<smallcaps / >? ? ?n? ? ? ? ?pharmaceutical compositions comprising a tartrate salt of-[2-(3-fluoro-5-methane-sulfonylphenoxy)ethyl](propyl)amine

Abstract

Pharmaceutical compositions comprising a tartrate salt of mesdopetam, and processes for the manufacture of said pharmaceutical compositions, are provided. The pharmaceutical compositions are useful in treating diseases such as L-DOPA induced dyskinesias.

Description

[0001] PHARMACEUTICAL COMPOSITIONS COMPRISING A TARTRATE SALT OF N- [2-(3-FLUORO-5-METHANE-SULFONYLPHENOXY)ETHYL](PROPYL)AMINE

[0002] The present disclosure relates to pharmaceutical compositions, including dosage forms, such as tablets or capsules, comprising mesdopetam monotartrate or hemitartrate salt. The disclosure also provides processes for manufacture of the said compositions, and uses of the said compositions in therapy.

[0003] BACKGROUND

[0004] The listing or discussion of any prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0005] 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 after initiation of standard dopamine replacement therapy, about 50% of patients with PD develop ON-phase involuntary movements, so called L-DOPA-induced dyskinesia (LID), in response to their medical treatment. LID is often the key complication that limits further dose increases in dopaminergic therapy. Moreover, treatment induced psychotic symptoms may also develop over time in a substantial proportion of patients. There are few options for the treatment and prevention of such long-term complications.

[0006] Mesdopetam ([2-(3-fluoro-5-methanesulfonylphenoxy)-ethyl](propyl)amine; IRL-790 and / or IPN60170; CAS 1403894-72-3) is one of a class of compounds described in WO 2012 / 143337 which are modulators of cortical and basal ganglia dopaminergic and N-methyl-D-aspartate (NMD A) receptor mediated glutamatergic neurotransmission. Such compounds are useful in the treatment of diseases that are responsive to modulation of dopaminergic and glutamatergic function in the central nervous system, and may be useful in the treatment of e.g. Parkinson’s disease, dyskinesias, and L-DOPA induced dyskinesias. Mesdopetam has the following structure in its free base form:

[0007] Preclinical studies in experimental animals suggest that mesdopetam helps ameliorate adverse effects such as LID without affecting the basic efficacy of antiparkinsonian medications. J. Pharmacol. Exp. Ther. 374:113-125, July 2020 discloses the preclinical pharmacology of mesdopetam as a novel dopamine transmission modulator for the treatment of motor and psychiatric complications for Parkinson’s disease. It was found that mesdopetam dose- dependently reduced adverse involuntary movements (AIMs), and that this alleviation of involuntary movements was not achieved at the cost of any impairment of the motor effects of L- DOPA as such, which was captured as rotational response to L-DOPA.

[0008] Salts of mesdopetam and related compounds are described in WO 2020 / 239568 and have been investigated in a recently completed Phase lib study. Pharmaceutical compositions comprising mesdopetam, and the use of such compositions in methods of treatment, are described in WO 2022 / 101227.

[0009] There is a need for pharmaceutical formulations of mesdopetam, e.g. formulations which provide the desired dosages for therapeutic use. There is also a need for such forms to have an economical and reliable manufacturing process for compliance with acceptance and regulatory parameters.

[0010] SUMMARY

[0011] It is an object of the present disclosure to provide mesdopetam monotartrate or hemitartrate salt in a form that is suitable for pharmaceutical compositions such as pharmaceutical compositions allowing for dosing uniformity. Further, it is an object of the present disclosure to provide aspects and / or advantages not provided by hitherto known technique.

[0012] In one aspect the present disclosure provides a pharmaceutical composition comprising mesdopetam monotartrate or hemitartrate salt, a diluent, a disintegrant, a lubricant, and optionally a glidant. In another aspect, the present disclosure provides solid particulate mesdopetam monotartrate or hemitartrate salt (e.g. the hemitartrate salt, such as the Z-hemitartrate salt) having a particle size distribution wherein D90 is <350 pm or <300 pm (e.g. <290 pm, <280 pm, <270 pm or <260 pm) and / or D50 is <150 pm (e.g. <140 pm , <120 pm, 100 pm, or <180 pm).

[0013] In another aspect, the present disclosure provides a process for preparing a pharmaceutical composition comprising mesdopetam monotartrate or hemitartrate salt, the process comprising:

[0014] (a) weighing and sieving mesdopetam monotartrate or hemitartrate salt, a diluent, a disintegrant, and optionally a glidant;

[0015] (b) blending the mesdopetam monotartrate or hemitartrate salt and about one third of the total amount of diluent to form a first pre-blend composition, and optionally sieving the first pre-blend composition;

[0016] (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;

[0017] (d) blending the first and second pre-blend compositions with 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;

[0018] (e) weighing and sieving a lubricant, and blending the lubricant with the first dry blend composition, optionally together with any additional excipients, flavorings, sweeteners and / or coloring agents, to form a final blend composition; and

[0019] (f) optionally compressing the final blend composition (e.g. to form a tablet) or filling the final blend composition into capsules (e.g. hard or soft capsules).

[0020] In another aspect, the present disclosure provides a pharmaceutical composition prepared by, or preparable by, the process, or any embodiments thereof, as described herein.

[0021] A further aspect provides a method of treatment comprising administering to a subject in need thereof a therapeutically effective amount of mesdopetam monotartrate or hemitartrate salt, wherein the mesdopetam monotartrate or hemitartrate salt is administered in a pharmaceutical composition as disclosed herein. In a related aspect, the disclosure provides the use of mesdopetam monotartrate or hemitartrate salt in the manufacture of a medicament, wherein the medicament is a pharmaceutical composition as disclosed herein. In another related aspect, the disclosure provides the use of a pharmaceutical composition as disclosed herein in the manufacture of a medicament. In a further related aspect, the disclosure provides a pharmaceutical composition as disclosed herein for use in therapy.

[0022] The present disclosure also provides a pharmaceutical composition as described herein or a mesdopetam monotartrate or hemitartrate salt as described herein for use in the treatment and / or prevention of a disease, disorder and / or condition which is selected from psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, dementia, age-related cognitive impairment, Autism spectrum disorders, ADHD, cerebral Palsy, Gilles de la Tourette's syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, Parkinson's disease, parkinsonian syndrome, dyskinesia, L-DOPA induced dyskinesias, Tardive dyskinesias, dystonia, tics and tremor dementia, Huntington's disease, movement disorder induced by drugs, restless legs, narcolepsy, Alzheimer's disease and disorder(s) related to Alzheimer's disease.

[0023] The present disclosure also provides the use of a pharmaceutical composition as described herein or a mesdopetam monotartrate or hemitartrate salt as described herein for the manufacture of a medicament for use in the treatment and / or prevention of a disease, disorder and / or condition which is selected from psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, dementia, age-related cognitive impairment, Autism spectrum disorders, ADHD, cerebral Palsy, Gilles de la Tourette's syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, Parkinson's disease, parkinsonian syndrome, dyskinesia, L-DOPA induced dyskinesias, Tardive dyskinesias, dystonia, tics and tremor dementia, Huntington's disease, movement disorder induced by drugs, restless legs, narcolepsy, Alzheimer's disease and disorder(s) related to Alzheimer's disease.

[0024] The present disclosure also provides a method for treating and / or preventing a disease, disorder and / or condition which is selected from psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, dementia, age-related cognitive impairment, Autism spectrum disorders, ADHD, cerebral Palsy, Gilles de la Tourette's syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, Parkinson's disease, parkinsonian syndrome, dyskinesia, L-DOPA induced dyskinesias, Tardive dyskinesias, dystonia, tics and tremor dementia, Huntington's disease, movement disorder induced by drugs, restless legs, narcolepsy, Alzheimer's disease and disorder(s) 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 as described herein or a mesdopetam monotartrate or hemitartrate salt as described herein.

[0025] BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIG. 1 shows an XRP diffractogram of mesdopetam L-hemitartrate. XRPD data were collected on a Bruker D8 Advance (2005) instrument. Radiation: Copper Ka, X=l.54180 A, Kp filter 0.020 mm Ni foil, anode voltage : 40 kV, anode current : 40 mA, detector : LynxEye (ID-position sensitive), slits 0.6 mm and 8 mm, step size 0.02 °, scan speed 0.2 s / step, Interval (20) (3 - 35)° in 20 scale.

[0027] FIG. 2 depicts an example of the process described herein. In Fig. 2, IPN60170 represents mesdopetam Z-hemi tartrate.

[0028] FIG. 3 depicts particle size distributions of mesdopetam L-hemitartrate when milled according to different parameters. Fig. 3A shows density distributions and Fig. 3B shows cumulative distributions. Particle size distributions were determined by wet laser diffraction at a concentration of 10 mg / mL in silicon oil. Triangles represent particles of mesdopetam L- hemitartrate which were milled at 6000 rpm using a conical mill with a 610 pm mesh. Circles represent particles of mesdopetam L-hemitartrate which were milled at 6000 rpm using a conical mill with a 279 pm mesh. Squares represent particles of mesdopetam L-hemitartrate which were milled at 6000 rpm using a conical mill with a 457 pm mesh.

[0029] FIG. 4 shows SEM micrographs of mesdopetam hemitartrate before and after milling with a mortar and pestle. FIG. 4A shows SEM micrographs of mesdopetam hemitartrate prior to milling, at two different magnifications. Crystals with a so-called “wheat sheaf’ structure are visible. FIG. 4B shows an SEM micrograph after size reduction using mortar and pestle. The particle size is noticeably reduced with size ranges in the order of tens of microns. Some larger particles of approx. 30-40 microns can be observed. The morphology of the milled particles is irregular with a plate like surface. DETAILED DESCRIPTION

[0030] Definitions

[0031] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods, devices, and materials are now described. All technical and patent publications cited herein are incorporated herein by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0032] Mesdopetam, also known as IRL-790 and IPN60170, has CAS Registry No. 1403894-72-3 and IUPAC name JV-[2-(3-fluoro-5-methylsulfonyl-phenoxy)ethyl]propane-l-amine. References herein to “mesdopetam free base” refer to the compound per se. Unless otherwise stated, references herein to “mesdopetam” without any further qualification include mesdopetam free base or a monotartrate or hemitartrate salt of mesdopetam. Thus, unless provided otherwise, the word “mesdopetam” means mesdopetam in free base form or a monotartrate or hemitartrate salt thereof.

[0033] All numerical designations, e.g., pH, temperature, time, concentration, molecular weight, etc., including ranges, are approximations which are varied ( + ) or ( - ) by increments of, e.g., 0.1 or 1.0, where appropriate. Where numerical designations are preceded by the term “about”, this is used to denote a conventional level of variability. For example, a numerical designation which is “about” a given value may vary by ± 10% of said value; alternatively, the variation may be ± 5%, ± 2%, or ± 1% of the value.

[0034] For the avoidance of doubt, any disclosure of a numerical range, e.g., “up to X” amount is intended to include the upper numerical limit X. Therefore, a disclosure of “up to 60 mg” includes 60 mg. Analogously, any disclosure of a numerical range is also intended to include the lower numerical limit, e.g., “from A to”, or “at least A”. Therefore, a disclosure of e.g. “from 5 mg to 50 mg” or “at least 5 mg” includes 5 mg.

[0035] As used herein, where a quantity of a substance is described in terms of a %, this is intended to refer to “% by weight” (also denoted %wt, wt%, %w / w, w / w%, %(w / w), (w / w)% and the like) unless otherwise indicated. As used in the specification and claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a diluent” includes a plurality of diluents, including mixtures thereof Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive. The term “including” is used herein to mean, and is used interchangeably with, the phrase “including but not limited to”.

[0036] As used herein, the term “comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, without excluding other elements. “Consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. “Consisting of’ shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this disclosure or process steps to produce a composition or achieve an intended result. Embodiments defined by each of these transition terms are within the scope of this disclosure. Use of the term “comprising” herein is intended to encompass, and to disclose, the corresponding statements in which the term “comprising” is replaced by “consisting essentially of’ or “consisting of’.

[0037] A “subject,” “individual”, or “patient” is used interchangeably herein, and refers to a vertebrate, such as a mammal. Mammals include, but are not limited to, rodents, farm animals, sport animals, pets, and primates; for example murines, rats, rabbits, simians, bovines, ovines, porcines, canines, felines, equines, and humans. In a particular embodiment, the mammal is a human.

[0038] “Administering” is defined herein as a means of providing an agent or a composition containing the agent to a subject in a manner that results in the agent being contacted with (e.g., being inside) the subject’s body. Such an administration can be by any route including, without limitation, oral, transdermal, transmucosal (e.g., by 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., oral or nasal). Administration may also involve providing a substance or composition to a part of the surface of the subject’s body, for example by topical administration to the skin. Pharmaceutical preparations are, of course, given by forms suitable for each administration route. “Treating” or “treatment” of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a patient that may be predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e. arresting or reducing the development of the disease or its clinical symptoms; and / or (3) relieving the disease, i.e. causing regression of the disease or its clinical symptoms.

[0039] The term “suffering” as it relates to the term “treatment” refers to a patient or individual who has been diagnosed with or is predisposed to the disease. A patient may also be referred to being “at risk of suffering” from a disease because of a history of disease in their family lineage or because of the presence of genetic mutations associated with the disease. A patient at risk of a disease has not yet developed all or some of the characteristic pathologies of the disease.

[0040] An “effective amount” or “therapeutically effective amount” is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications, or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, the route of administration, etc. It is understood, however, that specific dose levels of the therapeutic agents of the present disclosure for any particular subject depends upon a variety of factors including, for example, the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, the rate of excretion, the drug combination, the severity of the particular disorder being treated and the form of administration. Treatment dosages generally may be titrated to optimize safety and efficacy. Typically, dosage-effect relationships from in vitro and / or in vivo tests initially can provide useful guidance on the proper doses for patient administration. In general, one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vitro. Determination of these parameters is well within the skill of 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 “therapeutically 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 in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. Unless otherwise indicated, an amount of an active compound for administration (whether administered as a free base or as a salt form) refers to or is based on the amount of the compound in free base form. Therefore, unless otherwise stated, where dosages of mesdopetam are recited, these are calculated as the quantity of mesdopetam free base, such that the actual mass of a mesdopetam salt will be greater. For example, a 5 mg dose of mesdopetam free base corresponds to about 6.36 mg of mesdopetam hemitartrate.

[0041] As used herein, the phrase “in the treatment or prevention of’ (such as in the phrase “in the treatment or prevention of pain”) is meant to be equivalent to the phrase “in a method of treating or preventing” (such as in the phrase “in a method of treating or preventing pain”).

[0042] Where reference is made to a method of treatment and / or prevention of a disease using mesdopetam or a pharmaceutically acceptable salt thereof such as a monotartrate or hemitartrate salt thereof, these statements should be understood to include each of (i) mesdopetam or a pharmaceutically acceptable salt thereof such as a monotartrate or hemitartrate salt thereof for use in said method of treatment and / or prevention of disease; or mesdopetam or a pharmaceutically acceptable salt thereof for use such as a monotartrate or hemitartrate salt thereof in treating and / or preventing said disease; (ii) use of medsopetam or a pharmaceutically acceptable salt thereof such as a monotartrate or hemitartrate salt thereof in said method of treatment and / or prevention of disease; or use of mesdopetam or a pharmaceutically acceptable salt thereof in treating and / or preventing said disease; and (iii) use of mesdopetam or a pharmaceutically acceptable salt thereof such as a monotartrate or hemitartrate salt thereof for the manufacture of a medicament for treating and / or preventing said disease.

[0043] As used herein, the term “pharmaceutically acceptable excipient” encompasses any of the standard pharmaceutical excipients, including diluents and carriers, to enable mesdopetam, in free base form or pharmaceutically acceptable salt form (e.g. tartrate, such as hemitartrate, including L-hemitartrate) to be formulated for use in a medicinal preparation. Pharmaceutically acceptable excipients may, for example, be as described in Remington’s Pharmaceutical Sciences (20th ed., Mack Publishing Co. 2000). Such excipients include carriers such as a phosphate buffered saline solution, water, and emulsions, such as an oil / water or water / oil emulsion, and various types of wetting agents. Pharmaceutical compositions also can include stabilizers, preservatives, adjuvants, fillers, binders, lubricants, and the like. Suitable forms of mesdopetam include the free base form, including amorphous solid dispersions thereof, pharmaceutically acceptable salt forms such as a monotartrate or hemitartrate salt, including crystal forms thereof, and pharmaceutically acceptable co-crystal forms. Unless otherwise indicated, the term “pharmaceutically acceptable salt” includes acid addition salts between mesdopetam and any pharmaceutically acceptable acid (e.g., Bronsted acid) in any molar ratio permitted by the structure of the acid. For example, basic compounds may be provided as pharmaceutically acceptable acid addition salts with an acid such as HC1. The pharmaceutically acceptable salts of mesdopetam can be synthesized from the free base compound, which contains basic moieties, by mixing or reaction with a suitable acid, by conventional chemical methods. Generally, such salts can be prepared by mixing such as reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in water, or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Methods for forming salts are also known in the art (see, e.g., Berge et al., J Pharm Sci. (1977) 66:1-19). As used herein, the term “pharmaceutically acceptable” when used in connection with salts means a salt of a currently disclosed compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained. Examples of pharmaceutically acceptable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, tartaric acid, fumaric acid, maleic acid, malic acid, and the like. Examples of pharmaceutically acceptable salts include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-1 ,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gammahydroxybutyrate, glycolate, tartrate (e.g. monotartrate or hemitartrate), methanesulfonate, propanesulfonate, naphthalene-I-sulfonate, naphthalene-2-sulfonate, and mandelate salts and the like. In particular, the pharmaceutically acceptable salt may be tartaric acid.

[0044] In some embodiments, the salt is a crystalline solid (e.g., a salt crystal). In an embodiment, the crystalline salt form of mesdopetam is a crystalline hemitartrate salt as disclosed in, e.g., WO 2020 / 239568 (the content of which is hereby incorporated by reference in its entirety), with particular reference being made to page 9, line 25 to page 10, line 9 and Figure 1 of that document.

[0045] Isotopically-labeled compounds are also within the scope of the present disclosure. As used herein, an “isotopically-labeled compound” refers to mesdopetam, including pharmaceutical salts thereof, as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds (including salts) presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36C1, respectively. For instance, one or more of the hydrogen atoms of mesdopetam may be replaced with deuterium.

[0046] The reference works, patents, patent applications, and scientific literature, and other printed publications that are mentioned or referred to herein are hereby incorporated by reference in their entirety.

[0047] As those skilled in the art will appreciate, numerous changes and modifications may be made to the preferred embodiments of the invention without departing from the spirit of the invention. It is intended that all such variations fall within the scope of the invention.

[0048] Pharmaceutical compositions

[0049] In one aspect, the present disclosure provides a pharmaceutical composition comprising mesdopetam or a tartrate salt thereof such as a monotartrate or hemitartrate salt of mesdopetam, a diluent, a disintegrant, a lubricant, and optionally a glidant.

[0050] Suitable diluents include carbohydrates (e.g. saccharides and polysaccharides), pharmaceutically acceptable synthetic polymers, inorganic diluents, and mixtures thereof.

[0051] Suitable carbohydrates include cellulose (e.g. microcrystalline cellulose (such as silicified microcrystalline cellulose), powdered cellulose, or cellulose acetate), carboxymethylcellulose (e.g. carboxymethylcellulose calcium), alginate (e.g. sodium alginate or ammonium alginate), starch (e.g. pregelatinized starch, such as Starch 1500®), dextrates, dextrin, maltodextrin, sugars (e.g. dextrose, fructose, lactose (such as lactose monohydrate or spray-dried lactose), maltose, trehalose, or sucrose (such as compressible sugar or confectioner’s sugar)), sugar alcohols (e.g. erythritol, isomalt, lactitol, maltitol, mannitol, sorbitol, or xylitol), and mixtures thereof.

[0052] Suitable pharmaceutically acceptable synthetic polymers include povidone (such as crospovidone) and vinylpyrrolidone-vinyl acetate copolymers (such as Kollidon® VA64).

[0053] Suitable inorganic diluents include calcium carbonate, calcium phosphate (e.g. calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate (calcium phosphate dihydrate), or calcium phosphate tribasic), calcium sulfate, kaolin, magnesium carbonate, magnesium oxide, sodium chloride, and mixtures thereof.

[0054] In some embodiments the diluent may comprise, consist essentially of, or consist of, a carbohydrate or mixture of carbohydrates, e.g. as disclosed above.

[0055] In some embodiments the diluent may comprise, consist essentially of, or consist of, a pharmaceutically acceptable synthetic polymer or mixture of pharmaceutically acceptable synthetic polymers, e.g. as disclosed above.

[0056] In some embodiments the diluent may comprise, consist essentially of, or consist of, an inorganic diluent or mixture of inorganic diluents, e.g. as disclosed above.

[0057] In some embodiments the diluent may comprise, consist essentially of, or consist of, a mixture of at least one carbohydrate and at least one inorganic diluent, e.g. as disclosed above.

[0058] In some embodiments the diluent may comprise, consist essentially of, or consist of, a mixture of at least one carbohydrate and at least one pharmaceutically acceptable synthetic polymer, e.g. as disclosed above.

[0059] In some embodiments the diluent may comprise, consist essentially of, or consist of, a mixture of at least one pharmaceutically acceptable synthetic polymer and at least one inorganic diluent, e.g. as disclosed above.

[0060] In some embodiments the diluent is selected from cellulose (e.g. microcrystalline cellulose (such as silicified microcrystalline cellulose), powdered cellulose, or cellulose acetate), carboxymethylcellulose (e.g. carboxy methylcellulose calcium), dextrates, dextrin, dextrose, erythritol, fructose, isomalt, lactitol, lactose (e.g. lactose monohydrate or spray-dried lactose), maltitol, maltodextrin, maltose, mannitol, povidone, alginate (e.g. sodium alginate or ammonium alginate), sorbitol, starch (e.g. pregelatinized starch), sucrose, compressible sugar, confectioner’s sugar, trehalose, xylitol, calcium carbonate, calcium phosphate (e.g. calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate (calcium phosphate dihydrate), or calcium phosphate tribasic), calcium sulfate, kaolin, magnesium carbonate, magnesium oxide, sodium chloride, and mixtures thereof

[0061] In some embodiments the diluent is selected from cellulose (e.g. microcrystalline cellulose (such as silicified microcrystalline cellulose), powdered cellulose, or cellulose acetate), carboxymethylcellulose (e.g. carboxymethylcellulose calcium), alginate (e.g. sodium alginate or ammonium alginate), starch (e.g. pregelatinized starch), dextrates, dextrin, maltodextrin, and mixtures thereof

[0062] In some embodiments the diluent comprises, consists essentially of, or consists of, pregelatinized starch.

[0063] Suitable disintegrants include 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 hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, polacrilin potassium, povidone, sodium alginate, sodium starch glycolate, starch, pregelatinized starch, and mixtures thereof

[0064] In some embodiments the disintegrant comprises, consists essentially of, or consists of, sodium starch glycolate.

[0065] Suitable lubricants include 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, and mixtures thereof. In some embodiments the lubricant comprises, consists essentially of, or consists of, magnesium stearate.

[0066] In embodiments comprising a glidant, suitable glidants include tribasic calcium phosphate, powdered cellulose, colloidal silicon dioxide (e.g. Aerosil® 200), magnesium oxide, magnesium silicate, magnesium trisilicate, starch, talc, and mixtures thereof Where the glidant comprises magnesium silicate this is preferably employed in combination with silica.

[0067] In some embodiments the glidant comprises, consists essentially of, or consists of, colloidal silicon dioxide.

[0068] Some components may, in principle, function as two or more of diluent, disintegrant, lubricant and / or glidant. By way of non-limiting examples, crospovidone, microcrystalline cellulose, carboxymethylcellulose calcium and powdered cellulose may each function as a diluent or as a disintegrant; tribasic calcium phosphate and magnesium oxide may each function as a diluent or as a glidant; colloidal silicon dioxide may function as a disintegrant or as a glidant; talc may function as a lubricant or as a glidant; and sodium chloride may function as a diluent or as a lubricant. In such cases, the function performed by the respective component(s) may typically be influenced by the amount of the respective component(s) which is / are present. For example, microcrystalline cellulose may act as a diluent when present in amounts of 20-90% of the composition whereas it may act as a disintegrant when present in amounts of 15% and below. Where any given component may have more than one function, appropriate amounts (e.g. concentration ranges, such as % (e.g. wt%) amounts) to achieve a given function are known to the skilled person, and may be found e.g. in standard handbooks and reference works such as the Handbook of Pharmaceutical Excipients, 5thedition, Pharmaceutical Press (London / Chicago), 2006, edited by R.C. Rowe, P.J. Sheskey and S.C. Owen. For example, lubricants and glidants may typically be employed in amounts of about 0.1% to about 2% by weight, and disintegrants may typically be employed in amounts of up to about 10% by weight, whereas diluents may typically be employed in amounts greater than 20% by weight. Thus, in embodiments comprising any such component(s) having more than one use, any given such component will typically only be present as a diluent, a disintegrant, a glidant or a lubricant, with the function of such component(s) depending e.g. on the amount of such component(s) which is / are present as well as the identity of any further component(s) with which it is combined. The amount and identity of component(s) in the formulations disclosed herein can be selected appropriately by one of skill in the art to achieve the intended function. In this document, the terms formulation and composition are used interchangeably. Therefore, for instance, if microcrystalline cellulose is present as a diluent, a disintegrant which is not microcrystalline cellulose will also be present in an appropriate amount.

[0069] In embodiments of the compositions disclosed herein, the diluent comprises pregelatinized starch, the disintegrant comprises sodium starch glycolate, the glidant comprises colloidal silicon dioxide, and the lubricant comprises magnesium stearate. In embodiments of the compositions disclosed herein, the diluent consists essentially of pregelatinized starch, the disintegrant consists essentially of sodium starch glycolate, the glidant consists essentially of colloidal silicon dioxide, and the lubricant consists essentially of magnesium stearate. In embodiments of the compositions disclosed herein, the diluent consists of pregelatinized starch, the disintegrant consists of sodium starch glycolate, the glidant consists of colloidal silicon dioxide, and the lubricant consists of magnesium stearate.

[0070] In embodiments, the composition comprises mesdopetam or a tartrate salt thereof such as a monotartrate or hemitartrate salt thereof in an amount of about 3 to about 20 wt% on a dry solids basis. In embodiments, the composition comprises mesdopetam or a tartrate salt thereof such as a monotartrate or hemitartrate salt thereof in an amount of about 3 to about 18 wt%, or about 3 to about 14 wt% on a dry solids basis, such as about 3 to about 13 wt%, about 3 to about 5 wt%, about 7 to about 9 wt%, about 11 to about 13 wt%, or about 15 to about 17 wt%, e.g. about 4 wt%, about 8 wt%, about 13 wt% or about 17 wt%.

[0071] In embodiments, the composition comprises about 75 to about 95 wt% of diluent on a dry solids basis, such as about 75 to about 92 wt%, about 80 to about 92 wt%, about 80 to about 88 wt% or about 82 to about 87 wt%, e.g. about 91 wt%, about 87 wt%, about 83 wt% or about 79 wt%.

[0072] In embodiments, the composition comprises about 1 to about 5 wt% of disintegrant on a dry solids basis, such as about 2 to about 4 wt%, or about 3 to about 4 wt%, e.g. about 3%.

[0073] In embodiments, the composition comprises about 0.1 to about 1.0 wt% of lubricant on a dry solids basis, such as about 0.2 to about 0.8 wt%, about 0.3 to about 0.7 wt%, about 0.4 to about 0.6 wt%, or about 0.3 to about 0.5 wt%, e.g. about 0.5 wt%.

[0074] In embodiments, the composition comprises about 0.1 to about 1.5 wt% of glidant on a dry solids basis, such as about 0.5 to about 1.5 wt%, about 0.8 to about 1.3 wt%, about 0.9 to about 1.1 wt%, or about 1.0 to about 1.1 wt%, e.g. about 1 wt% such as about 1.0 wt%. In embodiments, the composition comprises about 3 wt% of disintegrant, about 1 wt% of glidant, and about 0.5 wt% of lubricant, all on a dry solids basis.

[0075] In embodiments, the composition comprises mesdopetam or a tartrate salt thereof such as a monotartrate or hemitartrate salt thereof in an amount of about 3 to about 20 wt%, diluent in an amount of about 75 to about 95 wt%, disintegrant in an amount of about 1 to about 5 wt%, lubricant in an amount of about 0.1 to about 1.0 wt%, and glidant in an amount of about 0.1 to about 1.5 wt%, all on a dry solids basis. In preferred embodiments the diluent is pregelatinized starch, the disintegrant is sodium starch glycolate, the glidant is colloidal silicon dioxide, and / or the lubricant is magnesium stearate.

[0076] In embodiments, the composition comprises mesdopetam or a tartrate salt thereof such as a monotartrate or hemitartrate salt thereof in an amount of about 3 to about 20 wt%, diluent in an amount of about 75 to about 95 wt%, disintegrant in an amount of about 3 wt%, lubricant in an amount of about 0.5 wt%, and glidant in an amount of about 1 wt% (e.g. about 1.0 wt%), all on a dry solids basis. In preferred embodiments the diluent is pregelatinized starch, the disintegrant is sodium starch glycolate, the glidant is colloidal silicon dioxide, and / or the lubricant is magnesium stearate.

[0077] In embodiments, the composition comprises mesdopetam or a tartrate salt thereof such as a monotartrate or hemi tartrate salt thereof in an amount of about 3 to about 5 wt% (e.g. about 4 wt%), diluent in an amount of about 90 to about 93 wt% (e.g. about 90.5 to about 92.5 wt%, such as about 91 wt%), disintegrant in an amount of about 3 wt%, lubricant in an amount of about 0.5 wt%, and glidant in an amount of about 1 wt% (e.g. about 1.0 wt%), all on a dry solids basis. In preferred embodiments the diluent is pregelatinized starch, the disintegrant is sodium starch glycolate, the glidant is colloidal silicon dioxide, and / or the lubricant is magnesium stearate.

[0078] In embodiments, the composition comprises mesdopetam or a tartrate salt thereof such as a monotartrate or hemitartrate salt thereof in an amount of about 7 to about 9 wt% (e.g. about 8 wt%, such as about 8.5 wt%), diluent in an amount of about 86 to about 89 wt% (e.g. about 86.5 to about 88.5 wt%, such as about 87 wt%), disintegrant in an amount of about 3 wt%, lubricant in an amount of about 0.5 wt%, and glidant in an amount of about 1 wt% (e.g. about 1.0 wt%), all on a dry solids basis. In preferred embodiments the diluent is pregelatinized starch, the disintegrant is sodium starch glycolate, the glidant is colloidal silicon dioxide, and / or the lubricant is magnesium stearate. In embodiments, the composition comprises mesdopetam or a tartrate salt thereof such as a monotartrate or hemi tartrate salt thereof in an amount of about 11 to about 13 wt% (e.g. about 12 to about 13 wt%, such as about 12.7 wt%), diluent in an amount of about 82 to about 85 wt% (e.g. about 82.5 to about 84.5 wt%, such as about 82.8 wt%), disintegrant in an amount of about 3 wt%, lubricant in an amount of about 0.5 wt%, and glidant in an amount of about 1 wt% (e.g. about 1.0 wt%), all on a dry solids basis. In preferred embodiments the diluent is pregelatinized starch, the disintegrant is sodium starch glycolate, the glidant is colloidal silicon dioxide, and / or the lubricant is magnesium stearate.

[0079] In embodiments, the composition comprises mesdopetam or a tartrate salt thereof such as a monotartrate or hemitartrate salt thereof in an amount of about 15.5 to about 17.5 wt% (e.g. about 16 to about 17.5 wt%, such as about 17.0 wt%), diluent in an amount of about 78 to about 80 wt% (e.g. about 78.5 to about 79.5 wt%, such as about 78.5 wt%), disintegrant in an amount of about 3 wt%, lubricant in an amount of about 0.5 wt%, and glidant in an amount of about 1 wt% (e.g. about 1.0 wt%), all on a dry solids basis. In preferred embodiments the diluent is pregelatinized starch, the disintegrant is sodium starch glycolate, the glidant is colloidal silicon dioxide, and / or the lubricant is magnesium stearate.

[0080] It will be self-evident to one of skill in the art that, in all embodiments of the compositions disclosed herein, the total wt% of components, calculated on a dry solids basis, cannot exceed 100%. One of skill in the art will therefore understand that the amounts of the respective components identified can be varied as appropriate (e.g. within the wt% ranges identified) in order not to exceed 100%. For instance, one of skill in the art may first determine the wt% amounts of each of mesdopetam or the pharmaceutically acceptable salt thereof such as a monotartrate or hemitartrate thereof, diluent, disintegrant, lubricant and (if present) glidant, and then make up the balance by selecting the amount of diluent accordingly (i.e. to attain a maximum amount of no more than 100 wt% when summed over all components of the composition).

[0081] The compositions disclosed herein may further comprise one or more additional pharmaceutically acceptable excipients, flavorings, sweeteners and / or coloring agents, provided that the total of all components (i.e. the total content of mesdopetam or the tartrate salt thereof such as a monotartrate or hemitartrate salt thereof, diluent, disintegrant, lubricant, glidant (if present) and diluent, together with any additional pharmaceutically acceptable excipients, flavorings, sweeteners and / or coloring agents) does not exceed 100 wt%. In some embodiments, coloring agents may be used to introduce a uniformity of appearance to the product and / or to protect any light-sensitive ingredients. Suitable coloring agents 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, coloring agents may be included within the capsule shell, within the capsule fill, or both.

[0082] In embodiments of the compositions disclosed herein, mesdopetam or the tartrate salt thereof such as a monotartrate or hemitartrate salt thereof is provided in an amount corresponding to from about 2 to about 10 mg of mesdopetam free base, such as from about 2 to about 8, from about 2.5 to about 5.0, from about 2.5 to about 7.5, from about 2.5 to about 10.0, from about 5.0 to about 10.0, or from about 5.0 to about 7.5 mg of mesdopetam free base.

[0083] In embodiments of the compositions disclosed herein, mesdopetam or the tartrate salt thereof such as a monotartrate or hemitartrate salt thereof is provided in an amount corresponding to about 2.5 mg of mesdopetam free base (e.g. about 3.2 mg of mesdopetam hemitartrate, such as mesdopetam L-hemitartrate, such as 3.18 mg).

[0084] In embodiments of the compositions disclosed herein, mesdopetam or the tartrate salt thereof such as the hemitartrate salt thereof is provided in an amount corresponding to about 5.0 mg of mesdopetam free base (e.g. about 6.4 mg of mesdopetam hemitartrate, such as mesdopetam L- hemitartrate, such as 6.36 mg).

[0085] In embodiments of the compositions disclosed herein, mesdopetam or the hemitartrate salt thereof such as a monotartrate or hemitartrate salt thereof is provided in an amount corresponding to about 7.5 mg of mesdopetam free base (e.g. about 9.5 mg of mesdopetam hemitartrate, such as mesdopetam L-hemitartrate, such as 9.54 mg).

[0086] In embodiments of the compositions disclosed herein, mesdopetam or the tartrate salt thereof such as a monotartrate or hemitartrate salt thereof is provided in an amount corresponding to about 10.0 mg of mesdopetam free base (e.g. about 12.7 mg of mesdopetam hemitartrate, such as mesdopetam L-hemitartrate, such as 12.72 mg).

[0087] Mesdopetam can form a pharmaceutically acceptable salt together with a pharmaceutically acceptable acid such as tartaric acid. Examples of pharmaceutically acceptable acids include those identified in the “Definitions” section above. In embodiments, mesdopetam may be presented as a tartrate salt. Because tartaric acid has two carboxylic acid groups, it can form salts with differing molar ratios of mesdopetam to tartrate (the conjugate base of tartaric acid). For example, the salt in which there is about a one to one molar ratio of tartrate to mesdopetam may be referred to as a monotartrate salt, and the salt in which there is about a one to two molar ratio of tartrate to mesdopetam (or equivalently, about a 1:0.5 molar ratio of mesdopetam to tartrate) may be referred to as mesdopetam hemitartrate (also referred to as mesdopetam ’ / --tartrate). The term “tartrate” as employed herein encompasses all possible stoichiometries, i.e. molar ratios, including 1:1 and hemitartrate salts, unless otherwise specified. Other dibasic acids such as, e.g., fumaric, succinic, maleic and malic acids may also form more than one stoichiometry with mesdopetam by analogy.

[0088] It will be appreciated that the chemical structure of the mesdopetam monotartrate salt, i.e. a salt wherein the molar ratio of mesdopetam and tartaric acid is 1:1, may be depicted as indicated below:

[0089] Further, it will be appreciated that the chemical structure of the mesdopetam hemitartrate salt, i.e. a salt wherein the molar ratio of mesdopetam and tartaric acid is 1:0.5, may be depicted as indicated below:

[0090] Moreover, the skilled person understands that one or both of the acid protons of the tartaric acid forming part of the monotartrate salt or hemitartrate salt of mesdopetam may be attached to the nitrogen atom of mesdopetam or shared between the nitrogen atom of mesdopetam and the tartaric acid and this is encompassed by the chemical structures depicted herein. For instance, the hemitartrate salt of of mesdopetam may be represented as shown below wherein one of the acidic protons of the tartaric acid is attached to the nitrogen of mesdopetam:

[0091] The tartrate salt can exist in various stereoisomeric forms. Tartaric acid has three stereoisomers: L-( + )-tartaric acid (also referred to simply as L-tartaric acid or dextrotartaric acid) and its enantiomer, levotartaric acid or D-( - )-tartaric acid (also referred to as D-tartaric acid), and the achiral form, mesotartaric acid. The L or D designation does not indicate the acid's ability to rotate the plane of polarized light. Any of the stereoisomers of tartaric acid can be used to prepare mesdopetam salts, including mesdopetam hemitartrate. For example, the salt can be formed from only one of the stereoisomers, or a combination thereof. The tartrate salt (e.g. the hemitartrate salt) may thus be selected from D-tartrate, L- tartrate, mesotartaric acid or racemic D, L-tartrate. In a specific embodiment, the tartrate salt (e.g. the hemitartrate salt) is L-tartrate. "L-tartrate" means that the tartrate salt (e.g. the hemitartrate salt) is formed from L-tartaric acid. Racemic D, L-tartrate means that both D-tartrate and L-tartrate were used in the preparation of the salt. The amount of D-tartrate in racemic D, L-tartrate may be greater than, equal to, or less than the amount of L-tartrate present.

[0092] When the stereochemistry is named (as in, for example, L-( + )-tartaric acid) or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by 30 weight pure relative to the other stereoisomers. When a single enantiomer is named (as in, for example, L-(+)-tartaric acid) or depicted by structure, the depicted or named enantiomer is at least 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer. "Racemate" or "racemic mixture" means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light.

[0093] In embodiments of the compositions disclosed herein, mesdopetam is provided in the form of a tartrate salt (e.g. a 1:1 tartrate salt or a hemitartrate salt). In certain embodiments, mesdopetam is provided as an L-tartrate salt, such as the mono-L-tartrate salt or as the L-hemitartrate salt (% L-tartrate salt). In other embodiments, mesdopetam is provided as a D-tartrate salt, such as the mono-D-tartrate salt or as the hemi -D-tartrate salt (% D-tartrate salt). In particular embodiments, the tartrate salt of mesdopetam (e.g. the 1:1 tartrate salt or the hemitartrate salt, e.g. the 1:1 L- tartrate salt or the L-hemitartrate salt) is provided in an amount corresponding to about 2 to about 10 mg of the free base or about 2 to about 8 mg of the free base, e.g. about 2.5 mg, about 5.0 mg, about 7.5 mg or about 10.0 mg of the free base. Thus, for example, when mesdopetam is provided in the form of a hemitartrate salt (e.g. a L-hemitartrate salt) it may be provided in an amount of about 2.5 to about 12.7 mg of the hemitartrate salt, such as about 3.2, about 6.4, about 9.5 or about 12.7 mg, which correspond respectively to about 2.5, about 5.0, about 7.5 and about 10.0 mg of the free base. For instance, the compositions disclosed herein may comprise mesdopetam hemitartrate in amounts of 3.18, 6.36, 9.54 or 12.72 mg.

[0094] The compositions disclosed herein may be provided in the form of a bulk solid (such as a powder), e.g. a bulk solid for use in the formulation of a dosage form. Alternatively, the compositions disclosed herein may be provided as a finished dosage form such as an oral dosage form, e.g., a capsule (e.g., a soft or hard capsule) or a tablet (e.g., a chewable tablet, orally- disintegrating tablet, dispersible tablet, or a classic tablet or caplet), optionally wherein said finished dosage form comprises from about 2 to about 10 mg of mesdopetam (measured as the equivalent amount of free base), e.g. from 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 mesdopetam (measured as the equivalent amount of free base).

[0095] Tablets may be round, square, rectangular, spherical, oblong, oblate, oval, or any other suitable shape, including capsule-shaped (i.e., caplets). Tablets may optionally be scored for easier cutting, and may optionally be engraved.

[0096] In embodiments, the compositions described herein may be formulated for immediate release.

[0097] In embodiments, the compositions described herein may be formulated for oral administration.

[0098] In embodiments, the compositions are encapsulated, i.e. provided as a capsule (e.g. a capsule for oral administration) such as a soft or hard (“hard-shelled”) capsule. Soft capsules include soft gelatin capsules or modified starch capsules. Hard capsules include hard gelatin capsules or HPMC (hydroxypropylmethylcellulose) capsules.

[0099] Hard-shelled 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 enclosure for the solid material contained therein. The active pharmaceutical ingredient, i.e., the mesdopetam or a monotartrate or hemitartrate salt thereof, may be comprised as a powder, or as one or more granules or pellets within the capsule. Such granules or pellets may be manufactured by any suitable means, including roller compaction.

[0100] When packaged as active pharmaceutical ingredient (API), compositions of the present disclosure are typically provided as powders (either fine or coarse) and packaged into sterile containers, such as bags or drums.

[0101] In a particular embodiment, the composition comprises mesdopetam hemitartrate (e.g. mesdopetam Z-hemitartrate) in an amount of about 4 wt% (e.g. 4.24 wt%), diluent in an amount of about 91 wt% (e.g. 91.26 wt%), disintegrant in an amount of about 3 wt% (e.g. 3.00 wt%), lubricant in an amount of about 0.5 wt% (e.g. 0.50 wt%), and glidant in an amount of about 1 wt% (e.g. 1.00 wt%), all on a dry solids basis, 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. Optionally the composition is encapsulated, e.g. in an HPMC capsule.

[0102] In embodiments of the compositions disclosed herein, the mesdopetam or pharmaceutically acceptable salt thereof (e.g. the hemitartrate salt, such as the Z-hemitartrate salt) may be provided in the form of a hydrate, solvate, and / or polymorph (such as an anhydrous polymorph). In embodiments, the mesdopetam or pharmaceutically acceptable salt thereof (e.g. the hemitartrate salt, such as the Z-hemitartrate salt), including any hydrate, solvate, and / or polymorph (such as an anhydrous polymorph) thereof may be provided in a solid crystal form or in solid amorphous form.

[0103] In a particular embodiment, at least a particular percentage by weight of mesdopetam or the pharmaceutically acceptable salt thereof (e.g. the hemitartrate salt, such as the Z-hemitartrate salt) is crystalline. Particular 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 a percentage between 70% and 100%. Crystalline mesdopetam or the pharmaceutically acceptable salt thereof (e.g. the hemitartrate salt, such as the Z-hemitartrate salt) may be crystals of a single crystalline form, or a mixture of crystals of different single crystalline forms. A single crystalline form means mesdopetam or the pharmaceutically acceptable salt thereof (e.g. the hemitartrate salt, such as the Z-hemitartrate salt) as a single crystal or a plurality of crystals in which each crystal has the same crystal form. Thus, in another particular embodiment, at least a particular percentage by weight of mesdopetam or the pharmaceutically acceptable salt thereof (e.g. the hemitartrate salt, such as the Z-hemitartrate salt) is in a single crystalline form. Particular 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 a percentage between 70% and 100%. When a particular percentage by weight of mesdopetam or the pharmaceutically acceptable salt thereof (e.g. the hemitartrate salt, such as the Z-hemitartrate salt) is a single crystalline form, the remainder is some combination of amorphous mesdopetam or the pharmaceutically acceptable salt thereof (e.g. the hemitartrate salt, such as the Z-hemitartrate salt), and / or one or more other crystalline forms of mesdopetam or the pharmaceutically acceptable salt thereof (e.g. the hemitartrate salt, such as the Z-hemitartrate salt) excluding the single crystalline form. When the crystalline mesdopetam or the pharmaceutically acceptable salt thereof (e.g. the hemitartrate salt, such as the Z-hemitartrate salt) is defined as a specified percentage of one particular crystalline form, the remainder is made up of amorphous form and / or crystalline forms other than the one or more particular forms that are specified. Examples of a single crystalline form include mesdopetam hemitartrate salt (such as the L-hemitartrate salt) characterized by one or more XRPD properties as now discussed below.

[0104] In embodiments of the compositions disclosed herein, mesdopetam is provided in the form of solid crystalline mesdopetam hemitartrate (e.g. L-hemitartrate). In embodiments, crystalline mesdopetam hemitartrate (e.g. L-hemitartrate) may be in a solid crystalline form characterized by an XRP diffractogram comprising a peak at about 13.0 20, such as 13.02 20, and optionally at least one, at least two, at least three, or four further peak(s) selected from the following: about 12.4 20 (such as about 12.43 20) about 14.4 20 (such as about 14.40 20), about 21.1 20 (such as about 21.10 20), about 24.4 20 (such as about 24.36 20). In embodiments, the solid crystalline form of mesdopetam hemitartrate (e.g. L-hemitartrate) may be characterized by an XRP diffractogram comprising peaks at about 12.4 20, about 13.0 20, about 14.4 20, about 21.1 20, about 24.4 20, and optionally at least one further peak selected from the following: about 18.1 20, about 19.9 20. For instance, the XRP diffractogram may comprise peaks at about 12.43 20, about 13.02 20, about 14.40 20, about 18.07 20, about 19.92 20, about 21.10 20, about 24.36 20, and optionally at least one further peak selected from the following: about 19.62 20, about 21.44 20. In embodiments, the solid crystalline form of mesdopetam hemitartrate (e.g. L-hemitartrate) may be characterized by an XRP diffractogram corresponding to Figure 1. In embodiments, the XRP diffractogram is collected using Cu Ka radiation, e.g. with 1=1.54180 A. In embodiments, peak angles 20 are given to an accuracy of ±0.02° 20. In embodiments of the compositions disclosed herein, the mesdopetam or pharmaceutically acceptable salt thereof (e.g. the hemitartrate salt, such as the Z-hemitartrate salt), including any hydrate, solvate, and / or polymorph (such as an anhydrous polymorph) thereof, and including any solid crystal form or solid amorphous form thereof, e.g. any solid crystal form as defined above, may have a particle size distribution wherein D90 is <350 pm or <300 pm (e.g. <290 pm, <280 pm, <270 pm or <260 pm) and / or D50 is <150 pm (e.g. <140 pm , <120 pm, 100 pm, or <180 pm). In embodiments, Dio is <15 pm, e.g. <10 pm. In certain embodiments, D90 is <300 pm (e.g. <290 pm, <280 pm, <270 pm or <260 pm), D50 is <150 pm (e.g. <140 pm , <120 pm, <100 pm, or <80 pm), and Dio is <15 pm, e.g. <10 pm. In certain embodiments, D90 is <250 pm (e.g. <240 pm, <230 pm, or <220 pm) and / or D50 is <120 pm (e.g. <100 pm , <80 pm, or <75 pm). In certain embodiments, D90 is <250 pm (e.g. <240 pm, <230 pm, or <220 pm) and D50 is <120 pm (e.g. <100 pm , <80 pm, or <75 pm). In certain embodiments, D90 is <250 pm (e.g. <240 pm, <230 pm, or <220 pm), D50 is <120 pm (e.g. <100 pm , <80 pm, or <75 pm) and Dio is <15 pm, e.g. <10 pm. In embodiments, the particle size distribution may be determined by laser diffraction, e.g. wet laser diffraction (wet dispersion), for example at a concentration of 10 mg / ml in silicon oil.

[0105] In a related aspect, the present disclosure provides solid particulate mesdopetam or a pharmaceutically acceptable salt thereof (e.g. the hemitartrate salt, such as the Z-hemitartrate salt) have a particle size distribution wherein D90 is <350 pm or <300 pm (e.g. <290 pm, <280 pm, <270 pm or <260 pm) and / or D50 is <150 pm (e.g. <140 pm , <120 pm, 100 pm, or <180 pm). In embodiments, Dio is <15 pm, e.g. <10 pm. In certain embodiments, D90 is <300 pm (e.g. <290 pm, <280 pm, <270 pm or <260 pm), D50 is <150 pm (e.g. <140 pm , <120 pm, <100 pm, or <80 pm), and Dio is <15 pm, e.g. <10 pm. In certain embodiments, D90 is <250 pm (e.g. <240 pm, <230 pm, or <220 pm) and / or D50 is <120 pm (e.g. <100 pm , <80 pm, or <75 pm). In certain embodiments, D90 is <250 pm (e.g. <240 pm, <230 pm, or <220 pm) and D50 is <120 pm (e.g. <100 pm , <80 pm, or <75 pm). In certain embodiments, D90 is <250 pm (e.g. <240 pm, <230 pm, or <220 pm), D50 is <120 pm (e.g. <100 pm , <80 pm, or <75 pm) and Dio is <15 pm, e.g. <10 pm.

[0106] In embodiments, the particle size distribution may be determined by laser diffraction, e.g. wet laser diffraction (wet dispersion), for example at a concentration of 10 mg / ml in silicon oil. In embodiments, the solid particulate mesdopetam is provided in the form of solid crystalline mesdopetam hemitartrate (e.g. L-hemitartrate), e.g. having the XRPD characteristics as defined above.

[0107] It will be appreciated that the D values in relation to the particle size distribution are percentile values. For instance D90 may refer to the particle size below which 90% of all particles are found. In a similar way, D50 may refer to the particle size below which 50% of the particles are found and Dio may refer to the particle size below which 10% of the particles are found. It will be appreciated that the D value may be indicated with a majuscule or minuscule letter so that “D” and “d” are used interchangeably. For instance, D90 may be indicated as dgo and vice versa. The particle size distribution may be cumulative and / or based on volume. Further, the particle size may refer to the diameter of spherical particles or the equivalent diameter for non-spherical particles. In the latter case, shape factor analysis or the like may be used for arriving at the equivalent diameter value.

[0108] Surprisingly, it has been found that the herein described particle size distribution of the monotartrate salt and hemitartrate salt of mesdopetam allows for providing a uniform such as a homogenous distribution of the aforementioned salts (i.e. the API) in a composition such as a pharmaceutical composition. This is a particular advantage for pharmaceutical compositions wherein the API is present in a low dose such as a dosage from about 2 mg to about 10 mg of mesdopetam (measured as the equivalent amount of free base) as described herein where accurate dosing uniformity is known to be challenging.

[0109] Without wishing to be bound by theory, the present inventors believe that the irregular morphology of such particulate, crystalline mesdopetam hemitartrate, which has a plate-like surface, is particularly well suited to ensuring uniform distribution of such particles in a composition such as those disclosed herein, e.g. due to minimisation of particle agglomeration and / or improved distribution within a diluent such as pregelatinized starch.

[0110] Processes for preparing pharmaceutical compositions

[0111] In one aspect, the present disclosure provides a process for preparing a pharmaceutical composition comprising mesdopetam monotartrate or hemitartrate salt as described herein, the process comprising: (a) weighing and sieving mesdopetam monotartrate or hemitartrate salt as described herein, a diluent, a disintegrant, and optionally a glidant;

[0112] (b) blending the mesdopetam monotartrate or hemitartrate salt and about one third of the total amount of diluent to form a first pre-blend composition, and optionally sieving the first pre-blend composition;

[0113] (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;

[0114] (d) blending the first and second pre-blend compositions with 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;

[0115] (e) weighing and sieving a lubricant, and blending the lubricant with the first dry blend composition, optionally together with any additional excipients, flavorings, sweeteners and / or coloring agents, to form a final blend composition; and

[0116] (f) optionally compressing the final blend composition (e.g. to form a tablet) or filling the final blend composition into capsules (e.g. hard or soft capsules).

[0117] In embodiments, the blending in steps (b), (c) and / or (d) is performed in a blender tank.

[0118] In embodiments, the blending in step (d) comprises adding the first pre-blend composition to the second pre-blend composition in a blender tank (i.e. wherein the second pre-blend composition is present in the blender tank before the first pre-blend composition is introduced); introducing the disintegrant into the blender tank after the first pre-blend composition; and introducing about one third of the total amount of diluent into the blender tank after the disintegrant.

[0119] In embodiments, the blending in step (b) is performed for a time of from about 1 minute to about 15 minutes, e.g. from about 2 minutes to about 10 minutes, or from about 4 minutes to about 8 minutes. In embodiments, the blending in step (b) is performed for a time of about 6 minutes. In embodiments, the blending in step (b) is performed at a speed of about 10 rpm to about 20 rpm, e.g. about 15 rpm. In particular embodiments, the blending in step (b) is performed at about 15 rpm for about 6 minutes. In some embodiments, the first pre-blend composition is sieved after blending in step (b). In embodiments, the first pre-blend composition is sieved through a sieve having a mesh size of about 600 pm after blending in step (b). In embodiments, the blending in step (c) is performed for a time of from about 1 minute to about 15 minutes, e.g. from about 2 minutes to about 10 minutes, or from about 3 minutes to about 8 minutes. In embodiments, the blending in step (c) is performed for a time of about 5 minutes. In embodiments, the blending in step (c) is performed at a speed of about 10 rpm to about 20 rpm, e.g. about 15 rpm. In particular embodiments, the blending in step (c) is performed at about 15 rpm for about 5 minutes. In some embodiments, the second pre-blend composition is sieved after blending in step (c). In embodiments, the second pre-blend composition is sieved through a sieve having a mesh size of about 600 pm after blending in step (c).

[0120] In embodiments, the blending in step (d) is performed for a time of from about 15 minutes to about 45 minutes, e.g. from about 20 minutes to about 40 minutes, or from about 25 minutes to about 35 minutes. In embodiments, the blending in step (d) is performed for a time of about 30 minutes. In embodiments, the blending in step (d) is performed at a speed of about 10 rpm to about 20 rpm, e.g. about 15 rpm. In particular embodiments, the blending in step (d) is performed at about 15 rpm for about 30 minutes.

[0121] In embodiments, the blending in step (e) is performed for a time of from about 1 minute to about 15 minutes, e.g. from about 2 minutes to about 10 minutes, or from about 4 minutes to about 8 minutes. In embodiments, the blending in step (e) is performed for a time of about 6 minutes. In embodiments, the blending in step (e) is performed at a speed of about 10 rpm to about 20 rpm, e.g. about 15 rpm. In particular embodiments, the blending in step (e) is performed at about 15 rpm for about 6 minutes.

[0122] In embodiments, sieving in step (a) comprises sieving one or more of the mesdopetam or pharmaceutically acceptable salt thereof such as a monotartrate or hemitartrate salt thereof, diluent, disintegrant, and / or glidant through a sieve having a mesh size of about 600 pm. In one embodiment, each of the mesdopetam or pharmaceutically acceptable salt thereof such as a monotartrate or hemitartrate salt thereof, diluent, disintegrant, and glidant are sieved (e.g. separately sieved) through a sieve having a mesh size of about 600 pm.

[0123] In embodiments, sieving in step (b) comprises sieving the first pre-blend composition through a sieve having a mesh size of about 600 pm. In embodiments, sieving in step (c) comprises sieving the second pre-blend composition through a sieve having a mesh size of about 600 pm.

[0124] In embodiments, sieving in step (e) comprises sieving the lubricant through a sieve having a mesh size of about 600 pm.

[0125] In one embodiment, the present disclosure provides a process for preparing a pharmaceutical composition comprising mesdopetam monotartrate or hemitartrate salt as descried herein, the process comprising:

[0126] (a) weighing and sieving mesdopetam monotartrate or hemitartrate salt as described herein, a diluent, a disintegrant, and a glidant;

[0127] (b) blending the mesdopetam monotartrate or hemitartrate salt and about one third of the total amount of diluent to form a first pre-blend composition, and sieving the first pre-blend composition;

[0128] (c) preparing a second pre-blend composition comprising about one third of the total amount of diluent, wherein preparing the second pre-blend composition comprises blending about one third of the diluent with the glidant; and sieving the second pre-blend;

[0129] (d) blending the first and second pre-blend compositions with disintegrant and about one third of the total amount of diluent to form a first dry blend composition, and sieving the first dry blend composition;

[0130] (e) weighing and sieving a lubricant, and blending the lubricant with the first dry blend composition, optionally together with any additional excipients, flavorings, sweeteners and / or coloring agents, to form a final blend composition; and

[0131] (f) optionally compressing the final blend composition (e.g. to form a tablet) or filling the final blend composition into capsules (e.g. hard or soft capsules).

[0132] In one embodiment, the present disclosure provides a process for preparing a pharmaceutical composition comprising mesdopetam monotartrate or hemitartrate salt as described herein, the process comprising:

[0133] (a) weighing and sieving mesdopetam monotartrate or hemitartrate salt as described herein, a diluent, a disintegrant, and a glidant;

[0134] (b) blending the mesdopetam monotartrate or hemitartrate salt and about one third of the total amount of diluent to form a first pre-blend composition, and sieving the first pre-blend composition; (c) preparing a second pre-blend composition comprising about one third of the total amount of diluent, wherein preparing the second pre-blend composition comprises blending about one third of the diluent with the glidant; and sieving the second pre-blend;

[0135] (d) blending the first and second pre-blend compositions with disintegrant and about one third of the total amount of diluent to form a first dry blend composition, wherein preparing the first dry blend composition comprises: i. adding the first pre-blend composition to the second pre-blend composition in a blender tank; ii. adding the disintegrant to the first and second pre-blend compositions in the blender tank; iii. adding about one third of the total amount of diluent to the first and second preblend compositions and disintegrant in the blender tank; and iv. blending the first and second pre-blend compositions, disintegrant, and diluent in the blender tank; and sieving the first dry blend composition;

[0136] (e) weighing and sieving a lubricant, and blending the lubricant with the first dry blend composition, optionally together with any additional excipients, flavorings, sweeteners and / or coloring agents, to form a final blend composition; and

[0137] (f) optionally compressing the final blend composition (e.g. to form a tablet) or filling the final blend composition into capsules (e.g. hard or soft capsules).

[0138] In a further embodiment, the present disclosure provides a process for preparing a pharmaceutical composition comprising mesdopetam monotartrate or hemitartrate salt as described herein, the process comprising:

[0139] (a) weighing and sieving mesdopetam monotartrate or hemitartrate salt as described herein, a diluent, a disintegrant, and a glidant, wherein each of the mesdopetam or pharmaceutically acceptable salt thereof, the diluent, the disintegrant and the glidant are separately sieved through a sieve having a mesh size of about 600 pm;

[0140] (b) blending the mesdopetam monotartrate or hemitartrate salt and about one third of the total amount of diluent to form a first pre-blend composition, wherein blending is performed for about 6 minutes at about 15 rpm, and sieving the first pre-blend composition through a sieve having a mesh size of about 600 pm;

[0141] (c) preparing a second pre-blend composition comprising about one third of the total amount of diluent, wherein preparing the second pre-blend composition comprises blending about one third of the diluent with the glidant, wherein blending is performed for about 5 minutes at about 15 rpm; and sieving the second pre-blend through a sieve having a mesh size of about 600 pm;

[0142] (d) blending the first and second pre-blend compositions with disintegrant and about one third of the total amount of diluent to form a first dry blend composition, wherein preparing the first dry blend composition comprises: i. adding the first pre-blend composition to the second pre-blend composition in a blender tank; ii. adding the disintegrant to the first and second pre-blend compositions in the blender tank; iii. adding about one third of the total amount of diluent to the first and second preblend compositions and disintegrant in the blender tank; and iv. blending the first and second pre-blend compositions, disintegrant, and diluent in the blender tank, wherein blending is performed for about 30 minutes at about 15 rpm; and sieving the first dry blend composition through a sieve having a mesh size of about 600 pm;

[0143] (e) weighing and sieving a lubricant, wherein the lubricant is sieved through a sieve having a mesh size of about 600 pm; and blending the lubricant with the first dry blend composition, optionally together with any additional excipients, flavorings, sweeteners and / or coloring agents, wherein blending is performed for about 6 minutes at about 15 rpm, to form a final blend composition; and

[0144] (f) optionally compressing the final blend composition (e.g. to form a tablet) or filling the final blend composition into capsules (e.g. hard or soft capsules).

[0145] In all embodiments of the processes disclosed herein, the mesdopetam monotartrate or hemitartrate salt, the diluent, the disintegrant, the glidant and the lubricant may be selected in accordance with any of the compositions which are disclosed herein.

[0146] Thus, in a particular embodiment, the present disclosure provides a process for preparing a pharmaceutical composition comprising mesdopetam hemitartrate, the process comprising:

[0147] (a) weighing and sieving mesdopetam hemitartrate (e.g. L-hemitartrate), pregelatinized starch, sodium starch glycolate, and colloidal silicon dioxide, wherein each of the mesdopetam or pharmaceutically acceptable salt thereof, the pregelatinized starch, the sodium starch glycolate and the colloidal silicon dioxide are separately sieved through a sieve having a mesh size of about 600 pm;

[0148] (b) blending the mesdopetam hemi tartrate (e.g. L-hemitartrate) and about one third of the total amount of pregelatinized starch to form a first pre-blend composition, wherein blending is performed for about 6 minutes at about 15 rpm, and sieving the first pre-blend composition through a sieve having a mesh size of about 600 pm;

[0149] (c) preparing a second pre-blend composition comprising about one third of the total amount of pregelatinized starch, wherein preparing the second pre-blend composition comprises blending about one third of the total amount of pregelatinized starch with the colloidal silicon dioxide, wherein blending is performed for about 5 minutes at about 15 rpm; and sieving the second pre-blend through a sieve having a mesh size of about 600 pm;

[0150] (d) blending the first and second pre-blend compositions with the sodium starch glycolate and about one third of the total amount of pregelatinized starch to form a first dry blend composition, wherein preparing the first dry blend composition comprises: i. adding the first pre-blend composition to the second pre-blend composition in a blender tank; ii. adding the sodium starch glycolate to the first and second pre-blend compositions in the blender tank; iii. adding about one third of the total amount of pregelatinized starch to the first and second pre-blend compositions and disintegrant in the blender tank; and iv. blending the first and second pre-blend compositions, sodium starch glycolate, and pregelatinized starch in the blender tank, wherein blending is performed for about 30 minutes at about 15 rpm; and sieving the first dry blend composition through a sieve having a mesh size of about 600 pm;

[0151] (e) weighing and sieving magnesium stearate, wherein the magnesium stearate is sieved through a sieve having a mesh size of about 600 pm; and blending the magnesium stearate with the first dry blend composition, optionally together with any additional excipients, flavorings, sweeteners and / or coloring agents, wherein blending is performed for about 6 minutes at about 15 rpm, to form a final blend composition; and

[0152] (f) optionally compressing the final blend composition (e.g. to form a tablet) or filling the final blend composition into capsules (e.g. hard or soft capsules, such as HPMC capsule shells). In embodiments of the processes disclosed herein, the mesdopetam or pharmaceutically acceptable salt thereof (e.g. the hemitartrate salt, such as the Z-hemitartrate salt) in step (a) may be provided in the form of a hydrate, solvate, and / or polymorph (such as an anhydrous polymorph). In embodiments, the mesdopetam or pharmaceutically acceptable salt thereof (e.g. the hemitartrate salt, such as the Z-hemitartrate salt) in step (a), including any hydrate, solvate, and / or polymorph (such as an anhydrous polymorph) thereof, may be provided in a solid crystal form or in solid amorphous form.

[0153] In particular embodiments, at least a particular percentage by weight of mesdopetam or the pharmaceutically acceptable salt thereof (e.g. the hemitartrate salt, such as the Z-hemitartrate salt) is crystalline. For example, at least a particular percentage by weight of mesdopetam or the pharmaceutically acceptable salt thereof (e.g. the hemitartrate salt, such as the Z-hemitartrate salt) is in a single crystalline form. Suitable percentages of crystallinity and / or single crystalline forms, and properties of such crystalline forms (e.g. determined according to XRP) are discussed in connection with the compositions disclosed herein.

[0154] In embodiments, the mesdopetam or pharmaceutically acceptable salt thereof (e.g. the hemitartrate salt, such as the Z-hemitartrate salt), including any hydrate, solvate, and / or polymorph (such as an anhydrous polymorph) thereof, and including any solid crystal form or solid amorphous form thereof, may be milled prior to step (a), e.g. to attain a desired particle size or particle size distribution. In embodiments milling may take place at a speed of from about 5500 to about 7500 rpm, e.g. from about 6000 to about 7000 rpm. In embodiments milling is performed using a conical mill. In embodiments milling is performed for up to about 15 minutes, e.g. from about 5 to about 10 minutes or from about 5 to about 8 minutes. In embodiments the mill (e.g. the conical mill) has a grid with a mesh size of from about 200 to about 800 pm, about 400 to about 650 pm, or about 450 to about 550 pm, such as about 279 pm, about 457 pm, or about 610 pm. In one embodiment milling is performed using a conical mill at a speed of about 6000 rpm, optionally with a grid having a mesh size of about 457 pm.

[0155] In embodiments, the mesdopetam or pharmaceutically acceptable salt thereof (e.g. the hemitartrate salt, such as the Z-hemitartrate salt) in step (a), including any hydrate, solvate, and / or polymorph (such as an anhydrous polymorph) thereof, and including any solid crystal form or solid amorphous form thereof (e.g. any solid crystal form as defined with respect to the compositions disclosed herein), may have a particle size distribution (e.g. after milling) wherein D90 is <350 pm or <300 pm (e.g. <290 pm, <280 pm, <270 pm or <260 pm) and / or D50 is <150 pm (e.g. <140 pm , <120 pm, 100 pm, or <180 pm). In embodiments, Dio is <15 pm, e.g. <10 pm. In certain embodiments, D90 is <300 pm (e.g. <290 pm, <280 pm, <270 pm or <260 pm), D50 is <150 pm (e.g. <140 pm , <120 pm, <100 pm, or <80 pm), and Dio is <15 pm, e.g. <10 pm. In certain embodiments, D90 is <250 pm (e.g. <240 pm, <230 pm, or <220 pm) and / or D50 is <120 pm (e.g. <100 pm , <80 pm, or <75 pm). In certain embodiments, D90 is <250 pm (e.g. <240 pm, <230 pm, or <220 pm) and D50 is <120 pm (e.g. <100 pm , <80 pm, or <75 pm). In certain embodiments, D90 is <250 pm (e.g. <240 pm, <230 pm, or <220 pm), D50 is <120 pm (e.g. <100 pm , <80 pm, or <75 pm) and Dio is <15 pm, e.g. <10 pm. In embodiments, the particle size distribution may be determined by laser diffraction, e.g. wet laser diffraction (wet dispersion), for example at a concentration of 10 mg / ml in silicon oil. In embodiments, the mesdopetam is provided in the form of solid crystalline mesdopetam hemitartrate (e.g. L- hemitartrate), e.g. having the XRPD characteristics as defined above.

[0156] In another aspect, the present disclosure provides a composition prepared by, or preparable by, the process, or any embodiments thereof, as described herein.

[0157] Methods of treatment

[0158] A further aspect provides a method of treatment comprising administering to a subject in need thereof a therapeutically effective amount of mesdopetam monotartrate or hemitartrate salt, wherein the mesdopetam monotartrate or hemitartrate salt is administered in a pharmaceutical composition as disclosed herein. In a related aspect, the disclosure provides the use of mesdopetam or monotartrate or hemitartrate salt in the manufacture of a medicament, wherein the medicament is a pharmaceutical composition as disclosed herein. In another related aspect, the disclosure provides the use of a pharmaceutical composition as disclosed herein in the manufacture of a medicament. In a further related aspect, the disclosure provides a pharmaceutical composition as disclosed herein for use in therapy.

[0159] As described above, it is believed by the present inventors that solid particulate mesdopetam monotartrate or hemitartrate salt as described herein (e.g. the hemi tartrate salt, such as the L- hemitartrate salt) having a particle size distribution as described above, e.g. solid crystalline mesdopetam hemitartrate (e.g. L-hemitartrate) having such a particle size distribution, and optionally having the XRPD characteristics as defined above, is particularly well suited to the preparation of pharmaceutical compositions. Accordingly, the present disclosure also provides a method of treatment comprising administering to a subject such as a human in need thereof a therapeutically effective amount of mesdopetam monotartrate or hemitartrate salt, wherein the mesdopetam monotartrate or hemitartrate salt is solid particulate mesdopetam monotartrate or hemitartrate salt (e.g. the hemitartrate salt, such as the Z-hemitartrate salt) as disclosed herein. In a related aspect, the disclosure provides the use of mesdopetam monotartrate or hemitartrate salt in the manufacture of a medicament, wherein mesdopetam monotartrate or hemitartrate salt is solid particulate mesdopetam monotartrate or hemitartrate salt (e.g. the hemi tartrate salt, such as the Z-hemitartrate salt) as disclosed herein. In another related aspect, the disclosure provides the use of mesdopetam or monotartrate or hemitartrate salt in the manufacture of a medicament, wherein mesdopetam monotartrate or hemitartrate salt is solid particulate mesdopetam monotartrate or hemitartrate salt (e.g. the hemitartrate salt, such as the Z-hemitartrate salt) as disclosed herein. In a further related aspect, the disclosure provides solid particulate mesdopetam monotartrate or hemitartrate salt (e.g. the hemitartrate salt, such as the Z-hemitartrate salt) as disclosed herein for use in therapy.

[0160] The present disclosure also provides a pharmaceutical composition as described herein or a mesdopetam monotartrate or hemitartrate salt as described herein for use in the treatment and / or prevention of a disease, disorder and / or condition which is selected from psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, dementia, age-related cognitive impairment, Autism spectrum disorders, ADHD, cerebral Palsy, Gilles de la Tourette's syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, Parkinson's disease, parkinsonian syndrome, dyskinesia, L-DOPA induced dyskinesias, Tardive dyskinesias, dystonia, tics and tremor dementia, Huntington's disease, movement disorder induced by drugs, restless legs, narcolepsy, Alzheimer's disease and disorder(s) related to Alzheimer's disease.

[0161] The present disclosure also provides the use of a pharmaceutical composition as described herein or a mesdopetam monotartrate or hemitartrate salt as described herein for the manufacture of a medicament for use in the treatment and / or prevention of a disease, disorder and / or condition which is selected from psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, dementia, age-related cognitive impairment, Autism spectrum disorders, ADHD, cerebral Palsy, Gilles de la Tourette's syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, Parkinson's disease, parkinsonian syndrome, dyskinesia, L-DOPA induced dyskinesias, Tardive dyskinesias, dystonia, tics and tremor dementia, Huntington's disease, movement disorder induced by drugs, restless legs, narcolepsy, Alzheimer's disease and disorder(s) related to Alzheimer's disease.

[0162] The present disclosure also provides a method for treating and / or preventing a disease, disorder and / or condition which is selected from psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, dementia, age-related cognitive impairment, Autism spectrum disorders, ADHD, cerebral Palsy, Gilles de la Tourette's syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, Parkinson's disease, parkinsonian syndrome, dyskinesia, L-DOPA induced dyskinesias, Tardive dyskinesias, dystonia, tics and tremor dementia, Huntington's disease, movement disorder induced by drugs, restless legs, narcolepsy, Alzheimer's disease and disorder(s) 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 as described herein or a mesdopetam monotartrate or hemitartrate salt as described herein.

[0163] In embodiments, the methods of treatment and pharmaceutical compositions disclosed herein are suitable for the treatment and / or prevention of a disease, disorder and / or condition which is selected from psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, dementia, age-related cognitive impairment, Autism spectrum disorders, ADHD, cerebral Palsy, Gilles de la Tourette's syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, Parkinson's disease, parkinsonian syndrome, dyskinesia, L-DOPA induced dyskinesias, Tardive dyskinesias, dystonia, tics and tremor dementia, Huntington's disease, movement disorder induced by drugs, restless legs, narcolepsy, Alzheimer's disease and disorder(s) related to Alzheimer's disease. For instance, the disease, disorder and / or condition may be schizophrenia, L-DOPA induced dyskinesias and / or Huntington's disease.

[0164] In embodiments, the pharmaceutical compositions disclosed herein may be administered to a subject (e.g. a human subject) so as to provide a dosage of mesdopetam corresponding to an amount of the free base from about 2 mg (e.g. about 2.0 mg) to about 10 mg (e.g. about 10.0 mg), such as about 2.5 mg, about 5.0 mg or about 7.5 mg. Administration of such dosage amounts may take place once, twice, or more than twice daily. In certain embodiments, mesdopetam monotartrate or hemitartrate salt is administered in one or more doses in a first amount and then administered in one or more doses in a second amount, wherein said second amount is lower than said first amount, and wherein both the first amount and the second amount are independently administered in pharmaceutical compositions as disclosed herein. Optionally, the first amount corresponds to an amount of about 7.5 up to about 10.0 mg and / or the second amount corresponds to an amount of about 2.5 to about 5.0 mg of the free base. In all embodiments of the treatments and therapies as described herein, mesdopetam monotartrate or hemitartrate salt may if desired be administered twice per day, e.g. in twice daily dosages each corresponding to one of the aforementioned amounts, wherein administration takes place in a composition as described herein. Such dosages may, for example, be given once in the morning and once in the evening. In an embodiment mesdopetam monotartrate or hemitartrate salt may be administered in two equal daily dosages, e.g. two dosages per day each corresponding to about 7.5 mg, such as about 7.5 mg in the morning and about 7.5 mg in the evening; or two dosages per day each corresponding to about 5.0 mg, such as about 5.0 mg in the morning and about 5.0 mg in the evening; or two dosages per day each corresponding to about 2.5 mg such as about 2.5 mg in the morning and 2.5 mg in the evening.

[0165] In all embodiments of the treatments and therapies as described herein, mesdopetam monotartrate or hemitartrate salt thereof may if desired be administered in a total daily dosage of from about 4.0 mg up to about 20.0 mg, e.g. in a total daily dosage of about 5.0 mg to about 15.0 mg, such as about 5.0 mg to about 10.0 mg, wherein administration takes place using a composition as described herein.

[0166] In embodiments, the pharmaceutical compositions disclosed herein may be administered to a subject (e.g. a human subject) who has been diagnosed with Parkinson’s Disease or who has been determined as being at risk of developing Parkinson’s Disease.

[0167] In embodiments, the pharmaceutical compositions disclosed herein may be administered to a subject (e.g. a human subject) who has been identified as being at risk for developing dyskinesias. In embodiments, the subject may have been identified as having one or more of the following risk factors for developing dyskinesias: diagnosis with Parkinson’s Disease below the age of 60 years; cumulative L-DOPA exposure (e.g. according to Levodopa equivalent daily dose (LEDD)); the subject is female; severity of motor and functional impairment (e.g. as assessed by MDS-UPDRS Part III score); non-tremor dominant clinical phenotype; genetic risk score (e.g. polygenic risk score) and anxiety (see, e.g., npj Parkinson’s Disease 33:1-6 (2018), the entire contents of which are incorporated herein by reference).

[0168] In embodiments, the pharmaceutical compositions disclosed herein may be administered to a subject before dyskinesias have occurred. Additionally, or alternatively, the pharmaceutical compositions may be administered without being preceded by administration of a pharmaceutical drug for Parkinson’s disease. Thus, the pharmaceutical compositions may be administered without precedent administration of a pharmaceutical drug for Parkinson’s disease such as L-DOPA or a pharmaceutically acceptable salt thereof. Thus, the pharmaceutical compositions disclosed herein may be administered to a subject who has not experienced dyskinesias, e.g. a subject who has not experienced L-DOPA induced dyskinesias. Such subjects may, for example, be patients (e.g. human patients) who are already undergoing a course of treatment with a pharmaceutical drug for Parkinson’s disease, e.g. with L-DOPA or a pharmaceutically acceptable salt thereof, but who have not yet exhibited dyskinetic symptoms (e.g. LIDs).

[0169] Thus, in certain embodiments, a composition as disclosed herein may be administered to a subject (preferably a human subject) who has been undergoing a course of treatment with a pharmaceutical drug for Parkinson’s disease (e.g. with L-DOPA or a pharmaceutically acceptable salt thereof) for at least 1 day, at least 1 week, at least 1 month or at least 1 year (e.g. at least 4, 5, 6, 7, 8, 9 or 10 years) prior to first being administered with a composition as disclosed herein. In further embodiments, a subject who has not experienced dyskinesias may be a subject who has not previously been administered a pharmaceutical drug for Parkinson’s disease, i.e. a subject (e.g. a human patient) who has not undergone or is not undergoing a course of treatment with a pharmaceutical drug for Parkinson’s disease (e.g. L-DOPA or a pharmaceutically acceptable salt thereof) prior to commencing treatment with the compositions disclosed herein. In an embodiment, such a subject may undergo “pre -treatment” with a composition as disclosed herein prior to commencing a course of treatment with a pharmaceutical drug for Parkinson’s disease, such as L-DOPA or a pharmaceutically acceptable salt thereof. Thus, the compositions disclosed herein may be administered to the subject (e.g. a human subject) at least 1 day, at least 1 week, at least 1 month or at least 1 year prior to the subject being administered with a pharmaceutical drug for the treatment of Parkinson’s disease (e.g. L-DOPA or a pharmaceutically acceptable salt thereof) for the first time. In such embodiments the subject may thus undergo a course of “pretreatment” in which a composition as disclosed herein is repeatedly administered to the subject e.g. on a daily or twice-daily basis for at least 1 day, at least 1 week, at least 1 month or at least 1 year, prior to being administered with a pharmaceutical drug for the treatment of Parkinson’s disease for the first time. In another embodiment, the subject may commence treatment with a pharmaceutical drug for Parkinson’s disease (e.g. L-DOPA or a pharmaceutically acceptable salt thereof) on the same day that they also commence treatment with a composition as disclosed herein. Thus, the subject may be administered with (i) a composition disclosed herein and (ii) the pharmaceutical drug for Parkinson’s disease such that the subject receives their first doses of both the composition as disclosed herein and the pharmaceutical drug for Parkinson’s disease within 24 hours of one another. In such an embodiment the composition as disclosed herein and the pharmaceutical drug for Parkinson’s disease may be administered simultaneously, or the composition as disclosed herein may be administered before the pharmaceutical drug for Parkinson’s disease, or the pharmaceutical drug for Parkinson’s disease may be administered before the composition as disclosed herein.

[0170] In embodiments, the compositions as disclosed herein may be administered together with administration of a drug for the treatment of Parkinson’s Disease (e.g. L-DOPA or a pharmaceutically acceptable salt thereof) or may be administered before or after the administration of such a drug. Thus a composition as disclosed herein may be administered to a subject simultaneously with a pharmaceutical drug for Parkinson’s disease (e.g. L-DOPA or a pharmaceutically acceptable salt thereof). Alternatively a composition as disclosed herein may be administered to a subject before a pharmaceutical drug for Parkinson’s disease (e.g. L-DOPA or a pharmaceutically acceptable salt thereof), or a pharmaceutical drug for Parkinson’s disease (e.g. L-DOPA or a pharmaceutically acceptable salt thereof) may be administered to a subject before a composition as disclosed herein. Where a composition as disclosed herein is administered before the pharmaceutical drug for Parkinson’s disease (e.g. L-DOPA or a pharmaceutically acceptable salt thereof), or vice versa, the administration of the composition as disclosed herein and the administration of the pharmaceutical drug for Parkinson’s disease may take place within a time period of from 1 second to 24 hours, such as from about 1 minute to about 24 hours, such as from about 1 minute to about 12 hours, such as from about 1 minute to about 6 hours, such as from about 1 minute to about 1 hour.

[0171] In embodiments, the pharmaceutical compositions disclosed herein are suitable for use in preventing or reducing sensitization to a drug for Parkinson’s disease, e.g. preventing or reducing sensitization to L-DOPA or a pharmaceutically acceptable salt thereof. In certain embodiments, prevention or reduction of sensitization to a drug for Parkinson’s disease comprises administering mesdopetam or a pharmaceutically acceptable salt thereof to a subject who has not experienced dyskinesias (e.g. L-DOPA induced dyskinesias), wherein mesdopetam monotartrate or hemitartrate salt is administered in a composition as disclosed herein. In certain embodiments, prevention or reduction of sensitization to a pharmaceutical drug for Parkinson’s disease comprises administering mesdopetam monotartrate or hemitartrate salt to a subject who has been undergoing a course of treatment with a pharmaceutical drug for Parkinson’s disease (e.g. L- DOPA or a pharmaceutically acceptable salt thereof) for at least 1 day prior to administration of the compound of mesdopetam monotartrate or hemitartrate salt to the subject for the first time, wherein mesdopetam monotartrate or hemitartrate salt is administered in a composition as disclosed herein. In certain embodiments, prevention or reduction of sensitization to a pharmaceutical drug for Parkinson’s disease comprises administering mesdopetam monotartrate or hemirartrate salt to a subject such as a human who has not previously been administered a pharmaceutical drug for Parkinson’s disease, e.g. a subject who has not previously been administered L-DOPA or a pharmaceutically acceptable salt thereof, wherein mesdopetam monotartrate or hemitartrate salt is administered in a composition as disclosed herein. In certain embodiments, mesdopetam monotartrate or hemitartrate salt is administered in a composition as disclosed herein at least 1 day prior to administration of a pharmaceutical drug for Parkinson’s disease (e.g. L-DOPA or a pharmaceutically acceptable salt thereof) to the subject for the first time.

[0172] *******

[0173] Having been generally disclosed herein, the following non-limiting examples are provided to further illustrate this disclosure.

[0174] EXAMPLES

[0175] Abbreviations

[0176] MDS-UPDRS The International Parkinson and Movement Disorder Society sponsored revision of the Unified Parkinson's Disease Rating Scale pm micrometer(s) micron micrometer(s) mm millimeter(s) rpm revolutions per minute

[0177] XRP X Ray Powder

[0178] XRPD X Ray Powder Diffractogram

[0179] Example 1 A: Milling of the API

[0180] Hammer milling was performed using a Fitzmill LI A Comminuting Mill. Hammer milling of mesdopetam L-hemitartrate with hammer rotation speed of 7000 rpm and collecting screen opening of 800 pm resulted in a particle size distribution as described in Table 1.

[0181] Hammer milling was performed using a Fitzmill L1A Comminuting Mill. Hammer milling of mesdopetam L-hemitartrate with hammer rotation speed of 7000 rpm and collecting screen opening of 800 pm resulted in a particle size distribution as described in Table 1. Conical milling can offer increased throughput / capacity and reduced loss of API as compared with a hammer mill. Although this type of mill can afford lower precision for hard-to-mill APIs, it can be seen from Table 1 that using a conical mill can afford a more uniform API particle size distribution, with particles generally of smaller size than achieved with hammer milling. Smaller particle sizes assist in achieving a homogeneous (uniform) blend with the excipients in a formulation. Without wishing to be bound by theory, it is thought that the smaller particle size facilitates coating of the diluent which acts as a “carrier”, thus improving the uniformity of the blend.

[0182] Selection of an appropriate grid size (also called screen size, mesh size, or sieve size) can affect the capacity of the mill and the particle size of the milled API.

[0183] Particle size distribution was measured by wet dispersion sample laser light diffraction (Mastersizer 2000, Malvern Panalytical) at a concentration of 10 mg / ml in silicon oil.

[0184] An additional parameter to show the width of the size distribution is the span. The span of a size distribution is defined as: Span = (d90 - dl0) / d50, and gives an indication of how far the 10 percent and 90 percent points are apart, normalized with the midpoint. The lower (i.e. closer to 0) the span value, the more uniform and consistent the size of the particles.

[0185]

[0186] Unmilled and milled API were used in the preparation of a blended composition according to the process of Figure 2 and as described in Example 2.

[0187] Blend uniformity was measured by percentage content of API after 15 minutes and 45 minutes of blending, as well as at the filling stage (Step 3). Particle size distribution (RSD%) was also measured. As used herein RSD stands for relative standard deviation such as relative standard deviation of the median particle size. Preferred acceptance values for blend uniformity are: min. no less than 90% of expected value, max. no greater than 110% of expected value, average between 95-105% of expected value, RSD% <5%. Results are shown in Table 2. Bold values are outside the preferred acceptance criteria.

[0188] Table 2

[0189] It can be seen from Table 2 that hammer milling at 7000 rpm with a mesh size of 800 pm produced API particles which resulted in a subsequent blend which did not conform with the preferred acceptance criteria. Conical milling at the same rpm and mesh size brought the parameters within preferred acceptance criteria.

[0190] While the unmilled API results in a subsequent blend which does conform with preferred acceptance criteria, the conical milled API affords an improved (narrower) particle size distribution and uniformity of API content. This is an important advantage for blend uniformity, which is required to ensure capsule content uniformity. This advantage can be of particular importance with low dosages of API, e.g. about 10 mg and below.

[0191] Milling speed was found to be particularly important in achieving a good API particle size distribution and subsequent blend uniformity. All grid sizes employed with the conical mill at 6000 rpm were found to result in acceptable API size distributions and blend uniformity, although smaller grids were found to result in higher losses (poorer yields) of milled API while the use of a 610 pm grid was found to result in a weakly bimodal particle size distribution (Figure 3A). Conical milling at 6000 rpm with a 457 pm grid afforded good conformity with preferred acceptance criteria and also a suitable balance between blendability and loss of API.

[0192] As shown by the data in Table 2, conical milling resulted in acceptable homogeneity of blends within 15 minutes whereas hammer milling would appear to require >45 minutes.

[0193] Without wishing to be bound by theory, it is thought that blending for longer than 15 minutes when employing conical milling may lead to “de-blending”, in which the elements in the blend begin to separate.

[0194] Example IB: Recrystallisation of mesdopetam hemitartrate

[0195] Recrystallized API was found to have the properties shown in Table 3.

[0196] Table 3 Although recrystallized API was found to have a more homogeneous particle size distribution than native or milled API, blends prepared with recrystallized API were less uniform.

[0197] Example 2: Capsule blends

[0198] Capsule blends are prepared containing API and excipients as set out in Tables 4 and 5. Such blends may be prepared according to the processes of the present disclosure, e.g. the methods of Example 3.

[0199] Table 4: Composition of mesdopetam drug product

[0200] [a]: Mesdopetam quantity is corrected regarding presence of tartrate. Conversion factor: molecular mass of mesdopetam free base = 275.34 g / mol. molecular mass of mesdopetam ’A L- tartrate salt: 350.38 g / mol, therefore the correction factor is: 350.38 / 275.34 = 1.2725

[0201] [b]: Pregelatinized Starch amount is adjusted according to mesdopetam purity Table 5: Composition of mesdopetam drug product

[0202] [c]: total fill weight = 75.01 mg using 2 decimal places, due to rounding. In the compositions identified above in Tables 4 and 5, HPMC capsules are employed. However, alternative capsule shells such as hard gelatin shells may also be used. HPMC shells are slower - dissolving than hard gelatin capsule shells. Gelatine shells have a higher water content than HMPC shells (13% to 15% water in hard gelatine capsule shells) which may in some cases lead to faster degradation of their contents.

[0203] Example 3: preparation of compositions

[0204] The process for preparing a blend of mesdopetam (API), e.g. for filling into capsules in accordance with Example 2, is depicted in Figure 2 and described below.

[0205] Step A: Weighing

[0206] Mesdopetam hemitartrate, pregelatinized starch, sodium starch glycolate, and colloidal silicon dioxide are weighed and sieved separately through a 600 pm sieve.

[0207] Step B: Blending

[0208] One third (approximately 33%) of the pregelatinized starch and all of the mesdopetam hemitartrate are transferred directly into a blender tank and blended for 6 minutes at 15 rpm. The resulting blend (pre-blend 1) is then sieved through a 600 pm sieve.

[0209] A further one third (approximately 33%) of the pregelatinized starch and all of the colloidal silicon dioxide are transferred directly into a blender tank and blended for 5 minutes at 15 rpm. The resulting blend (pre-blend 2) is then sieved through a 600 pm sieve.

[0210] The sieved pre-blend 2, the sieved pre-blend 1, the sodium starch glycolate, and the final one third (approximately 33%) of the pregelatinized starch are transferred in that order into a blender tank and blended for 30 minutes at 15 rpm.

[0211] Step C: Lubrication

[0212] Magnesium stearate is weighed and sieved through a 600 pm sieve before being transferred directly into the blender drum and blended for 6 minutes at 15 rpm.

[0213] Step D: Capsule filling

[0214] The final blend composition is filled into capsules using a semi-automatic filling machine. During capsule filling, samples are collected for in-process capsule length control and appearance check. All capsules are de-dusted and 100% weight controlled. Capsules with individual weight outside of the acceptance limits (± 7.5%) are discarded.

[0215] Capsules are checked for absence of metal with appropriate equipment and inspected for final appearance. The bulk capsules are transferred into double clear polyethylene bags with desiccant and sealed with cable ties.

[0216] Step E: Primary packaging

[0217] The bulk capsules are visually inspected for appearance. Accepted capsules are packaged into HDPE bottles (84 capsules per 100 mL bottle), which are secured with a child-resistant polypropylene, tamper-evident screw cap system. The bottles are then checked for appearance.

[0218] Example 4: characteristics of solid particulate mesdopetam hemitartrate

[0219] Figure 4A shows two representative micrographs of crystalline mesdopetam Z-hemitartrate obtained using scanning electron microscopy (SEM). Briefly, mesdopetam L-hemitartrate powder was gold coated using an Agar sputter coater and imaged using a LEO 1430VP Scanning Electron Microscope (SEM). The accelerating voltage was 10 kV at a working distance of 10 mm.

[0220] As shown in Figure 4A, the crystals show a “wheat sheaf’ structure, with columnar like elements which resembles “hand reaped wheat sheaves”. This compacted morphology suggests high hardness of the particles. The particle size ranges from 240 pm to 600 pm.

[0221] Figure 4B shows a representative optical image of the API after size reduction using mortar and pestle. The particle size is noticeable reduced with a size ranges in the order of tens of microns. Some larger particles of approximately 30-40 pm can be observed. The morphology of the milled particles is irregular with a plate like surface which resembles that of pregelatinized starch, e.g. Starch 1500®. This diluent has similar irregular particles with flat surfaces covered in crevices. Pregelatinized starch could thus act as a carrier for the smaller fraction of the API particles, and the API could distribute within the crevices of the starch facilitating uniform distribution and minimising API agglomeration.

[0222] Comparison of the XRP diffractograms of unmilled crystalline mesdopetam Z-hemitartrate with those of crystalline mesdopetam Z-hemitartrate after milling for 15 minutes at 7000 rpm with a Fitzmill LI A Comminuting Mill indicated that the material remained crystalline on milling, with little or no change in XRPD characteristic peaks. Example 5

[0223] In this example, crystalline mesdopetam Z-hemitartrate was milled using a Quadro CoMill with rotation speed of 6000 rpm for 24 minutes which resulted in the following particle size distribution:

[0224] Dio = 7.9 pm

[0225] D50 = 86 pm

[0226] D90 = 305 pm

[0227] The particle size distribution was measured by wet dispersion sample laser light diffraction (Mastersizer 3000, Malvern Instrument Ltd) in 0.1 % (w / w) Span 85 in n-heptane.

[0228] References

[0229] 1. WO 2012 / 143337

[0230] 2. J. Pharmacol. Exp. Ther. 374:113-125, July 2020

[0231] 3. WO 2020 / 239568

[0232] 4. WO 2022 / 101227

[0233] 5. Remington’s Pharmaceutical Sciences, 20th ed., Mack Publishing Co. 2000

[0234] 6. Berge et al., J Pharm Sci. (1977) 66: 1-19

[0235] 7. Handbook of Pharmaceutical Excipients, 5thedition, Pharmaceutical Press (London / Chicago), 2006, edited by R.C. Rowe, P. J. Sheskey and S.C. Owen

[0236] 8. npj Parkinson’s Disease 33:1-6 (2018)

Claims

CLAIMS1. A pharmaceutical composition comprising a solid particulate crystalline hemitartrate salt of mesdopetam, said hemitartrate salt of mesdopetam being a combination of mesdopetam and tartaric acid in a molar ratio of 1 : 0.5 :0.5 mesdopetam tartaric acid said hemitartrate salt having a particle size distribution wherein D90 is <350 pm and / or D50 is <150 pm, a diluent, a disintegrant, a lubricant, and optionally a glidant.

2. The pharmaceutical composition according to claim 1, wherein D90 is < 300 pm, <290 pm, <280 pm, <270 pm or <260 pm and / or D50 is <140 pm , <120 pm, 100 pm, or <80 pm.

3. The pharmaceutical composition according to claim 1 or 2, wherein D90 is <300 pm.

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 1-4, 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 mesdopetam is characterized by an XRP diffractogram comprising a peak at 13.0 20, and optionally at least one, at least two, at least three, or four further peak(s) selected from the following: 12.4 20, 14.4 20, 21.1 20, 24.4 20.

8. The pharmaceutical composition according to any one of the preceding claims, wherein the solid particulate crystalline hemitartrate salt of mesdopetam is characterized by an XRP diffractogram comprising peaks at 12.4 20, 13.0 2 0 , 14.4 20, 21.1 20, 24.4 20 and optionally at least one further peak selected from the following: 19.62 20, 21.44 20.

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

12. The pharmaceutical composition according to any of the preceding claims, wherein the composition comprises:(i) solid particulate crystalline mesdopetam hemitartrate salt in an amount of 3 to 5 wt%, diluent in an amount of 90 to 93 wt%, disintegrant in an amount of 3 wt%,lubricant in an amount of 0.5 wt%, and glidant in an amount of 1 wt%, all on a dry solids basis;(ii) solid particulate crystalline mesdopetam hemitartrate salt in an amount of 7 to 9 wt%, diluent in an amount of 86 to 89 wt%, disintegrant in an amount of 3 wt%, lubricant in an amount of 0.5 wt%, and glidant in an amount of 1 wt%, all on a dry solids basis;(iii) solid particulate crystalline mesdopetam hemitartrate salt in an amount of 11 to 13 wt%, diluent in an amount of 82 to 85 wt%, disintegrant in an amount of 3 wt%, lubricant in an amount of 0.5 wt%, and glidant in an amount of 1 wt%, all on a dry solids basis; or(iv) solid particulate crystalline mesdopetam hemitartrate salt in an amount of 5 to17.5 wt%, diluent in an amount of 78 to 80 wt%, disintegrant in an amount of 3 wt%, lubricant in an amount of 0.5 wt%, and glidant in an amount of 1 wt%, all on a dry solids basis.

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

14. The pharmaceutical composition according to any of the preceding claims , wherein: the diluent comprises cellulose, carboxymethylcellulose, alginate, starch, dextrates, dextrin, maltodextrin, one or more sugars, one or more sugar alcohols, a 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 hydroxypropyl cellulose, 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 thereof15. The pharmaceutical composition according to any one of the preceding of 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 according to any of the preceding claims, wherein the solid particulate crystalline mesdopetam hemitartrate salt is provided in an amount corresponding to from about 2 to about 10 mg of mesdopetam free base.

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

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

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

20. A solid particulate crystalline hemitartrate salt of mesdopetam characterized by a particle size distribution wherein D90 is <350 pm or <300 pm and / or D50 is <150 pm.

21. The solid particulate crystalline hemitartrate salt of mesdopetam according to claim 20, wherein wherein D90 is < 300 pm, <290 pm, <280 pm, <270 pm or <260 pm and / or D50 is <140 pm, <120 pm, 100 pm, or <80 pm.

22. The solid particulate crystalline hemitartrate salt of mesdopetam according to claim 20 or 21 wherein D90 is < 300 pm,.

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

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

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

26. The solid particulate crystalline hemitartrate salt of mesdopetam according to any one of claims 20-25 characterized by an XRP diffractogram comprising a peak at 13.0 20, and optionally at least one, at least two, at least three, or four further peak(s) selected from the following: 12.4 20, 14.4 20, 21.1 20, 24.4 20.

27. The solid particulate crystalline hemitartrate salt of mesdopetam according to any one of claims 20-26 characterized by characterized by an XRP diffractogram comprising peaks at 12.4 20, 13.0 2 0 , 14.4 20, 21.1 20, 24.4 20 and optionally at least one further peak selected from the following: 19.62 20, 21.4420.

28. The solid particulate crystalline hemitartrate salt of mesdopetam according to any one of claims 20-27 characterized by an XRP diffractogram corresponding to Figure 1.

29. A process for preparing a pharmaceutical composition according to any one of claims 1-19, the process comprising:a) weighing and sieving solid particulate crystalline mesdopetam hemitartrate salt as defined in any one of claims 1-28, a diluent, a disintegrant, and optionally a glidant; b) blending the solid particulate crystalline mesdopetam hemitartrate salt and 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 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 additional excipients, flavorings, sweeteners and / or coloring agents, to form a final blend composition; and f) optionally compressing the final blend composition or filling the final blend composition into capsules.

30. The process according to claim 29, wherein the process comprises: a) weighing and sieving solid particulate crystalline mesdopetam as defined in any one of claims 1-28 , a diluent, a disintegrant, and a glidant; b) blending the solid particulate crystalline mesdopetam hemitartrate salt and about one third of the total amount of diluent to form a first pre-blend composition, and sieving the first pre-blend composition; c) preparing a second pre-blend composition comprising about one third of the total amount of diluent, wherein preparing the second pre-blend composition comprises blending about one third of the diluent with the glidant; and sieving the second pre-blend composition; d) blending the first and second pre-blend compositions with disintegrant and about one third of the total amount of diluent to form a first dry blend composition, wherein preparing the first dry blend composition comprises: i. adding the first pre-blend composition to the second pre-blend composition in a blender tank;ii. adding the disintegrant to the first and second pre-blend compositions in the blender tank; iii. adding about one third of the total amount of diluent to the first and second pre-blend compositions and disintegrant in the blender tank; and iv. blending the first and second pre-blend compositions, disintegrant, and diluent in the blender tank; and 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 additional excipients, flavorings, sweeteners and / or coloring agents, 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 capsules such as hard or soft capsules.

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

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

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

34. The process according to any of claims 29 to 33, wherein the solid crystalline mesdopetam hemitartrate salt thereof is milled prior to step (a).

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

36. A pharmaceutical composition according to any one of claims 1-19 or 35 for use in treating and / or preventing a disease, disorder and / or condition which is selected from psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive- compulsive disease, dementia, age-related cognitive impairment, Autism spectrum disorders, ADHD, cerebral Palsy, Gilles de la Tourette's syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, Parkinson's disease, parkinsonian syndrome, dyskinesia, L-DOPA induced dyskinesias, Tardive dyskinesias, dystonia, tics and tremor dementia, Huntington's disease, movement disorder induced by drugs, restless legs, narcolepsy, Alzheimer's disease and disorder(s) 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 dyskinesias 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 dosage from 2 mg to 10 mg such as 2.5 mg, 5.0 mg or 7.5 mg, optionally wherein said composition is administered once, twice, or more than twice daily.

39. A method for treating and / or preventing a disease, disorder and / or condition which is selected from psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, dementia, age-related cognitive impairment, Autism spectrum disorders, ADHD, cerebral Palsy, Gilles de la Tourette's syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, Parkinson's disease, parkinsonian syndrome, dyskinesia, L-DOPA induced dyskinesias, Tardive dyskinesias, dystonia, tics and tremor dementia, Huntington's disease, movement disorder induced by drugs, restless legs, narcolepsy, Alzheimer's disease and disorder(s) related to Alzheimer's disease, wherein the method comprises administering to a subject such as a human in need thereofa therapeutically effective amount of a pharmaceutical composition according to any of claims 1-19 or 35.

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

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

42. Use of a pharmaceutical composition according to any one of claims 1-19 or 35 for the manufacture of medicament for the treatment of a disease, disorder and / or condition which is selected from psychosis, schizophrenia, schizophreniform disorder, bipolar disorder, psychotic disorder, drug induced psychotic disorder, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, dementia, age-related cognitive impairment, Autism spectrum disorders, ADHD, cerebral Palsy, Gilles de la Tourette's syndrome, brain injury, sleep disorder, sexual disorder, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, Parkinson's disease, parkinsonian syndrome, dyskinesia, L-DOPA induced dyskinesias, Tardive dyskinesias, dystonia, tics and tremor dementia, Huntington's disease, movement disorder induced by drugs, restless legs, narcolepsy, Alzheimer's disease and disorder(s) related to Alzheimer's disease.

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

44. The use according to claim 42 or 43, wherein the pharmaceutical composition is administered in a dosage from 2 mg to 10 mg such as 2.5 mg, 5.0 mg or 7.5 mg, optionally wherein said composition is administered once, twice, or more than twice daily.

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