Pharmaceutical composition comprising tartrate of n-[2-(3-fluoro-5-methylsulfonylphenoxy) 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

[0001] This disclosure relates to pharmaceutical compositions comprising dosage forms such as tablets or capsules, which contain mesdopetam monotartrate or hemitartrate. This disclosure also provides methods for manufacturing said compositions and their use in therapeutic applications. Background Technology

[0002] Any enumeration or discussion of any previously published documents in this specification should not necessarily be construed as an admission that such documents are part of the prior art or common 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 (also known as 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 a compound of a class described in WO 2012 / 143337, which is a regulator 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 conditions such as Parkinson's disease, movement disorders, and L-DOPA-induced movement disorders. Madopertan in its free base form has the following structure:

[0005] Preclinical studies in laboratory animals have shown that ledopertan helps reduce adverse reactions such as LID without affecting the fundamental 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 published in July 2020 in J. Pharmacol. Exp. Ther. 374:113-125. Ledopertan was found to dose-dependently reduce adverse involuntary movements (AIM), and this reduction in AIM was not achieved at the expense of any impairment of the motor function of L-DOPA itself, but rather was captured as a rotational response to L-DOPA.

[0006] Salts of ledoperamide 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 therapeutic applications are described in WO 2022 / 101227.

[0007] The drug formulation of levodopa is needed. For example Formulations providing the dosage required for therapeutic use. Such formulations also require economical and reliable manufacturing methods to meet acceptance and regulatory parameters. Summary of the Invention

[0008] One object of this disclosure is to provide a form of levodopatan monotartrate or hemitartrate 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 technologies known to date.

[0009] On the one hand, this disclosure provides pharmaceutical compositions comprising ledopertan monotartrate or hemitartrate, a diluent, a disintegrant, a lubricant, and optionally a flow aid.

[0010] On the other hand, this disclosure provides solid particulate ledopetan monotartrate or hemitartrate ( For example hemitartaric acid salts, such as L - hemitartaric acid salt), which has D in it 90 <350 μm or <300 μm ( For example <290 μm, <280 μm, <270 μm or <260 μm) and / or D 50 <150 μm ( For example Particle size distribution (<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 ledoperamide monotartrate or hemitartrate, the method comprising: (a) Weigh and sieve the medopetan monotartrate or hemitartrate, diluent, disintegrant and optional flow aid. (b) Mixing medopetan monotartrate or hemitartrate with about one-third of the total amount of 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 diluent, optionally wherein preparing the second premixed composition includes blending about one-third of the diluent with a flow aid; and optionally sieving the second premix; (d) The first and second premixed compositions are blended with a disintegrant and about one-third of the total amount of a diluent to form a first dry mix composition, and optionally the first dry mix composition is sieved. (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 the final blend composition; and (f) Optionally compress the final blend composition ( For example To form tablets) or to fill the final blended composition into capsules ( For example In hard capsules or soft capsules.

[0012] On the other hand, this disclosure provides pharmaceutical compositions that can be prepared by or through 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 the 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 use in a therapy.

[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 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.

[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 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. Attached Figure Description

[0017] Figure 1 The XRP diffraction pattern of metopetan L-hemitartaric acid is shown. XRPD data were collected on a Bruker D8 Advance (2005) instrument. Radiation: Copper K α λ = 1.54180 Å, K β 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 speed: 0.2 s / step; Interval in 2θ scale (2θ) (3 – 35).

[0018] Figure 2Examples of the methods described in this paper are depicted. Figure 2 In this context, IPN60170 represents Levodopa. L - Hemitartaric acid salt.

[0019] Figure 3 The particle size distribution of metopetan L-hemitartaric acid was depicted when it was ground according to different parameters. Figure 3 A shows the density distribution, and Figure 3 B 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, milled at 6000 rpm using a conical mill with a 610 μm mesh. Circles represent particles of levodopa-L-hemitartaric acid, milled at 6000 rpm using a conical mill with a 279 μm mesh. Squares represent particles of levodopa-L-hemitartaric acid, milled at 6000 rpm using a conical mill with a 457 μm mesh.

[0020] Figure 4 shows SEM images of medopetan hemitartaric acid before and after grinding with a mortar and pestle. Figure 4A The images show SEM micrographs of medopetan hemitartaric acid before grinding at two different magnifications. Crystals with a so-called "wheat sheaf" structure are visible. Figure 4B SEM micrographs of the particles after size reduction using a mortar and pestle are shown. The particle size is significantly reduced, ranging from tens of micrometers. Some larger particles of approximately 30 to 40 micrometers are observed. The morphology of the ground particles is irregular, with plate-like surfaces. Detailed Implementation

[0021] definition 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. While 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 prior art prior to this disclosure.

[0022] Madoparin, also known as IRL-790 and IPN60170, has CAS registration number 1403894-72-3 and IUPAC name [missing information]. N-[2-(3-fluoro-5-methylsulfonyl-phenoxy)ethyl]propane-1-amine. The "metoprolol free base" mentioned in this article refers to the compound... itself Unless otherwise stated, the term "Medupasteur" as used herein without any further qualification includes the free base of medoprateur or its monotartrate or hemitartrate. Therefore, unless otherwise specified, the term "medoprateur" means medoprateur 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 ​​that vary (+) 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 typical level of variability. For example, a numerical name "about" for a given value may vary by ±10% of said value; alternatively, the variation may be ±5%, ±2%, or ±1% of that value.

[0024] To avoid ambiguity, any disclosure of a numerical range, such as "up to X," is intended to include the upper limit X. Therefore, 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, such as "A to" or "at least A." Therefore, For example The disclosure of “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 % 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 the context clearly indicates otherwise. For example, the term “diluent” includes a variety of diluents, including mixtures thereof. Unless specifically stated or obvious from the context, the term “or” should be understood as inclusive as used herein. 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, "consistently composed of" should mean excluding other elements that are of any significance to the purposes described. Thus, a composition consisting essentially 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. "Constitutes of" should mean excluding other components beyond the trace elements and numerous method steps for administering the compositions of this disclosure or for producing the compositions or achieving the desired results. Examples 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 "consistently composed of" or "composes of".

[0028] The terms “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, sporting animals, 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] "Administration" is defined herein as the delivery of a drug or a composition containing a drug to a subject in a manner that results in contact between the drug and 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., through the vagina, rectum, or oral mucosa), by injection (e.g., subcutaneous, intravenous, parenteral, intraperitoneal, or into the central nervous system), or by inhalation (e.g., orally or nasally). Administration can also involve delivering 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 forms 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 "affected" means a patient or individual who has been diagnosed with the disease or is susceptible to it. Patients may also be described as "at risk of developing 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] "Effective amount" or "therapeutic effective amount" is a quantity sufficient to achieve a beneficial or desired outcome. An effective amount can be administered, applied, or administered in a single or multiple doses. This delivery depends on many variables, including the duration of use of a single dose unit, the bioavailability of the therapeutic agent, the route of administration, etc. However, it is understood that the specific dose level of the therapeutic agent of this disclosure 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, in vitro and / or in vivo The dose-response relationship tested can initially provide useful guidance for determining the appropriate dose to be administered to the patient. Generally, it is desirable to administer a quantity of compound that effectively achieves the desired effect. In vitro The effective concentration was found to correspond to a serum level. 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 the 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 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 its free base form. Therefore, unless otherwise stated, when referring to dosages of levodopatan, these dosages are calculated based on the amount of levodopatan free base, resulting in a larger actual mass of levodopatan salt. For example, a 5 mg dose of levodopatan free base corresponds to approximately 6.36 mg of levodopatan hemitartarate.

[0034] As used in this article, 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 methods of treatment or prevention” (such as in the phrase “in methods of treatment or prevention of pain”).

[0035] When referring to methods of treating and / or preventing diseases using levodopa or its pharmaceutically acceptable salts, such as its monotartrate or hemitartrate salts, these statements should be understood to include each of the following: (i) levodopa or its pharmaceutically acceptable salts, such as its monotartrate or hemitartrate salts, for the treatment and / or prevention of said diseases; or levodopa or its pharmaceutically acceptable salts, such as its monotartrate or hemitartrate salts, for the treatment and / or prevention of said diseases; (ii) the use of levodopa or its pharmaceutically acceptable salts, such as its monotartrate or hemitartrate salts, in said methods of treating and / or preventing diseases; or the use of levodopa or its pharmaceutically acceptable salts in the treatment and / or prevention of said diseases; and (iii) the use of levodopa or its pharmaceutically acceptable salts, 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) in a pharmaceutical formulation. 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 ledopetan include its free base form, including its amorphous solid dispersion; pharmaceutically acceptable salt forms such as monotartrate or hemitartrate, including its crystalline form; and pharmaceutically acceptable eutectic forms. Unless otherwise stated, the term "pharmaceutically acceptable salt" includes acid addition salts formed between ledopetan 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 ledopetan 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 PharmSci. (1977) 66:1-19). As used herein, the term "pharmaceutically acceptable" when used in conjunction with a salt means 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, propynylates, oxalates, malonates, succinates, octanoates, sebacic acid salts, 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 (… For example Tartaric acid salts include mono- or hemi-tartaric acid salts, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. In particular, pharmaceutically acceptable salts can be tartaric acid.

[0038] In some embodiments, the salt is a crystalline solid (e.g., salt crystals). In embodiments, the crystalline salt form of ledopatan is a crystalline hemitaritate, such as those disclosed in [the literature / document / etc.]. WO 2020 / 239568 (the contents of which are incorporated herein by reference in their entirety), with particular reference to pages 9, lines 25 to 10, lines 9. Figure 1 .

[0039] Isotope-labeled compounds are also within the scope of this disclosure. As used herein, "isotope-labeled compound" means, as described herein, levodopatan, 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... 2 H, 3 H, 13 C 14 C 15 N、 18 O、17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. For example, one or more hydrogen atoms in medopetan can be replaced by deuterium.

[0040] All references, patents, patent applications, scientific literature, and other printed publications mentioned or cited in this article 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 present invention without departing from the spirit of the invention. All such changes are intended to fall within the scope of the invention.

[0042] Pharmaceutical Composition On the one hand, this disclosure provides pharmaceutical compositions comprising levodopam or its tartrate salts, such as monotartrate or hemitartrate of levodopam, a diluent, a disintegrant, a lubricant, and optionally a flow aid.

[0043] Suitable diluents include carbohydrates ( For example Sugars and polysaccharides), pharmaceutically acceptable synthetic polymers, inorganic diluents and mixtures thereof.

[0044] Suitable carbohydrates include cellulose ( For example Microcrystalline cellulose (such as siliconized microcrystalline cellulose), powdered cellulose or cellulose acetate), carboxymethyl cellulose ( For example Carboxymethyl cellulose calcium), alginate ( For example Sodium alginate or ammonium alginate), starch ( For example Pregelatinized starch, such as Starch 1500®, glucose binders, dextrin, maltodextrin, sugar ( For example Glucose, fructose, lactose (such as lactose monohydrate or spray-dried lactose), maltose, trehalose, or sucrose (such as compressible sugar or powdered sugar), sugar alcohols ( For example Erythritol, isomaltitol, lactitol, maltitol, mannitol, sorbitol or xylitol) and mixtures thereof.

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

[0046] Suitable inorganic diluents include calcium carbonate and calcium phosphate. For example Anhydrous dicalcium phosphate, dicalcium 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. For example As disclosed above.

[0048] In some embodiments, the diluent may comprise, consist substantially of, or consist of a pharmaceutically acceptable synthetic polymer or a mixture of pharmaceutically acceptable synthetic polymers. For example As disclosed above.

[0049] In some embodiments, the diluent may comprise, consist substantially of, or consist of an inorganic diluent or a mixture of inorganic diluents. For example As 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. For example As 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. For example As 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. For example As disclosed above.

[0053] In some embodiments, the diluent is selected from cellulose ( For example Microcrystalline cellulose (such as siliconized microcrystalline cellulose), powdered cellulose or cellulose acetate), carboxymethyl cellulose ( For example Carboxymethyl cellulose calcium), glucose binder, dextrin, glucose, erythritol, fructose, isomaltitol, lactitol, lactose ( For example Lactose monohydrate or spray-dried lactose), maltitol, maltodextrin, maltose, mannitol, povidone, alginate ( For example Sodium alginate or ammonium alginate), sorbitol, starch ( For example Pregelatinized starch), sucrose, compressible sugar, powdered sugar, trehalose, xylitol, calcium carbonate, calcium phosphate ( example likeAnhydrous 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 ( For example Microcrystalline cellulose (such as siliconized microcrystalline cellulose), powdered cellulose or cellulose acetate), carboxymethyl cellulose ( For example Carboxymethyl cellulose calcium), alginate ( For example Sodium alginate or ammonium alginate), starch ( For example 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, potassium polacolin, povidone, sodium alginate, sodium glycolate starch, starch, pregelatinized starch, and mixtures thereof.

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

[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 (… For example Aerosil® 200), magnesium oxide, magnesium silicate, magnesium trisilicate, starch, talc, and mixtures thereof. When the gliding agent contains magnesium silicate, it is preferably used in combination with silica.

[0061] In some embodiments, the flow aid comprises 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 the following: diluent, disintegrant, lubricant, and / or flow aid. 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 amounts from 20% to 90% of the composition, and as a disintegrant when present in amounts of 15% or less. When any given component can have more than one function, the appropriate amount to achieve the given function ( For example Concentration range, such as % ( For example The amount (wt%) is known to those skilled in the art and can be For example Standard manuals and reference works, such as Handbook of Pharmaceutical Excipients Found in 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, gliding agent, or lubricant, the function of which depends on... For example The amount of such components present and the properties of any other components combined with them. 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, 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 is composed of pregelatinized starch, the disintegrant is composed of sodium glycolate starch, the flow aid is composed of colloidal silica, and the lubricant is composed of magnesium stearate.

[0064] In examples, the composition comprises about 3 wt% to about 20 wt% of ledopatan or its tartrate salts, such as its monotartrate or hemitartrate salts, based on dry solids. In examples, the composition comprises about 3 wt% to about 18 wt%, or about 3 wt% to about 14 wt% of ledopatan or its tartrate salts, such as its monotartrate or hemitartrate salts, based on dry solids, 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 Approximately 4 wt%, approximately 8 wt%, approximately 13 wt%, or approximately 17 wt%.

[0065] In the embodiments, 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 Approximately 91 wt%, approximately 87 wt%, approximately 83 wt%, or approximately 79 wt%.

[0066] In the examples, the composition comprises about 1 wt% to about 5 wt% of a disintegrant on a dry solids basis, such as about 2 wt% to about 4 wt% or about 3 wt% to about 4 wt%. For example Approximately 3 wt%.

[0067] In embodiments, the composition comprises about 0.1 wt% to about 1.0 wt% of a lubricant on a dry solids basis, 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 Approximately 0.5 wt%.

[0068] In the embodiments, the composition comprises about 0.1 wt% to about 1.5 wt% of a flow aid based on dry solids, 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 Approximately 1 wt%, such as approximately 1.0 wt%.

[0069] In the examples, 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 embodiments, 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 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 preferred embodiments, 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 the examples, the composition comprises about 3 wt% to about 20 wt% of aliquots of levodopa 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. For example Approximately 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 the examples, the composition comprises about 3 wt% to about 5 wt% ( For example The amount of levodopa or its tartrate salts, such as monotartrate or hemitartrate, is approximately 4 wt%, approximately 90 wt% to approximately 93 wt%. For example The amount of diluent is approximately 90.5 wt% to approximately 92.5 wt%, such as approximately 91 wt%, the amount of disintegrant is approximately 3 wt%, the amount of lubricant is approximately 0.5 wt%, and the amount of lubricant is approximately 1 wt%. For example The amount of the gliding agent is approximately 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 gliding agent is colloidal silica, and / or the lubricant is magnesium stearate.

[0073] In the examples, the composition comprises about 7 wt% to about 9 wt% ( For example About 8 wt%, such as about 8.5 wt%) of levodopa or its tartrate salts such as its monotartrate or hemitartrate, about 86 wt% to about 89 wt% For example The amount of diluent is approximately 86.5 wt% to approximately 88.5 wt%, such as approximately 87 wt%, the amount of disintegrant is approximately 3 wt%, the amount of lubricant is approximately 0.5 wt%, and the amount of lubricant is approximately 1 wt%. For exampleThe amount of the gliding agent is approximately 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 gliding agent is colloidal silica, and / or the lubricant is magnesium stearate.

[0074] In the examples, the composition comprises about 11 wt% to about 13 wt% ( For example The amounts of levodopa or its tartrate salts, such as its monotartrate or hemitartrate salts, are approximately 12 wt% to approximately 13 wt%, such as approximately 12.7 wt%, approximately 82 wt% to approximately 85 wt%. For example The amount of diluent is approximately 82.5 wt% to approximately 84.5 wt%, such as approximately 82.8 wt%, the amount of disintegrant is approximately 3 wt%, the amount of lubricant is approximately 0.5 wt%, and the amount of lubricant is approximately 1 wt%. For example The amount of the gliding agent is approximately 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 gliding agent is colloidal silica, and / or the lubricant is magnesium stearate.

[0075] In the examples, the composition comprises about 15.5 wt% to about 17.5 wt% ( For example The amounts of levodopa or its tartrate salts, such as monotartrate or hemitartrate, in amounts of about 16 wt% to about 17.5 wt%, such as about 17.0 wt%, about 78 wt% to about 80 wt% ( For example Approximately 78.5 wt% to approximately 79.5 wt% (e.g., approximately 78.5 wt%) of diluent, approximately 3 wt% of disintegrant, approximately 0.5 wt% of lubricant, and approximately 1 wt% ( For example The amount of the gliding agent is approximately 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 gliding agent is colloidal silica, and / or the lubricant is magnesium stearate.

[0076] It will be self-evident 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, cannot exceed 100%. Therefore, those skilled in the art will understand that the determined amounts of the individual components can be appropriately varied. For example Within the identified wt%, so as not to exceed 100%. For example, a person skilled in the art can first determine the wt% of each of levodopatan or its pharmaceutically acceptable salts such as its monotartrate or hemitartrate salts, diluents, disintegrants, lubricants, and (if present) gliding agents, and then balance the amount of diluent accordingly. Right nowWhen all components of the composition are added together, the maximum amount is no more than 100 wt%.

[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 is ( Right now The total amount of ledoperamide or its tartrate salts, such as monotartrates or hemitartrates, diluents, disintegrants, lubricants, glidants (if present), and any other pharmaceutically acceptable excipients, flavoring agents, sweeteners, and / or colorants shall not exceed 100 wt%. In some embodiments, the colorant may be used to make the product appear uniform and / or to 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 contained within the capsule shell, within the capsule filler, or both.

[0078] In embodiments of the compositions disclosed herein, ledopastatin 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 ledopastatin 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 ledopastatin free base.

[0079] In the examples of the compositions disclosed herein, the dosage corresponds to approximately 2.5 mg of levodopatan free base ( For example The amount of Ledopetan hemi-tartrate, such as Ledopetan L-hemi-tartrate, such as 3.18 mg, is provided as Ledopetan or its tartrate salts, such as its monotartrate or hemi-tartrate salts.

[0080] In the examples of the compositions disclosed herein, the dosage corresponds to approximately 5.0 mg of levodopatan free base ( For example The amount of Ledopetan hemitartarate, such as Ledopetan L-hemitartarate, such as 6.36 mg, is provided as Ledopetan or its tartrate salts, such as its hemitartarate salts.

[0081] In the examples of the compositions disclosed herein, the dosage corresponds to approximately 7.5 mg of levodopatan free base ( For exampleThe amount of Ledopetan hemitartarate, such as Ledopetan L-hemitartarate, such as 9.54 mg, is provided as Ledopetan or its hemitartarate, such as its monotartarate or hemitartarate.

[0082] In the examples of the compositions disclosed herein, the dosage corresponds to approximately 10.0 mg of levodopatan free base ( For example Ledopetan or its tartrates, such as its monotartrate or hemitartrate, are provided in amounts of approximately 12.7 mg of Ledopetan hemitartrate, such as Ledopetan L-hemitartrate, such as 12.72 mg.

[0083] Madopetan 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 the examples, Madopetan may be present in the form of a tartrate salt. Because tartaric acid has two carboxylic acid groups, it can form salts with different molar ratios of Madopetan and tartrate (the conjugate base of tartaric acid). For example, a salt in which the molar ratio of tartrate to Madopetan is about 1:1 can be called a monotartrate, and a salt in which the molar ratio of tartrate to Madopetan is about 1:2 (or equivalently, a molar ratio of Madopetan to tartrate is about 1:0.5) can be called hemitartrate Madopetan (also known as Madopetan 1 / 2-tartrate). Unless otherwise stated, the term "tartrate" as used herein encompasses all possible stoichiometry. Right now Molar ratios include 1:1 and hemitartaric acid. Similarly, other dicarboxylic acids such as For example Fumaric acid, succinic acid, maleic acid, and malic acid can also form more than one stoichiometric amount with levodopatan.

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

[0085] Furthermore, it should be understood that the chemical structure of ledopetan hemitartaric acid salt (i.e., a salt in which the molar ratio of ledopetan 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, which form part of the mono- or hemi-tartrate salt of ledopetan, may be attached to or shared between the nitrogen atom of ledopetan and the tartaric acid, and this is covered in the chemical structures described herein. For example, a hemi-tartrate salt of ledopetan can be represented as follows, wherein one of the acidic protons of tartaric acid is attached to the nitrogen atom of ledopetan:

[0087] Tartrates 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, a 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" means 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 can be greater than, equal to or less than the amount of L-tartrate present.

[0088] When a stereoisomer 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 (e.g., in L-(+)-tartaric acid) or described by structure, 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. "Racemate" 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 the embodiments of the compositions disclosed herein, ledopatan is in the form of tartrate ( For example It is provided in the form of 1:1 tartrate or hemitartrate. In some embodiments, ledopetan is provided in... L -Provided in tartrate form, such as mono- L -Tartrate or as L-hemitartarate (1 / 2) L -Tartrate). In other embodiments, ledopatan is used as... D -Provided in tartrate form, such as mono- D -Tartrate or hemi- D -Tartrate (1 / 2) D-Tartrate). In a specific embodiment, the tartrate of doxepin ( For example 1:1 tartrate or hemi-tartrate, For example 1:1 L-tartrate or L-hemitartrate) in the form of approximately 2 mg to approximately 10 mg of free base or approximately 2 mg to approximately 8 mg of free base ( For example It is provided in amounts of approximately 2.5 mg, 5.0 mg, 7.5 mg, or 10.0 mg of free base. Therefore, for example, when ledopatan is administered as hemitartaric acid ( For example When provided in the form of L-hemitartaric acid, it may be provided in amounts of about 2.5 mg to about 12.7 mg of hemitartaric acid, 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 levodopatan hemitartaric acid.

[0090] The compositions disclosed herein can 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, such as 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 can be round, square, rectangular, spherical, oval, flattened, ovoid, or any other suitable shape, including capsules (i.e., capsule tablets). Tablets may optionally be scored for easy cutting and may optionally be engraved.

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

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

[0094] In the embodiments, the composition is encapsulated. Right now As capsules ( For example Capsules for oral administration are provided. ， Such as soft capsules or hard (“hard-shell”) capsules. Soft capsules include soft gelatin capsules or modified starch capsules. Hard capsules include hard gelatin capsules or HPMC (hydroxypropyl methylcellulose) capsules.

[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 the solid material. The active pharmaceutical ingredient, namely levodopatan or its monotartrate or hemitartrate salt, 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 method, including crushing.

[0096] When packaged as an active pharmaceutical ingredient (API), the compositions disclosed herein are typically provided in powder form (fine or coarse powder) and packaged in sterile containers, such as bags or drums.

[0097] In a particular embodiment, the composition contains about 4 wt% ( For example 4.24 wt% of the amount of levodopatan hemitartarate ( For example Dopperam L - Hemitartaric acid), approximately 91 wt% ( For example A diluent of 91.26 wt%, approximately 3 wt% For example 3.00 wt% of disintegrant, approximately 0.5 wt% of disintegrant. For example 0.50 wt% of lubricant and about 1 wt% of lubricant. For example The composition contains 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 Encapsulated in HPMC capsules.

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

[0099] In certain embodiments, at least a specific weight percentage of levodopatan or a pharmaceutically acceptable salt thereof ( For example hemitartaric acid salts, such as L(-Hemitartaric acid salt) 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 levodopatan or its pharmaceutically acceptable salts ( For example hemitartaric acid salts, such as L α-Hemitartic acid salts can be monocrystalline or mixtures of different monocrystalline forms. Monocrystalline form refers to levodopatan or a pharmaceutically acceptable salt thereof. For example hemitartaric acid salts, such as L α-hemitartaric acid salt) is 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 levodopatan or a pharmaceutically acceptable salt thereof ( For example hemitartaric acid salts, such as L (-Hemitartaric acid salt) is a single crystalline 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 levodopatan or its pharmaceutically acceptable salt ( For example hemitartaric acid salts, such as L When the α-hemitartaric acid salt is in a single crystal form, the remainder is amorphous levodopatan or a pharmaceutically acceptable salt thereof. For example hemitartaric acid salts, such as L (-hemitartaric acid) and / or levodopatan or a pharmaceutically acceptable salt thereof ( For example hemitartaric acid salts, such as L A combination of one or more other crystal forms (excluding single crystal forms) of hemitarite. When crystallized, levodopatan or its pharmaceutically acceptable salts ( For example hemitartaric acid salts, such as L L-hemitartaric acid salts are defined as a specific crystal form in a specified percentage, with the remainder consisting of amorphous forms and / or crystal forms other than the specified one or more specific crystal forms. Examples of a single crystal form include medopetan hemitartaric acid salts (such as L-hemitartaric acid salts), characterized by one or more XRPD properties as described below.

[0100] In the embodiments of the compositions disclosed herein, ledopasteuron is in the form of solid crystalline ledopasteuron hemitartaric acid salt ( example likeThe form of L-hemitartaric acid (L-hemitartaric acid) is provided. In the embodiments, crystalline ledopetan hemitartaric acid (L-hemitartaric acid) is provided. For example L-hemitartaric acid (L-hemitartaric acid) can exist in solid crystalline form. ， The characteristic feature is 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), and about 24.4 2θ (such as about 24.36 2θ). In an embodiment, levodopatan hemitartaric acid ( For example The solid crystalline form of L-hemitartaric acid 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 examples, levodopatan hemitartaric acid ( For example The solid crystalline form of L-hemitartaric acid is characterized by its XRP diffraction pattern corresponding to... Figure 1 In this embodiment, Cu Kα radiation is used. For example XRP diffraction patterns were collected at λ = 1.54180 Å. In this embodiment, the peak angle 2θ was given an accuracy of ±0.02° 2θ.

[0101] In the examples of the compositions disclosed herein, levodopatan or a pharmaceutically acceptable salt thereof ( For example hemitartaric acid salts, for example L - Hemitaritate salts, including any of their hydrates, solvates and / or polymorphs (such as anhydrous polymorphs), and including any of their solid crystalline or solid amorphous forms, For example Any solid crystal form as defined above can have D. 90 <350 μm or <300 μm ( For example <290 μm, <280 μm, <270 μm or <260 μm) and / or D 50 <150μm ( For example Particle size distribution (<140 μm, <120 μm, 100 μm, or <180 μm). In the examples, D 10<15 μm, For example <10μm. In some embodiments, D 90 <300 μm ( For example <290 μm, <280 μm, <270 μm or <260 μm), D 50 <150 μm ( For example <140 μm, <120 μm, <100 μm or <80 μm), and D 10 <15 μm, For example <10 μm. In some embodiments, D 90 <250 μm ( For example <240 μm, <230 μm or <220 μm) and / or D 50 <120 μm ( For example <100 μm, <80 μm, or <75 μm). In some embodiments, D 90 <250 μm ( For example <240 μm, <230 μm or <220 μm) and D 50 <120 μm ( example like <100 μm, <80 μm, or <75 μm). In some embodiments, D 90 <250 μm ( For example <240 μm, <230 μm or <220μm), D 50 <120 μm ( For example <100 μm, <80 μm or <75 μm), and D 10 <15 μm, For example <10 μm. In the examples, the particle size distribution can be determined by laser diffraction. For example Wet laser diffraction (wet dispersion), for example, in silicone oil at a concentration of 10 mg / ml.

[0102] In related respects, this disclosure provides solid granules of levodopatan or a pharmaceutically acceptable salt thereof ( For example hemitartaric acid salts, such as L - hemitartaric acid salt), which has D in it 90 <350 μm or <300 μm ( For example <290 μm, <280 μm, <270 μm or <260 μm) and / or D 50 <150 μm ( For example Particle size distribution (<140 μm, <120 μm, 100 μm, or <180 μm). In the examples, D 10 <15 μm, For example<10 μm. In some embodiments, D 90 <300 μm ( For example <290 μm, <280 μm, <270 μm or <260 μm), D 50 <150 μm ( For example <140 μm, <120 μm, <100 μm or <80 μm), and D 10 <15μm, For example <10 μm. In some embodiments, D 90 <250 μm ( For example <240 μm, <230 μm or <220 μm) and / or D 50 <120 μm ( For example <100 μm, <80 μm, or <75 μm). In some embodiments, D 90 <250 μm ( For example <240 μm, <230 μm or <220 μm) and D 50 <120 μm ( For example <100 μm, <80 μm, or <75 μm). In some embodiments, D 90 <250 μm ( For example <240 μm, <230 μm or <220 μm), D 50 <120 μm ( For example <100 μm, <80 μm or <75 μm), and D 10 <15μm, For example <10 μm.

[0103] In this embodiment, the particle size distribution can be determined by laser diffraction. For example Wet laser diffraction (wet dispersion), for example, in silicone oil at a concentration of 10 mg / ml.

[0104] In the embodiments, solid particle ledopetan is in the form of solid crystalline ledopetan hemitarite ( For example It is provided in the form of L-hemitartaric acid salt. For example It has the XRPD characteristics defined above.

[0105] It should be understood that the D value associated with particle size distribution is the percentile value. For example, D... 90 This can refer to particle size, where particles smaller than this size account for 90% of the total particles. Similarly, D... 50 This can refer to particle size, where particles smaller than this size account for 50% of the total particles, and D 10This can refer to particle size, where particles smaller than this size account for 10% of the total particles. It should be understood that the D value can be indicated using uppercase or lowercase letters, making "D" and "d" interchangeable. For example, D... 90 It can be represented as d 90 Conversely, particle size distribution can be cumulative and / or volume-based. 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, the particle size distribution of the monotartrate and hemitartrate salts of ledoperamide described herein has been found to allow for a uniform distribution (e.g., homogeneous distribution) of the aforementioned salts (i.e., the API) in compositions, such as pharmaceutical compositions. This is particularly advantageous for pharmaceutical compositions where the API is present in low doses, such as doses of ledoperamide from about 2 mg to about 10 mg (measured in equivalent amounts of free base) as described herein, where accurate dose uniformity is known to be challenging.

[0107] Not wanting 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 the diluent (such as pregelatinized starch).

[0108] Method for preparing pharmaceutical compositions On one hand, this disclosure provides a method for preparing a pharmaceutical composition comprising ledoperamide monotartrate or hemitartrate as described herein, the method comprising: (a) Weigh and sieve the medopetan monotartrate or hemitartrate, diluent, disintegrant and optional flow aid described herein; (b) Mixing medopetan monotartrate or hemitartrate with about one-third of the total amount of 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 diluent, optionally wherein preparing the second premixed composition includes blending about one-third of the diluent with a flow aid; and optionally sieving the second premix; (d) The first and second premixed compositions are blended with a disintegrant and about one-third of the total amount of a diluent to form a first dry mix composition, and optionally the first dry mix composition is sieved. (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 the final blend composition; and (f) Optionally compress the final blend composition ( For example To form tablets) or to fill the final blended composition into capsules ( For example In hard capsules or soft capsules.

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

[0110] In an embodiment, the blending in step (d) includes adding the first premixed composition to the second premixed composition in the mixer tank. Right now (wherein the second premixed composition is present in the mixer tank before the first premixed composition is introduced); after the first premixed composition, the disintegrant is introduced into the mixer tank; after the disintegrant is introduced, approximately one-third of the total amount of diluent is introduced into the mixer tank.

[0111] In some embodiments, the blending in step (b) 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 some embodiments, the blending in step (b) is performed for approximately 6 minutes. In some embodiments, the blending in step (b) 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 (b) is performed at approximately 15 rpm for approximately 6 minutes. In some embodiments, the first premixed composition is sieved after blending in step (b). In some embodiments, the first premixed composition is sieved through a sieve with a mesh size of approximately 600 μm after blending in step (b).

[0112] In some embodiments, the blending in step (c) is performed for approximately 1 minute to approximately 15 minutes, for example, approximately 2 minutes to approximately 10 minutes, or approximately 3 minutes to approximately 8 minutes. In some embodiments, the blending in step (c) is performed for approximately 5 minutes. In some embodiments, the blending in step (c) 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 (c) is performed at approximately 15 rpm for approximately 5 minutes. In some embodiments, the second premixed composition is sieved after blending in step (c). In some embodiments, the second premixed composition is sieved through a sieve with a mesh size of approximately 600 μm after blending in step (c).

[0113] In one embodiment, the blending in step (d) is performed for approximately 15 to approximately 45 minutes, for example, approximately 20 to approximately 40 minutes, or approximately 25 to approximately 35 minutes. In another embodiment, the blending in step (d) is performed for approximately 30 minutes. In yet another embodiment, the blending in step (d) is performed at a speed of approximately 10 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 one 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 another embodiment, the blending in step (e) is performed for approximately 6 minutes. In yet another 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) involves sieving one or more of the following: levodopatan or its pharmaceutically acceptable salts, such as its monotartrate or hemitartrate salts, diluents, disintegrants, and / or glidants, through a sieve with a mesh size of about 600 μm. In one embodiment, each of the following is sieved through a sieve with a mesh size of about 600 μm: levodopatan or its pharmaceutically acceptable salts, such as its monotartrate or hemitartrate salts, diluents, disintegrants, and glidants. For example (Separate screening).

[0116] In an embodiment, the sieving in step (b) includes 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) includes 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 approximately 600 μm.

[0119] In one embodiment, this disclosure provides a method for preparing a pharmaceutical composition comprising the medopetan monotartrate or hemitartrate as described herein, the method comprising: (a) Weigh and sieve the medopetan monotartrate or hemitartrate, diluent, disintegrant and flow aid described herein; (b) Mixing medopetan monotartrate or hemitartrate 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 includes blending about one-third of the diluent with a flow aid; and sieving the second premix; (d) The first and second premixed compositions are blended with a disintegrant and about one-third of the total amount of a diluent to form a first dry mix composition, and the first dry mix composition is sieved. (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 the final blend composition; and (f) Optionally compress the final blend composition ( For example To form tablets) or to fill the final blended composition into capsules ( For example In hard capsules or soft capsules.

[0120] In one embodiment, this disclosure provides a method for preparing a pharmaceutical composition comprising the medopetan monotartrate or hemitartrate as described herein, the method comprising: (a) Weigh and sieve the medopetan monotartrate or hemitartrate, diluent, disintegrant and flow aid described herein; (b) Mixing medopetan monotartrate or hemitartrate 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 includes blending about one-third of the diluent with a flow aid; and sieving the second premix; (d) Blending the first and second premixed compositions with a disintegrant and about one-third of the total amount of a diluent to form a first dry-mixed composition, wherein preparing the first dry-mixed composition comprises: i. Add the first premixed composition to the second premixed composition in the mixer tank; ii. Add the disintegrant to the first and second premixed compositions in the mixer tank; iii. 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 the first dry-mixed composition is screened; (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 the final blend composition; and (f) Optionally compress the final blend composition ( For example To form tablets) or to fill the final blended composition into capsules ( For example In hard capsules or soft capsules.

[0121] In another embodiment, this disclosure provides a method for preparing a pharmaceutical composition comprising the levodopatan monotartrate or hemitartrate described herein, the method comprising: (a) Weigh and sieve the medopetan monotartrate or hemitartrate, diluent, disintegrant and glidant as described herein, wherein each of medopetan or its pharmaceutically acceptable salts, diluent, disintegrant and glidant is sieved through a sieve with a mesh size of about 600 μm. (b) Mixing medopetan monotartrate or hemitartrate with about one-third of the total amount of diluent to form a first premixed composition, wherein the mixing is carried out at about 15 rpm for about 6 minutes, and the first premixed composition is sieved through a sieve with a mesh size of about 600 μm. (c) Prepare a second premixed composition comprising about one-third of the total amount of diluent, wherein preparing the second premixed composition comprises mixing about one-third of the diluent with a flow aid, wherein the mixing is carried out at about 15 rpm for about 5 minutes; and sieve the second premixed composition through a sieve with a mesh size of about 600 μm; (d) Blending the first and second premixed compositions with a disintegrant and about one-third of the total amount of a diluent to form a first dry-mixed composition, wherein preparing the first dry-mixed composition comprises: i. Add the first premixed composition to the second premixed composition in the mixer tank; ii. Add the disintegrant to the first and second premixed compositions in the mixer tank; iii. 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. The first and second premixed compositions, disintegrant and diluent are co-mixed in a mixer tank, wherein the mixing is carried out at about 15 rpm for about 30 minutes; The first dry mixture was then sieved through a sieve with a mesh size of approximately 600 μm. (e) Weighing and sieving the lubricant, wherein the lubricant is sieved through a sieve with a mesh size of approximately 600 μm; and optionally blending the lubricant with the first dry blend composition with any additional excipients, flavoring agents, sweeteners and / or coloring agents, wherein blending is carried out at approximately 15 rpm for approximately 6 minutes to form the final blend composition; and (f) Optionally compress the final blend composition ( For exampleTo form tablets) or to fill the final blended composition into capsules ( For example In hard capsules or soft capsules.

[0122] In all embodiments of the methods disclosed herein, medopetan monotartrate or hemitartrate, diluents, disintegrants, flow aids, and lubricants may be selected from any of the compositions disclosed herein.

[0123] Therefore, in a specific embodiment, the present invention provides a method for preparing a pharmaceutical composition comprising ledoperamide hemitartarate, the method comprising: (a) Para-dopasteurate hemitartarate ( For example L-hemitartaric acid salt), pregelatinized starch, sodium glycolate starch and colloidal silica were weighed and sieved, wherein each of medopetan or a pharmaceutically acceptable salt thereof, pregelatinized starch, sodium glycolate starch and colloidal silica was sieved through a sieve with a mesh size of approximately 600 μm. (b) Medopetan hemitartaric acid salt ( For example L-hemitartaric acid is blended 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) Prepare 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 the blending is carried out at about 15 rpm for about 5 minutes; and sieve the second premixed composition through a sieve with a mesh size of about 600 μm. (d) Blending the first and second premixed compositions with sodium glycolate starch and about one-third of the total amount of pregelatinized starch to form a first dry-mixed composition, wherein preparing the first dry-mixed composition comprises: i. Add the first premixed composition to the second premixed composition in the mixer tank; ii. Add sodium glycolate starch to the first and second premixed compositions in the mixer tank; iii. Add approximately one-third of the total amount of pregelatinized starch to the first and second premixed compositions and disintegrant in the mixer tank; and iv. The first and second premixed compositions, sodium glycolate starch and pregelatinized starch are blended in a mixer tank, wherein the blending is carried out at about 15 rpm for about 30 minutes; The first dry mixture was then sieved through a sieve with a mesh size of approximately 600 μm. (e) Weighing and sieving magnesium stearate, wherein the magnesium stearate is sieved through a sieve with a mesh size of approximately 600 μm; and optionally blending the magnesium stearate with the first dry blend composition with any additional excipients, flavoring agents, sweeteners and / or coloring agents, wherein blending is carried out at approximately 15 rpm for approximately 6 minutes to form the final blend composition; and (f) Optionally compress the final blend composition ( For example To form tablets) or to fill the final blended composition into capsules ( For example Hard capsules or soft capsules, such as HPMC capsule shells).

[0124] In embodiments of the methods disclosed herein, levodopatan or a pharmaceutically acceptable salt thereof in step (a) example like hemitartaric acid salts, such as L (-Hemitaritate) can be provided in the form of hydrates, solvates, and / or polymorphs (such as anhydrous polymorphs). In the examples, the levodopatan or a pharmaceutically acceptable salt thereof in step (a) For example hemitartaric acid salts, such as L - Hemitaritate salts, including any of their hydrates, solvates and / or polymorphs (such as anhydrous polymorphs), may be provided in solid crystalline or solid amorphous form.

[0125] In certain embodiments, at least a specific weight percentage of levodopatan or a pharmaceutically acceptable salt thereof ( For example hemitartaric acid salts, such as L (-Hemitaritate) is crystalline. For example ， At least a specific weight percentage of dapoxetine or a pharmaceutically acceptable salt thereof For example hemitartaric acid salts, such as L - Hemitaritate) is a single crystalline form. Suitable percentages of crystallinity and / or single crystalline form, as well as the characteristics of such crystalline forms, are discussed in conjunction with the compositions disclosed herein. For example (Determined based on XRP).

[0126] In the examples, levodopatan or a pharmaceutically acceptable salt thereof ( For example hemitartaric acid salts, such as L - Hemitaritate 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 ground prior to step (a). For example To obtain the desired particle size or particle size distribution. In an embodiment, grinding can be performed at a speed of approximately 5500 rpm to approximately 7500 rpm. For exampleApproximately 6000 rpm to approximately 7000 rpm. In an embodiment, a conical grinder is used for grinding. In an embodiment, grinding is performed for a maximum of approximately 15 minutes, for example, approximately 5 to approximately 10 minutes or approximately 5 to approximately 8 minutes. In an embodiment, the grinder ( For example A conical grinder has mesh sizes 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 meshes 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 with a mesh size of about 457 μm.

[0127] In the embodiments, levodopatan or a pharmaceutically acceptable salt thereof in step (a) For example hemitartaric acid salts, such as L - Hemitaritate salts, including any of their hydrates, solvates and / or polymorphs (such as anhydrous polymorphs), and including any of their solid crystalline or solid amorphous forms ( For example As defined with respect to any solid crystal form of the compositions disclosed herein, it may have the following particle size distribution ( For example (After grinding) D 90 <350 μm or <300 μm ( For example <290 μm, <280 μm, <270 μm or <260 μm) and / or D 50 <150 μm ( For example <140 μm, <120 μm, 100 μm, or <180 μm). In the examples, D 10 <15 μm, For example <10 μm. In some embodiments, D 90 <300 μm ( For example <290 μm, <280 μm, <270 μm or <260 μm), D 50 <150 μm ( For example <140 μm, <120 μm, <100 μm or <80 μm), and D 10 <15 μm, For example <10 μm. In some embodiments, D 90 <250 μm ( For example <240 μm, <230 μm or <220 μm) and / or D 50 <120μm ( For example <100 μm, <80 μm, or <75 μm). In some embodiments, D 90 <250 μm ( For example <240 μm, <230 μm or <220 μm) and D 50 <120 μm ( For example <100 μm, <80 μm, or <75 μm). In some embodiments, D 90 <250 μm ( example like <240 μm, <230 μm or <220 μm), D 50 <120 μm ( For example <100 μm, <80 μm or <75 μm), and D 10 <15 μm, For example <10 μm. In the examples, the particle size distribution can be determined by laser diffraction. For example Wet laser diffraction (wet dispersion), for example, in silicone oil at a concentration of 10 mg / ml. In the examples, ledopasteuron was prepared as solid crystalline ledopasteuron hemitartaric acid salt (... For example It is provided in the form of L-hemitartaric acid salt. For example It has the XRPD characteristics defined above.

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

[0129] Treatment On the other hand, a treatment method is provided, 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 ledopetan monotartrate or hemitartrate ( For example hemitartaric acid salts, such as L (-Hybrid tartaric acid) has the particle size distribution described above. For example Solid crystalline medopetan hemitarite with such a particle size distribution and optionally with XRPD characteristics as defined above ( For exampleL-hemitartaric acid (L-hemitartaric acid) is particularly suitable for use in the preparation of pharmaceutical compositions. Therefore, this disclosure also provides a treatment method comprising administering to a subject of need, such as a human, a therapeutically effective amount of ledopertan monotartaric acid or hemitartaric acid, wherein the ledopertan monotartaric acid or hemitartaric acid is in the form of solid granules as disclosed herein. example like hemitartaric acid salts, such as L - Hemitartaric acid salt). In related aspects, this disclosure provides the use of ledopetan monotartrate or hemitartaric acid salt in the manufacture of a pharmaceutical, wherein the ledopetan monotartrate or hemitartaric acid salt is a solid particulate ledopetan monotartrate or hemitartaric acid salt as disclosed herein ( For example hemitartaric acid salts, such as L -Hemitartaric acid salt). In another related aspect, this disclosure provides for the use of ledopatan or its monotartaric acid salt or hemitartaric acid salt in the manufacture of a pharmaceutical, wherein the ledopatan monotartaric acid salt or hemitartaric acid salt is a solid particulate ledopatan monotartaric acid salt or hemitartaric acid salt as disclosed herein ( For example hemitartaric acid salts, such as L - Hemitartaric acid salt). In a further related aspect, this disclosure provides solid particulate ledopatan monotartaric acid salt or hemitartaric acid salt for therapeutic use as disclosed herein. For example hemitartaric acid salts, such as L - Hemitartaric acid salt).

[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 syndrome, narcolepsy, Alzheimer's disease, and disorders associated with Alzheimer's disease. For example, the disease, disorder, and / or condition may be schizophrenia, L-DOPA-induced movement disorders, and / or Huntington's disease.

[0135] In the examples, the pharmaceutical compositions disclosed herein may be administered to a subject ( For example Human subjects), to provide approximately 2 mg ( For example Approximately 2.0 mg) to approximately 10 mg For example Doses of ledopetan containing a free base of 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, ledopetan monotartrate or hemitartrate is administered as a first dose of one or more doses, followed by a second dose of one or more doses, wherein the second dose is less than the first dose, and wherein both the first and second doses are administered independently in the pharmaceutical compositions disclosed herein. Optionally, the first dose corresponds to an amount of about 7.5 mg to about 10.0 mg and / or the second dose 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, ledopetan monotartrate or hemitartrate may be administered twice daily if desired. example like The dosage is twice daily, each dose corresponding to one of the aforementioned amounts, wherein the composition described herein is administered. Such dosages 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 exampleThe dosage is twice daily, each time corresponding to about 7.5 mg, such as about 7.5 mg in the morning and about 7.5 mg in the evening; or twice daily, each time corresponding to about 5.0 mg, such as about 5.0 mg in the morning and about 5.0 mg in the evening; or twice daily, each time corresponding to about 2.5 mg, such as about 2.5 mg in the morning and about 2.5 mg in the evening.

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

[0137] In the embodiments, the pharmaceutical compositions disclosed herein can be administered to subjects who have been diagnosed with Parkinson's disease or have been identified as being at risk of developing Parkinson's disease. For example Human subjects).

[0138] In the embodiments, the pharmaceutical compositions disclosed herein may be administered to subjects who have been identified as being at risk of developmental motor disorders. For example Human subjects). In this embodiment, subjects may have been identified as having one or more of the following risk factors for developing movement disorders: diagnosis of Parkinson's disease before the age of 60; cumulative L-DOPA exposure ( For example Based on the levodopa equivalent daily dose (LEDD); the subjects were female; the severity of motor and functional impairments ( For example Assessment via MDS-UPDRS Part III scoring; non-tremor dominant clinical phenotype; genetic risk score ( For example (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 can be administered to a subject prior to the onset of movement disorders. Alternatively or additionally, the pharmaceutical compositions can be administered without prior administration of Parkinson's disease medication. Therefore, the pharmaceutical compositions can be administered without prior administration of Parkinson's disease medication such as L-DOPA or a pharmaceutically acceptable salt thereof. Thus, the pharmaceutical compositions disclosed herein can be administered to subjects who have not experienced movement disorders. For example Subjects who have not experienced L-DOPA-induced motor dysfunction. Such subjects may include, for example, those already receiving Parkinson's disease medication (…). For exampleTreatment with L-DOPA or its pharmaceutically acceptable salts, but without showing symptoms of movement disorder ( For example Patients with LID (LID) For example Human patients).

[0140] Therefore, in some embodiments, the compositions disclosed herein can be applied to individuals who have already received Parkinson's disease medication prior to the first administration of the compositions disclosed herein. For example L-DOPA or its pharmaceutically acceptable salts) treatment for at least 1 day, at least 1 week, at least 1 month, or at least 1 year ( For example Subjects (preferably human subjects) for at least 4, 5, 6, 7, 8, 9, or 10 years. In a further embodiment, subjects who have not experienced movement disorders can be subjects who have not previously received Parkinson's disease medication. Right now Prior to starting treatment with the compositions disclosed herein, the patient had not received or was receiving any Parkinson's disease medications. example like Subjects undergoing treatment with L-DOPA or its pharmaceutically acceptable salts ( For example Human patients). In embodiments, such subjects may receive “pretreatment” with the compositions disclosed herein prior to initiating a treatment course with a Parkinson’s disease drug (e.g., L-DOPA or a pharmaceutically acceptable salt thereof). Therefore, the compositions disclosed herein can be administered to subjects (for the first time) For example Human subjects) were given drugs used to treat Parkinson's disease ( For example L-DOPA (or a pharmaceutically acceptable salt thereof) is administered to the subject at least one day, at least one week, at least one month, or at least one year prior to the initial administration of a drug for the treatment of Parkinson's disease. In such embodiments, the subject may thus receive a "pre-treatment" process in which the composition disclosed herein is repeatedly administered to the subject prior to the initial administration of a drug for the treatment of Parkinson's disease. For example Once daily or twice daily for at least one day, at least one week, at least one month, or at least one year. In another embodiment, the subject may begin treatment with a Parkinson's disease drug on the same day they also begin treatment with the compositions disclosed herein. For example L-DOPA or a pharmaceutically acceptable salt thereof can be used for treatment. Therefore, a 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 the embodiments, the compositions disclosed herein can be used with a drug for treating Parkinson's disease ( For exampleL-DOPA or a pharmaceutically acceptable salt thereof may be administered together with, or may be administered before or after, such a drug. Therefore, the compositions disclosed herein may be administered to a subject concurrently with a Parkinson's disease drug (e.g., L-DOPA or a pharmaceutically acceptable salt thereof). Alternatively, the compositions may be administered concurrently with a Parkinson's disease drug (e.g., L-DOPA or a pharmaceutically acceptable salt thereof). For example The composition disclosed herein may be administered to the subject prior to L-DOPA or a pharmaceutically acceptable salt thereof, or a Parkinson's disease drug may be administered to the subject prior to the composition disclosed herein. example like L-DOPA or its pharmaceutically acceptable salts). When used in Parkinson's disease medications ( For example The compositions disclosed herein may be administered prior to the use of L-DOPA or a pharmaceutically acceptable salt thereof, or vice versa The application of the compositions disclosed herein and the application of the Parkinson's disease medication can 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 the embodiments, the pharmaceutical compositions disclosed herein are suitable for preventing or reducing allergic reactions to medications used to treat Parkinson's disease. For example To prevent or reduce allergy to L-DOPA or its pharmaceutically acceptable salts. In some embodiments, prevention or reduction of allergy to Parkinson's disease drugs includes administration to those who have not experienced motor dysfunction ( For example Subjects with L-DOPA-induced dyskinesia are given ledopetan or a pharmaceutically acceptable salt thereof, wherein ledopetan monotartrate or hemitartrate is administered in the composition disclosed herein. In some embodiments, prevention or reduction of allergy to Parkinson's disease drugs includes administering ledopetan monotartrate or hemitartrate to subjects who have been receiving a treatment course of Parkinson's disease drug (e.g., L-DOPA or a pharmaceutically acceptable salt thereof) for at least 1 day prior to the first administration of the compound ledopetan monotartrate or hemitartrate to the subject, wherein ledopetan monotartrate or hemitartrate is administered in the composition disclosed herein. In some embodiments, prevention or reduction of allergy to Parkinson's disease drugs includes administering ledopetan monotartrate or hemitartrate to subjects, such as those who have not previously received Parkinson's disease drugs (e.g., individuals who have not previously received Parkinson's disease drugs). For example Subjects who have not previously received L-DOPA or a pharmaceutically acceptable salt thereof, wherein ledopetan monotartrate or hemitartrate is administered in the composition disclosed herein. In some embodiments, ledopetan monotartrate or hemitartrate is administered in the composition disclosed herein at least 1 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] Example abbreviation MDS-UPDRS, a revised and unified Parkinson's disease rating scale sponsored by the International Parkinson's and Movement Disorders Association. µm micrometer micron mm rpm revolutions per minute XRPX-ray powder XRPDX Powder Diffraction Example 1A: API grinding Hammer milling was performed using a Fitzmill L1A mill. Ledopetan was milled at a hammer speed of 7000 rpm and a collection sieve aperture of 800 µm. L The particle size distribution of the 1-hemitartaric acid obtained by hammer milling is shown in Table 1.

[0146] Hammer milling was performed using a Fitzmill L1A mill. Ledopetan was milled at a hammer speed of 7000 rpm and a collection sieve aperture of 800 µm. L - Hemitartaric acid was hammer milled, and the resulting particle size distribution is shown in Table 1. Compared to hammer mills, conical mills can increase yield / capacity and reduce API loss. Although this type of mill provides lower precision for hard-to-mill APIs, as can be seen from Table 1, using a conical mill 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 facilitates homogeneous (uniform) blending with excipients in the formulation. Without being bound by theory, it is believed that smaller particle size is beneficial for the coating of diluents that act as "carriers," thereby improving the uniformity of the blend.

[0147] Choosing the right mesh size (also known as screen size, mesh size, or sieve size) will affect the capacity of the grinder and the particle size of the ground API.

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

[0149] Another parameter that indicates 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 using the midpoint). The lower the span value (i.e., closer to 0), the more uniform the particle size.

[0150] Table 1

[0151] according to Figure 2 The method described in Example 2 uses unground and ground APIs to prepare blend compositions.

[0152] Blending uniformity was measured by the percentage API content after blending for 15 minutes and 45 minutes, as well as during 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 the median particle size. Preferred acceptable values ​​for blending uniformity were: 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 an RSD% < 5%. The results are shown in Table 2. Bold values ​​exceed the preferred acceptable criteria.

[0153] Table 2

[0154] As shown in Table 2, hammer milling at 7000 rpm and a mesh size of 800 µm produced API particles that caused the subsequent blends to fail to meet the preferred acceptance criteria. Conical milling at the same speed and mesh size resulted in parameters that met the preferred acceptance criteria.

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

[0156] The study found that grinding speed is particularly important for achieving good API particle size distribution and subsequent blending uniformity. It was found that at 6000 rpm, all mesh sizes used in a conical mill produced acceptable API particle size distribution and blending uniformity, although smaller meshes led to higher API loss (poorer yield), and a 610 µm mesh was found to result in a weaker bimodal particle size distribution. Figure 3A). Conical milling using a 457 µm mesh at a rotation speed of 6000 rpm provides better consistency with preferred acceptance criteria and achieves an appropriate balance between blendability and API loss.

[0157] As shown in Table 2, conical milling achieved acceptable blend homogeneity within 15 minutes, while hammer milling appeared 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 "deblending," in which the elements in the blend begin to separate.

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

[0160] Table 3

[0161] Although recrystallized APIs were found to have a more homogeneous particle size distribution than natural or ground APIs, blends prepared with recrystallized APIs were not very uniform.

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

[0163] Table 4 The ingredients of the drug domperidone

[0164] [a]: The amount of ledopetan was corrected for the presence of tartrate. Conversion factor: Molecular weight of ledopetan free base = 275.34 g / mol. Molecular weight of ledopetan 1 / 2 L-tartrate: 350.38 g / mol, therefore the correction factor is: 350.38 / 275.34 = 1.2725 [b]: The amount of pregelatinized starch is adjusted according to the purity of levodopa. Table 5 The ingredients of the drug domperidone

[0165] [c]: Rounded to 2 decimal places, total filler weight = 75.01 mg.

[0166] HPMC capsules were used in the compositions identified in Tables 4 and 5 above. However, alternative capsule shells, such as hard gelatin shells, can also be used. HPMC shells dissolve more slowly than hard gelatin capsule shells. Gelatin shells have a higher water content than HMPC shells (hard gelatin capsule shells contain 13% to 15% water), which may lead to faster degradation of their contents in some cases.

[0167] Example 3: Preparation of the composition A method for preparing blends of levodopa (API), For example The method for filling the capsule according to Example 2 is as follows: Figure 2 As shown and described below.

[0168] Step A: Weighing Weigh out metopetan hemitartaric acid, pregelatinized starch, sodium glycolate starch and colloidal silica, and sieve them through a 600 µm sieve.

[0169] Step B: Blending One-third (approximately 33%) of the pregelatinized starch and all of the metopetran hemitartarate were directly transferred to a mixer 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 blended at 15 rpm for 5 minutes. The resulting blend (premix 2) was then sieved through a 600 µm sieve.

[0171] Transfer the sieved premix 2, sieved premix 1, sodium glycolate starch, and the last third (approximately 33%) of pregelatinized starch into a mixer tank in this order and mix at 15 rpm for 30 minutes.

[0172] Step C: Lubrication Magnesium stearate was weighed and sieved through a 600 µm sieve, then transferred directly to a mixing tank and mixed 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 dust-free and 100% weight-controlled. Capsules exceeding the acceptable weight limit (±7.5%) were discarded.

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

[0175] Transfer the bulk capsules to a double-layered transparent polyethylene bag containing desiccant and seal it with a cable tie.

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

[0177] Example 4: Characteristics of solid granular levodopatan hemitartaric acid Figure 4A Crystalline levodopatan obtained using scanning electron microscopy (SEM) is shown. L- Two representative micrographs of hemi-tartrate. In short, the application of Agar sputtering coating to Madoparin. L-hemitartaric acid The powder was gold-plated and imaged using a LEO 1430VP scanning electron microscope (SEM). The accelerating voltage was 10 kV at a working distance of 10 mm.

[0178] like Figure 4A As shown, the crystals exhibit a "sheave" 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 Representative optical images of API after size reduction using a mortar and pestle are shown. The particle size is significantly reduced, ranging from tens of micrometers. Some larger particles, approximately 30 μm to 40 μm, are 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 flat surfaces covered by 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] Unground crystallized levodopatan L - XRP diffraction pattern of hemitartaric acid salt and crystallized levodopatan after grinding at 7000 rpm for 15 minutes using a Fitzmill L1A mill. L A comparison of the XRP diffraction patterns of the hemitaritate showed that the material remained crystalline during grinding, with little or no change in the XRPD characteristic peaks.

[0181] Example 5 In this example, crystalline levodopatan was milled using a Quadro CoMill at a speed of 6000 rpm.L -After 24 minutes of semi-tartaric acid treatment, the following particle size distribution was obtained: D 10 = 7.9 µm D 50 = 86 µm D 90 = 305 µm 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, edited by RC Rowe, PJ Sheskey, and SCOwen. 8.npj Parkinson's Disease 33:1-6 (2018)

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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