Compositions and methods for treating dyskinesia

Abstract

The present disclosure relates to compositions and methods of treating dyskinesia using pharmaceutical compositions comprising 3-Methylmethcathinone (3MMC), or a pharmaceutically acceptable salt thereof.

Description

[0001] Attorney Docket No.: 15691.0016-00304 COMPOSITIONS AND METHODS FOR TREATING DYSKINESIA Cross-Reference To Related Applications [1] This application claims the benefit of priority of U.S. Provisional Patent Application No.63 / 515,897, filed on July 27, 2023, the contents of which are incorporated herein in their entirety. Field of the Disclosure [2] The present disclosure relates to compositions and methods for treating dyskinesias such as tardive dyskinesia. Background of the Disclosure [3] Dyskinesias are characterized by the development in a subject of abnormal involuntary movements and may manifest as chorea (irregular, involuntary movements of the body, especially the face and extremities) or dystonia (disorder or lack of muscle tonicity). Dyskinesia can be tardive or acute. [4] Tardive dyskinesia (TD) is a chronic disorder of the nervous system, characterized by involuntary, irregular rhythmic movements of the mouth, tongue, and facial muscles. The upper extremities also may be involved. These movements may be accompanied, to a variable extent, by other involuntary movements and movement disorders. These include rocking, writhing, or twisting movements of the trunk (tardive dystonia), forcible eye closure (tardive blepharospasm), an irresistible impulse to move continually (tardive akathisia), jerking movements of the neck (tardive spasmodic torticollis), and disrupted respiratory movements (respiratory dyskinesia). The vast majority of TD cases are caused by the prolonged use of antipsychotic drugs (neuroleptics). A relatively small number are caused by the use of other medications, such as metoclopramide, that, like neuroleptics, block dopamine receptors. TD often manifests or worsens in severity after neuroleptic drug therapy is discontinued. Resumption of neuroleptic therapy will temporarily suppress the involuntary movements, but may aggravate them in the long run. [5] TD affects approximately 15-20% of patients treated with neuroleptic drugs (Khot et al., Neuroleptics and Classic Tardive Dyskinesia, in Lang A E, Weiner W J (eds.): Drug Induced Movement Disorders, Futura Publishing Co., 1992, pp.121-166). The cumulative incidence of TD is substantially higher in women, in older people, and in those being treated with neuroleptics for conditions other than schizophrenia, such as bipolar disorder (see, e.g., Hayashi et al., Clin. Neuropharmacol, 19:390, 1996; Jeste et al., Arch. Gen. Psychiatry, 52:756, 1995). Unlike the acute motor side effects of Attorney Docket No.: 15691.0016-00304 neuroleptic drugs, TD does not respond in general to antiparkinsonian drugs (Decker et al., New Eng. J. Med., October 7, p.861, 1971). [6] TD is also associated with a variable degree of cognitive impairment. Cognitive dysfunction associated with TD may involve attention, concentration, memory, or executive functions such as judgment or abstract reasoning (see, e.g., Sachdev et al., Acta Psychiatr Scand 93:451, 1996; Waddington & Youssef, Psychol. Med.26:681, 1996; Swartz, Neuropsychobiology, 32:115, 1995). The cognitive impairment associated with TD usually is seen as a marker of underlying differences in brain function that predispose the patient to TD. However, it may also be due to the TD itself, and may be either irreversible, or partially reversible if the TD is successfully treated. [7] The pathophysiology of TD has not been established definitively. It is well known that blockade of dopamine receptors will lead to an increased number of dopamine receptors, and therefore to an increased sensitivity to dopamine of striatal neurons (see, e.g., Andrews, Can J Psych 39:576, 1994; Casey, in Psychopharmacology: The Fourth Generation of Progress, Raven Press, 1995). The first major hypothesis about the pathophysiology of TD was that TD was the result of this hypersensitivity of striatal neurons to dopamine. In support of the “dopamine supersensitivity” hypothesis, it is noted that dopamine agonists can aggravate the disorder (Bezchibnyk-Butler & Remington, Can J. Psych., 39:74, 1994). However, the dopamine supersensitivity hypothesis is not compatible with the observation that TD and Parkinsonism (a dopamine deficiency state) infrequently exist together in the same patient. [8] Other studies have suggested that irreversible cases of TD may be related to excitotoxic damage to the basal ganglia (Andreassen & Jorgensen, Pharmacol. Biochem. Behav., 49(2):309-312, 1994; Tsai et al.: Am J Psych, September 155:9, 1207-13, 1998). An acquired deficiency of the inhibitory neurotransmitter GABA has also been implicated in the development of TD (Delfs et al. Experimental Neurol., 133:175-188, 1995). [9] A widely studied animal mode of TD, that of vacuous chewing movements (VCM) in rats, has yielded evidence for a glutamate-based excitotoxic mechanism in the development of the disorder (Meshul et al; Psychopharmacology (Berl), 125:238-47, 1996 June; Andreassen et al; Br J Pharmacol, 199:751-7, 1996 October). When administered to rats with VCM, ethanol acutely decreases the animals’ orofacial movements. This effect is prevented if the rats are pre-treated with a benzodiazepine inverse agonist, suggesting that it is mediated by stimulation of GABA-A receptors by Attorney Docket No.: 15691.0016-00304 ethanol (Stoessl, Pharmacol. Biochem. Behav. July, 54:541-6, 1996 July). Stoessl suggests that “GABAergic stimulation” deserves further investigation in the treatment of TD. Stoessl does not, however, advance the idea of treating TD with combined GABA agonism and NMDA antagonism, nor suggest using acamprosate as a treatment for TD.

[0010] The physical manifestations of TD can resemble movement disorders associated with degenerative diseases, such as Huntington’s disease and Parkinson’s disease. Patients with TD can show chorea (quick, irregular movements of the extremities) indistinguishable from that seen in cases of Huntington's disease. Neck, trunk and limb movements of TD can be indistinguishable from those of the “peak-dose dyskinesia” associated with prolonged treatment of Parkinson’s disease with levodopa.

[0011] Recent research suggests that Vitamin E can reduce symptoms of TD modestly (Lohr & Caliguiri, J Clin Psychiatry 57;167, 1996; Dabiri et al. Am. J. Psychiatry, June, 151(6):925-926, 1994). GABA agonists such as baclofen and various benzodiazepines have also been the subject of some positive reports and are widely used in practice to ameliorate the symptoms of TD, probably because their low toxicity justifies their use despite their limited efficacy. (Gardos & Cole, Psychopharmacology: The Fourth Generation of Progress, eds. Bloom and Kupfer, pp.1503-1510, 1995). This review only cited reports of variable benefits associated with other agents including propranolol, clonidine, cholinergic agonists, buspirone and calcium-channel antagonists. However, none of these has become a generally accepted treatment for either the movement or cognitive disorders associated with TD.

[0012] U.S. Pat. No.5,602,150 proposes that co-administration of taurine or taurine derivatives together with neuroleptics, might prevent the emergence of tardive movement disorders, on the theory that the latter are due to excitotoxic damage against which taurine would protect. The recommendation of taurine is based on studies in a single animal model. The experiments reported do not deal with any therapeutic effects of taurine on established movements, either in the presence of continued neuroleptic therapy or otherwise. Neither the patent nor the experiments cited in it predict or imply that taurine or derivatives will be beneficial for established movement disorders.

[0013] Medications for treating tardive dyskinesia, such as Valbenazine, have been known to have side effects including sleepiness and depression. These in turn have been observed to frequently cause more patients to discontinue treatment. Thus, there remains a need for new treatments for TD that have greater efficacy and fewer side effects than those currently available. Attorney Docket No.: 15691.0016-00304

[0014] 3-Methylmethcathinone (3MMC) inhibits norepinephrine (NET), serotonin (SERT) and dopamine (DAT) transporters. The chemical structure of 3MMC is: of , appreciation of music and awareness of senses. Higher doses of 3-MMC may cause anxiety, altered vision, sweating, insomnia, dizziness, confusion, loss of coordination, and convulsions. However, these side-effects may surprisingly be reduced and / or controlled when selected doses and regimens disclosed herein for treating patients with symptoms associated with dyskinesia.

[0016] N-acylethanolamines (NAEs) are lipid-derived signaling molecules. They are formed when one of several types of acyl groups is linked to the nitrogen atom of ethanolamine. Examples of N-acylethanolamines 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).

[0017] 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 and 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. This concept was further supported by growing evidence that PEA production and inactivation can occur independently of AEA and 2-AG production and inactivation. Much of the biological effects of PEA on cells can be attributed to its affinity to peroxisome proliferator-activated receptor (PPAR), particularly PPAR-alpha and Attorney Docket No.: 15691.0016-00304 PPAR-gamma. PEA was shown to have an affinity to cannabinoid-like G-coupled receptors GPR55 and GPR119 as well as the transient receptor potential vanilloid type 1 receptor (TRPV1). PEA has been shown to have anti-inflammatory, anti-nociceptive, neuro-protective, and anti-convulsant properties. Summary of the Disclosure

[0018] As mentioned above, there is an unmet medical need for improved dyskinesia treatments. Here, according to some embodiments, 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 dyskinesia or one or more symptoms of dyskinesia, 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 dyskinesia or one or more symptoms of dyskinesia. The present disclosure provides pharmaceutical compositions comprising 3MMC, or pharmaceutically acceptable salts thereof, and their use in preventing and / or treating dyskinesia, or for reducing one or more symptoms of dyskinesia. The disclosure further provides pharmaceutical compositions comprising 3MMC, or pharmaceutically acceptable salts thereof, or combinations of 3MMC, or pharmaceutically acceptable salts thereof and N- acylethanolamines, or pharmaceutically acceptable salts thereof, for example, palmitoylethanolamide (“PEA”) for use in the same treatments. In some embodiments, the present disclosure relates to methods for corrective prevention and / or treatment of antipsychotic-induced dyskinesia or any other indication amenable to treatment of dyskinesia, including, but not limited to tardive dyskinesia

[0019] 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 dyskinesias such as tardive dyskinesia.

[0020] The present disclosure encompasses pharmaceutical compositions comprising combinations of 3MMC, or salts thereof, and N-acylethanolamines, or salts thereof for use in a method for preventing and / or treating dyskinesia, or for reducing one or more symptoms of dyskinesia. In some embodiments, the N-acylethanolamine or salt Attorney Docket No.: 15691.0016-00304 thereof is PEA or a salt thereof. In some embodiments, these compositions comprise therapeutically effective dosages and may be employed in a variety of methods.

[0021] The present disclosure provides methods for preventing and / or treating dyskinesia. Particularly, the present disclosure provides methods for treating tardive dyskinesia.

[0022] The present disclosure provides, in one aspect, a composition comprising a therapeutically effective amount of 3MMC and at least one pharmaceutically acceptable carrier, for use in preventing tardive dyskinesia in a subject in need, or for treating, preventing and / or reducing one or more symptoms of tardive dyskinesia.

[0023] The present disclosure provides, in one aspect, a composition comprising a therapeutically effective amount of 3MMC 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 tardive dyskinesia in a subject in need, or for treating and / or reducing one or more symptoms of tardive dyskinesia.

[0024] The present disclosure provides, in another aspect, a nasal spray formulation comprising a therapeutically effective amount of 3MMC or a salt thereof and at least one pharmaceutically acceptable carrier for use in treating tardive dyskinesia in a subject in need thereof. The nasal spray formulation may be self-delivered by the patient. In some embodiments, the spray further comprises an N-acylethanolamine such as PEA, or a salt thereof.

[0025] The present disclosure provides, in one aspect, a composition comprising 3MMC, or salts thereof, and N-acylethanolamines, or salts thereof for use in preventing tardive dyskinesia in a subject in need, or for preventing and / or reducing one or more symptoms of tardive dyskinesia.

[0026] The present disclosure provides, in one aspect, a composition comprising combinations of 3MMC, or salts thereof, and N-acylethanolamines, or salts thereof, for use in treating tardive dyskinesia in a subject in need, or for treating and / or reducing one or more symptoms of tardive dyskinesia.

[0027] The present disclosure provides, in one aspect, a method of treating or improving at least one symptom associated with dyskinesia, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 3-Methylmethcathinone (3-MMC), or a pharmaceutically acceptable salt thereof.

[0028] The present disclosure provides, in one aspect, a method of treating or improving at least one symptom associated with dyskinesia, comprising administering to a subject Attorney Docket No.: 15691.0016-00304 in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 3-Methylmethcathinone (3-MMC), or a pharmaceutically acceptable salt thereof, and an N-acylethanolamine, or a pharmaceutically acceptable salt thereof. Detailed Description of the Disclosure Compositions

[0029] In some embodiments, the present disclosure provides pharmaceutical compositions comprising 3MMC, or pharmaceutically acceptable salts thereof, e.g., for compositions for preventing and / or treating dyskinesia, or for reducing one or more symptoms of dyskinesia. In some embodiments, the present disclosure relates to methods of using the pharmaceutical compositions for corrective treatment of medication-induced dyskinesia. In some embodiments, the present disclosure relates to methods of using the pharmaceutical compositions for corrective treatment of antipsychotic-induced dyskinesia.

[0030] The formulations and compositions disclosed herein may comprise 3MMC or any pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt. In some embodiments, the salt is 2- (methylamino)-1-(3-methylphenyl)-1-propanone, monohydrochloride. In some embodiments, the salt is a hydrobromide, sulphate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate or gluconate salt.

[0031] In some embodiments, pharmaceutical compositions of the present disclosure comprising 3MMC 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.

[0032] In some embodiments, the present disclosure provides the composition in the form of a nasal spray comprising a therapeutically effective amount of 3MMC and at least one pharmaceutically acceptable carrier for use in treating a dyskinesia, e.g., tardive dyskinesia, in a subject in need thereof. The nasal spray may be self-delivered by the patient. In some embodiments, the present disclosure provides an oral composition comprising a therapeutically effective amount of 3MMC and at least one pharmaceutically acceptable carrier for use in treating a dyskinesia, e.g., tardive dyskinesia, in a subject in need thereof. In some embodiments, the present disclosure provides an intravenous composition comprising a therapeutically effective amount of 3MMC and at least one pharmaceutically acceptable carrier for use in treating a dyskinesia, e.g., tardive dyskinesia, in a subject in need thereof. In some embodiments, the present disclosure provides a topical composition comprising a therapeutically Attorney Docket No.: 15691.0016-00304 effective amount of 3MMC and at least one pharmaceutically acceptable carrier for use in treating a dyskinesia, e.g., tardive dyskinesia, in a subject in need thereof.

[0033] In some embodiments, 3MMC 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. In some embodiments, the 3MMC 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, 120 mg, 125 mg, 130 mg, 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. Each possibility represents a separate embodiment of the present disclosure. In some embodiments, the dose is 50 mg. In some embodiments, the dose ranges from about 60 mg to 260 mg.

[0034] In some embodiments, the pharmaceutical composition comprises a unit dose of 3MMC or a pharmaceutically acceptable salt thereof. In other embodiments, 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.

[0035] 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.

[0036] In some embodiments, the pharmaceutical composition is present in a unit dosage form ranging from 20 mg to 1000 mg of 3MMC or pharmaceutically acceptable salt thereof. In some embodiments, the amount of 3MMC, 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 3MMC or a pharmaceutically acceptable salt thereof. In some embodiments, the Attorney Docket No.: 15691.0016-00304 3MMC or pharmaceutically acceptable salt thereof is in a unit dosage form of 50 mg. In certain embodiments, 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 3MMC or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, the pharmaceutical composition comprises a concentration of 3MMC 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. In certain embodiments, the pharmaceutical composition comprises a concentration of 3MMC or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 0.2 to about 0.5 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 / kg to about 7.5 mg / kg, about 7.5 mg / kg to about 8.0 mg / kg, about 8.0 mg / kg to about 8.5 mg / kg, about 8.5 mg / kg to about 9.0 mg / kg, about 9.0 mg / kg to about 9.5 mg / kg, about 9.5 mg / kg to about 10.0 mg / kg. In certain embodiments, the pharmaceutical composition comprises a concentration of 3MMC 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. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the pharmaceutical composition comprises a concentration of 3MMC 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 Attorney Docket No.: 15691.0016-00304 mg / kg, less than about 9.0 mg / kg, less than about 9.5 mg / kg, or about 10.0 mg / kg bodyweight. Each possibility represents a separate embodiment of the present disclosure.

[0038] In certain embodiments, the pharmaceutical composition comprises a concentration of 3MMC 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 0.2 mg / kg to about 8.0 mg / kg, about 0.2 mg / kg to about 8.5 mg / kg, about 0.2 mg / kg to about 9.0 mg / kg, about 0.2mg / kg to about 9.5 mg / kg, or about 0.2 mg / kg to about 10.0 mg / kg body weight. Each possibility represents a separate embodiment of the present disclosure.

[0039] In certain embodiments, the pharmaceutical composition comprises a concentration of 3MMC 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 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 mg / kg to 8.5 mg / kg, 0.2 mg / kg to 9.0 mg / kg, 0.2 mg / kg to 9.5 mg / kg, or 0.2 mg / kg to 10.0 mg / kg body weight. Each possibility represents a separate embodiment of the present disclosure.

[0040] In some embodiments, 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 3MMC or a pharmaceutically acceptable salt thereof is a solid or liquid form composition. In some embodiments, the pharmaceutical composition comprising 3MMC or a pharmaceutically acceptable salt thereof is a nasal spray composition.

[0041] In some embodiments, 3MMC 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 Attorney Docket No.: 15691.0016-00304 embodiments, the composition comprises the 3MMC dissolved in saline. In some embodiments, the saline comprises a 0.9 wt % aqueous sodium chloride solution.

[0042] In a further embodiment, the 3MMC dissolved in a pharmaceutically acceptable carrier, e.g., saline, is in a concentration of 5 x 105nM to 20 x 105nM. In some embodiments, the 3MMC is in a concentration of 7.22 x 105nM to 19.26 x 105nM. In some embodiments, the 3MMC is in a concentration of 14.43 x 105 nM.

[0043] In some embodiments, 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). In some embodiments, the nasal spray is capable of providing sprayed droplets with a size distribution having a D10 ranging from about 0.5 μm to about 6 μm. In some embodiments, the nasal spray may provide sprayed droplets with a size distribution having a D10 of 0.6 μm, a D50 of 2.3 μm, a D90 of 5.2 μm, a SPAN of not more than 2.0, and a % Volume of <5.2 μm of less than 25 V%, said formulation having a viscosity of 1.1 cps.

[0044] In some embodiments, the droplets are produced by a nasal spray device capable of providing a droplet having a size distribution D50 between 30-70 µm, and a D90 < 200 µm. In some embodiments, the droplet size distribution has a D90 >10 µm in diameter during administration. In some embodiments, the droplet size distribution has a D10 from about 5 µm to about 40 µm during administration. In some embodiments, the droplet size distribution has a D50 from about 20 µm to 80 µm during administration. In some embodiments, the droplet size distribution has a D90 from about 50 µm to 700 µm during administration. In some embodiments, the nasal spray device has a spray plume that has an ovality ratio from about 1.0 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.) In some embodiments, 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 Attorney Docket No.: 15691.0016-00304 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. In an embodiment, 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. In some embodiments, the dose to be delivered is metered by the spray pump, which is preferably finger or hand-actuated. In some embodiments, 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. It may be designed to administer the intended dose with multiple sprays, e.g., two sprays, e.g., one in each nostril, or as a single spray, e.g., in one nostril, or to vary the dose in accordance with the body weight or maturity of the patient. Without being bound by theory, the spray device may improve penetration of the active into the body without creating undue discomfort. In some embodiments, 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. Again without being bound by theory, 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.

[0045] In some embodiments, the nasal spray dosing of 3MMC may range from 20 mg / ml to 300 mg / ml. In some embodiments, the nasal spray 3MMC dosing may range from 3 to 10 doses per day. In some embodiments, the nasal spray 3MMC may be administered after an initial oral dose of 3MMC at an earlier point in time during the day.

[0046] 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. In some embodiments, the 3MMC 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 3MMC 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).

[0047] In certain embodiments, 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 Attorney Docket No.: 15691.0016-00304 combination thereof. Each possibility represents a separate embodiment of the present disclosure.

[0048] In certain embodiments, the N-acylethanolamine is PEA or a salt thereof. In certain embodiments, the N-acylethanolamine consists of PEA or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the pharmaceutically acceptable salt of the N- acylethanolamine, e.g., of the PEA, is a hydrochloride salt. In some embodiments, the salt is 2-(methylamino)-1-(3-methylphenyl)-1-propanone, monohydrochloride. In some embodiments, the salt is a hydrobromide, sulphate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate or gluconate salt.

[0050] In certain embodiments, a pharmaceutical composition comprising 3MMC comprises about 200-1800 mg of an N-acylethanolamine (e.g., PEA) or a salt thereof. In certain embodiments, 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. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, 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. In certain embodiments, 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 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. Each possibility represents a separate embodiment of the present disclosure. In some embodiments, the N-acylethanolamine, or pharmaceutically Attorney Docket No.: 15691.0016-00304 acceptable salt thereof, is administered at a dose ranging from about 2.5 mg / kg to 36.0 mg / kg body weight N-acylethanolamine.

[0051] In some embodiments, a pharmaceutical composition disclosed herein comprises a therapeutically-effective amount of 3MMC or a salt thereof and at least one N-acylethanolamine or a salt thereof, wherein the molar ratio between the 3MMC and the N-acylethanolamine is between about 1:1 to about 1:120. In any of the above embodiments, the N-acylethanolamine is PEA or a salt thereof.

[0052] In certain embodiments, the molar ratio between the 3MMC, or a pharmaceutically acceptable salt thereof, and the N-acylethanolamine, or a pharmaceutically acceptable salt thereof, is between about 1:1 to about 1:5. In certain embodiments, the molar ratio between the 3MMC and the N-acylethanolamine is between about 1:7 to about 1:10, about 1:10 to about 1:20, between about 1:15 to about 1:30, between about 1:20 to about 1:40, between about 1:25 to about 1:50, between about 1:30 to about 1:60, between about 1:40 to about 1:75, between about 1:50 to about 1:80, between about 1:60 to about 1:100, between about 1:50 to about 1:100, between about 1:50 to about 1:110, or between about 1:50 to about 1:120. Each possibility represents a separate embodiment of the present disclosure. In any of the above embodiments, the N-acylethanolamine is PEA or a salt thereof.

[0053] In certain embodiments, the molar ratio between the 3MMC, or a pharmaceutically acceptable salt thereof, and the N-acylethanolamine, or a pharmaceutically acceptable salt thereof, is between about 1:7 to about 1:120. In certain embodiments, the molar ratio between the 3MMC and the N-acylethanolamine is between about 1:7 to about 1:110, about 1:7 to about 1:100, about 1:7 to about 1:90, about 1:7 to about 1:80, about 1:7 to about 1:70, about 1:7 to about 1:60, about 1:7 to about 1:50, about 1:7 to about 1:40, about 1:7 to about 1:30, about 1:7 to about 1:20, about 1:5 to about 1:20, about 1:1 to about 1:20, or about 1:1 to about 1:10. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the molar ratio between the 3MMC and the N-acylethanolamine is between about 1:25 to about 1:120. In certain embodiments, the molar ratio between the 3MMC and the N-acylethanolamine is between about 1:25 to about 1:150, about 1:25 to about 1:140, about 1:25 to about 1:130, about 1:25 to about 1:120, 1:25 to about 1:110, about 1:25 to about 1:100, about 1:25 to about 1:90, about 1:25 to about 1:80, about 1:25 to about 1:70, about 1:25 to about 1:60, about 1:25 to about 1:50, about 1:25 to about 1:40, about 1:25 to about 1:30. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the molar ratio between Attorney Docket No.: 15691.0016-00304 the 3MMC and the N-acylethanolamine is between 1:50 to about 1:150, about 1:50 to about 1:140, about 1:50 to about 1:130, about 1:50 to about 1:120, 1:50 to about 1:110, about 1:50 to about 1:100, about 1:50 to about 1:90, about 1:50 to about 1:80, about 1:50 to about 1:70, or about 1:50 to about 1:60. In certain embodiments, the molar ratio between the 3MMC and the N-acylethanolamine is about 1:75 to about 1:150, about 1:75 to about 1:140, about 1:75 to about 1:130, about 1:75 to about 1:120, 1:75 to about 1:110, about 1:75 to about 1:100, about 1:75 to about 1:90, about 1:75 to about 1:80. In certain embodiments, the molar ratio between the 3MMC and the N-acylethanolamine is about 1:100 to about 1:150, about 1:100 to about 1:140, about 1:100 to about 1:130, about 1:100 to about 1:120, or 1:100 to about 1:110. In certain embodiments, the molar ratio between the 3MMC and the N-acylethanolamine is about 1:110 to about 1:150, about 1:110 to about 1:140, about 1:110 to about 1:130, about 1:110 to about 1:120. In certain embodiments, the molar ratio between the 3MMC and the N-acylethanolamine is about 1:90 to about 1:150, about 1:90 to about 1:140, about 1:90 to about 1:130, about 1:90 to about 1:120, 1:90 to about 1:110, about 1:90 to about 1:100. In certain embodiments, the molar ratio between the 3MMC and the N-acylethanolamine is about 1:80 to about 1:150, about 1:80 to about 1:140, about 1:80 to about 1:130, about 1:80 to about 1:120, 1:80 to about 1:110, about 1:80 to about 1:100, or about 1:80 to about 1:90. In certain embodiments, the molar ratio between the 3MMC and the N- acylethanolamine is about 1:40 to about 1:150, about 1:40 to about 1:140, about 1:40 to about 1:130, about 1:40 to about 1:120, 1:40 to about 1:110, about 1:40 to about 1:100, about 1:40 to about 1:90, about 1:40 to about 1:80, about 1:40 to about 1:70, about 1:40 to about 1:60, or about 1:40 to about 1:50. Each possibility represents a separate embodiment of the present disclosure. In any of the above embodiments, the N- acylethanolamine is PEA or a salt thereof.

[0054] In certain embodiments, without being bound by theory, the N- acylethanolamine increases the therapeutic potency of the 3MMC compared to the same pharmaceutical composition without the N-acylethanolamine. In certain embodiments, the N-acylethanolamine decreases the required therapeutic dosage of the 3MMC compared to the same pharmaceutical composition without the N- acylethanolamine. In certain embodiments, the N-acylethanolamine expands the therapeutic window of the 3MMC compared to the same pharmaceutical composition without the N-acylethanolamine. Formulations Attorney Docket No.: 15691.0016-00304

[0055] In various embodiments, formulations suitable for oral administration 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 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.

[0056] 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.

[0057] For solid compositions, 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. In some embodiments, 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. For example, 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 Attorney Docket No.: 15691.0016-00304 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. et al, "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science Et Technology, 51 (4), 166-171 (1997).

[0058] 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 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. These 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.

[0059] 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. A variety of 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. More generally, the preparation can take a solid, semi-solid, or liquid form.

[0060] 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. For example, a commercially available spray pump with a delivery volume of 50 or 100 μL is available from, for example, Valois (Congers, N.Y.) with spray tips in adult size and pediatric size. In one embodiment, the composition comprised of 3MMC via an aerosol spray in a daily volume of between about 10 ml to 100mL. Attorney Docket No.: 15691.0016-00304

[0061] The liquid preparation can be produced by known procedures. For example, 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. Exemplary 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.

[0062] In certain embodiments, the pharmaceutical composition is formulated for systemic administration. In certain embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration. In certain embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the pharmaceutical composition is formulated for oral administration. In certain embodiments, the pharmaceutical composition is formulated for oral mucosal administration. In certain embodiments, the pharmaceutical composition is formulated for nasal administration. In certain embodiments, the pharmaceutical composition is formulated for sublingual administration.

[0063] In some embodiments of the present disclosure, 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.

[0064] 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 Attorney Docket No.: 15691.0016-00304 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, phosphoric acid which affords a phosphoric acid addition salt, toluenesulfonic acid which affords a p-toluenesulfonic acid addition salt, succinic acid which affords a succinic acid addition salt, sulfuric acid which affords a sulfuric acid addition salt, tartaric acid which affords a tartaric acid addition salt and trifluoroacetic acid which affords a trifluoroacetic acid addition salt. Each of these acid addition salts can be either a mono-addition salt or a poly-addition salt, as these terms are defined herein.

[0065] In some embodiments, 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. Examples of 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.

[0066] Depending on the stoichiometric proportions between the basic or acidic charged group(s) in the compound (e.g., amine group(s)) and the counter-ion in the salt, the acid or base additions salts can be either mono-addition salts or poly-addition salts.

[0067] 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. The phrase “poly-addition salt”, as used herein, 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.

[0068] Further, in any one of the embodiments disclosed herein, a compound disclosed herein, including a salt thereof, may be in a form of a solvate or a hydrate thereof. The term “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. The term “hydrate” refers to a solvate where the solvent is water. Attorney Docket No.: 15691.0016-00304

[0069] Techniques for formulation are well known in the art, and may be found, e.g. in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa. Pharmaceutical 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.

[0070] 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. In soft capsules, the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Formulations for oral administration may be in dosages suitable for the chosen route of administration. For buccal and sublingual administration, the compositions may take the form of tablets or lozenges formulated in conventional manner or in adhesive carriers. Alternatively, 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

[0071] In some embodiments, the present disclosure provides methods for treating dyskinesia by administering any one or more of the compositions and formulations discussed above. In some embodiments, dyskinesia may include tremor, chorea, dystonia, myoclonus, and / or torticollis. In some embodiments, dyskinesia may include dyskinesia associated with Parkinson’s disease. In some embodiments, the dyskinesia is tardive dyskinesia. In some embodiments, dyskinesia may include dyskinesia associated with myoclonus. In some embodiments, dyskinesia may include dyskinesia associated with Tourette syndrome.

[0072] In some embodiments, the tardive dyskinesia is a result of one or more antipsychotic medicines (i.e. neuroleptics), e.g., used to treat mental illnesses. In some embodiments, the mental illness is selected from schizophrenia, schizoaffective disorder, bipolar disorder, distress, anxiety disorders and seasonal affective disorder. In some embodiments, the antipsychotic medicines are selected from the group comprising chlorpromazine, haloperidol, fluphenazine, zuclopentixol, biperiden, paliperdone, dopamine-2 (D2) receptor-blockers, aripiprazole, olanzapine, quetiapine and amisulpride. Attorney Docket No.: 15691.0016-00304

[0073] In some embodiments, the pharmaceutical composition comprising 3MMC or pharmaceutically acceptable salt thereof is administered daily. In some embodiments, the pharmaceutical composition comprising 3MMC or pharmaceutically acceptable salt thereof is administered twice, three times, four times, or five times daily. In some embodiments, a treatment disclosed above is administered on demand, e.g., self-administered, based on the patient’s experience of TD 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.

[0074] The amount of 3MMC 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. In some embodiments, the 3MMC is administered intermittently, such as on a monthly or yearly basis. In some embodiments, the 3MMC is administered as needed to treat the TD as determined by the subject. In some embodiments, the 3MMC is administered for a period of time sufficient to treat dyskinesia, which may range from within one day to one or more years, depending on the severity of the symptoms and responsiveness to treatment. In some embodiments, a nasal spray dosage of 3MMC may be administered after the administration of an oral dosage. For instance, after an initial oral dose of 3MMC has been administered at a patient’s rising, a nasal spray dosage of 3MMC may be administered to the patient at a later point of time during the day. In some embodiments, nasal spray dosing may comprise 3 to 10 doses per day.

[0075] In some embodiments, the present disclosure provides a composition comprising a therapeutically effective amount of 3MMC, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, e.g., any of those discussed above, for use in preventing dyskinesia, e.g., tardive dyskinesia, in a subject in need, or for preventing and / or reducing one or more symptoms of dyskinesia, e.g., tardive dyskinesia.

[0076] In some embodiments, the present disclosure provides a composition comprising a therapeutically effective amount of 3MMC, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, e.g., any of those discussed above, for use in treating tardive dyskinesia in a subject in need, or for treating and / or reducing one or more symptoms of tardive dyskinesia. In some embodiments, the present disclosure provides a method of treating tardive dyskinesia comprising administering to a subject in need thereof a therapeutically effective amount Attorney Docket No.: 15691.0016-00304 of a pharmaceutical composition comprising 3-MMC or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the present disclosure provides a composition comprising a therapeutically effective amount of 3MMC, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier, in combination with N-acylethanolamines, or pharmaceutically acceptable salts thereof, for example, palmitoylethanolamide (“PEA”), e.g., any of those discussed above, to prevent dyskinesia, or prevent and / or reduce one or more symptoms of dyskinesia. In some embodiments, the type of dyskinesia is tardive dyskinesia.

[0078] In some embodiments, the present disclosure provides a composition comprising a therapeutically effective amount of 3MMC and at least one pharmaceutically acceptable carrier, in combination with N-acylethanolamines, or pharmaceutically acceptable salts thereof, for example, palmitoylethanolamide (“PEA”), e.g., any of those discussed above, to treat dyskinesia, or treat and / or reduce or one or more symptoms of dyskinesia.

[0079] In some embodiments, the present disclosure provides methods for treating tardive dyskinesia or for reducing one or more symptoms of dyskinesia by administering a composition disclosed herein. In some embodiments, the composition comprises 3MMC or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises 3MMC or a pharmaceutically acceptable salt thereof and an N-acylethanolamine or a pharmaceutically acceptable salt thereof. In some embodiments, the N-acylethanolamine or a pharmaceutically acceptable salt thereof is PEA or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt. In some embodiments, the salt is 2-(methylamino)-1-(3-methylphenyl)-1-propanone, monohydrochloride. In some embodiments, the salt is a hydrobromide, sulphate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate or gluconate salt. In certain embodiments, the N- acylethanolamine consists of PEA.

[0080] In some embodiments, the present disclosure relates to methods of using any of the pharmaceutical compositions disclosed above for corrective treatment of medication-induced dyskinesia. In some embodiments, the present disclosure relates to methods of using the pharmaceutical compositions for corrective treatment of antipsychotic-induced dyskinesia.

[0081] In some embodiments, the methods disclosed herein further comprise administering one or more additional therapeutic agents. In some embodiments, the one Attorney Docket No.: 15691.0016-00304 or more additional therapeutic agents may comprise taurine or taurine derivatives, memantine or a similar NMDA receptor blocker, and / or acamprostate.

[0082] In some embodiments, the methods disclosed herein comprise delivering a nasal spray formulation for treating tardive dyskinesia in a subject in need, comprising the steps of: providing a spray of 3MMC having a saline solution formulation in a concentration of 0.003M to 0.009MM, delivering a spray of said formulation to a subject’s nose having a spray characteristic comprising droplets with a size distribution having a D10 of X μm, a D50 of Y μm, a D90 of Z μm, a SPAN of not more than W, and a % volume of <P μm of less than V%, said formulation having a viscosity of Q cps; wherein the nasal spray formulation comprises a therapeutically effective amount of 3MMC or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0083] In some embodiments, the methods disclosed herein reduce tardive dyskinesia, e.g., as measured by a change in the Abnormal Involuntary Movement Scale (AIMS), e.g., by at least 1-3 points. In some embodiments, the present disclosure provides a method of reducing tardive dyskinesia as measured by a standardized mean difference for a change in the Abnormal Involuntary Movement Scale (AIMS), e.g., by at least 1-3 points. The AIMS test has a total of twelve items rating involuntary movements of various areas of the patient's body. These items are rated on a five-point scale of severity from 0–4. The scale is rated from 0 (none), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe). A rating of 2 or higher on the AIMS scale may provide evidence of tardive dyskinesia. Definitions

[0084] As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0085] The term "about" as used herein in relation to a value, a plurality of values or a range of values defined by a lowest and highest values means a value which is 10% lower and / or higher than the corresponding value, plurality of values or range of values. For example, 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", and 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 Attorney Docket No.: 15691.0016-00304 there between, depending on the nature of the parameter and measurement. In some embodiments, the term "about" when used with regard to a dose amount means that the dose may vary by + / - 10%. When a range of values is listed, it is intended to encompass each value and sub-range within the range.

[0086] 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.

[0087] The term "carrier" as used herein 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.

[0088] 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.

[0089] The term “dyskinesia” used herein means the development in a subject of abnormal involuntary movements. These movements may manifest as chorea (irregular, involuntary movements of the body, especially the face and extremities) or dystonia (disorder or lack of muscle tonicity). Such movements include ballistic movements and athetoid movements of the trunk, limbs and facial musculature. Dyskinesia may be either acute or tardive.

[0090] 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. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, 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. Attorney Docket No.: 15691.0016-00304

[0091] The term "excipient" as used herein refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Examples, without limitation, of 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.

[0092] As used herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.

[0093] The phrase "pharmaceutically acceptable" as used herein 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. Preferably, and particularly where a formulation is used in humans, 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).

[0094] The phrase "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.

[0095] The phrase “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.

[0096] The phrase "pharmaceutical 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.

[0097] The term “preventing” as used herein, 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 onset. The term "salt" as used herein 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. Attorney Docket No.: 15691.0016-00304

[0098] As used herein, the term "subject" refers to a warm-blooded animal, such as a human that would benefit biologically, medically or in quality of life from a treatment.

[0099] The term "treating" as used herein, 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.

[0100] The phrase “unit dose” as used herein 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.

[0101] When a range of values is listed, it is intended to encompass each value and sub-range within the range.

[0102] The dimensions and values disclosed herein are not to be understood as being strictly limited to the exact numerical values recited. Instead, unless otherwise specified, each such dimension is intended to mean both the recited value and a functionally equivalent range surrounding that value. For example, a dimension disclosed as "10 μm" is intended to mean "about 10 μm".

[0103] Whenever 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.

[0104] Toxicity and therapeutic efficacy may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (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 LD50 / ED50. Compositions that exhibit large therapeutic indices are preferable.

[0105] 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. Reports 50(4):219-244 (1966) and the following Table for Equivalent Surface Area Dosage Factors). Attorney Docket No.: 15691.0016-00304 Table 1. Equivalent Surface Area Dosage Factors. To: Mouse Rat Monkey Dog Human From: (20 g) (150 g) (3.5 kg) (8 kg) (60 kg) Mouse 1 ½ 1 / 4 1 / 6 1 / 12 Rat 2 1 1 / 2 1 / 4 1 / 7 Monkey 4 2 1 3 / 5 1 / 3 Dog 6 4 3 / 5 1 1 / 2 Human 12 7 3 2 1

[0106] The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Generally, 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.

[0107] While the present disclosure has been described with reference to certain embodiments, it will be understood by those skilled in the art that various changes may be made, and equivalents may be substituted without departing from the scope of the present disclosure. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the present disclosure without departing from its scope. Therefore, it is intended that the present disclosure is not limited to the particular embodiment disclosed, but that the present disclosure will include all embodiments falling within the scope of the appended claims. Examples

[0108] The examples and preparations provided below further illustrate and exemplify the compounds as disclosed herein and methods of preparing such compounds. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations. Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples. Example 1:

[0109] Patient 1 is a 45-year-old male in psychiatric treatment for 8 years. Tardive dyskinesia occurred following 2 days of sleep deprivation and excessive alcohol and cocaine use. TD presented as uncontrollable shaking of the right hand. Attorney Docket No.: 15691.0016-00304

[0110] A single oral dose of 50 mg of 3MMC resulted in rapid alleviation of the symptoms of TD, as well as a sense of calmness and introspection. Further administration of 3MMC was not documented. Example 2:

[0111] Patient 2 is a 31 year old male in psychiatric treatment for 5 years. Patient 2 was diagnosed with bipolar disorder I as well as addiction to cannabis and cocaine. Patient 2 noted severe, moderate and mild involuntary movements of the facial muscles including jaw clenching and tongue sucking as well as neck and hand tremors over the period of 3 months which occurred in response to periods of insomnia, in states of “daydreaming” (absence of concentrated awareness), combined cannabis use and stressful situations, reflecting on past traumas and withdrawal from antipsychotics as well as during treatment by antipsychotics.

[0112] Following withdrawal of catecholaminergic medication, Patient 2 followed a regimen of self-administered initial doses of 3MMC ranging from 64mg to 256 mg. This treatment regimen resulted in effective and swift reduction of his symptoms of TD from moderate and severe to minimal and mild involuntary movements of the arms and neck. Patient 2 noted that 3MMC was most effective for him when administered after morning meal and exercise (e.g. cycling).

[0113] Patient 2 typically took an initial dose of 128 mg-256 mg orally after rising, and used a nasal spray with 25.6 mg / ml 3MMC in water every 0.5-1.5 hours, which provided greatest relief for Patient 2. Patient 2 noted that exceeding this regimen had little effect in improving his symptoms, and that higher doses may even reduce the potency of the 3MMC for addressing the symptoms of TD. Example 3:

[0114] Patient 3 is a 60-year-old male who has been diagnosed with Schizophrenia, and abusive drug use (including amphetamines, cannabis, and cocaine). Patient 3 was treated for the Schizophrenia with various medications over the course of 12 years, resulting in dependency on antipsychotics including Olanzapine, Trevecta, Risperidal, Paliperidone, Aripropazol and Haldol. Patient 3 suffers from TD symptoms including tongue protrusions, grimacing of the face and involuntary neck movements.

[0115] Patient 3 typically took an initial oral dose of 128mg of 3MMC following rising, and then used 3MMC nasal spray for maintenance. Typically, patient 3 administered the 3MMC in a nasal spray consisting of 256mg in 10ml (25.6mg / ml) every 0.5-1.5 hours, resulting in anywhere from 3 to 10 doses nasally per day. Attorney Docket No.: 15691.0016-00304

[0116] Patient 3 noted that 3MMC treatments facilitate coping with symptoms stemming from the use of and withdrawal from prescribed antipsychotics, and most importantly, alleviated the tendency towards suicidal thoughts. Example 4:

[0117] Patient 4 is a 67-year-old female in psychiatric treatment for more than 10 years. Tardive Dyskinesia occurred in Patient 4 following administration and during the course of treatment through depot which releases a small amount of anti-psychotic medication every day during the month (Trevecta, 100mg), manifesting in shaking of the hands and uncontrollable jaw movements, along with excessive salivation and labored breathing.

[0118] After an initial oral dose of 64-256 mg with rising, Patient 4 followed with nasal administration of 3MMC suspension (12.8 mg / ml), provided in two sprays of 5 ml in each nostril, which was effective in swiftly alleviating the symptoms of TD which on the Abnormal Involuntary Movement Scale (AIMS) reduced the score from 4 = severe distress and movement from to 1=minimal and 2=mild distress and involuntary movement. Patient 4 noted that she became more aware of involuntary movements and was better able to apply conscious effort to cope with them through treatment. Thus, 3MMC allowed patient 4 to reduce the frequency of occurrence of involuntary movements and their impact on her life. Example 5:

[0119] Patient 5 is a 28-year-old female in psychiatric treatment for 6 years. Patient 5 was diagnosed as Bipolar Disorder type I and suffered bouts of over 3 months of depression. Tardive Dyskinesia occurred in Patient 5 following administration of a monthly depot of antipsychotic medication, including most recently Olanzapine and historically antipsychotics including Trivecta and Citalopram. In Patient 5 TD manifested in severe shaking of the arms and head.

[0120] Patient 5’s TD symptoms were alleviated from severe to minimal and mild in distress and frequency of occurrence following access to at-will nasal administration of 3MMC suspension (via a nasal spray). Patient 5 continued prophylactic and / or symptom-related self-administration of 3MMC nasal spray following release to home care. Example 6:

[0121] Patient 6 is a 24-year-old female in psychiatric treatment for 8 years. Tardive Dyskinesia occurred in Patient 6 following years of treatment with dopamine blockers and traditional antipsychotics of which the most recent is Haldol and is often Attorney Docket No.: 15691.0016-00304 triggered by appearing in public and / or returning to locations or situations that have triggered TD in the past. Patient 6 has been treated for her schizophrenia by other antipsychotics and neuroleptics including Zuclopenthixol and Prozac.

[0122] Patient 6 also noticed that her symptoms of moderate bouts of involuntary movements over the course of 3 months went from a scale of 4 to 1 on the Abnormal Involuntary Movement Scale (AIMS) with administration of 30-50 mg / day of 3MMC in a nasal spray, over the course of 3 months. Patient 6 was given the choice of up to 5 nasal spray medication moments a day, each comprising of 10mg. Patient 6 sprays approximately 4mg in each nostril every 30 minutes throughout the first part of the day, stopping approximately 3 hours before retiring at bedtime.

[0123] Patient 6 also noted therapeutic benefits of 3MMC administration in conjunction with Cognitive Behavioural Therapy (CBT) and (PMT) Psycho-Motor Therapy. Patient 6 reported that 3MMC caused immediate alleviation of the TD symptoms, better enabling the CBT to aid her in coping with the TD. Example 7:

[0124] Patient 7 is a 26-year-old female in psychiatric treatment for Schizophrenia for 1.5 years. Tardive Dyskinesia occurred in Patient 7 following elevated doses of, or extended treatment with medications including Lithium, Depakine, Diazepam, Seroquel and Risperidone. Patient 7 experienced severe shaking of arms, legs and head, as well as uncontrollable jaw, tongue and lip movements. Patient 7 also reported using approx.1 gram of cocaine / day (“to maintain sociability”), withdrawal of which leads to anxiety and panic attacks, exacerbating her TD symptoms. These resulted in involuntary movements that cause severe, moderate and mild distress and involuntary movement. These also occurred during sleep and lead to insomnia.

[0125] Oral administration of 50-80 mg of 3MMC was effective in relieving the TD symptoms for Patient 7. After initial oral administration, Patient 7 self-administered occasional nasal insufflations (8 mg) as needed (in response to recurrence of the TD symptoms). Patient 7 also noted that the 3-MMC boosts his self-confidence and rendered the “voices I experience[d]” from the Schizophrenia more bearable. Example 8:

[0126] Patient 8 is a 53-year-old male out-patient in psychiatric treatment for 16 years. Tardive Dyskinesia occurred in Patient 8 following administration of antipsychotic medication (e.g. Cicordinon), resulting in uncontrollable shaking of the head and neck as well as jaw, lips and tongue. Attorney Docket No.: 15691.0016-00304

[0127] Administration of Akineton (biperiden) was ineffective in controlling TD symptoms. In contrast, nasal administration of 3MMC was effective in relieving the TD symptoms for Patient 8. Typically, Patient 8 begins the day with an orally administered initial dose of 128 mg of 3MMC and maintenance for recurrence of TD symptoms via 3MMC nasal spray, and further re-dosing, as per need, with nasal spray of 25.6mg / ml 3MMC in suspension.

[0128] Taken together, these data show the clinical efficacy of 3MMC administration for Tardive Dyskinesia. In particular, patients who have adopted a regimen of initial oral administration of relatively larger doses (64-256 mg) followed by occasional nasal administration of smaller doses (4-25 mg) through the remainder of the day and in response to perceived TD triggers, have reported significant relief of the TD symptoms, and reduced dependence on traditional pharmacological anti-psychotic and psychotropic medication.

Claims

Attorney Docket No.: 15691.0016-00304 WHAT IS CLAIMED IS:

1. A method of treating or improving at least one symptom associated with dyskinesia, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 3-Methylmethcathinone (3-MMC), or a pharmaceutically acceptable salt thereof.

2. A method of treating or improving at least one symptom associated with dyskinesia, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 3-Methylmethcathinone (3-MMC), or a pharmaceutically acceptable salt thereof, and an N-acylethanolamine, or a pharmaceutically acceptable salt thereof, preferably PEA or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 or 2, wherein the composition is a unit dosage form composition.

4. The method of any one of claims 1 to 3, wherein the pharmaceutical composition is a solid or liquid form composition.

5. The method of any one of claims 1 to 4, wherein the pharmaceutical composition is a nasal spray formulation.

6. The method of claim 5, wherein the nasal spray formulation is capable of providing 3 to 10 doses.

7. The method of claim 1, wherein the 3-MMC is in an amount of about 0.1 mg to about 270 mg.

8. The method of claim 1, wherein the pharmaceutical composition is packaged as a single unit dose or as a plurality of single unit doses, and wherein the unit dosage form comprises from 20 to 1000 mg of 3-MMC, or a pharmaceutically acceptable salt thereof.

9. The method of claim 1, wherein the unit dosage form comprises from about 0.2 mg / kg to 10.0 mg / kg body weight of 3-MMC, or a pharmaceutically acceptable salt thereof.

10. The method of claim 1, wherein the pharmaceutical composition is a free- flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, or a syrup.

11. The method of any one of claims 1 and 3-10, further comprising an N- acylethanolamine, or a pharmaceutically acceptable salt thereof, preferably wherein the N-acylethanolamine is selected from N palmitoylethanolamine (PEA), Me- palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, or aAttorney Docket No.: 15691.0016-00304 pharmaceutically acceptable salt thereof, preferably wherein the N-acylethanolamine is PEA, or a pharmaceutically acceptable salt thereof.

12. The method of any one of claims 2-10, wherein the N-acylethanolamine is selected from N palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, or a pharmaceutically acceptable salt thereof, preferably wherein the N-acylethanolamine is PEA, or a pharmaceutically acceptable salt thereof.

13. The method of any one of claims 2-12, wherein the 3-MMC, or pharmaceutically acceptable salt thereof is present in an amount of about 0.1 mg to about 270 mg, and / or the N-acylethanolamine, or a pharmaceutically acceptable salt thereof, ranges from 200 to 1800 mg, preferably wherein the N-acylethanolamine is PEA.

14. The method of any one of claims 3-13, wherein the unit dosage form comprises 20 to 300 mg of 3-MMC or a pharmaceutically acceptable salt thereof, and / or the unit dosage form comprises 200 to 1800 mg of N-acylethanolamine, or a pharmaceutically acceptable salt thereof, preferably wherein the N-acylethanolamine is PEA.

15. The method of any one of claims 3-14, wherein the unit dosage form comprises from about 0.2 mg / kg to 10.0 mg / kg body weight of 3-MMC, or a pharmaceutically acceptable salt thereof, and / or the unit dosage form comprises from 2.5 mg / kg to 36 mg / kg body weight of N-acylethanolamine, or pharmaceutically acceptable salt thereof, preferably wherein the N-acylethanolamine is PEA.

16. The method of any one of claims 1 to 15, wherein the subject has a preexisting condition, wherein the condition is schizophrenia, bipolar disorder, depression, suicidal ideation, alcohol abuse, drug abuse, or sleep deprivation.

17. The method of any one of claims 1-16, where the at least one symptom comprises insomnia, involuntary muscle movements, tremor, tongue protrusions, grimacing, daydreaming, and / or suicidal thoughts.

18. The method of any one of claims 1-17, wherein the subject has drug induced dyskinesia.

19. The method of claim 18, wherein the drug is selected from Olanzapine, Trevecta, Risperidal, Paliperidone, Aripropazol, Citalopraom, Haldol, Zuclopenthixol, Prozac, Lithium, Depakine, Diazepam, Cicordinon, and / or Seroquel.

20. The method of claim 18, wherein the drug is an antipsychotic agent.Attorney Docket No.: 15691.0016-00304 21. The method of any one of claims 1-20, wherein the subject has tardive dyskinesia.

22. The method of any one of claims 1-21, wherein the administration is for a period of time sufficient to treat dyskinesia.

23. The method of any one of claims 1-22, wherein the subject is administered an oral and / or nasal dose of the pharmaceutical composition.

24. The method of any one of claims 1-23, wherein the subject is administered a unit dose of the pharmaceutical composition.

25. The method of claim 22 or 23, wherein the subject is administered a nasal spray of the pharmaceutical composition, preferably 3 to 10 doses per day.

26. The method of claim 25, wherein the subject is administered a nasal spray dose of the pharmaceutical composition after having been administered an oral dose of the pharmaceutical composition.

27. The method of any one of claims 1-26, wherein the subject is administered a single unit dose or a plurality of single unit doses of the pharmaceutical composition.

28. The method of any one of claims 1-27, wherein the 3-MMC, or a pharmaceutically acceptable salt thereof, is administered to the subject in an amount of about 0.1 mg to about 260 mg.

29. The method of any one of claims 1-28, wherein the pharmaceutical composition comprises about 20 mg / ml to 300 mg / ml of 3MMC or a pharmaceutically acceptable salt thereof.

30. The method of any one of claims 2-29, wherein the N-acylethanolamine, or a pharmaceutically acceptable salt thereof is PEA or a pharmaceutically acceptable salt thereof.

31. The method of any one of claims 2-30, wherein the 3-MMC, or a pharmaceutically acceptable salt thereof, and the N-acylethanolamine, or a pharmaceutically acceptable salt thereof, are administered in a single composition or in simultaneous or sequential compositions.

32. The method of any one of claims 2-31, wherein the pharmaceutical composition comprises about 200 to 1800 mg of N-acylethanolamine, or a pharmaceutically acceptable salt thereof, preferably wherein the N-acylethanolamine is PEA.

33. The method of any one of claims 2-32, wherein the subject is administered about 2.5 mg / kg to 36 mg / kg body weight of the N-acylethanolamine, orAttorney Docket No.: 15691.0016-00304 pharmaceutically acceptable salt thereof, preferably wherein the N-acylethanolamine is PEA.

34. The method of any one of claims 1-33, wherein the pharmaceutical composition is administered at least daily.

35. The method of any one of claims 1-34, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

36. The method of any one of claims 1-35, wherein the pharmaceutical composition is a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, a syrup, or other format suitable for oral and / or nasal administration.

37. A pharmaceutical composition comprising 3-Methylmethcathinone (3- MMC), or a pharmaceutically acceptable salt thereof, an N-acylethanolamine, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier and / or excipient.

38. The pharmaceutical composition of claim 37, wherein the composition is a unit dosage form composition.

39. The pharmaceutical composition of claim 37 or 38, wherein the pharmaceutical composition is a solid or liquid form composition.

40. The pharmaceutical composition of any one of claims 37 to 39, wherein the pharmaceutical composition is a nasal spray formulation.

41. The pharmaceutical composition of claim 40, wherein the nasal spray formulation is capable of providing 3 to 10 doses.

42. The pharmaceutical composition of claim 37 or 38, wherein the 3-MMC is in an amount of about 0.1 mg to about 270 mg.

43. The pharmaceutical composition of claim 38, wherein the pharmaceutical composition is packaged as a single unit dose or as a plurality of single unit doses, and wherein the unit dosage form comprises from 20 to 1000 mg of 3-MMC, or a pharmaceutically acceptable salt thereof.

44. The pharmaceutical composition of claim 38, wherein the unit dosage form comprises from about 0.2 mg / kg to 10.0 mg / kg body weight of 3-MMC, or a pharmaceutically acceptable salt thereof.

45. The pharmaceutical composition of any one of claims 37-44, wherein the N-acylethanolamine is selected from N palmitoylethanolamine (PEA), Me- palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, or aAttorney Docket No.: 15691.0016-00304 pharmaceutically acceptable salt thereof, preferably wherein the N-acylethanolamine is PEA, or a pharmaceutically acceptable salt thereof.

46. The pharmaceutical composition of claim 45, wherein the N- acylethanolamine is PEA or a pharmaceutically acceptable salt thereof.

47. The pharmaceutical composition of any one of claims 37-46, wherein the pharmaceutical composition is formulated for oral administration.

48. The pharmaceutical composition of any one of claims 37-47, wherein the 3-MMC, or pharmaceutically acceptable salt thereof is present in an amount of about 0.1 mg to about 270 mg, and / or the N-acylethanolamine, or a pharmaceutically acceptable salt thereof, ranges from 200 to 1800 mg, preferably wherein the N- acylethanolamine is PEA.

49. The pharmaceutical composition of any one of claims 38 to 48, wherein the unit dosage form comprises 20 to 300 mg of 3-MMC or a pharmaceutically acceptable salt thereof, and / or the unit dosage form comprises 200 to 1800 mg of N- acylethanolamine, or a pharmaceutically acceptable salt thereof, preferably wherein the N-acylethanolamine is PEA.

50. The pharmaceutical composition of any one of claims 38 to 48, wherein the unit dosage form comprises from about 0.2 mg / kg to 10.0 mg / kg body weight of 3- MMC, or a pharmaceutically acceptable salt thereof, and / or the unit dosage form comprises from 2.5 mg / kg to 36 mg / kg body weight of N-acylethanolamine, or pharmaceutically acceptable salt thereof, preferably wherein the N-acylethanolamine is PEA.

51. The pharmaceutical composition of any one of claims 37 to 50, wherein the pharmaceutical composition is a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, or a syrup.

52. A composition comprising 3-Methylmethcathinone (3-MMC), or a pharmaceutically acceptable salt thereof for use in a method of treating or improving at least one symptom associated with dyskinesia, the method comprising administering to a subject in need thereof a therapeutically effective amount of the composition.

53. The composition for use according to claim 52, wherein the composition is a unit dosage form composition.

54. The composition for use according to claims 52 or 53, wherein the pharmaceutical composition is a solid or liquid form composition.

55. The composition for use according to any one of claims 52 to 54, wherein the pharmaceutical composition is a nasal spray formulation.Attorney Docket No.: 15691.0016-00304 56. The composition for use according to claim 55, wherein the nasal spray formulation is capable of providing 3 to 10 doses.

57. The composition for use according to claim 52, wherein the 3-MMC is in an amount of about 0.1 mg to about 270 mg.

58. The composition for use according to claim 55, wherein the pharmaceutical composition is packaged as a single unit dose or as a plurality of single unit doses, and wherein the unit dosage form comprises from 20 to 1000 mg of 3-MMC, or a pharmaceutically acceptable salt thereof.

59. The composition for use according to claim 55, wherein the unit dosage form comprises from about 0.2 mg / kg to 10.0 mg / kg body weight of 3-MMC, or a pharmaceutically acceptable salt thereof.

60. The composition for use according to claim 55, wherein the pharmaceutical composition is a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, or a syrup.

61. A composition comprising 3-Methylmethcathinone (3-MMC), or a pharmaceutically acceptable salt thereof, and an N-acylethanolamine, or a pharmaceutically acceptable salt thereof, preferably PEA or a pharmaceutically acceptable salt thereof, for use in a method of treating or improving at least one symptom associated with dyskinesia, the method comprising administering to a subject in need thereof a therapeutically effective amount of the composition, e.g. the composition of any one of claims 37-51.

62. The composition for use according to any one of claims 55 to 61, wherein the subject has a preexisting condition, wherein the condition is schizophrenia, bipolar disorder, depression, suicidal ideation, alcohol abuse, drug abuse, or sleep deprivation.

63. The composition for use according to any one of claims 55 to 61, wherein the at least one symptom comprises insomnia, involuntary muscle movements, tremor, tongue protrusions, grimacing, daydreaming, and / or suicidal thoughts.

64. The composition for use according to any one of claims 55-63, wherein the subject has drug induced dyskinesia.

65. The composition for use according to claim 64, wherein the drug is selected from Olanzapine, Trevecta, Risperidal, Paliperidone, Aripropazol, Citalopraom, Haldol, Zuclopenthixol, Prozac, Lithium, Depakine, Diazepam, Cicordinon, and / or Seroquel.

66. The composition for use according to claim 64, wherein the drug is an antipsychotic agent.Attorney Docket No.: 15691.0016-00304 67. The composition for use according to any one of claims 55-66, wherein the subject has tardive dyskinesia.

68. The composition for use according to any one of claims 55-67, wherein the administration is for a period of time sufficient to treat dyskinesia.

69. The composition for use according to any one of claims 55-68, wherein the subject is administered an oral and / or nasal dose of the composition.

70. The composition for use according to any one of claims 55-69, wherein the subject is administered a unit dose of the composition.

71. The composition for use according to any one of claims 55 to 70, wherein the subject is administered a nasal spray of the composition, preferably 3 to 10 doses per day.

72. The composition for use according to claim 71, wherein the subject is administered a nasal spray dose of the composition after having been administered an oral dose of the composition.

73. The composition for use according to any one of claims 55-72, wherein the subject is administered a single unit dose or a plurality of single unit doses of the composition.

74. The composition for use according to any one of claims 55-73, wherein the 3-MMC, or a pharmaceutically acceptable salt thereof, is administered to the subject in an amount of about 0.1 mg to about 260 mg.

75. The composition for use according to any one of claims 55-74, wherein the composition comprises from about 0.2 mg / kg to 10.0 mg / kg body weight of 3-MMC, or a pharmaceutically acceptable salt thereof.

76. The composition for use according to any one of claims 55-75, wherein the composition comprises about 20 mg / ml to 300 mg / ml of 3-MMC or a pharmaceutically acceptable salt thereof.

77. The composition for use according to any one of claims 55-76, wherein the N-acylethanolamine, or a pharmaceutically acceptable salt thereof is PEA or a pharmaceutically acceptable salt thereof.

78. The composition for use according to any one of claims 55-77, wherein the 3-MMC, or a pharmaceutically acceptable salt thereof, and the N-acylethanolamine, or a pharmaceutically acceptable salt thereof, are administered in a single composition or in simultaneous or sequential compositions.

79. The composition for use according to any one of claims 55-78, wherein the composition comprises about 200 to 1800 mg of N-acylethanolamine, or aAttorney Docket No.: 15691.0016-00304 pharmaceutically acceptable salt thereof, preferably wherein the N-acylethanolamine is PEA.

80. The composition for use according to any one of claims 55-79, wherein the subject is administered about 2.5 mg / kg to 36 mg / kg body weight of the N- acylethanolamine, or pharmaceutically acceptable salt thereof, preferably wherein the N-acylethanolamine is PEA.

81. The composition for use according to any one of claims 55-80, wherein the composition is administered at least daily.

82. The composition for use according to any one of claims 55-81, wherein the composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

83. The composition for use according to any one of claims 55-82, wherein the composition is a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, a syrup, or other format suitable for oral and / or nasal administration.

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