d) is performed at a speed of approximately 10 rpm to approximately 20 rpm, for example, approximately 15 rpm. In a particular embodiment, the blending in step (d) is performed at approximately 15 rpm for approximately 30 minutes.

[0114] In an embodiment, the blending in step (e) is performed for approximately 1 minute to approximately 15 minutes, for example, approximately 2 minutes to approximately 10 minutes, or approximately 4 minutes to approximately 8 minutes. In an embodiment, the blending in step (e) is performed for approximately 6 minutes. In an embodiment, the blending in step (e) is performed at a speed of approximately 10 rpm to approximately 20 rpm, for example, approximately 15 rpm. In a particular embodiment, the blending in step (e) is performed at approximately 15 rpm for approximately 6 minutes.

[0115] In an embodiment, the sieving in step (a) comprises sieving one or more of the following: ledopetan or a pharmaceutically acceptable salt thereof, such as its monotartrate or hemitartrate, a diluent, a disintegrant, and / or a flow aid, through a sieve with a mesh size of about 600 μm. In one embodiment, each of the following is sieved (e.g., individually) through a sieve with a mesh size of about 600 μm: ledopetan or a pharmaceutically acceptable salt thereof, such as its monotartrate or hemitartrate, a diluent, a disintegrant, and a flow aid.

[0116] In an embodiment, the sieving in step (b) comprises sieving the first premixed composition through a sieve with a mesh size of about 600 μm.

[0117] In an embodiment, the sieving in step (c) comprises sieving the second premixed composition through a sieve with a mesh size of about 600 μm.

[0118] In an embodiment, the sieving in step (e) includes sieving the lubricant through a sieve with a mesh size of about 600 μm.

[0119] In one embodiment, this disclosure provides a method for preparing a pharmaceutical composition comprising ledopertan monotartrate or hemitartrate as described herein, the method comprising: (a) weighing and sieving ledopertan monotartrate or hemitartrate, a diluent, a disintegrant, and a flow aid as described herein; (b) blending ledopertan monotartrate or hemitartrate with about one-third of the total amount of diluent to form a first premix composition, and sieving the first premix composition; (c) preparing a second premix composition comprising about one-third of the total amount of diluent, wherein preparing the second premix composition comprises blending about one-third of the diluent with a flow aid; and sieving the second premix; (d) blending the first and second premix compositions with a disintegrant and about one-third of the total amount of diluent to form a first dry mix composition, and sieving the first dry mix composition; (e) Weighing and sieving the lubricant and blending it with the first dry blend composition, optionally with any additional excipients, flavoring agents, sweeteners and / or coloring agents, to form a final blend composition; and (f) optionally compressing the final blend composition (e.g. to form tablets) or filling the final blend composition into capsules (e.g., hard capsules or soft capsules).

[0120] In one embodiment, this disclosure provides a method for preparing a pharmaceutical composition comprising ledopertan monotartrate or hemitartrate as described herein, the method comprising: (a) weighing and sieving ledopertan monotartrate or hemitartrate, a diluent, a disintegrant, and a gliding agent as described herein; (b) blending ledopertan monotartrate or hemitartrate with about one-third of the total amount of diluent to form a first premix composition, and sieving the first premix composition; (c) preparing a second premix composition comprising about one-third of the total amount of diluent, wherein preparing the second premix composition comprises blending about one-third of the diluent with a gliding agent; and sieving the second premix; (d) blending the first and second premix compositions with a disintegrant and about one-third of the total amount of diluent to form a first dry mix composition, wherein preparing the first dry mix composition comprises: i. adding the first premix composition to the second premix composition in a mixer tank; ii. Adding a disintegrant to the first and second premixed compositions in a mixer can; iii. Adding about one-third of the total amount of diluent to the first and second premixed compositions and the disintegrant in the mixer can; and iv. Blending the first and second premixed compositions, the disintegrant, and the diluent in the mixer can; and sieving the first dry blend composition; (e) Weighing and sieving the lubricant and blending the lubricant with the first dry blend composition, optionally with any additional excipients, flavoring agents, sweeteners, and / or coloring agents, to form a final blend composition; and (f) Optionally compressing the final blend composition (e.g., to form tablets) or filling the final blend composition into capsules (e.g., hard capsules or soft capsules).

[0121] In another embodiment, this disclosure provides a method for preparing a pharmaceutical composition comprising ledopetan monotartrate or hemitartrate as described herein, the method comprising: (a) weighing and sieving ledopetan monotartrate or hemitartrate, a diluent, a disintegrant, and a gliding agent as described herein, wherein each of ledopetan or a pharmaceutically acceptable salt thereof, the diluent, the disintegrant, and the gliding agent is sieved through a sieve with a mesh size of about 600 μm; (b) blending ledopetan monotartrate or hemitartrate with about one-third of the total amount of the diluent to form a first premixed composition, wherein blending is performed at about 15 rpm for about 6 minutes, and sieving the first premixed composition through a sieve with a mesh size of about 600 μm; (c) preparing a second premixed composition comprising about one-third of the total amount of the diluent, wherein preparing the second premixed composition comprises blending about one-third of the diluent with a gliding agent, wherein blending is performed at about 15 rpm for about 6 minutes, and sieving the first premixed composition through a sieve with a mesh size of about 600 μm; (d) The first and second premixed compositions are blended with a disintegrant and about one-third of the total amount of diluent to form a first dry mix, wherein the preparation of the first dry mix comprises: i. adding the first premixed composition to the second premixed composition in a mixer tank; ii. adding a disintegrant to the first and second premixed compositions in a mixer tank; iii. adding about one-third of the total amount of diluent to the first and second premixed compositions and the disintegrant in a mixer tank; and iv. blending the first and second premixed compositions, the disintegrant and the diluent in a mixer tank, wherein blending is carried out at about 15 rpm for about 30 minutes; and the first dry mix is ​​sieved through a sieve with a mesh size of about 600 μm; (e) the lubricant is weighed and sieved, wherein the lubricant is sieved through a sieve with a mesh size of about 600 μm. The lubricant is sieved through a sieve of μm; and the lubricant is optionally blended with any additional excipient, flavoring agent, sweetener and / or coloring agent, wherein the blending is carried out at about 15 rpm for about 6 minutes to form a final blend composition; and (f) optionally the final blend composition is compressed (e.g. to form tablets) or the final blend composition is filled into capsules (e.g., hard capsules or soft capsules).

[0122] In all embodiments of the methods disclosed herein, the medopetan monotartrate or hemitartrate, diluent, disintegrant, glidant and lubricant may be selected according to any of the compositions disclosed herein.

[0123] Therefore, in a particular embodiment, the present invention provides a method for preparing a pharmaceutical composition comprising ledopetan hemitartarate, the method comprising: (a) weighing and sieving ledopetan hemitartarate (e.g., L-hemitartarate), pregelatinized starch, sodium glycolate starch and colloidal silica, wherein each of ledopetan or a pharmaceutically acceptable salt thereof, pregelatinized starch, sodium glycolate starch and colloidal silica is sieved through a sieve with a mesh size of about 600 μm; (b) blending ledopetan hemitartarate (e.g., L-hemitartarate) with about one-third of the total amount of pregelatinized starch to form a first premix composition, wherein the blending is carried out at about 15 rpm for about 6 minutes, and the first premix composition is sieved through a sieve with a mesh size of about 600 μm; (c) Preparing a second premixed composition comprising about one-third of the total amount of pregelatinized starch, wherein preparing the second premixed composition comprises blending about one-third of the total amount of pregelatinized starch with colloidal silica, wherein blending is performed at about 15 rpm for about 5 minutes; and sieving the second premix through a sieve with a mesh size of about 600 μm; (d) Blending the first and second premixed compositions with sodium glycolate and about one-third of the total amount of pregelatinized starch to form a first dry mix, wherein preparing the first dry mix comprises: i. adding the first premixed composition to the second premixed composition in a mixer tank; ii. adding sodium glycolate to the first and second premixed compositions in a mixer tank; iii. adding about one-third of the total amount of pregelatinized starch to the first and second premixed compositions and a disintegrant in a mixer tank; and iv. blending the first and second premixed compositions, sodium glycolate, and pregelatinized starch in a mixer tank, wherein blending is performed at about 15 rpm for about 30 minutes; and sieving the first dry mix through a sieve with a mesh size of about 600 μm. (e) Magnesium stearate is weighed and sieved, wherein the magnesium stearate is sieved through a sieve with a mesh size of about 600 μm; and the magnesium stearate is optionally blended with the first dry blend composition with any additional excipient, flavoring agent, sweetener and / or coloring agent, wherein the blending is carried out at about 15 rpm for about 6 minutes to form the final blend composition; and (f) the final blend composition is optionally compressed (e.g. to form tablets) or the final blend composition is filled into capsules (e.g., hard capsules or soft capsules, such as HPMC capsule shells).

[0124] In embodiments of the methods disclosed herein, the levodopatan or a pharmaceutically acceptable salt thereof (e.g., hemitartaric acid salt, such as L-hemitartaric acid salt) in step (a) may be provided in the form of a hydrate, a solvate and / or a polymorph (e.g., anhydrous polymorph).In embodiments, the ledopetan or a pharmaceutically acceptable salt thereof (e.g., hemitartaric acid salts, such as L-hemitartaric acid salts), including any hydrates, solvates, and / or polymorphs thereof (such as anhydrous polymorphs), in step (a) may be provided in solid crystalline or solid amorphous form.

[0125] In certain embodiments, at least a specific weight percentage of ledopetan or a pharmaceutically acceptable salt thereof (e.g., hemitartaric acid salts, such as L-hemitartaric acid salts) is crystalline. For example, at least a specific weight percentage of ledopetan or a pharmaceutically acceptable salt thereof (e.g., hemitartaric acid salts, such as L-hemitartaric acid salts) is a monocrystalline form. Suitable percentages of crystallinity and / or monocrystalline form, as well as the characteristics of such crystal forms (e.g., determined according to XRP), are discussed in conjunction with the compositions disclosed herein. In the specification, pages 18 / 29, CN 121620362 A

[0126] In the embodiments, ledoperamide or a pharmaceutically acceptable salt thereof (e.g., hemitartaric acid salts, such as L-hemitartaric acid salts), including any hydrates, solvates and / or polymorphs thereof (such as anhydrous polymorphs), and including any solid crystalline or solid amorphous form thereof, may be milled prior to step (a), for example to obtain the desired particle size or particle size distribution. In the embodiments, milling may be performed at a speed of about 5500 rpm to about 7500 rpm, for example, about 6000 rpm to about 7000 rpm. In the embodiments, milling is performed using a conical mill. In the embodiments, milling is performed for a maximum of about 15 minutes, for example, about 5 to about 10 minutes or about 5 to about 8 minutes. In one embodiment, the grinder (e.g., a conical grinder) has a mesh size of about 200 μm to about 800 μm, about 400 μm to about 650 μm, or about 450 μm to about 550 μm, such as a mesh of about 279 μm, about 457 μm, or about 610 μm. In one embodiment, grinding is performed using a conical grinder at a speed of about 6000 rpm, optionally using a mesh size of about 457 μm.

[0127] In an embodiment, the ledopetan or a pharmaceutically acceptable salt thereof (e.g., a hemitartaric acid salt, such as L-hemitartaric acid salt) in step (a), including any hydrate, solvate, and / or polymorph (such as anhydrous polymorph), and including any solid crystalline form or solid amorphous form (e.g., any solid crystalline form as defined with respect to the compositions disclosed herein), may have the following particle size distribution (e.g., after grinding) wherein D90 < 350 μm or < 300 μm (e.g., < 290 μm, < 280 μm, < 270 μm, or < 260 μm) and / or D50 < 150 μm (e.g., < 140 μm, < 120 μm, 100 μm, or < 180 μm). In an embodiment, D10 < 15 μm, for example < 10 μm.In some embodiments, D90 < 300 μm (e.g., <290 μm, <280 μm, <270 μm, or <260 μm), D50 < 150 μm (e.g., <140 μm, <120 μm, <100 μm, or <80 μm), and D10 < 15 μm, for example, <10 μm. In some embodiments, D90 < 250 μm (e.g., <240 μm, <230 μm, or <220 μm) and / or D50 < 120 μm (e.g., <100 μm, <80 μm, or <75 μm). In some embodiments, D90 < 250 μm (e.g., <240 μm, <230 μm, or <220 μm) and D50 < 120 μm (e.g., <100 μm, <80 μm, or <75 μm). In some embodiments, D90 < 250 μm (e.g., < 240 μm, < 230 μm, or < 220 μm), D50 < 120 μm (e.g., < 100 μm, < 80 μm, or < 75 μm), and D10 < 15 μm, e.g., < 10 μm. In embodiments, the particle size distribution can be determined by laser diffraction, e.g., wet laser diffraction (wet dispersion), e.g., at a concentration of 10 mg / ml in silicone oil. In embodiments, ledopetan is provided as solid crystalline ledopetan hemitarite (e.g., L-hemitarite), e.g., having XRPD characteristics as defined above.

[0128] On the other hand, this disclosure provides compositions prepared by the methods described herein or any embodiments thereof, or compositions that can be prepared by the methods described herein or any embodiments thereof.

[0129] Another aspect of the treatment method provides a treatment method comprising administering a therapeutically effective amount of ledoperamide monotartrate or hemitartrate to a subject in need, wherein the ledoperamide monotartrate or hemitartrate is administered in a pharmaceutical composition disclosed herein. In a related aspect, this disclosure provides the use of ledoperamide or monotartrate or hemitartrate in the manufacture of a medicament, wherein the medicament is a pharmaceutical composition disclosed herein. In another related aspect, this disclosure provides the use of the pharmaceutical compositions disclosed herein in the manufacture of a medicament. In a further related aspect, this disclosure provides pharmaceutical compositions as disclosed herein for use in a therapy.

[0130] As stated above, the inventors believe that the solid particulate ledoperamide monotartrate or hemitartrate (e.g., hemitartrate, such as L-hemitartrate) described herein has a particle size distribution as described above, for example, solid crystalline ledoperamide hemitartrate (e.g., L-hemitartrate) having such a particle size distribution and optionally having the XRPD characteristics as defined above is particularly suitable for the preparation of pharmaceutical compositions.Therefore, this disclosure also provides treatment methods comprising administering a therapeutically effective amount of ledopetan monotartrate or hemitartrate to a subject of need, such as a human, wherein the ledopetan monotartrate or hemitartrate is a solid particulate form of ledopetan monotartrate or hemitartrate as disclosed herein (e.g., hemitartrate, such as L-hemitartrate). In a related aspect, this disclosure provides the use of ledopetan monotartrate or hemitartrate in the manufacture of a pharmaceutical product, wherein the ledopetan monotartrate or hemitartrate is a solid particulate form of ledopetan monotartrate or hemitartrate as disclosed herein (e.g., hemitartrate, such as L-hemitartrate). In another related aspect, this disclosure provides the use of ledopetan or its monotartrate or hemitartrate in the manufacture of a medicament, wherein the ledopetan monotartrate or hemitartrate is a solid particulate ledopetan monotartrate or hemitartrate as disclosed herein (e.g., hemitartrate, such as L-hemitartrate). In a further related aspect, this disclosure provides solid particulate ledopetan monotartrate or hemitartrate (e.g., hemitartrate, such as L-hemitartrate) for therapeutic purposes as disclosed herein.

[0131] This disclosure also provides pharmaceutical compositions described herein or ledopetan monotartrate or hemitartrate described herein for the treatment and / or prevention of diseases, disorders and / or conditions selected from: psychosis, schizophrenia, schizophrenia-like disorders, bipolar disorder, psychotic disorders, drug-induced psychotic disorders, mood disorders, anxiety disorders, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Tourette syndrome, brain injury, sleep disorders, sexual dysfunction, eating disorders, obesity, headache, pain in a condition characterized by increased muscle tone, Parkinson's disease, Parkinson's syndrome, movement disorders, L-DOPA-induced movement disorders, tardive dyskinesia, dystonia, tic and tremor dementia, Huntington's disease, drug-induced movement disorders, restless legs, narcolepsy, Alzheimer's disease and disorders associated with Alzheimer's disease.

[0132] This disclosure also provides the use of the pharmaceutical compositions described herein or the ledopetan monotartrate or hemitartrate described herein in the manufacture of a medicament for the treatment and / or prevention of diseases, disorders and / or conditions selected from: psychosis, schizophrenia, schizophrenia-like disorders, bipolar disorder, psychotic disorders, drug-induced psychotic disorders, mood disorders, anxiety disorders, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Tourette syndrome, brain injury, sleep disorders, sexual dysfunction, eating disorders, obesity, headache, pain in a condition characterized by increased muscle tone, Parkinson's disease, Parkinson's syndrome, movement disorders, L-DOPA-induced movement disorders, tardive dyskinesia, dystonia, tic and tremor dementia, Huntington's disease, drug-induced movement disorders, restless legs, narcolepsy, Alzheimer's disease and disorders associated with Alzheimer's disease.

[0133] This disclosure also provides methods for treating and / or preventing diseases, disorders and / or conditions selected from: psychosis, schizophrenia, schizophrenia-like disorders, bipolar disorder, psychotic disorders, drug-induced psychotic disorders, mood disorders, anxiety disorders, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorders, ADHD, cerebral palsy, Tourette syndrome, brain injury, sleep disorders, sexual dysfunction, eating disorders, obesity, headache, pain in a condition characterized by increased muscle tone, Parkinson's disease, Parkinson's syndrome, movement disorders, L-DOPA-induced movement disorders, tardive dyskinesia, dystonia, tic and tremor dementia, Huntington's disease, drug-induced movement disorders, restless legs, narcolepsy, Alzheimer's disease and Alzheimer's disease-related disorders, wherein the method comprises administering a therapeutically effective amount of the pharmaceutical composition described herein or the levodopa monotartrate or hemitartrate described herein to a subject in need, such as a human.

[0134] In the embodiments, the treatment methods and pharmaceutical compositions disclosed herein are suitable for treating and / or preventing diseases, disorders and / or conditions selected from: psychosis, schizophrenia, schizophrenia-like disorders, bipolar disorder, psychotic disorders, drug-induced psychotic disorders, mood disorders, anxiety disorders, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Tourette syndrome, brain injury, sleep disorders, sexual dysfunction, eating disorders, obesity, headache, pain in a condition characterized by increased muscle tone, Parkinson's disease, Parkinson's syndrome, movement disorders, L-DOPA-induced movement disorders, tardive dyskinesia, dystonia, tic and tremor dementia, Huntington's disease, drug-induced movement disorders, restless legs, narcolepsy, Alzheimer's disease and disorders related to Alzheimer's disease. (Instructions for Use, page 20 / 29, CN 121620362 A) For example, the disease, disorder, and / or condition may be schizophrenia, L-DOPA-induced movement disorder, and / or Huntington's disease.

[0135] In embodiments, the pharmaceutical compositions disclosed herein may be administered to a subject (e.g., a human subject) to provide a dose of ledopertan corresponding to a free base amount of about 2 mg (e.g., about 2.0 mg) to about 10 mg (e.g., about 10.0 mg), such as about 2.5 mg, about 5.0 mg, or about 7.5 mg. Such doses may be administered once, twice, or more daily. In some embodiments, ledopertan monotartrate or hemitartrate is administered in a first amount of one or more doses, followed by a second amount of one or more doses, wherein the second amount is less than the first amount, and wherein both the first and second amounts are administered independently in the pharmaceutical compositions disclosed herein. Optionally, the first amount corresponds to an amount of about 7.5 mg to about 10.0 mg and / or the second amount corresponds to an amount of free base of about 2.5 mg to about 5.0 mg. In all embodiments of the treatments and therapies described herein, if desired, ledopatan monotartrate or hemitartrate may be administered twice daily, for example, twice daily doses corresponding to one of the foregoing amounts, wherein the administration is carried out in the composition described herein. Such doses may be given, for example, once in the morning and once in the evening. In one embodiment, ledopatan monotartrate or hemitartrate may be administered in two equal daily doses, for example, twice daily doses corresponding to about 7.5 mg each time, such as about 7.5 mg in the morning and about 7.5 mg in the evening; or twice daily doses corresponding to about 5.0 mg each time, such as about 5.0 mg in the morning and about 5.0 mg in the evening; or twice daily doses corresponding to about 2.5 mg each time, such as about 2.5 mg in the morning and 2.5 mg in the evening.

[0136] In all embodiments of the treatments and therapies described herein, if desired, ledopertan monotartrate or its hemitartrate salt may be administered at a total daily dose of about 4.0 mg to about 20.0 mg, for example, about 5.0 mg to about 15.0 mg, such as about 5.0 mg to about 10.0 mg, wherein the administration is made using the compositions described herein.

[0137] In embodiments, the pharmaceutical compositions disclosed herein may be administered to subjects (e.g., human subjects) who have been diagnosed with Parkinson's disease or who have been identified as being at risk of developing Parkinson's disease.

[0138] In embodiments, the pharmaceutical compositions disclosed herein may be administered to subjects (e.g., human subjects) who have been identified as being at risk of developing motor disorders. In the embodiments, the subject may have been identified as having one or more of the following risk factors for developing a movement disorder: a diagnosis of Parkinson's disease before the age of 60; cumulative L-DOPA exposure (e.g., based on the levodopa equivalent daily dose (LEDD)); the subject being female; the severity of the movement and functional impairment (e.g., assessed by the MDS-UPDRS Part III score); a nontremor dominant clinical phenotype; a genetic risk score (e.g., a polygenic risk score); and anxiety (see, for example, npj Parkinson's Disease 33:1-6 (2018), the entire contents of which are incorporated herein by reference).

[0139] In the embodiments, the pharmaceutical compositions disclosed herein may be administered to the subject prior to the occurrence of a movement disorder. Alternatively or alternatively, the pharmaceutical compositions may be administered without prior administration of a Parkinson's disease medication. Thus, the pharmaceutical compositions may be administered without prior administration of a Parkinson's disease medication such as L-DOPA or a pharmaceutically acceptable salt thereof. Thus, the pharmaceutical compositions disclosed herein may be administered to subjects who have not experienced a movement disorder, such as subjects who have not experienced L-DOPA-induced movement disorders. Such subjects may be, for example, patients (e.g., human patients) who have already received treatment with Parkinson's disease drugs (e.g., L-DOPA or a pharmaceutically acceptable salt thereof) but have not yet exhibited symptoms of movement disorder (e.g., LID).

[0140] Therefore, in some embodiments, the compositions disclosed herein may be administered to subjects (preferably human subjects) who have received treatment with Parkinson's disease drugs (e.g., L-DOPA or a pharmaceutically acceptable salt thereof) for at least 1 day, at least 1 week, at least 1 month, or at least 1 year (e.g., at least 4, 5, 6, 7, 8, 9, or 10 years) prior to the first administration of the compositions disclosed herein.In a further embodiment, the subject who has not experienced movement disorders can be a subject who has not previously received Parkinson's disease medication, i.e., a subject (e.g., a human patient) who has not received or is receiving a course of treatment with Parkinson's disease medication (e.g., L-DOPA or a pharmaceutically acceptable salt thereof, as described on pages 21 / 29 of the specification, CN 121620362 A) prior to initiating a course of treatment with Parkinson's disease medication (e.g., L-DOPA or a pharmaceutically acceptable salt thereof). In embodiments, such a subject may receive "pretreatment" with the composition disclosed herein prior to initiating a course of treatment with Parkinson's disease medication (e.g., L-DOPA or a pharmaceutically acceptable salt thereof). Therefore, the composition disclosed herein can be administered to a subject (e.g., a human subject) at least 1 day, at least 1 week, at least 1 month, or at least 1 year before the first administration of a medication for treating Parkinson's disease (e.g., L-DOPA or a pharmaceutically acceptable salt thereof) to the subject. In such embodiments, the subject may therefore undergo a “pre-treatment” process in which the composition disclosed herein is repeatedly administered to the subject, for example, once or twice daily for at least one day, at least one week, at least one month, or at least one year, prior to the first administration of a drug for treating Parkinson’s disease. In another embodiment, the subject may begin treatment with a Parkinson’s disease drug (e.g., L-DOPA or a pharmaceutically acceptable salt thereof) on the same day they also begin treatment with the composition disclosed herein. Thus, the subject may be administered (i) the composition disclosed herein and (ii) a Parkinson’s disease drug such that the subject receives a first dose of both the composition disclosed herein and the Parkinson’s disease drug sequentially within 24 hours. In such embodiments, the composition disclosed herein and the Parkinson’s disease drug may be administered simultaneously, or the composition disclosed herein may be administered before the Parkinson’s disease drug, or the Parkinson’s disease drug may be administered before the composition disclosed herein.

[0141] In embodiments, the composition disclosed herein may be administered together with a drug for treating Parkinson’s disease (e.g., L-DOPA or a pharmaceutically acceptable salt thereof), or may be administered before or after the administration of such a drug. Therefore, the compositions disclosed herein can be administered to subjects concurrently with a Parkinson's disease medication (e.g., L-DOPA or a pharmaceutically acceptable salt thereof). Alternatively, the compositions disclosed herein may be administered to subjects prior to a Parkinson's disease medication (e.g., L-DOPA or a pharmaceutically acceptable salt thereof), or may be administered to subjects prior to the compositions disclosed herein.When the compositions disclosed herein are administered before or after a Parkinson's disease medication (e.g., L-DOPA or a pharmaceutically acceptable salt thereof), the administration of the compositions disclosed herein and the administration of the Parkinson's disease medication may be carried out over a time period of 1 second to 24 hours, such as about 1 minute to about 24 hours, such as about 1 minute to about 12 hours, such as about 1 minute to about 6 hours, such as about 1 minute to about 1 hour.

[0142] In embodiments, the pharmaceutical compositions disclosed herein are suitable for preventing or reducing allergies to medications for treating Parkinson's disease, such as preventing or reducing allergies to L-DOPA or a pharmaceutically acceptable salt thereof. In some embodiments, preventing or reducing allergies to Parkinson's disease medications includes administering levodopa or a pharmaceutically acceptable salt thereof to a subject who has not experienced a movement disorder (e.g., L-DOPA-induced movement disorder), wherein levodopa monotartrate or hemitartrate is administered with the compositions disclosed herein. In some embodiments, prevention or reduction of allergy to Parkinson's disease drugs includes administering ledopertan monotartrate or hemitartrate to a subject who has been receiving a treatment course of Parkinson's disease drug (e.g., L-DOPA or a pharmaceutically acceptable salt thereof) for at least one day prior to the first administration of the compound to the subject, wherein the ledopertan monotartrate or hemitartrate is administered with the compositions disclosed herein. In some embodiments, prevention or reduction of allergy to Parkinson's disease drugs includes administering ledopertan monotartrate or hemitartrate to a subject, such as a person who has not previously received Parkinson's disease drugs (e.g., a subject who has not previously received L-DOPA or a pharmaceutically acceptable salt thereof), wherein the ledopertan monotartrate or hemitartrate is administered with the compositions disclosed herein. In some embodiments, ledopertan monotartrate or hemitartrate is administered with the compositions disclosed herein at least one day prior to the first administration of a Parkinson's disease drug (e.g., L-DOPA or a pharmaceutically acceptable salt thereof) to the subject.

[0143]

[0144] As generally disclosed herein, the following non-limiting examples are provided to further illustrate this disclosure.

[0145] Examples Abbreviations Specification 22 / 29 pages 28 CN 121620362 A MDS-UPDRS Revised Unified Parkinson's Disease Rating Scale Sponsored by the International Parkinson's and Movement Disorders Association µm micron micron mm millimeter rpm revolutions per minute XRP X-ray powder XRP X-ray powder diffraction Example 1A: Grinding of API was performed using a Fitzmill L1A milling machine. Lidopetan L-hemitartaric acid was hammer-ground at a hammer speed of 7000 rpm and a collection sieve aperture of 800 µm, and the resulting particle size distribution is shown in Table 1.

[0146] Hammer grinding was performed using a Fitzmill L1A milling machine.The particle size distribution of levodopa-L-hemitartaric acid was obtained by hammer milling at a hammer speed of 7000 rpm and a collection sieve aperture of 800 µm, as shown in Table 1. Compared with hammer milling, conical milling can increase yield / capacity and reduce API loss. Although this type of milling provides lower precision for hard-to-mill APIs, it can be seen from Table 1 that using conical milling can provide a more uniform API particle size distribution, and the particle size is generally smaller than that achieved by hammer milling. Smaller particle size helps to achieve homogeneous (uniform) blending with excipients in the formulation. It is not desirable to be bound by theory, but it is thought that smaller particle size is beneficial for the coating of diluents that act as "carriers", thereby improving the uniformity of the blend.

[0147] The selection of appropriate mesh size (also known as sieve size, mesh size or sieve size) will affect the capacity of the mill and the particle size of the ground API.

[0148] Particle size distribution was measured by wet dispersion sample laser diffraction (Mastersizer 2000, Malvern Panalytical) at a concentration of 10 mg / ml in silicone oil.

[0149] Another parameter showing the width of the size distribution is the span. The span of the size distribution is defined as: span = (d90 – d10) / d50, and gives an indication of the distance between the 10% and 90% points (normalized by the midpoint). The lower the span value (i.e., closer to 0), the more uniform the particle size.

[0150] Table 1 Specification 23 / 29 pages 29 CN 121620362 A

[0151] According to the method described in Figure 2 and Example 2, the blend composition was prepared using unground and ground API.

[0152] Blending uniformity was measured by the percentage content of API after blending for 15 minutes and 45 minutes and at the filling stage (step 3). Particle size distribution (RSD%) was also measured. As used herein, RSD represents relative standard deviation, such as the relative standard deviation of median particle size. Preferred acceptance values ​​for blend uniformity are: a minimum value not less than 90% of the expected value, a maximum value not greater than 110% of the expected value, an average value between 95% and 105% of the expected value, and RSD% < 5%. The results are shown in Table 2. Bold values ​​exceed the preferred acceptance criteria.

[0153] Table 2 Specification 24 / 29 pages 30 CN 121620362 A

[0154] As can be seen from Table 2, hammer milling at a speed of 7000 rpm and a mesh size of 800 µm produces API particles that cause subsequent blends to fail to meet the preferred acceptance criteria. Conical milling at the same speed and mesh size makes the parameters meet the preferred acceptance criteria.

[0155] While subsequent blends from unmilled API do meet the preferred acceptance criteria, conical milling of API provides improved (narrower) particle size distribution and uniformity of API content.This is an important advantage for blend homogeneity, which is essential to ensure uniform capsule content. This advantage is particularly important for low-dose APIs (e.g., about 10 mg and below).

[0156] Studies have found that grinding speed is particularly important for achieving good API particle size distribution and subsequent blend homogeneity. Studies have found that all grid sizes used in conical mills at 6000 rpm produce acceptable API particle size distribution and blend homogeneity, although smaller grids result in higher API loss (poorer yield), and a 610 µm grid was found to result in a weaker bimodal particle size distribution (Figure 3A). Conical milling at 6000 rpm using a 457 µm grid provides better consistency with preferred acceptance criteria and achieves a proper balance between blendability and API loss.

[0157] As the data in Table 2 show, conical milling achieves acceptable blend homogeneity within 15 minutes, while hammer milling appears to require >45 minutes.

[0158] Not wanting to be bound by theory, it is believed that when using a conical mill, a blending time exceeding 15 minutes may lead to "de-blending," in which the elements in the blend begin to separate.

[0159] Example 1B: Recrystallization of Ledopetan hemitartarate The recrystallized API was found to have the properties shown in Table 3.

[0160] Table 3 Specification 25 / 29 pages 31 CN 121620362 A

[0161] Although it was found that recrystallized API has a more homogeneous particle size distribution than natural API or milled API, blends prepared with recrystallized API are not very uniform.

[0162] Example 2: Capsule blends The preparation of capsule blends contains API and excipients, as shown in Tables 4 and 5. Such blends can be prepared according to the methods of this disclosure, such as the method of Example 3.

[0163] Table 4: Composition of Ledopetan Pharmaceutical

[0164] [a]: The amount of Ledopetan was corrected for the presence of tartrate. Conversion factor: Molecular weight of free base of ledopetan = 275.34 g / mol. Molecular weight of 1 / 2 L-tartrate of ledopetan: 350.38 g / mol, therefore the positive factor on page 26 / 29 of the instruction manual, CN 121620362 A, is: 350.38 / 275.34 = 1.2725 [b]: The amount of pregelatinized starch is adjusted according to the purity of ledopetan. Table 5: Composition of ledopetan pharmaceutical product

[0165] [c]: Rounded to two decimal places, total filler weight = 75.01 mg.

[0166] In the compositions identified in Tables 4 and 5 above, HPMC capsules are used. However, alternative capsule shells, such as hard gelatin shells, can also be used. HPMC shells dissolve more slowly than hard gelatin capsule shells.The water content of the gelatin shell is higher than that of the HMPC shell (the water content in hard gelatin capsule shells is 13% to 15%), which may lead to faster degradation of its contents in some cases.

[0167] Example 3: Preparation of the composition A method for preparing a blend of levodopatan (API), for example for filling into capsules according to Example 2, is shown in Figure 2 and described below.

[0168] Step A: Weighing The levodopatan hemitartaric acid, pregelatinized starch, sodium glycolate starch and colloidal silica were weighed and sieved through a 600 µm sieve.

[0169] Step B: Blending One-third (about 33%) of the pregelatinized starch and all of the levodopatan hemitartaric acid were directly transferred to a blender tank and blended at 15 rpm for 6 minutes. The resulting blend (premix 1) was then sieved through a 600 µm sieve.

[0170] The remaining one-third (approximately 33%) of the pregelatinized starch and all the colloidal silica were directly transferred to a mixer tank and mixed at 15 rpm for 5 minutes. The resulting blend (premix 2) was then sieved through a 600 µm sieve.

[0171] The sieved premix 2, the sieved premix 1, the sodium glycolate starch, and the last one-third (approximately 33%) of the pregelatinized starch were transferred to a mixer tank in this order and mixed at 15 rpm for 30 minutes.

[0172] Step C: Lubricate and weigh magnesium stearate and sieve it through a 600 µm sieve, then transfer it directly to a mixing tank and mix at 15 rpm for 6 minutes.

[0173] Step D: Capsule filling The final blend composition was filled into capsules using a semi-automatic filling machine. During capsule filling, samples were collected for in-process capsule length control and appearance inspection. All capsules were dusted and 100% weight controlled. Capsules with a single weight exceeding the acceptable limit (±7.5%) are discarded.

[0174] Use appropriate equipment to check that the capsules are free of metal and inspect the final appearance.

[0175] Transfer the bulk capsules to double-layered transparent polyethylene bags containing desiccant and seal them with cable ties.

[0176] Step E: Primary Packaging Visually inspect the appearance of the bulk capsules. Pack the accepted capsules in HDPE bottles (84 capsules per 100 mL volumetric flask) and seal them with a child-proof, tamper-evident nut system. Then inspect the appearance of the bottles.

[0177] Example 4: Characteristics of Solid Particulate Ledopetan Hemitartaric Acid Figure 4A shows two representative micrographs of crystalline ledopetan L-hemitartaric acid obtained using a scanning electron microscope (SEM). Briefly, ledopetan L-hemitartaric acid powder was gold-plated using an Agar sputtering coating machine and imaged using a LEO 1430VP scanning electron microscope (SEM).The accelerating voltage is 10 kV at a working distance of 10 mm.

[0178] As shown in Figure 4A, the crystals exhibit a “bundle of wheat” structure with columnar elements resembling “hand-harvested sheaves of wheat.” This dense morphology indicates high particle hardness. The particle size ranges from 240 μm to 600 μm.

[0179] Figure 4B shows a representative optical image of API after size reduction using a mortar and pestle. The particle size is significantly reduced, ranging in the tens of micrometers. Some larger particles of approximately 30 μm to 40 μm can be observed. The morphology of the ground particles is irregular, with a plate-like surface, similar to pregelatinized starch, such as Starch 1500®. This diluent has similar irregular particles with a flat surface covered with cracks. Therefore, pregelatinized starch can act as a carrier for smaller fractions of API particles, and the API can be distributed within the cracks of the starch, promoting uniform distribution and minimizing API agglomeration.

[0180] A comparison of the XRP diffraction pattern of unground crystalline Ledopetan L-hemitartaric acid with that of crystalline Ledopetan L-hemitartaric acid ground at 7000 rpm for 15 minutes using a Fitzmill L1A mill shows that the material remained crystalline during grinding, with little or no change in the XRPD characteristic peaks.

[0181] Example 5 In this example, crystalline Ledopetan L-hemitartaric acid was ground at 6000 rpm for 24 minutes using a Quadro CoMill, yielding the following particle size distribution: D10 = 7.9 µm (Pages 28 / 29, CN 121620362 A) D50 = 86 µm D90 = 305 µm The particle size distribution was measured by wet dispersion laser diffraction (Mastersizer 3000, Malvern Instrument Ltd) in 0.1% (w / w) Span 85 in n-heptane.

[0182] References 1. WO 2012 / 143337 2. J. Pharmacol. Exp. Ther. 374:113-125, July 2020 3. WO 2020 / 239568 4. WO 2022 / 101227 5. Remington's Pharmaceutical Sciences, 20th edition, Mack Publishing Co. 2000 6. Berge et al., J Pharm Sci. (1977) 66:1-19 7. Handbook of Pharmaceutical Excipients, 5th edition, Pharmaceutical Press (London / Chicago), 2006, RC Rowe, PJ Sheskey and SCOwen eds. 8. npj Parkinson's Disease 33:1-6 (2018) Instructions for Use 29 / 29 pages 35 CN 121620362 A Figure 1 Figure 1 / 6, page 36, CN 121620362 A, Figure 2; Figure 2 / 6, page 37, CN 121620362 A, Figure 2 (continued); Figure 3 / 6, page 38, CN 121620362 A, Figure 3; Figure 4 / 6, page 39, CN 121620362 A, Figure 4A; Figure 5 / 6, page 40, CN 121620362 A, Figure 4B; Figure 6 / 6, page 41, CN 121620362 A.

Claims

1. A pharmaceutical composition comprising: a solid particulate crystalline hemitartrate salt of mefridumate, said hemitartrate salt of mefridumate is a combination of mefridumate and tartaric acid in a molar ratio of 1 :0.5: The hemitartrate salt has a particle size distribution with D 90 <350 μm and / or D 50 <150 μm, a diluent, a disintegrant, a lubricant, and optionally a glidant.

2. The pharmaceutical composition of claim 1, wherein D 90 <300 μm, <290 μm, <280 μm, <270 μm, or <260 μm; and / or D 50 <140 μm, <120 μm, 100 μm, or <80 μm.

3. The pharmaceutical composition according to claim 1 or 2, wherein D 90 <300 μm.

4. The pharmaceutical composition according to any one of the preceding claims, wherein the tartaric acid is L-(+)-tartaric acid and / or D-(-)-tartaric acid.

5. The pharmaceutical composition according to any one of the preceding claims, wherein the tartaric acid is L-(+)-tartaric acid.

6. The pharmaceutical composition according to any one of claims 1 to 4, wherein the tartaric acid is D-(-)-tartaric acid.

7. The pharmaceutical composition according to any one of the preceding claims, wherein the solid particulate crystalline hemitartrate salt of mefridumate is characterized by an XRP diffractogram comprising a peak at 13.0 2Q and optionally at least one, at least two, at least three or four further peaks selected from 12.4 2Q, 14.4 2Q, 21.1 2Q, 24.4 2Q.

8. The pharmaceutical composition according to any one of the preceding claims, wherein the solid particulate crystalline hemitartrate salt of mefridumate is characterized by an XRP diffractogram comprising peaks at 12.4 2Q, 13.0 2Q, 14.4 2Q, 21.1 2Q, 24.4 2Q and optionally at least one further peak selected from 19.62 2Q, 21.44 2Q.

9. The pharmaceutical composition according to any one of the preceding claims, wherein the solid particulate crystalline hemitartrate salt of mefridumate is characterized by an XRP diffractogram corresponding to Figure 1.

10. The pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises solid particulate crystalline mefridumate hemitartrate salt in an amount of 3 wt% to 20 wt% on a dry solids basis.

11. The pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises: solid particulate crystalline mefridumate hemitartrate salt in an amount of about 3 wt% to about 20 wt%, a diluent in an amount of 75 wt% to 95 wt%, a disintegrant in an amount of 1 wt% to 5 wt%, a lubricant in an amount of 0.1 wt% to 1.0 wt%, and a glidant in an amount of 0.1 wt% to 1.5 wt%, all on a dry solids basis.

12. The pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises: (i) solid particulate crystalline mefridumate hemitartrate salt in an amount of 3 wt% to 5 wt%, a diluent in an amount of 90 wt% to 93 wt%, a disintegrant in an amount of 3 wt%, a lubricant in an amount of 0.5 wt%, and a glidant in an amount of 1 wt%, all on a dry solids basis; (ii) solid particulate crystalline mefridumate hemitartrate salt in an amount of 7 wt% to 9 wt%, a diluent in an amount of 86 wt% to 89 wt%, a disintegrant in an amount of 3 wt%, a lubricant in an amount of 0.5 wt%, and a glidant in an amount of 1 wt%, all on a dry solids basis. a lubricant in an amount of 0.5 wt%, and a glidant in an amount of 1 wt%, all on a dry solids basis; (iii) solid particulate crystalline metolazone hemi-tartrate in an amount of 11 wt% to 13 wt%, a diluent in an amount of 82 wt% to 85 wt%, a disintegrant in an amount of 3 wt%, a lubricant in an amount of 0.5 wt%, and a glidant in an amount of 1 wt%, all on a dry solids basis; or (iv) solid particulate crystalline metolazone hemi-tartrate in an amount of 5 wt% to 17.5 wt%, a diluent in an amount of 78 wt% to 80 wt%, a disintegrant in an amount of 3 wt%, a lubricant in an amount of 0.5 wt%, and a glidant in an amount of 1 wt%, all on a dry solids basis.

13. The pharmaceutical composition of any one of the preceding claims, wherein the diluent comprises a carbohydrate, a pharmaceutically acceptable synthetic polymer, an inorganic diluent, or a mixture thereof.

14. The pharmaceutical composition of any one of the preceding claims, wherein: the diluent comprises cellulose, carboxymethylcellulose, alginates, starch, dextrates, dextrin, maltodextrin, one or more sugars, one or more sugar alcohols, vinylpyrrolidone-vinyl acetate copolymer, calcium carbonate, calcium phosphate, calcium sulfate, kaolin, magnesium carbonate, magnesium oxide, sodium chloride, or any mixture thereof; the disintegrant comprises alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, chitosan, colloidal silicon dioxide, croscarmellose sodium, crospovidone, docusate sodium, guar gum, low-substituted hydroxypropylcellulose, magnesium aluminum silicate, methylcellulose, polacrilin potassium, povidone, sodium alginate, sodium starch glycolate, starch, pregelatinized starch, or any mixture thereof; the lubricant comprises calcium stearate, magnesium stearate, zinc stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, leucine, medium-chain triglycerides, mineral oil, light mineral oil, myristic acid, palmitic acid, polyethylene glycol, polyoxyethylene stearate, potassium benzoate, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, hydrogenated vegetable oil, sucrose fatty acid ester, or any mixture thereof; and the glidant, if present, comprises tribasic calcium phosphate, powdered cellulose, colloidal silicon dioxide, magnesium oxide, magnesium silicate, magnesium trisilicate, starch, talc, or any mixture thereof.

15. The pharmaceutical composition of any one of the preceding claims, wherein the diluent is pregelatinized starch, the disintegrant is sodium starch glycolate, the glidant is colloidal silicon dioxide, and / or the lubricant is magnesium stearate.

16. The pharmaceutical composition of any one of the preceding claims, wherein the solid particulate crystalline metolazone hemi-tartrate is provided in an amount corresponding to about 2 mg to about 10 mg of metolazone free base.

17. The pharmaceutical composition of any one of the preceding claims, wherein the composition is formulated for immediate release.

18. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is formulated for oral administration.

19. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is encapsulated.

20. A solid granular crystalline hemitartrate salt of medrotopate characterized by, wherein D 90 <350 μm or <300 μm and / or D 50 a particle size distribution of < 150 μm.

21. The solid particulate crystalline hemi-tartrate salt of medrotopit according to claim 20, wherein D 90 <300 μm, <290 μm, <280 μm, <270 μm or <260 μm and / or D 50 <140 μm, <120 μm, 100 μm or <80 μm.

22. The solid particulate crystalline hemi-tartrate salt of medrotopit according to claim 20 or 21, wherein D 90 <300 μm.

23. The solid particulate crystalline hemitartrate salt of meptinidate according to any one of claims 20 to 22, wherein the tartrate is L-(+)-tartrate and / or D-(-)-tartrate.

24. The solid particulate crystalline hemitartrate salt of meptinidate according to any one of claims 20 to 23, wherein the tartrate is L-(+)-tartrate.

25. The solid particulate crystalline hemitartrate salt of meptinidate according to any one of claims 20 to 23, wherein the tartrate is D-(-)-tartrate.

26. The solid particulate crystalline hemi-tartrate salt of medrotopate according to any one of claims 20 to 25, characterized in that the XRP diffractogram comprises a peak at 13.0 2Q and optionally at least one, at least two, at least three or four further peaks selected from 12.4 2Q, 14.4 2Q, 21.1 2Q, 24.4 2Q.

27. The solid particulate crystalline hemi-tartrate salt of medrotopetate according to any one of claims 20 to 26, characterized in that the XRP diffractogram comprises a peak at 12.4 2Q, 13.0 2Q, 14.4 2Q, 21.1 2Q, 24.4 2Q and optionally at least one further peak selected from 19.62 2Q, 21.44 2Q.

28. The solid particulate crystalline hemi-tartrate salt of medrotopetate according to any one of claims 20 to 27, characterized in that the XRP diffractogram corresponds to Figure 1.

29. A method for preparing a pharmaceutical composition according to any one of claims 1 to 19, the method comprising: a) weighing and sieving a solid particulate crystalline meptinidate hemitartrate salt as defined in any one of claims 1 to 28, a diluent, a disintegrant and optionally a glidant; b) blending the solid particulate crystalline meptinidate hemitartrate salt with about one third of the total amount of diluent to form a first pre-blend composition, and optionally sieving the first pre-blend composition; c) preparing a second pre-blend composition comprising about one third of the total amount of diluent, optionally wherein preparing the second pre-blend composition comprises blending about one third of the diluent with the glidant; and optionally sieving the second pre-blend; d) blending the first and second pre-blend compositions with a disintegrant and about one third of the total amount of diluent to form a first dry blend composition, and optionally sieving the first dry blend composition; e) weighing and sieving a lubricant and blending the lubricant with the first dry blend composition, optionally together with any further excipients, flavourings, sweeteners and / or colourings, to form a final blend composition; and f) optionally compressing the final blend composition or filling the final blend composition into a capsule.

30. The method according to claim 29, wherein the method comprises: a) weighing and sieving a solid particulate crystalline meptinidate as defined in any one of claims 1 to 28, a diluent, a disintegrant and a glidant; b) blending the solid particulate crystalline meptinibutat hemisalt with about one third of the total amount of diluent to form a first pre-mix composition, and sieving the first pre-mix composition; c) preparing a second pre-mix composition comprising about one third of the total amount of diluent, wherein preparing the second pre-mix composition comprises blending about one third of the diluent with the glidant; and sieving the second pre-mix composition; d) blending the first and second pre-mix compositions with a disintegrant and about one third of the total amount of diluent to form a first dry mix composition, wherein preparing the first dry mix composition comprises: i. adding the first pre-mix composition to the second pre-mix composition in a blender jar; ii. adding the disintegrant to the first and second pre-mix compositions in the blender jar; iii. adding about one third of the total amount of diluent to the first and second pre-mix compositions and disintegrant in the blender jar; and iv. blending the first and second pre-mix compositions, disintegrant, and diluent in the blender jar; and sieving the first dry mix composition; e) weighing and sieving a lubricant and blending the lubricant with the first dry mix composition, optionally with any additional excipients, flavourings, sweeteners, and / or colourings, to form a final blend composition; and f) optionally compressing the final blend composition to form a compressed composition such as a tablet or filling the final blend composition into a capsule such as a hard or soft capsule.

31. The method of claim 29 or claim 30, wherein the blending in step (b) is performed for a time of about 1 minute to about 15 minutes; the blending in step (c) is performed for a time of about 1 minute to about 15 minutes; the blending in step (d) is performed for a time of about 15 minutes to about 45 minutes; and / or the blending in step (e) is performed for a time of about 1 minute to about 15 minutes.

32. The method of any one of claims 29 to 31, wherein the blending in steps (b), (c), (d), and / or (e) is performed at a speed of about 10 rpm to about 20 rpm.

33. The method of any one of claims 29 to 32, wherein the diluent, the disintegrant, the lubricant, and / or the glidant are as defined in any one of claims 13 to 15.

34. The method of any one of claims 29 to 33, wherein the solid crystalline meptinibutat hemisalt thereof is milled prior to step (a).

35. A pharmaceutical composition obtained or obtainable by the method of any one of claims 29 to 34.

36. The pharmaceutical composition according to any one of claims 1 to 19 or 35 for use in the treatment and / or prevention of a disease, disorder and / or condition selected from the group consisting of: psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug-induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Tourette’s syndrome, brain injury, sleep disorder, sexual dysfunction, eating disorder, obesity, pain in conditions characterized by increased muscle tone, Parkinson’s disease, Parkinsonism, dyskinesia, L-DOPA-induced dyskinesia, tardive dyskinesia, dystonia, tic and tremor dementia, Huntington’s disease, drug-induced dyskinesia, restless legs, narcolepsy, Alzheimer’s disease and disorders related to Alzheimer’s disease.

37. The pharmaceutical composition for use according to claim 36, wherein the disease, disorder and / or condition is schizophrenia, L-DOPA-induced dyskinesia and / or Huntington’s disease.

38. The pharmaceutical composition for use according to claim 36 or 37, wherein the pharmaceutical composition is administered in a dose of 2 mg to 10 mg, such as 2.5 mg, 5.0 mg or 7.5 mg, optionally wherein the composition is administered once, twice or more than twice a day.

39. A method for the treatment and / or prevention of a disease, disorder and / or condition selected from the group consisting of: psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug-induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Tourette’s syndrome, brain injury, sleep disorder, sexual dysfunction, eating disorder, obesity, pain in conditions characterized by increased muscle tone, Parkinson’s disease, Parkinsonism, dyskinesia, L-DOPA-induced dyskinesia, tardive dyskinesia, dystonia, tic and tremor dementia, Huntington’s disease, drug-induced dyskinesia, restless legs, narcolepsy, Alzheimer’s disease and disorders related to Alzheimer’s disease, wherein the method comprises administering to a subject, such as a human, in need thereof, a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 19 or 35.

40. The method according to claim 39, wherein the disease, disorder and / or condition is schizophrenia, L-DOPA-induced dyskinesia and / or Huntington’s disease.

41. The method according to claim 39 or 40, wherein the therapeutically effective amount is 2 mg to 10 mg, such as 2.5 mg, 5.0 mg or 7.5 mg, optionally wherein the composition is administered once, twice or more than twice a day.

42. Use of a pharmaceutical composition according to any one of claims 1 to 19 or 35 for the manufacture of a medicament for the treatment of a disease, disorder and / or condition selected from the group consisting of: psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, substance-induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disorder, dementia, age-related cognitive impairment, autism spectrum disorder, ADHD, cerebral palsy, Tourette’s syndrome, brain injury, sleep disorder, sexual dysfunction, eating disorder, obesity, pain in a condition characterized by increased muscle tone, Parkinson’s disease, Parkinsonism, dyskinesia, L-DOPA-induced dyskinesia, tardive dyskinesia, dystonia, tics and tremor dementia, Huntington’s disease, drug-induced movement disorder, restless leg, narcolepsy, Alzheimer’s disease and a disorder associated with Alzheimer’s disease.

43. The use according to claim 42, wherein the disease, disorder and / or condition is schizophrenia, L-DOPA-induced dyskinesia and / or Huntington’s disease.

44. The use according to claim 42 or 43, wherein the pharmaceutical composition is administered at a dose of 2 mg to 10 mg, such as 2.5 mg, 5.0 mg or 7.5 mg, optionally wherein the composition is administered once, twice or more than twice a day.

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