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WO2025196662A1 - Compositions et méthodes de traitement de troubles alimentaires - Google Patents

Compositions et méthodes de traitement de troubles alimentaires

Info

Publication number
WO2025196662A1
WO2025196662A1 PCT/IB2025/052881 IB2025052881W WO2025196662A1 WO 2025196662 A1 WO2025196662 A1 WO 2025196662A1 IB 2025052881 W IB2025052881 W IB 2025052881W WO 2025196662 A1 WO2025196662 A1 WO 2025196662A1
Authority
WO
WIPO (PCT)
Prior art keywords
mmc
composition
pharmaceutically acceptable
acceptable salt
use according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2025/052881
Other languages
English (en)
Inventor
Adi Zuloff-Shani
Ezekiel Golan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Clearmind Labs Corp
Original Assignee
Clearmind Labs Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Clearmind Labs Corp filed Critical Clearmind Labs Corp
Publication of WO2025196662A1 publication Critical patent/WO2025196662A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • Eating disorders are among the top ten leading causes of disability among young women and have one of the highest mortality rates compared to other mental disorders (Mathers et al., The Medical Journal of Australia, 172(12):592-6 (2000); Millar et al., Am J Psychiatry.162(4):753-7 (2005)). [4] Eating disorders are typically characterized by irregular eating habits and extreme anxiety or apprehension about weight or body type. Other symptoms may include insufficient or excessive food intake and purging, which may ultimately impair an individual’s physical and/or mental health.
  • eating disorders examples include anorexia nervosa, bulimia nervosa, pica, rumination disorders, avoidant/restrictive eating disorders, and binge eating disorders. Eating disorders may severely impact adequate nutrition in an individual, and thus can result in serious harm to one’s body. In fact, eating disorders can cause significant harm to the heart, digestive system, kidneys, bone health, teeth, and mouth, and can lead to other serious conditions such as anemia, electrolyte imbalance, low blood pressure, and in some cases, death (Millar et al., Am J Psychiatry.162(4):753-7 (2005)). [5] Treatment for eating disorders often involves a combination of psychological therapy (psychotherapy), nutrition education, and medical monitoring.
  • Patent Publication 20110207718 discloses therapeutic Attorney Docket No.: 15691.0017-00304 use of a cathinone, 4-methyl-methcathinone (“4-MMC”) as a psychostimulant to treat epilepsy, bipolar disorder, or attention deficit hyperactivity disorder.
  • Another cathinone is 3- methylmethcathinone “(3-MMC”) with the chemical name 2-(methylamino)-1-(3-methylphenyl)-1- propanone, and the general formula C 11 H 15 NO.
  • 3-methylmethcathinone interacts at the receptor level and noradrenaline within the central nervous system.
  • N-acylethanolamines are lipid-derived signaling molecules. They are formed when one of several types of acyl groups is linked to the nitrogen atom of ethanolamine.
  • N-acylethanolamines examples include anandamide (the amide of arachidonic acid (20:4 omega-6) and ethanolamine), N-Palmitoylethanolamine (the amide of palmitic acid (16:0) and ethanolamine), N-Oleoylethanolamine (the amide of oleic acid (18:1) and ethanolamine), N- Stearoylethanolamine (the amide of stearic acid (18:0) and ethanolamine) and N- Docosahexaenoylethanolamine (the amide of docosahexaenoic acid (22:6) and ethanolamine).
  • anandamide the amide of arachidonic acid (20:4 omega-6) and ethanolamine
  • N-Palmitoylethanolamine the amide of palmitic acid (16:0) and ethanolamine
  • N-Oleoylethanolamine the amide of oleic acid (18:1 and ethanolamine
  • N- Stearoylethanolamine the amide of stearic acid
  • Palmitoylethanolamide (PEA, also known as N-(2-hydroxyethyl) hexadecanamide; Hydroxyethylpalmitamide; palmidrol; N-palmitoylethanolamine; and palmitylethanolamide) is an endogenous fatty acid amide, belonging to the class of nuclear factor agonists.
  • the chemical structure of PEA is: .
  • PEA has been demonstrated to bind to a receptor in the cell exerts a variety of biological functions related to chronic pain and inflammation. Studies have shown that PEA interacts with distinct non-CB1/CB2 receptors, suggesting that PEA utilizes a unique “parallel” endocannabinoid signaling system.
  • the present disclosure provides for using safe and effective specific dosages and dose ranges of 3-MMC or salts thereof to prevent and/or treat eating disorders or one or more symptoms of eating disorders, either alone or in conjunction with one or more additional therapeutic agent such as PEA or a salt thereof. Accordingly, the disclosure also encompasses using safe and effective combinations with N- acylethanolamines, or pharmaceutically acceptable salts thereof, for example, palmitoylethanolamide (“PEA”), to prevent and/or treat eating disorders or one or more symptoms of eating disorders.
  • PDA palmitoylethanolamide
  • the present disclosure provides pharmaceutical compositions comprising 3- MMC, or pharmaceutically acceptable salts thereof, and their use in preventing and/or treating eating disorders, or for reducing one or more symptoms of eating disorders.
  • the disclosure further provides pharmaceutical compositions comprising 3-MMC, or pharmaceutically acceptable salts thereof, or combinations of 3-MMC, or pharmaceutically acceptable salts thereof and N-acylethanolamines, or pharmaceutically acceptable salts thereof, for example, palmitoylethanolamide (“PEA”) for use in the same treatments.
  • PDA palmitoylethanolamide
  • the present disclosure relates, in part, to compositions and methods for potentiating therapeutic effects and/or reducing side-effects of 3-MMC or pharmaceutically acceptable salts thereof.
  • the present disclosure provides pharmaceutical compositions comprising 3-MMC, or pharmaceutically acceptable salts thereof, or combinations of 3-MMC, or pharmaceutically acceptable salts thereof, for example, PEA and methods for their use in a variety of indications amenable to treatment, including, but not limited to treating eating disorders.
  • the present disclosure encompasses pharmaceutical compositions comprising combinations of 3-MMC, or salts thereof, and N-acylethanolamines, or salts thereof for use in a method for preventing and/or treating eating disorders, or for reducing one or more symptoms of eating disorders.
  • the N-acylethanolamine or salt thereof is PEA or a salt thereof.
  • these compositions comprise therapeutically effective dosages and may be employed in a variety of methods.
  • the present disclosure provides methods for preventing and/or treating psychological disorders. Particularly, the present disclosure provides methods for treating eating disorders.
  • the present disclosure provides, in one aspect, a composition comprising a therapeutically effective amount of 3-MMC and at least one pharmaceutically acceptable carrier, for use in preventing eating disorders in a subject in need, or for treating, preventing and/or reducing one or more symptoms of eating disorders.
  • the present disclosure provides, in one aspect, a composition comprising a therapeutically effective amount of 3-MMC or a salt thereof, a therapeutically effective amount of PEA, or a salt thereof, and at least one pharmaceutically acceptable carrier, for use in treating an eating disorder in a subject in need, or for treating and/or reducing one or more symptoms of an eating disorder.
  • a nasal spray formulation comprising a therapeutically effective amount of 3-MMC or a salt thereof and at least one pharmaceutically acceptable carrier for use in treating an eating disorder in a subject in need thereof.
  • the nasal spray formulation may be self-delivered by the patient.
  • the spray further comprises an N-acylethanolamine such as PEA, or a salt thereof.
  • the present disclosure provides, in one aspect, a composition comprising 3- MMC, or salts thereof, and N-acylethanolamines, or salts thereof for use in preventing an eating disorder in a subject in need, or for preventing and/or reducing one or more symptoms of an eating disorder.
  • a composition comprising combinations of 3-MMC, or salts thereof, and N-acylethanolamines, or salts thereof, for use in treating an eating disorder in a subject in need, or for treating and/or reducing one or more symptoms of an eating disorder.
  • the present disclosure provides, in one aspect, a method of treating or improving at least one symptom associated with psychological disorders, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 3-MMC, or a pharmaceutically acceptable salt thereof.
  • a method of treating or improving at least one symptom associated with a psychological disorder comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 3-MMC, or a pharmaceutically acceptable salt thereof, and an N-acylethanolamine, or a pharmaceutically acceptable salt thereof.
  • compositions comprising 3-MMC, or pharmaceutically acceptable salts thereof, e.g., for preventing and/or treating a psychological disorder, or for reducing one or more symptoms of a psychological disorder, such as an eating disorder.
  • the formulations and compositions disclosed herein may comprise 3-MMC or any pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt is a hydrochloride salt.
  • the salt is 2-(methylamino)-1-(3- methylphenyl)-1-propanone, monohydrochloride.
  • the salt is a hydrobromide, sulphate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, or gluconate salt.
  • pharmaceutical compositions of the present disclosure comprising 3-MMC or a salt thereof is formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, intravenous, topical, and/or aerosol administration.
  • the present disclosure provides the composition in the form of a nasal spray comprising a therapeutically effective amount of 3-MMC and at least one pharmaceutically acceptable carrier for use in treating a psychological disorder, e.g., an eating disorder, in a subject in need thereof.
  • the nasal spray may be self-delivered by the patient.
  • the present disclosure provides an oral composition comprising a therapeutically effective amount of 3-MMC and at least one pharmaceutically acceptable carrier for use in treating a psychological disorder, e.g., an eating disorder, in a subject in need thereof.
  • the present disclosure provides an intravenous composition comprising a therapeutically effective amount of 3-MMC and at least one pharmaceutically acceptable carrier for use in treating a psychological disorder, e.g., an eating disorder, in a subject in need thereof.
  • the present disclosure provides a topical composition comprising a therapeutically effective amount of 3-MMC and at least one pharmaceutically acceptable carrier for use in treating a psychological disorder, e.g., an eating disorder, in a subject in need thereof.
  • a psychological disorder e.g., an eating disorder
  • 3-MMC or a pharmaceutically acceptable salt thereof is present in a composition (e.g., one that is administered to a subject) in an amount of about 0.1 mg to about 150 mg.
  • 3-MMC or a pharmaceutically acceptable salt thereof is present in a composition in an amount of about 0.1 mg to about 270 mg.
  • the 3-MMC or the pharmaceutically acceptable salt thereof is administered to said subject in an amount (a dose) of about 0.5 mg, 1.0 mg, 1.5 mg, 2.5 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, Attorney Docket No.: 15691.0017-00304 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, or 270 mg.
  • a dose of about 0.5
  • the dose is 50 mg. In some embodiments, the dose range about 10 mg to about 20 mg, or about 1.0 mg to about 90 mg. In some embodiments, the dose ranges from about 60 mg to 260 mg. [27] In some embodiments, 3-MMC or a pharmaceutically acceptable salt thereof is present in a composition in an amount of about 10 mg to about 270 mg.
  • the amount ranges from about 20 mg to about 270 mg, about 25 mg to about 270 mg, about 30 mg to about 270 mg, about 35 mg to about 270 mg, about 40 mg to about 270 mg, about 45 mg to about 270 mg, about 50 mg to about 270 mg, about 55 mg to about 270 mg, about 60 mg to about 270 mg, about 65 mg to about 270 mg, about 70 mg to about 270 mg, about 75 mg to about 270 mg, about 80 mg to about 270 mg, about 85 mg to about 270 mg, about 90 mg to about 270 mg, about 95 mg to about 270 mg, about 100 mg to about 270 mg, about 105 mg to about 270 mg, about 110 mg to about 270 mg, about 115 mg to about 270 mg, about 120 mg to about 270 mg, about 125 mg to about 270 mg, about 130 mg to about 270 mg, about 135 mg to about 270 mg, about 140 mg to about 270 mg, about 145 mg to about 270 mg, about 150 mg to about 20 mg to about
  • 3-MMC or a pharmaceutically acceptable salt thereof is present in a composition in an amount of about 10 mg to about 260 mg, about 10 mg to about 255 mg, about 10 mg to about 250 mg, about 10 mg to about 245 mg, about 10 mg to about 240 mg, about 10 mg to about 235 mg, about 10 mg to about 230 mg, about 10 mg to about 225 mg, about 10 mg to about 220 mg, about 10 mg to about 215 mg, about 10 mg to about 210 mg, about 10 mg to about 200 mg, about 10 mg to about 195 mg, about 10 mg to about 190 mg, about 10 mg to about 185 mg, about 10 mg to about 180 mg, about 10 mg to about 175 mg, about 10 mg to about 170 mg, about 10 mg to about 165 mg, about 10 mg to about 160 mg, about 10 mg to about 155 mg, about 10 mg to about 150 mg, about 10 mg to about 145 mg, about 10 mg to about 140 mg, about 10 mg to about 135 mg, about 10 mg to about 130 mg
  • the pharmaceutical composition is a solid form composition. In some embodiments, the pharmaceutical composition is a gel. In still other embodiments, the pharmaceutical composition is a liquid form composition. [30] In additional embodiments, the pharmaceutical composition is packaged as a single unit dose or as a plurality of single unit doses. In some embodiments, the unit dose is in a composition formulated for nasal or oral administration. In certain embodiments, the dosage unit is formulated as a gel, a powder or a spray. In certain embodiments, the dosage unit is formulated as a liquid. In certain embodiments, the dosage unit is formulated as a gel. In certain embodiments, the dosage unit is formulated as a powder. In certain embodiments, the dosage unit is formulated as a spray.
  • the pharmaceutical composition is present in a unit dosage form ranging from 20 mg to 1000 mg of 3-MMC or pharmaceutically acceptable salt thereof. In some embodiments, the amount of 3-MMC, or pharmaceutically acceptable salt thereof, in the unit dosage form ranges from about 20 mg to about 300 mg. In certain embodiments, the pharmaceutical composition comprises a unit dose of about 20 to about 1000 mg 3MMC or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises a unit dose of about 20 mg 3-MMC or a pharmaceutically acceptable salt thereof. In some embodiments, the 3MMC or pharmaceutically acceptable salt thereof is in a unit dosage form of 50 mg.
  • the pharmaceutical composition comprises a unit dose of about 25 mg, about 35 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg 3-MMC or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises a concentration of 3-MMC or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 0.2 mg/kg to about 10 mg/kg body weight.
  • the pharmaceutical composition comprises a concentration of 3-MMC or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 0.2 to about 0.5 Attorney Docket No.: 15691.0017-00304 mg/kg, about 0.5 to about 1.0 mg/kg, about 1.0 to about 1.5 mg/kg, about 1.5 to about 2.0 mg/kg, about 2.0 mg/kg to about 2.5 mg/kg, about 2.5 mg/kg to about 3.0 mg/kg, about 3.5 mg/kg to about 4.0 mg/kg, about 4.0 mg/kg to about 4.5 mg/kg, about 4.5 mg/kg to about 5.0 mg/kg, about 5.0 mg/kg to about 5.5 mg/kg body weight, about 5.5 mg/kg to about 6.0 mg/kg, about 6.5 mg/kg to about 7.0 mg/kg, about 7.0 mg
  • the pharmaceutical composition comprises a concentration of 3-MMC or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 0.2 mg/kg, about 0.5 mg/kg, about 1.0 mg/kg, about 1.5 mg/kg, about 2.0 mg/kg, about 2.5 mg/kg, about 3.0 mg/kg, about 3.5 mg/kg, about 4.0 mg/kg, about 4.5 mg/kg, or about 5.0 mg/kg bodyweight.
  • the pharmaceutical composition comprises a concentration of 3-MMC or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 0.5 mg/kg, less than about 0.5 mg/kg, less than about 1.0 mg/kg, less than about 1.5 mg/kg, less than about 2.0 mg/kg, less than about 2.5 mg/kg, less than about 3.0 mg/kg, less than about 3.5 mg/kg, less than about 4.0 mg/kg, less than about 4.5 mg/kg, less than about 5.0 mg/kg, less than about 5.5 mg/kg, less than about 6.0 mg/kg, less than about 6.5 mg/kg, less than about 7.0 mg/kg, less than about 7.5 mg/kg, less than about 8.0 mg/kg, less than about 8.5 mg/kg, less than about 9.0 mg/kg, less than about 9.5 mg/kg, or about 10.0 mg/kg bodyweight.
  • the pharmaceutical composition comprises a concentration of 3-MMC or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 0.2 mg/kg to about 0.5 mg/kg, about 0.2 mg/kg to about 1.0 mg/kg, about 0.2 mg/kg to about 1.5 mg/kg, about 0.2 mg to about 2.0 mg/kg, about 0.2 mg/kg to about 2.5 mg/kg, about 0.2 mg/kg to about 3.0 mg/kg, about 0.2 mg/kg to about 3.5 mg/kg, about 0.2 mg/kg to about 4.0 mg/kg, about 0.2 mg/kg to about 4.5 mg/kg, about 0.2 mg/kg to about 5.0 mg/kg, about 0.2 mg/kg to about 5.5 mg/kg, about 0.2 mg/kg to about 6.0 mg/kg, about 0.2 mg/kg to about 6.5 mg/kg, about 0.2 mg/kg to about 7.0 mg/kg, about 0.2 mg/kg to about 7.5 mg/kg, about
  • the pharmaceutical composition comprises a concentration of 3-MMC or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 0.2 mg/kg to 0.5 mg/kg, 0.2 mg/kg to 1.0 mg/kg, 0.2 mg/kg to 1.5 mg/kg, 0.2 mg/kg to 2.0 mg/kg, 0.2 mg/kg to 2.5 mg/kg, 0.2 mg/kg to 3.0 mg/kg, 0.2 mg/kg to 3.5 mg/kg, 0.2 mg/kg to 4.0 mg/kg, 0.2 mg/kg to 4.5 mg/kg, 0.2 mg/kg to 5.0 mg/kg, 0.2 mg/kg Attorney Docket No.: 15691.0017-00304 to 5.5 mg/kg, 0.2 mg/kg to 6.0 mg/kg, 0.2 mg/kg to 6.5 mg/kg, 0.2 mg/kg to 7.0 mg/kg, 0.2 mg/kg to 7.5 mg/kg, 0.2 mg/kg to 8.0 mg/kg, 0.2
  • the composition is suitable for administration orally. In some embodiments, the composition is suitable for administration in a nasal spray. In some embodiments, the pharmaceutical composition comprising 3-MMC or a pharmaceutically acceptable salt thereof is a solid or liquid form composition. In some embodiments, the pharmaceutical composition comprising 3-MMC or a pharmaceutically acceptable salt thereof is a nasal spray composition. [36] In some embodiments, 3-MMC or a pharmaceutically acceptable salt thereof forms a part of a composition which further comprises a pharmaceutically acceptable carrier. Any pharmaceutically suitable carrier may be used. In some embodiments, the composition comprises the 3-MMC dissolved in saline.
  • the saline comprises a 0.9 wt % aqueous sodium chloride solution.
  • the 3-MMC dissolved in a pharmaceutically acceptable carrier, e.g., saline is in a concentration of 5 x 10 5 nM to 20 x 10 5 nM. In some embodiments, the 3-MMC is in a concentration of 7.22 x 10 5 nM to 19.26 x 10 5 nM. In some embodiments, the 3-MMC is in a concentration of 14.43 x 10 5 nM.
  • a nasal spray is provided, which is capable of providing sprayed droplets with a size distribution measured by D10, D50, and D90 volume diameter percentiles, wherein D(x) represents that x% of particles in the size distribution are smaller than a specific particle size.
  • the D values may be expressed as 10%, 50% and 90% of the cumulative volume in a sample respectively.
  • the size distribution of the spray droplets may also be measured by a SPAN number, which is reported as (D90 ⁇ D10)/D50).
  • the nasal spray is capable of providing sprayed droplets with a size distribution having a D10 ranging from about 0.5 ⁇ m to about 6 ⁇ m.
  • the nasal spray may provide sprayed droplets with a size distribution having a D10 of 0.6 ⁇ m, a D50 of 2.3 ⁇ m, a D90 of 5.2 ⁇ m, a SPAN of not more than 2.0, and a % Volume of ⁇ 5.2 ⁇ m of less than 25 V%, said formulation having a viscosity of 1.1 cps.
  • the droplets are produced by a nasal spray device capable of providing a droplet having a size distribution D50 between 30-70 ⁇ m, and a D90 ⁇ 200 ⁇ m.
  • the droplet size distribution has a D90 >10 ⁇ m in diameter during administration.
  • the droplet size distribution has a D10 from about 5 ⁇ m to about 40 ⁇ m during administration. In some embodiments, the droplet size distribution has a D50 from about 20 ⁇ m to 80 ⁇ m during administration. In some embodiments, the droplet size distribution has a D90 from about 50 ⁇ m to 700 ⁇ m during administration.
  • the nasal spray device has a spray plume that has an ovality ratio from about 1.0 Attorney Docket No.: 15691.0017-00304 to 2.5, wherein the ovality ratio is defined as the ratio of D max (i.e., the longest diameter that passes through the center of gravity (COG) of the spray pattern and extends to the perimeter of the true shape of the spray pattern) to D min (i.e., the shortest diameter that passes through the COG and extends to the perimeter of the true shape of the spray pattern.)
  • the nasal spray device has a spray plume width from about 25 to about 70 mm during administration, wherein the spray plume width is measured as the width of the plume at a given distance (e.g., 3cm) from the spray nozzle, and a spray plume angle from about 15 to about 70 degrees during administration, wherein the spray plume angle is measured as the angle of the emitted plume measured from the vertex of the spray cone and spray nozzle.
  • the device may comprise a reservoir and means for expelling the pharmaceutical dose in the form of a spray, wherein a quantity of the pharmaceutical composition is contained within the reservoir.
  • the device comprises a pump spray device in which the means for expelling a single or multiple doses comprises a metering pump, or a sterile single dose disposable device.
  • the dose to be delivered is metered by the spray pump, which is preferably finger or hand-actuated.
  • the device is programmed to dispense one or more pharmaceutical doses.
  • the nasal spray may be designed for discharge of multiple spray doses, e.g., 1 to 10 or more.
  • the spray device may improve penetration of the active into the body without creating undue discomfort.
  • the dimension(s) of the emission hole(s) at the tip of the device spout are such that the liquid emitted comes out in a diffuse spray of small droplets.
  • larger or concentrated droplets may contain enough active to induce an unwanted burning sensation in the inner nose which may lead to an interruption of the treatment.
  • the nasal spray dosing of 3-MMC may range from about 0.01 mg/mL to about 100 mg/mL. In some embodiments, the nasal spray dosing of 3-MMC ranges from 0.01 mg/mL to 50 mg/mL. In some embodiments, the nasal spray dosing of 3-MMC ranges from 0.01 mg/mL to 27.0 mg/mL. In some embodiments, the nasal spray dosing of 3- MMC ranges from 2.0 mg/mL to 100 mg/mL. In some embodiments, the nasal spray dosing of 3-MMC ranges from 2.0 mg/mL to 50 mg/mL. In some embodiments, the nasal spray dosing of 3-MMC ranges from 2.0 mg/mL to 27.0 mg/mL.
  • the nasal spray dosing of 3-MMC ranges from 20 mg/mL to 300 mg/mL. In some embodiments, the nasal spray dosing of 3-MMC may range from 2.0 mg/mL to 30 mg/mL. In some embodiments, the nasal spray 3- MMC dosing may range from 3 to 10 doses per day. In some embodiments, the nasal spray 3- MMC may be administered after an initial oral dose of 3-MMC at an earlier point in time during the day. Attorney Docket No.: 15691.0017-00304 [41] In some embodiments, the pharmaceutical compositions discussed above may further comprise one or more additional active agent such as an N-acylethanolamine, or salts thereof.
  • additional active agent such as an N-acylethanolamine, or salts thereof.
  • the 3-MMC or a salt thereof and at least one N- acylethanolamine or a salt thereof are packaged in separate units, e.g., vials, within a kit. In some embodiments, the 3-MMC or a salt thereof and at least one N-acylethanolamine or a salt thereof are in a single vial (e.g., in a single formulation).
  • the N-acylethanolamine is selected from the group consisting of N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), salts thereof and any combination thereof.
  • PDA N-palmitoylethanolamine
  • Me-PEA Me-palmitoylethanolamide
  • OEA palmitoylisopropylamide
  • PIA palmitoylisopropylamide
  • salts thereof oleoylethanolamine
  • the N-acylethanolamine is PEA or a salt thereof.
  • the N-acylethanolamine consists of PEA or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of the N- acylethanolamine is a hydrochloride salt.
  • the salt is 2- (methylamino)-1-(3-methylphenyl)-1-propanone, monohydrochloride.
  • the salt is a hydrobromide, sulphate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate or gluconate salt.
  • a pharmaceutical composition comprising 3-MMC comprises about 200-1800 mg of an N-acylethanolamine (e.g., PEA) or a salt thereof.
  • the pharmaceutical composition comprises about 250-1550 mg, about 300-1200 mg, about 350-950 mg, about 400-700 mg, about 450-600 mg or about 500-550 mg N- acylethanolamine or a salt thereof. In some embodiments, the pharmaceutical composition comprises about 600-1200 mg N-acylethanolamine or a salt thereof. Each possibility represents a separate embodiment of the present disclosure.
  • the pharmaceutical composition comprises at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, at least about 400, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about 850 mg, at least about 900 mg, at least about 950 mg, at least about 1000 mg, at least about 1050 mg, at least about 1100 mg, at least about 1150 mg, at least about 1200 mg, at least about 1250 mg, at least about 1300 mg, at least about 1350 mg, at least about 1400 mg, at least about 1450 mg, at least about 1500 mg, at least about 1550 mg, at least about 1600 mg, at least about 1650 mg, at least about 1700 mg, at least about 1750 mg or at least about 1800 mg N-acylethanolamine or a salt thereof.
  • the pharmaceutical composition comprises about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 Attorney Docket No.: 15691.0017-00304 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg or about 1800 mg N-acylethanolamine or a salt thereof.
  • the pharmaceutical composition comprises about 800 mg N-acylethanolamine or a salt thereof. Each possibility represents a separate embodiment of the present disclosure.
  • the N-acylethanolamine, or pharmaceutically acceptable salt thereof is administered at a dose ranging from about 2.5 mg/kg to 36.0 mg/kg body weight N- acylethanolamine.
  • a nasal spray dosing of N-acylethanolamine may range from 20 mg/mL to 180 mg/mL.
  • the nasal spray 3-N-acylethanolamine dosing may range from 3 to 10 doses per day.
  • the nasal spray N- acylethanolamine dosing may be administered after an initial oral dose of N-acylethanolamine at an earlier point in time during the day.
  • the N-acylethanolamine is PEA or a salt thereof.
  • a pharmaceutical composition disclosed herein comprises a therapeutically-effective amount of 3-MMC or a salt thereof and at least one N- acylethanolamine or a salt thereof, wherein the molar ratio between the 3-MMC and the N- acylethanolamine is between about 1:0.02 and about 1:10000.
  • the N-acylethanolamine is PEA or a salt thereof.
  • the molar ratio between the 3-MMC and the N- acylethanolamine is between about 1:0.2 and about 1:9000. In certain embodiments, the molar ratio between the 3-MMC and the N-acylethanolamine is between about 1:0.2 and about 1:8000, about 1: 0.2 and about 1:7000, about 1: 0.2 and about 1:6000, about 1: 0.2 and about 1:5000, about 1: 0.2 and about 1:4000, about 1: 0.2 and about 1:3000, about 1: 0.2 and about 1:2000, about 1: 0.2 and about 1:1000, about 1:0.2 and about 1:900, about 1: 0.2 and about 1:800, about 1:0.2 and about 1:700, about 1:0.2 and about 1:600, about 1:0.2 and about 1:500, about 1:0.2 and about 1:400, about 1:0.2 and about 1:300, about 1:0.2 and about 1:200, about 1:0.2 and about 1:150, about 1:0.2 and about 1:120, about 1:0.2 and
  • the molar ratio between the 3-MMC and the N- acylethanolamine is between about 1:0.5 and about 1:10000. In certain embodiments, the molar ratio between the 3-MMC and the N-acylethanolamine is between about 1:0.5 and about 1:9000, about 1:0.5 and about 1:8000, about 1: 0.5 and about 1:7000, about 1: 0.5 and about 1:6000, about 1: 0.5 and about 1:5000, about 1: 0.5 and about 1:4000, about 1: 0.5 and about Attorney Docket No.: 15691.0017-00304 1:3000, about 1: 0.5 and about 1:2000, about 1: 0.5 and about 1:1000, about 1:0.5 and about 1:900, about 1: 0.5 and about 1:800, about 1:0.5 and about 1:700, about 1:0.5 and about 1:600, about 1:0.5 and about 1:500, about 1:0.5 and about 1:400, about 1:0.5 and about 1
  • the molar ratio between the 3-MMC and the N- acylethanolamine is between about 1:1 and about 1:10000. In certain embodiments, the molar ratio between the 3-MMC and the N-acylethanolamine is between about 1:1 and about 1:9000, about 1:1 and about 1:8000, about 1:1 and about 1:7000, about 1:1 and about 1:6000, about 1:1 and about 1:5000, about 1:1 and about 1:4000, about 1:1 and about 1:3000, about 1:1 and about 1:2000, about 1:1 and about 1:1000, about 1:1 and about 1:900, about 1:1 and about 1:800, about 1:1 and about 1:700, about 1:1 and about 1:600, about 1:1 and about 1:500, about 1:1 and about 1:400, about 1:1 and about 1:300, about 1:1 and about 1:200, about 1:1 and about 1:150, about 1:1 and about 1:120, about 1:1 and about 1:100, about 1:1 and about 1:90, about 1:1 and about 1:80, about 1:1 and about 1:70, about
  • the molar ratio between the 3-MMC and the N- acylethanolamine is between about 1:5 and about 1:10000. In certain embodiments, the molar ratio between the 3-MMC and the N-acylethanolamine is between about 1:5 and about 1:9000, about 1:5 and about 1:8000, about 1:5 and about 1:7000, about 1:5 and about 1:6000, about 1:5 and about 1:5000, about 1:5 and about 1:4000, about 1:5 and about 1:3000, about 1:5 and about 1:2000, about 1:5 and about 1:1000, about 1:5 and about 1:900, about 1:5 and about 1:800, about 1:5 and about 1:700, about 1:5 and about 1:600, about 1:5 and about 1:500, about 1:5 and about 1:400, about 1:5 and about 1:300, about 1:5 and about 1:200, about 1:5 and about 1:150, about
  • the molar ratio between the 3-MMC and the N- acylethanolamine is between about 1:10 and about 1:10000. In certain embodiments, the molar ratio between the 3-MMC and the N-acylethanolamine is between about 1:10 and about 1:9000, about 1:10 and about 1:8000, about 1:10 and about 1:7000, about 1:10 and about 1:6000, Attorney Docket No.: 15691.0017-00304 about 1:10 and about 1:5000, about 1:10 and about 1:4000, about 1:10 and about 1:3000, about 1:10 and about 1:2000, about 1:10 and about 1:1000, about 1:10 and about 1:900, about 1:10 and about 1:800, about 1:10 and about 1:700, about 1:10 and about 1:600, about 1:10 and about 1:500, about 1:10 and about 1:400, about 1:10 and about 1:300, about 1:10 and about 1:200, about 1:10 and about 1:150, about 1:10 and about
  • the molar ratio between the 3-MMC, or a pharmaceutically acceptable salt thereof, and the N-acylethanolamine, or a pharmaceutically acceptable salt thereof is between about 1:1 and about 1:5.
  • the molar ratio between the 3-MMC and the N-acylethanolamine is between about 1:7 and about 1:10, about 1:10 and about 1:20, between about 1:15 and about 1:30, between about 1:20 and about 1:40, between about 1:25 and about 1:50, between about 1:30 and about 1:60, between about 1:40 and about 1:75, between about 1:50 and about 1:80, between about 1:60 and about 1:100, between about 1:50 and about 1:100, between about 1:50 and about 1:110, or between about 1:50 and about 1:120.
  • the N-acylethanolamine is PEA or a salt thereof.
  • the molar ratio between the 3-MMC, or a pharmaceutically acceptable salt thereof, and the N-acylethanolamine, or a pharmaceutically acceptable salt thereof is between about 1:1 and about 1:120.
  • the molar ratio between the 3-MMC and the N-acylethanolamine is between about 1:7 and about 1:120, 1:7 and about 1:110, about 1:7 and about 1:100, about 1:7 and about 1:90, about 1:7 and about 1:80, about 1:7 and about 1:70, about 1:7 and about 1:60, about 1:7 and about 1:50, about 1:7 and about 1:40, about 1:7 and about 1:30, about 1:7 and about 1:20, about 1:5 and about 1:20, about 1:1 and about 1:20, or about 1:1 and about 1:10.
  • the molar ratio between the 3-MMC and the N-acylethanolamine is between about 1:25 and about 1:120. In certain embodiments, the molar ratio between the 3-MMC and the N-acylethanolamine is between about 1:25 and about 1:150, about 1:25 and about 1:140, about 1:25 and about 1:130, about 1:25 and about 1:120, about 1:25 and about 1:110, about 1:25 and about 1:100, about 1:25 and about 1:90, about 1:25 and about 1:80, about 1:25 and about 1:70, about 1:25 and about 1:60, about 1:25 and about 1:50, about 1:25 and about 1:40, or about 1:25 and about 1:30.
  • the molar ratio between the 3-MMC and the N-acylethanolamine is between 1:50 and about 1:150, about 1:50 and about 1:140, about 1:50 and about 1:130, about 1:50 and about 1:120, about 1:50 and about 1:110, about 1:50 and about 1:100, about 1:50 and about Attorney Docket No.: 15691.0017-00304 1:90, about 1:50 and about 1:80, about 1:50 and about 1:70, or about 1:50 and about 1:60.
  • the molar ratio between the 3-MMC and the N-acylethanolamine is between about 1:75 and about 1:150, about 1:75 and about 1:140, about 1:75 and about 1:130, about 1:75 and about 1:120, about 1:75 and about 1:110, about 1:75 and about 1:100, about 1:75 and about 1:90, or about 1:75 and about 1:80.
  • the molar ratio between the 3-MMC and the N-acylethanolamine is between about 1:100 and about 1:150, about 1:100 and about 1:140, about 1:100 and about 1:130, about 1:100 and about 1:120, or about 1:100 and about 1:110.
  • the molar ratio between the 3-MMC and the N-acylethanolamine is between about 1:110 and about 1:150, about 1:110 and about 1:140, about 1:110 and about 1:130, or about 1:110 and about 1:120. In certain embodiments, the molar ratio between the 3-MMC and the N-acylethanolamine is between about 1:90 and about 1:150, about 1:90 and about 1:140, about 1:90 and about 1:130, about 1:90 and about 1:120, about 1:90 and about 1:110, or about 1:90 and about 1:100.
  • the molar ratio between the 3-MMC and the N-acylethanolamine is between about 1:80 and about 1:150, about 1:80 and about 1:140, about 1:80 and about 1:130, about 1:80 and about 1:120, about 1:80 and about 1:110, about 1:80 and about 1:100, or about 1:80 and about 1:90.
  • the molar ratio between the 3-MMC and the N-acylethanolamine is between about 1:40 and about 1:150, about 1:40 and about 1:140, about 1:40 and about 1:130, about 1:40 and about 1:120, about 1:40 and about 1:110, about 1:40 and about 1:100, about 1:40 and about 1:90, about 1:40 and about 1:80, about 1:40 and about 1:70, about 1:40 and about 1:60, or about 1:40 and about 1:50.
  • the N-acylethanolamine is PEA or a salt thereof.
  • the N-acylethanolamine increases the therapeutic potency of the 3-MMC compared to the same pharmaceutical composition without the N-acylethanolamine. In certain embodiments, the N-acylethanolamine decreases the required therapeutic dosage of the 3-MMC compared to the same pharmaceutical composition without the N-acylethanolamine. In certain embodiments, the N- acylethanolamine expands the therapeutic window of the 3-MMC compared to the same pharmaceutical composition without the N-acylethanolamine.
  • Formulations [56] In various embodiments, formulations suitable for oral administration are provided.
  • Such formulations may be presented in discrete units, such as capsules, cachets, lozenges, vials, syringes, or tablets, each containing a predetermined amount of a compound of the present disclosure as a solid such as powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association at least one compound of the present disclosure as the active Attorney Docket No.: 15691.0017-00304 compound and a carrier or excipient (which may constitute one or more accessory ingredients).
  • the carrier may be a solid or a liquid, or both, and may be formulated with at least one compound described herein as the active compound in a unit-dose formulation, for example, a tablet, which may contain from about 0.05% to about 95% by weight of the at least one active compound.
  • Other pharmacologically active substances may also be present including other compounds.
  • the formulations of the present disclosure may be prepared by any known techniques of pharmacy for admixing the components. [57] In some embodiments, the composition is in the form of a powder, tablet, capsule, lozenge, liquid, concentrate, syrup, hydrogel, aerosol, spray, micelle, nasal spray, or liposome.
  • conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Liquid pharmacologically administrable compositions can be prepared by, for example, dissolving or dispersing, at least one active compound of the present disclosure and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
  • formulations may be prepared by uniformly admixing the at least one active compound of the present disclosure with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • a tablet may be prepared by compressing or molding a powder or granules of at least one compound of the present disclosure, which may be optionally combined with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, at least one compound of the present disclosure in a free-flowing form, such as a powder or granules, which may be optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s).
  • Molded tablets may be made by molding, in a suitable machine, where the powdered form of at least one compound of the present disclosure is moistened with an inert liquid diluent.
  • Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.
  • Such carriers and procedures include those described in the following references: Powell, M.F. et al, "Compendium of Excipients for Parenteral Formulations", PDA Journal of Pharmaceutical Science ft Technology 52(5), 238-311 (1998); Strickley, R.G “Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1" PDA Journal of Pharmaceutical Science & Technology 53(6), 324- 349 (1999); and Nema, S.
  • formulations suitable for aerosol administration comprising the pharmaceutical composition disclosed herein include, for example, aqueous and non-aqueous, isotonic sterile solutions, which can contain anti-oxidants, buffers, bacteriostats, and/or solutes, as well as Attorney Docket No.: 15691.0017-00304 aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and/or preservatives, alone or in combination with other suitable components, which can be made into aerosol formulations to be administered via inhalation.
  • aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
  • a nasal preparation comprising any of the compositions described in the preceding embodiments can take a variety of forms for administration in nasal drops, nasal spray, gel, ointment, cream, powder or suspension, using a dispenser or other device as needed.
  • dispensers and delivery vehicles are known in the art, including single- dose ampoules, atomizers, nebulizers, pumps, nasal pads, nasal sponges, nasal capsules, and the like.
  • the preparation can take a solid, semi-solid, or liquid form.
  • a liquid preparation may be administered as a nasal spray or as nasal drops, using devices known in the art, including nebulizers capable of delivering selected volumes of formulations as liquid-droplet aerosols.
  • nebulizers capable of delivering selected volumes of formulations as liquid-droplet aerosols.
  • a commercially available spray pump with a delivery volume of 50 or 100 ⁇ L is available from, for example, Valois (Congers, N.Y.) with spray tips in adult size and pediatric size.
  • the composition comprised of 3- MMC via an aerosol spray in a daily volume of between about 10 mL to 100 mL.
  • the liquid preparation can be produced by known procedures.
  • an aqueous preparation for nasal administration can be produced by dissolving, suspending, or emulsifying the polypeptide and the steroid compounds in water, buffer, or other aqueous medium, or in an oleaginous base, such as a pharmaceutically-acceptable oil like olive oil, lanoline, silicone oil, glycerin, fatty acids, and the like. It will be appreciated that excipients necessary for formulation, stability, and/or bioavailability can be included in the preparation.
  • excipients include sugars (glucose, sorbitol, mannitol, sucrose), uptake enhancers (chitosan), thickening agents and stability enhancers (celluloses, polyvinyl pyrrolidone, starch, etc.), buffers, preservatives, and/or acids and bases to adjust the pH.
  • the pharmaceutical composition is formulated for systemic administration.
  • the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration.
  • the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. Each possibility represents a separate embodiment of the present disclosure.
  • the pharmaceutical composition is formulated for oral administration.
  • the pharmaceutical composition is formulated for oral mucosal administration.
  • the pharmaceutical composition is formulated for nasal administration.
  • the pharmaceutical composition is formulated for sublingual administration.
  • the formulation comprises a pharmaceutically acceptable salt of a compound disclosed herein.
  • the salt may be an acid addition salt comprising at least one basic (e.g., amine) group of the compound which is in a positively charged form (e.g., an ammonium ion), in combination with at least one counter-ion, derived from the selected acid, that forms a pharmaceutically acceptable salt.
  • a basic (e.g., amine) group of the compound which is in a positively charged form e.g., an ammonium ion
  • at least one counter-ion derived from the selected acid, that forms a pharmaceutically acceptable salt.
  • the acid addition salts may include a variety of organic and inorganic acids, such as, but not limited to, hydrochloric acid which affords a hydrochloric acid addition salt, hydrobromic acid which affords a hydrobromic acid addition salt, acetic acid which affords an acetic acid addition salt, ascorbic acid which affords an ascorbic acid addition salt, benzenesulfonic acid which affords a besylate addition salt, camphorsulfonic acid which affords a camphorsulfonic acid addition salt, citric acid which affords a citric acid addition salt, maleic acid which affords a maleic acid addition salt, malic acid which affords a malic acid addition salt, methanesulfonic acid which affords a methanesulfonic acid (mesylate) addition salt, naphthalenesulfonic acid which affords a naphthalenesulfonic acid addition salt, oxalic acid which affords an oxalic acid addition salt,
  • a pharmaceutically acceptable salt of a compound disclosed herein may optionally be a base addition salt comprising at least one group of the compound which is in a form of an anion, in combination with at least one counter ion (i.e., cation) that forms a pharmaceutically acceptable salt.
  • suitable cations include metal cations of metals such as, but not limited to, sodium, potassium, magnesium, and calcium or ammonium.
  • Each of these base addition salts can be either a mono-addition salt or a poly- addition salt, as these terms are defined herein.
  • the acid or base additions salts can be either mono-addition salts or poly-addition salts.
  • the phrase “mono-addition salt”, as used herein, refers to a salt in which the stoichiometric ratio between the counter-ion and charged form of the compound is 1:1, such that the addition salt includes one molar equivalent of the counter-ion per one molar equivalent of the compound.
  • poly-addition salt refers to a salt in which the stoichiometric ratio between the counter-ion and the charged form of the compound is greater than 1:1 and is, for example, 2:1, 3:1, 4:1 and so on, such that the addition salt includes two or more molar equivalents of the counter-ion per one molar equivalent of the compound.
  • a compound disclosed herein, including a salt thereof may be in a form of a solvate or a hydrate thereof.
  • solvate refers to a complex of variable stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, and so on), which is formed by a solute (the 2-aminoindan derivatives described herein) and a solvent, whereby the solvent does not interfere with the biological activity of the solute.
  • solute the 2-aminoindan derivatives described herein
  • hydrate refers to a solvate where the solvent is water.
  • compositions of the present disclosure may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
  • Pharmaceutical compositions that can be used orally include stiff or soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Formulations for oral administration may be in dosages suitable for the chosen route of administration.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner or in adhesive carriers.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., a sterile, pyrogen-free, water-based solution, before use.
  • Therapeutic Uses [72]
  • the present disclosure provides methods for treating a psychological disorder such as an eating disorder by administering any one or more of the compositions and formulations discussed above.
  • an eating disorder may include anorexia nervosa, bulimia nervosa, pica, rumination disorder, an avoidant/restrictive eating disorders, and/or a binge eating disorder.
  • the pharmaceutical composition comprising 3-MMC or pharmaceutically acceptable salt thereof (and optionally further comprising an NAE such as PEA) is administered daily.
  • the pharmaceutical composition comprising 3-MMC or pharmaceutically acceptable salt thereof (and optionally further comprising an NAE such as PEA) is administered twice, three times, four times, or five times daily.
  • a treatment disclosed above is administered on demand, e.g., self-administered, based on the patient’s experience of eating disorder symptoms.
  • a chosen dosage at any given administration may vary depending upon the requirements of the patient and the severity of the condition being treated.
  • the amount of 3-MMC administered may be dependent on the subject being treated, the subject’s weight, the manner of administration and the judgment of the prescribing physician. For example, a dosing schedule may involve the daily or semi-daily administration at a perceived dosage of about 16 mg to 128 mg.
  • the 3-MMC is administered intermittently, such as on a daily, once weekly, or once monthly basis.
  • the 3-MMC is administered as needed to treat the eating disorder as determined by the subject.
  • the 3-MMC is administered for a period of time sufficient to treat an eating disorder, which may range from within one day to one or more years, depending on the severity of the symptoms and responsiveness to treatment.
  • a nasal spray dosage of 3-MMC may be administered after the administration of an oral dosage. For instance, after an initial oral dose of 3-MMC has been administered at a patient’s rising, a nasal spray dosage of 3-MMC may be administered to the patient at a later point of time during the day.
  • nasal spray dosing may comprise 3 to 10 doses per day.
  • the present disclosure provides a composition comprising a therapeutically effective amount of 3-MMC, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, e.g., any of those discussed above, for use in preventing an eating disorder in a subject in need, or for preventing and/or reducing one or more symptoms of an eating disorder.
  • the present disclosure provides a composition comprising a therapeutically effective amount of 3-MMC, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, e.g., any of those discussed above, for use in treating an eating disorder in a subject in need, or for treating and/or reducing one or more symptoms of an eating disorder.
  • the present disclosure provides a method of treating an eating disorder comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 3-MMC or a pharmaceutically acceptable salt thereof.
  • a composition comprising a therapeutically effective amount of 3-MMC, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier, in combination with an N-acylethanolamine, or a pharmaceutically acceptable salt thereof, for example, palmitoylethanolamide (“PEA”), e.g., any of those discussed above, to prevent an eating disorder, or prevent and/or reduce one or more symptoms of an eating disorder.
  • PDA palmitoylethanolamide
  • the present disclosure provides a composition comprising a therapeutically effective amount of 3-MMC and at least one pharmaceutically acceptable carrier, in combination with an N-acylethanolamine, or a pharmaceutically acceptable salt thereof, for example, palmitoylethanolamide (“PEA”), e.g., any of those discussed above, to treat an eating disorder, or treat and/or reduce or one or more symptoms of an eating disorder.
  • PDA palmitoylethanolamide
  • the present disclosure provides methods for treating an eating disorder or for reducing one or more symptoms of an eating disorder by administering a composition disclosed herein.
  • the composition comprises 3-MMC or a pharmaceutically acceptable salt thereof.
  • the composition comprises 3- MMC or a pharmaceutically acceptable salt thereof and an N-acylethanolamine or a pharmaceutically acceptable salt thereof.
  • the N-acylethanolamine or a pharmaceutically acceptable salt thereof is PEA or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt is a hydrochloride salt.
  • the salt is 2-(methylamino)-1-(3-methylphenyl)-1-propanone, monohydrochloride.
  • the salt is a hydrobromide, sulphate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, or gluconate salt.
  • the N- acylethanolamine consists of PEA.
  • the methods disclosed herein comprise delivering a nasal spray formulation for treating an eating disorder in a subject in need, comprising the steps of: providing a spray of 3-MMC having a saline solution formulation in a concentration of 0.003M to 0.009M, delivering a spray of said formulation to a subject’s nose; wherein the nasal spray formulation comprises a therapeutically effective amount of 3-MMC or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
  • the methods disclosed herein reduce an eating disorder, e.g., as measured by a change in a global score of an Eating Disorder Examination (EDE) or an EDE questionnaire (EDE-Q), e.g., by at least 0.5-3 points.
  • EDE Eating Disorder Examination
  • EDE-Q EDE questionnaire
  • the EDE, and the self-report version, the EDE-Q measure an eating disorder psychopathology and may provide a measure of the range and severity of a feature of an eating disorder over a 28-day period.
  • the range, or frequency, of key behavioral features of an eating disorder may be measured in terms of number of episodes of the behavior and, in some instances, number of days on which the behavior has occurred.
  • the EDE and EDE-Q provide subscale scores reflecting the severity of aspects of an eating disorder.
  • the subscales may be categorized as Restraint, Eating Concern, Shape Concern, and Weight Concern, and a subject may be asked to provide a rating for a question in a subscale.
  • a subject may rate, from 0-6, the severity or frequency of which a feature was present or experienced during the preceding 28-day period.
  • a subject may be asked to rate a score, from 0-6, for how many days over the past four weeks they went 8 waking hours or more without eating (e.g., an “avoidance to food” category of the Restraint subscale).
  • the subject may rate a score of 0 if they did not avoid eating in an 8-hour period in any of the 28 days, a score of 1 if they avoided eating in an 8-hour period or more on 1 to 5 days, a score of 2 if they avoided eating in an 8-hour period or more on less than half of the four weeks (e.g., 6 to 12 days), a score of 3 if they avoided eating in an 8- hour period or more on half the days (e.g., 13 to 15 days), a score of 4 if they avoided eating for an 8-hour period or more on more than half the days (e.g., 16 to 22 days), a score of 5 if they Attorney Docket No.: 15691.0017-00304 avoided eating for an 8-hour period or more on almost every day (e.g., 23 to 27 days), or a score of 6 if they avoided eating for an 8-hour period or more every day.
  • a subject’s score may be averaged with other scores from other items of a subscale.
  • scores may be averaged for a subject’s frequency to restrict a total amount of food consumed, avoid eating altogether, avoid eating specific foods, or desire the sensation of an empty stomach to obtain an average score of a Restraint subscale.
  • scores may be averaged to obtain an average score of an Eating Concern, Shape Concern, and Weight Concern subscale.
  • items of the Eating Concern subscale include preoccupation with food, eating, or calories, fear of losing control over eating, eating in secret, fear of social eating, or guilt about eating.
  • Non-limiting examples of items of the Shape Concern subscale include a desire for a flat stomach, a preoccupation with shape or weight, valuing body shape, fear of weight gain, dissatisfaction of body shape, discomfort seeing body, avoidance of exposure, or feelings of fatness.
  • Non-limiting examples of items of the Weight Concern subscale include valuing body weight, reaction to prescribed weighing, preoccupation with body shape or body weight, dissatisfaction with body weight, or a desire to lose body weight.
  • An averaged score of all subscales measured in the EDE or EDE-Q e.g., the global score, may provide a number between 0 and 6.
  • An averaged score of 2 or more may indicate an eating disorder.
  • Some embodiments of the present disclosure provide a method to reduce an eating disorder, e.g., as measured by a change in an obtained score from other assessments or evaluations for a psychological disorder (e.g., eating disorder) besides EDE or EDE-Q.
  • an eating disorder e.g., as measured by a change in an obtained score from other assessments or evaluations for a psychological disorder (e.g., eating disorder) besides EDE or EDE-Q.
  • Non- limiting examples of other assessments or evaluations to measure a change in a psychological disorder using an acceptable scale include The Eating Disorder Assessment for DSM-5 (EDA- 5), Structure Interview for Anorexic and Bulimic Syndromes (SIAB-EX), Eating Pathology Symptoms Inventory-Clinician Rated Version (EPSI-CRV), Structured Clinical Interview for DSM-5 (SCID-5), Evaluation Semi-Structured Interview for Eating Disorders (ESSIEA), Eating Disorder Inventory (EDI), Eating Attitudes Test (EAT), Eating Disorders Recovery Endorsement Questionnaire (EDREQ), Clinical Impairment Scale (CIA), Eating Disorder Quality of Life Scale (EDQLS), Health Related Quality of Life in Eating Disorder (HeRQoLED), Eating Disorder Quality of Life (EDQOL), Quality of Life for Eating Disorders (QOL-ED), Physical Appearance Comparison Scale-3 (PACS-3), Difficulties in Emotion Regulation (DERS), UPPS-P Impulsive Behavior Scale, Hewitt Multidimensional Perfect
  • the phrase “about 1” means “0.9 to 1.1”
  • the phrase “about 1 or 2” means “0.9 to 1.1 or 1.8 to 2.2”
  • the phrase “about 1 to about 2” means “0.9 to 2.2”.
  • the term “about” when used before a numerical designation, e.g., temperature, time, amount, concentration, and such others, including a range, indicates approximations, which may vary, for example, by (+) or (-) 10%, 5%,1%, or any subrange or subvalue there between, depending on the nature of the parameter and measurement.
  • the term “about” when used with regard to a dose amount means that the dose may vary by +/- 10%.
  • the term "acute” as used herein refers to a condition with a relatively short course such as for a length of time ranging from days to weeks. The intensity of the diseases or conditions may be severe. Symptoms of the diseases or conditions may resolve over time.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can comprise sterile liquids, such as water and oils. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions may be employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E. W. Martin, 18th Edition.
  • the term "chronic” as used herein means that the length of time of the diseases or conditions of the disclosure can be weeks, months, or possibly years. The intensity of the diseases or conditions can differ according to various factors such as patient age, temperature, season, type of disease, etc. Symptoms of the diseases or conditions may worsen over time.
  • the term “eating disorder” used herein means the development in a subject of abnormal or persistent disturbances of eating patterns. These may lead to poor physical and/or psychological health. The abnormal or persistent disturbances of eating patterns may be caused by feelings of distress or concern about body shape or body weight, and may harm body composition and function (e.g., serious heart conditions and kidney failure).
  • an “eating disorder’ encompasses, inter alia, anorexia nervosa, bulimia nervosa, binge-eating disorders, avoidant/restrictive food intake disorder, pica, and rumination disorder.
  • An “eating disorder” may occur together with other psychiatric illnesses, such as, but not limited to, depression, substance abuse, and/or anxiety.
  • the term “unhealthy body weight” used herein encompasses a body mass index (BMI) that is outside of a range of 18.5 to 22.9 kilograms of body weight divided by height in meters squared (kg/m 2 ).
  • An unhealthy body weight may be a low body weight or a high body weight.
  • an “unhealthy low body weight” is a BMI that is below 18.5 kg/m 2 . In some embodiments, an “unhealthy low body weight” is a BMI below 16.0 kg/m 2 .
  • An “unhealthy high Attorney Docket No.: 15691.0017-00304 body weight” is a BMI above 35 kg/m 2 . In some embodiments, an “unhealthy high body weight” is a BMI above 40 kg/m 2 ..
  • the terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent being administered which will relieve to some extent one or more of the signs, symptoms, or side effects of the disease or condition being treated.
  • an “effective amount” for therapeutic uses may be the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient.
  • excipients examples include calcium carbonate, povidone K-30, crospovidone, silicon dioxide, magnesium stearate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, oils such as vegetable oils or fish oils, and polyethylene glycols.
  • excipients include calcium carbonate, povidone K-30, crospovidone, silicon dioxide, magnesium stearate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, oils such as vegetable oils or fish oils, and polyethylene glycols.
  • pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar toxicity when administered to an individual.
  • the term "pharmaceutically acceptable” may mean approved by a regulatory agency (for example, the U.S. Food and Drug Agency) or listed in a generally recognized pharmacopeia for use in animals (e.g., the U.S. Pharmacopeia).
  • pharmaceutically acceptable carrier refers to a carrier, an excipient or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. An adjuvant is included under these phrases.
  • pharmaceutically acceptable salt refers to a salt that does not cause significant irritation to an organism while not abrogating the biological activity and properties of the administered compound.
  • composition refers to a preparation comprising at least one active agent. It may comprise other chemical components such as physiologically suitable carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • preventing encompasses stopping the onset of one or more symptoms or side effects of a diseases or condition, or delaying or lessening or reducing the severity of one or more symptoms or side effects of the diseases or conditions once they do Attorney Docket No.: 15691.0017-00304 onset.
  • salt refers to any form of an active ingredient in which the active ingredient assumes an ionic form and is coupled to a counter ion (a cation or anion) or is in solution. This also includes complexes of the active ingredient with other molecules and ions, in particular complexes which are complexed by ion interaction.
  • subject refers to a warm-blooded animal, such as a human that would benefit biologically, medically or in quality of life from a treatment.
  • treating includes, but is not limited to, any one or more of the following: abrogating, ameliorating, inhibiting, attenuating, blocking, suppressing, reducing, delaying, halting, alleviating or preventing a disease or at least one or more symptoms or side effects of the disease or condition.
  • unit dose refers to a fixed amount, i.e., a unit of a compound within a composition that is to be administered to or taken by a subject.
  • a range of values is listed, it is intended to encompass each value and sub-range within the range.
  • the dimensions and values disclosed herein are not to be understood as being strictly limited to the exact numerical values recited.
  • each such dimension is intended to mean both the recited value and a functionally equivalent range surrounding that value.
  • a dimension disclosed as “10 ⁇ m” is intended to mean “about 10 ⁇ m”.
  • a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range.
  • the phrases "ranging/ranges between” a first indicate number and a second indicate number and “ranging/ranges from” a first indicate number "to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.
  • Toxicity and therapeutic efficacy may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
  • Compositions that exhibit large therapeutic indices are preferable.
  • Data obtained from the cell culture assays or animal studies can be used in formulating a range of dosage for use in humans.
  • Therapeutically effective dosages achieved in one animal model may be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother.
  • a therapeutically effective amount may vary with the subject's age, condition, and gender, as well as the severity of the medical condition in the subject.
  • the dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.
  • Example 1 3-MMC
  • Subjects of a first experimental group receive daily doses of a pharmaceutical composition comprising 3-MMC, or pharmaceutically acceptable salt therefore.
  • Subjects of a control group receive daily doses of a placebo with the same excipients as the pharmaceutical composition of the first experimental group, but with no active ingredient. The daily doses are administered to subjects at approximately the same time each day.
  • Subjects of both the first experimental group and control group are evaluated for adverse effects and any changes to vital signs after administration of the pharmaceutical composition.
  • Subjects of the first experimental group are administered daily doses of a pharmaceutical composition comprising 3-MMC, or pharmaceutically acceptable salt there at an escalating daily dose until a final amount is achieved.
  • the same protocol is also performed for subjects of the control group.
  • Subjects of the control group are informed they are following an escalating daily dose to a final amount of active ingredient, but are administered the same placebo (e.g., same excipients but no active ingredient) each day of the escalation schedule.
  • subjects of the first experimental group are administered the same amount of 3-MMC daily for up to 28 days. Subjects of the both the first experimental group and the control group are evaluated for adverse effects and any changes to vital signs after administration of the pharmaceutical composition.
  • subjects of both the first experimental and control group are evaluated to measure a symptom or a behavior associated with an eating disorder and a change in the symptom or behavior.
  • Day “pre-dosing” is prior to the administering subjects of the first experimental group and the control group the escalation dosing schedule.
  • Day “1” is the day subjects of the first experimental group first receive a pharmaceutical composition comprising a final amount of 3-MMC.
  • day “1” is the day subjects are informed they first receive a pharmaceutical composition comprising a final amount of 3-MMC.
  • Day “28” is the 28 th day subjects of the first experimental group receive a dose of a final amount of 3-MMC and the subjects of the control group are informed they receive a dose of a final amount of 3-MMC.
  • EEDE Eating Disorder Examination
  • the EDE provides subscale scores reflecting the severity of aspects of an eating disorder.
  • a response for symptoms or behaviors associated with an eating disorder is scored from 0 to 6, with 0 representing the absence of the symptom or behavior over a previous 28-day period and 6 representing the symptom or behavior occurring each day of the previous 28-day period.
  • a score for symptoms or behaviors for each subscale of the EDE are added.
  • days “pre-dosing”, day “1”, and day “28” a mean total EDE score, and a standard deviation of the mean EDE score is evaluated for both the experimental and the control group.
  • Example 2 PEA
  • Subjects of a second experimental group receive daily doses of a pharmaceutical composition comprising PEA, or pharmaceutically acceptable salt therefore at a unit dose of Attorney Docket No.: 15691.0017-00304 800 mg.
  • subjects of a control group receive daily doses of a placebo with the same excipients as the pharmaceutical composition of the second experimental group, but with no active ingredient. The daily doses are administered to subjects at approximately the same time each day.
  • Subjects of both the second experimental group and control group are evaluated for adverse effects and any changes to vital signs after administration of the pharmaceutical composition.
  • Subjects of the second experimental group are administered daily doses of a pharmaceutical composition comprising PEA, or pharmaceutically acceptable salt there at an escalating daily dose until a final amount is achieved.
  • the rest of the protocol as described above in Example 1 is performed to determine mean EDE scores and standard deviations of the mean EDE scores.
  • Example 3 3-MMC and PEA
  • Subjects of a third experimental group receive daily doses of a pharmaceutical composition comprising 3-MMC, or pharmaceutically acceptable salt therefore, and PEA, or pharmaceutically acceptable salt thereof.
  • subjects of a control group receive daily doses of a placebo with the same excipients as the pharmaceutical composition of the second experimental group, but with no active ingredients.
  • the daily doses are administered to subjects at approximately the same time each day.
  • Subjects of both the second experimental group and control group are evaluated for adverse effects and any changes to vital signs after administration of the pharmaceutical composition.
  • Subjects of the third experimental group are administered daily doses of a pharmaceutical composition comprising 3-MMC and PEA, or pharmaceutically acceptable salts thereof at an escalating daily dose as described above in Examples 1 and 2.
  • the rest of the protocol as described above in Example 1 is performed to determine mean EDE scores and standard deviations of the mean EDE scores.

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Abstract

La présente invention concerne des compositions et des méthodes de traitement d'états psychologiques, tels que des troubles de l'alimentation, à l'aide de compositions pharmaceutiques comprenant de la 3-méthylméthcathinone (3-MMC), ou un sel pharmaceutiquement acceptable de celle-ci.
PCT/IB2025/052881 2024-03-20 2025-03-19 Compositions et méthodes de traitement de troubles alimentaires Pending WO2025196662A1 (fr)

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