WO2025032103A1 - Compositions pharmaceutiques comprenant un sel de tartrate de n-[2-(3-fluoro-5-méthane-sulfonylphénoxy)éthyl](propyl)amine - Google Patents

Compositions pharmaceutiques comprenant un sel de tartrate de n-[2-(3-fluoro-5-méthane-sulfonylphénoxy)éthyl](propyl)amine Download PDF

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Publication number
WO2025032103A1
WO2025032103A1 PCT/EP2024/072281 EP2024072281W WO2025032103A1 WO 2025032103 A1 WO2025032103 A1 WO 2025032103A1 EP 2024072281 W EP2024072281 W EP 2024072281W WO 2025032103 A1 WO2025032103 A1 WO 2025032103A1
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Prior art keywords
mesdopetam
disorder
amount
disease
diluent
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English (en)
Inventor
Thibaut DUPONT
Clas Sonesson
Anne PETIT
Laurent Bertocchi
Marie Delporte
Didier Kubiak
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Irl 790 AB
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Irl 790 AB
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Priority to CN202480051310.8A priority Critical patent/CN121620362A/zh
Publication of WO2025032103A1 publication Critical patent/WO2025032103A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes

Definitions

  • 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.
  • Parkinson’s disease 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.
  • LID L-DOPA-induced dyskinesia
  • 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:
  • 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.
  • AIMs adverse involuntary movements
  • 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.
  • mesdopetam e.g. formulations which provide the desired dosages for therapeutic use.
  • formulations which provide the desired dosages for therapeutic use.
  • forms to have an economical and reliable manufacturing process for compliance with acceptance and regulatory parameters.
  • 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.
  • the present disclosure provides a pharmaceutical composition comprising mesdopetam monotartrate or hemitartrate salt, a diluent, a disintegrant, a lubricant, and optionally a glidant.
  • 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).
  • the present disclosure provides a process for preparing a pharmaceutical composition comprising mesdopetam monotartrate or hemitartrate salt, the process comprising:
  • 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;
  • the present disclosure provides a pharmaceutical composition prepared by, or preparable by, the process, or any embodiments thereof, as described herein.
  • 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.
  • 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.
  • the disclosure provides the use of a pharmaceutical composition as disclosed herein in the manufacture of a medicament.
  • the disclosure provides a pharmaceutical composition as disclosed herein for use in therapy.
  • 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
  • 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'
  • 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
  • FIG. 1 shows an XRP diffractogram of mesdopetam L-hemitartrate.
  • XRPD data were collected on a Bruker D8 Advance (2005) instrument.
  • Radiation: Copper K a , 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.
  • FIG. 2 depicts an example of the process described herein.
  • IPN60170 represents mesdopetam Z-hemi tartrate.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the mammal is a human.
  • 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.
  • 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.
  • 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.
  • 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.
  • dosage-effect relationships from in vitro and/or in vivo tests initially can provide useful guidance on the proper doses for patient administration.
  • 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.
  • an amount of an active compound for administration 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.
  • 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”).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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,
  • the pharmaceutically acceptable salt may be tartaric acid.
  • the salt is a crystalline solid (e.g., a salt crystal).
  • 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.
  • 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.
  • isotopes that can be incorporated into compounds (including salts) presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • one or more of the hydrogen atoms of mesdopetam may be replaced with deuterium.
  • the present disclosure provides a pharmaceutical composition
  • 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.
  • Suitable diluents include carbohydrates (e.g. saccharides and polysaccharides), pharmaceutically acceptable synthetic polymers, inorganic diluents, and mixtures thereof.
  • 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.
  • cellulose e.g. microcrystalline cellulose (such as si
  • Suitable pharmaceutically acceptable synthetic polymers include povidone (such as crospovidone) and vinylpyrrolidone-vinyl acetate copolymers (such as Kollidon® VA64).
  • 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.
  • calcium phosphate e.g. calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate (calcium phosphate dihydrate), or calcium phosphate tribasic
  • calcium sulfate 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 sodium chloride
  • the diluent may comprise, consist essentially of, or consist of, a carbohydrate or mixture of carbohydrates, e.g. as disclosed above.
  • 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.
  • the diluent may comprise, consist essentially of, or consist of, an inorganic diluent or mixture of inorganic diluents, e.g. as disclosed above.
  • 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.
  • 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.
  • 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.
  • 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.
  • cellulose e.g. microcrystalline cellulose (such as silicified microcrystalline cellulose), powdered cellulose, or cellulose acetate), carboxymethylcellulose (e.g. carboxy methylcellulose calcium), dextrates, dextrin, dextrose,
  • 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
  • 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 sodium chloride
  • 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
  • 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
  • the diluent comprises, consists essentially of, or consists of, pregelatinized starch.
  • 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
  • the disintegrant comprises, consists essentially of, or consists of, sodium starch glycolate.
  • 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.
  • the lubricant comprises, consists essentially of, or consists of, magnesium stearate.
  • 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.
  • the glidant comprises, consists essentially of, or consists of, colloidal silicon dioxide.
  • Some components may, in principle, function as two or more of diluent, disintegrant, lubricant and/or glidant.
  • 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.
  • the function performed by the respective component(s) may typically be influenced by the amount of the respective component(s) which is/are present.
  • 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.
  • appropriate amounts e.g. concentration ranges, such as % (e.g. wt%) amounts
  • % e.g. wt%) amounts
  • 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.
  • 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.
  • formulations disclosed herein can be selected appropriately by one of skill in the art to achieve the intended function.
  • 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.
  • the diluent comprises pregelatinized starch
  • the disintegrant comprises sodium starch glycolate
  • the glidant comprises colloidal silicon dioxide
  • the lubricant comprises magnesium stearate.
  • the diluent consists essentially of pregelatinized starch
  • the disintegrant consists essentially of sodium starch glycolate
  • the glidant consists essentially of colloidal silicon dioxide
  • the lubricant consists essentially of magnesium stearate.
  • the diluent consists of pregelatinized starch
  • the disintegrant consists of sodium starch glycolate
  • the glidant consists of colloidal silicon dioxide
  • the lubricant consists of magnesium stearate.
  • 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.
  • 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%.
  • 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%.
  • 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%.
  • 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%.
  • 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%.
  • 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.
  • 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.
  • the diluent is pregelatinized starch
  • the disintegrant is sodium starch glycolate
  • the glidant is colloidal silicon dioxide
  • the lubricant is magnesium stearate.
  • 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.
  • the diluent is pregelatinized starch
  • the disintegrant is sodium starch glycolate
  • the glidant is colloidal silicon dioxide
  • the lubricant is magnesium stearate.
  • 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.
  • the diluent is pregelatinized starch
  • the disintegrant is sodium starch glycolate
  • the glidant is colloidal silicon dioxide
  • the lubricant is magnesium stearate.
  • 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.
  • 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
  • the diluent is pregelatinized starch
  • the disintegrant is sodium starch glycolate
  • the glidant is colloidal silicon dioxide
  • the lubricant is magnesium stearate.
  • 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.
  • the diluent is pregelatinized starch
  • the disintegrant is sodium starch glycolate
  • the glidant is colloidal silicon dioxide
  • the lubricant is magnesium stearate.
  • 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.
  • the diluent is pregelatinized starch
  • the disintegrant is sodium starch glycolate
  • the glidant is colloidal silicon dioxide
  • the lubricant is magnesium stearate.
  • the total wt% of components cannot exceed 100%.
  • 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%.
  • 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).
  • 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%.
  • 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.
  • coloring agents may be included within the capsule shell, within the capsule fill, or both.
  • 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.
  • 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).
  • 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).
  • 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).
  • 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).
  • Mesdopetam can form a pharmaceutically acceptable salt together with a pharmaceutically acceptable acid such as tartaric acid.
  • pharmaceutically acceptable acids include those identified in the “Definitions” section above.
  • 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).
  • 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
  • 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).
  • 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 s
  • 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:
  • 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:
  • 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.
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • stereoisomer 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.
  • 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.
  • mesdopetam is provided in the form of a tartrate salt (e.g. a 1:1 tartrate salt or a hemitartrate salt).
  • mesdopetam is provided as an L-tartrate salt, such as the mono-L-tartrate salt or as the L-hemitartrate salt (% L-tartrate salt).
  • 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).
  • 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
  • the 1:1 tartrate salt or the 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.
  • 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.
  • the compositions disclosed herein may comprise mesdopetam hemitartrate in amounts of 3.18, 6.36, 9.54 or 12.72 mg.
  • 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.
  • 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).
  • 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.
  • compositions described herein may be formulated for immediate release.
  • compositions described herein may be formulated for oral administration.
  • 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.
  • a capsule e.g. a capsule for oral administration
  • hard capsules include soft gelatin capsules or modified starch capsules.
  • Hard capsules include hard gelatin capsules or HPMC (hydroxypropylmethylcellulose) capsules.
  • 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.
  • compositions of the present disclosure are typically provided as powders (either fine or coarse) and packaged into sterile containers, such as bags or drums.
  • 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.
  • the composition is encapsulated, e.g. in an HPMC capsule.
  • the mesdopetam or pharmaceutically acceptable salt thereof e.g. the hemitartrate salt, such as the Z-hemitartrate salt
  • the mesdopetam or pharmaceutically acceptable salt thereof may be provided in the form of a hydrate, solvate, and/or polymorph (such as an anhydrous polymorph).
  • 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.
  • mesdopetam or the pharmaceutically acceptable salt thereof 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
  • the 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.
  • at least a particular percentage by weight of mesdopetam or the pharmaceutically acceptable salt thereof 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%.
  • mesdopetam or the pharmaceutically acceptable salt thereof e.g. the hemitartrate salt, such as the Z-hemitartrate salt
  • 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
  • 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
  • the crystalline mesdopetam or the pharmaceutically acceptable salt thereof e.g. the hemitartrate salt, such as the Z-hemitartrate salt
  • 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.
  • mesdopetam is provided in the form of solid crystalline mesdopetam hemitartrate (e.g. L-hemitartrate).
  • crystalline mesdopetam hemitartrate e.g. L-hemitartrate
  • the solid crystalline form of mesdopetam 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.
  • 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.
  • the solid crystalline form of mesdopetam hemitartrate e.g.
  • L-hemitartrate may be characterized by an XRP diffractogram corresponding to Figure 1.
  • peak angles 20 are given to an accuracy of ⁇ 0.02° 20.
  • the mesdopetam or pharmaceutically acceptable salt thereof e.g. the hemitartrate salt, such as the Z-hemitartrate salt
  • the mesdopetam or pharmaceutically acceptable salt thereof 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).
  • Dio is ⁇ 15 pm, e.g. ⁇ 10 pm.
  • D90 is ⁇ 300 pm (e.g. ⁇ 290 pm, ⁇ 280 pm, ⁇ 270 pm or ⁇ 260 pm)
  • D50 is ⁇ 150 pm (e.g.
  • 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).
  • 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).
  • 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).
  • D90 is ⁇ 250 pm (e.g.
  • 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.
  • 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).
  • Dio is ⁇ 15 pm, e.g. ⁇ 10 pm.
  • D90 is ⁇ 300 pm (e.g.
  • D50 is ⁇ 150 pm (e.g. ⁇ 140 pm , ⁇ 120 pm, ⁇ 100 pm, or ⁇ 80 pm), and Dio is ⁇ 15 pm, e.g. ⁇ 10 pm.
  • 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).
  • D90 is ⁇ 250 pm (e.g. ⁇ 240 pm, ⁇ 230 pm, or ⁇ 220 pm) and D50 is ⁇ 120 pm (e.g.
  • 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.
  • 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.
  • 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.
  • D90 may refer to the particle size below which 90% of all particles are found.
  • 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.
  • D value may be indicated with a majuscule or minuscule letter so that “D” and “d” are used interchangeably.
  • 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.
  • 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.
  • a uniform such as a homogenous distribution of the aforementioned salts (i.e. the API) in a composition such as a pharmaceutical composition.
  • 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.
  • 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.
  • 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;
  • 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;
  • the blending in steps (b), (c) and/or (d) is performed in a blender tank.
  • 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.
  • 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).
  • the first pre-blend composition is sieved through a sieve having a mesh size of about 600 pm after blending in step (b).
  • 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.
  • the blending in step (c) is performed for a time of about 5 minutes.
  • the blending in step (c) is performed at a speed of about 10 rpm to about 20 rpm, e.g. about 15 rpm.
  • the blending in step (c) is performed at about 15 rpm for about 5 minutes.
  • the second pre-blend composition is sieved after blending in step (c).
  • the second pre-blend composition is sieved through a sieve having a mesh size of about 600 pm after blending in step (c).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • sieving in step (e) comprises sieving the lubricant through a sieve having a mesh size of about 600 pm.
  • the present disclosure provides a process for preparing a pharmaceutical composition comprising mesdopetam monotartrate or hemitartrate salt as descried herein, the process comprising:
  • the present disclosure provides a process for preparing a pharmaceutical composition comprising mesdopetam monotartrate or hemitartrate salt as described herein, the process comprising:
  • 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;
  • the present disclosure provides a process for preparing a pharmaceutical composition comprising mesdopetam monotartrate or hemitartrate salt as described herein, the process comprising:
  • 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;
  • 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.
  • 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.
  • the present disclosure provides a process for preparing a pharmaceutical composition comprising mesdopetam hemitartrate, the process comprising:
  • mesdopetam hemitartrate e.g. L-hemitartrate
  • pregelatinized starch sodium starch glycolate
  • 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;
  • 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;
  • 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.
  • the mesdopetam or pharmaceutically acceptable salt thereof e.g. the hemitartrate salt, such as the Z-hemitartrate salt
  • the mesdopetam or pharmaceutically acceptable salt thereof may be provided in the form of a hydrate, solvate, and/or polymorph (such as an anhydrous polymorph).
  • 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.
  • At least a particular percentage by weight of mesdopetam or the pharmaceutically acceptable salt thereof is crystalline.
  • at least a particular percentage by weight of mesdopetam or the pharmaceutically acceptable salt thereof 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.
  • the mesdopetam or pharmaceutically acceptable salt thereof may be milled prior to step (a), e.g. to attain a desired particle size or particle size distribution.
  • milling may take place at a speed of from about 5500 to about 7500 rpm, e.g. from about 6000 to about 7000 rpm.
  • milling is performed using a conical mill. In embodiments milling is performed for up to about 15 minutes, e.g.
  • the mill e.g. the conical mill
  • 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.
  • the mesdopetam or pharmaceutically acceptable salt thereof e.g. the hemitartrate salt, such as the Z-hemitartrate salt
  • the hemitartrate salt such as the Z-hemitartrate salt
  • the polymorph such as an anhydrous polymorph
  • any solid crystal form or solid amorphous form thereof e.g. any solid crystal form as defined with respect to the compositions disclosed herein
  • Dio is ⁇ 15 pm, e.g. ⁇ 10 pm.
  • 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)
  • Dio is ⁇ 15 pm, e.g. ⁇ 10 pm.
  • D90 is ⁇ 250 pm (e.g. ⁇ 240 pm, ⁇ 230 pm, or ⁇ 220 pm) and/or D50 is ⁇ 120 pm (e.g.
  • 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).
  • 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)
  • Dio is ⁇ 15 pm, e.g. ⁇ 10 pm.
  • the particle size distribution may be determined by laser diffraction, e.g.
  • 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.
  • the present disclosure provides a composition prepared by, or preparable by, the process, or any embodiments thereof, as described herein.
  • 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.
  • 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.
  • the disclosure provides the use of a pharmaceutical composition as disclosed herein in the manufacture of a medicament.
  • the disclosure provides a pharmaceutical composition as disclosed herein for use in therapy.
  • solid particulate mesdopetam monotartrate or hemitartrate salt as described herein e.g. the hemi tartrate salt, such as the L- hemitartrate salt
  • solid crystalline mesdopetam hemitartrate e.g. L-hemitartrate
  • XRPD characteristics as defined above
  • 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.
  • a subject such as a human in need thereof a therapeutically effective amount of mesdopetam monotartrate or hemitartrate salt
  • 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.
  • 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.
  • mesdopetam or monotartrate or hemitartrate salt is solid particulate mesdopetam monotartrate or hemitartrate salt (e.g.
  • 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.
  • solid particulate mesdopetam monotartrate or hemitartrate salt e.g. the hemitartrate salt, such as the Z-hemitartrate salt
  • 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
  • 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'
  • 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
  • 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.
  • the disease, disorder and/or condition may be schizophrenia, L-DOPA
  • 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.
  • a subject e.g. a human subject
  • 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.
  • 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.
  • 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.
  • mesdopetam monotartrate or hemitartrate salt may if desired be administered twice per day, e.g.
  • 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.
  • 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.
  • 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.
  • a subject e.g. a human subject
  • 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.
  • 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).
  • a subject e.g. a human subject
  • 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
  • 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).
  • a pharmaceutical drug for Parkinson’s disease e.g. with L-DOPA or a pharmaceutically acceptable salt thereof, but who have not yet
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a pharmaceutical drug for Parkinson’s disease e.g. L-DOPA or a pharmaceutically acceptable salt thereof
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a pharmaceutical drug for Parkinson’s disease e.g. L- DOPA or a pharmaceutically acceptable salt thereof
  • 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.
  • 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.
  • Selection of an appropriate grid size can affect the capacity of the mill and the particle size of the milled API.
  • 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.
  • 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.
  • 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.
  • 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.
  • Example IB Recrystallisation of mesdopetam hemitartrate
  • Recrystallized API was found to have the properties shown in Table 3.
  • 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.
  • HPMC capsules are employed.
  • 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.
  • Step A Weighing
  • 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.
  • 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.
  • 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.
  • 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.
  • Step D Capsule filling
  • 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.
  • 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.
  • Step E Primary packaging
  • 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.
  • Example 4 characteristics of solid particulate mesdopetam hemitartrate
  • FIG 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.
  • 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.
  • 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.
  • 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:
  • 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.

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Abstract

L'invention concerne des compositions pharmaceutiques comprenant un sel de tartrate de Mesdopetam, ainsi que des procédés de fabrication desdites compositions pharmaceutiques. Les compositions pharmaceutiques sont utiles dans le traitement de maladies telles que des dyskinésies induites par L-DOPA.
PCT/EP2024/072281 2023-08-07 2024-08-06 Compositions pharmaceutiques comprenant un sel de tartrate de n-[2-(3-fluoro-5-méthane-sulfonylphénoxy)éthyl](propyl)amine Pending WO2025032103A1 (fr)

Priority Applications (1)

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CN202480051310.8A CN121620362A (zh) 2023-08-07 2024-08-06 包含n-[2-(3-氟-5-甲磺酰基苯氧基)乙基](丙基)胺的酒石酸盐的药物组合物

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GB2312055.3 2023-08-07
GBGB2312055.3A GB202312055D0 (en) 2023-08-07 2023-08-07 Pharmaceutical compositions

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