Compositions comprising 5-methoxy-2-aminoindan for treatment of depression

Abstract

The present disclosure relates to pharmaceutical compositions comprising 5- methoxy-2-aminoindan, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier and / or excipient, and their use in methods of 5 treating depression by administrating said compositions to a subject in need thereof in a therapeutically effective amount.

Description

[0001] COMPOSITIONS COMPRISING 5-METHOXY-2-AMINOINDAN FOR TREATMENT OF DEPRESSION Cross-Reference To Related Applications

[0002] [1] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 492,837, filed on March 29, 2023, the contents of which are incorporated herein in their entirety.

[0003] Field of the Disclosure

[0004] [2] The present disclosure relates to compositions and methods for treatment of depression. The present disclosure provides pharmaceutical compositions comprising 5-methoxy-2-aminoindan (“MEAI”), or pharmaceutically acceptable salts thereof, and methods for their use in treatment of depression.

[0005] Background of the Disclosure

[0006] [3] Depression, or Major Depressive Disorder (MDD), is among the most disabling of all medical disorders with a lifetime prevalence of approximately 17% (Kessler et aL, Arch Gen Psychiatry. 62(6):593-602 (2005)). It frequently appears early in life, can run a chronic course, and adversely affect the prognosis of other medical illnesses, such as coronary vascular disease, diabetes, and osteoporosis.

[0007] [4] Depression is characterized by depressed mood, and markedly diminished interest or pleasure in activities. Other symptoms include significant weight loss or weight gain, decrease or increase in appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate or indecisiveness, recurrent thoughts of death, suicidal ideation or suicidal attempts. A variety of somatic symptoms may also be present. Though depressive feelings are common, especially after experiencing setbacks in life, depressive disorder is diagnosed only when the symptoms reach a threshold and last at least two weeks. Depression can vary in severity from mild to very severe. It is most often episodic but can be recurrent or chronic. Some people have only a single episode, with a full return to premorbid function. However, more than 50 percent of those who initially suffer a single major depressive episode eventually develop another.

[0008] [5] Depression is more common in women than in men. The point prevalence of unipolar depressive episodes is estimated to be 1 .9% for men and 3.2% for women, and 5.8% of men and 9.5% of women will experience a depressive episode in a 12- month period. These prevalence figures vary across populations and may be higher in some populations. A World Health Organization study has reported that depression is the leading global cause of years of life lived with disability and the fourth leading cause of disability-adjusted life-years. Disability-adjusted life-years refers to the reduction in an individual's productive life and is a measure that takes into account premature mortality (Murray et al., Lancet. 349(9063):1436-1442 (1997)).

[0009] [6] Current medications for the treatment of depression unfortunately take weeks to months to achieve their full effects and in the meantime, patients continue to suffer from their symptoms and continue to be at risk of self-harm as well as harm to their personal and professional lives. Indeed, the lag period of onset of action of several weeks of traditional antidepressants is recognized as a major limitation, resulting in considerable morbidity and high risk of suicidal behavior especially in the first 9 days of starting antidepressants (Jick et aL, Jama. 292(3) :338-343 (2004)).

[0010] [7] Thus, there remains an unmet need to provide an effective and rapid treatment for depression after administration.

[0011] [8] Compounds derived from 2-aminoindan have been shown to selectively bind to the dopamine D3 receptor. U.S. Pat. No. 5,708,018 discloses some 2- aminoindan derivatives and hypothesizes that these 2-aminoindan derivatives may be useful in treating CNS disorders associated with dopamine D3 receptor. One such compound is 5-methoxy-2-aminoindan (“MEAI”), which the chemical formula is:

[0012] [9] 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).

[0013]

[0010] The term "N-acylethanolamine" as used herein generally refers to a type of fatty acid amide, lipid-derived signaling molecules, formed when one of several types of acyl group is linked to the nitrogen atom of ethanolamine. These amides may be formed from a fatty acid and ethanolamine with the release of a molecule of water, but the known biological synthesis uses a specific phospholipase D to cleave the phospholipid unit from N-acylphosphatidylethanolamines. The suffixes -amine and - amide in these names each refer to the single nitrogen atom of ethanolamine that links the compound together: it is termed "amine" in ethanolamine because it is considered as a free terminal nitrogen in that subunit, while it is termed "amide" when it is considered in association with the adjacent carbonyl group of the acyl subunit. Names for these compounds may be encountered with either "amide" or "amine" in the present application and are interchangeable in meaning. The term "ethanolamine" is used in the generic sense and is meant to include mono-ethanolamine, di-ethanolamine, triethanolamine, and mixtures thereof.

[0014]

[0011] 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 o nuclear factor agonists. The chemical structure of PEA is:

[0015] PEA has been demonstrated to bind to a receptor in the cell nucleus (a nuclear receptor) 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 is 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 PPAR (particularly PPAR-. alpha, and PPAR-.gamma.). PEA has an affinity to cannabinoid-like G-coupled receptors GPR55 and GPR1 19 as well as the transient receptor potential vanilloid type 1 receptor (TRPV1 ). PEA has been shown to have anti-inflammatory, antinociceptive, neuro-protective, and anti-convulsant properties.

[0016] Summary of the Disclosure

[0017]

[0012] The present disclosure provides pharmaceutical compositions comprising MEAI, or pharmaceutically acceptable salts thereof. The present disclosure also provides pharmaceutical compositions comprising combinations of MEAI, or salts thereof, and N-acylethanolamines, or salts thereof. In some embodiments, the N- acylethanolamine or salt thereof is PEA or a salt thereof. In some embodiments, these compositions comprise dosages and may be employed in a variety of methods. Particularly, the present disclosure provides methods for preventing and / or treating depression.

[0013] The present disclosure provides, in one aspect, a pharmaceutical composition comprising a therapeutically-effective amount of MEAI or a pharmaceutically acceptable salt thereof. The present disclosure also provides, in another aspect, a pharmaceutical composition comprising a therapeutically-effective amount of a combination of MEAI or a salt thereof and at least one N-acylethanolamine or a salt thereof, wherein the molar ratio between the MEAI and the N-acylethanolamine is between about 1 :0.2 to about 1 :1000. In any of the above embodiments, the N- acylethanolamine is PEA or a salt thereof.

[0018]

[0014] In certain embodiments, the molar ratio between the MEAI and the N- acylethanolamine is between about 1 :0.2 to about 1 :5. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is between about 1 :0.22 to about 1 :4.5, about 1 :0.25 to about 1 :4, between about 1 :0.28 to about 1 :3.5, between about 1 :0.33 to about 1 :3, between about 1 :0.4 to about 1 :2.5, between about 1 :0.5 to about 1 :2 or about 1 :1 . 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.

[0019]

[0015] In certain embodiments, the molar ratio between the MEAI and the N- acylethanolamine is between about 1 :15 to about 1 :1000. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is between about 1 :16 to about 1 :900, about 1 :17 to about 1 :800, about 1 :18 to about 1 :700, about 1 :19 to about 1 :600, about 1 :20 to about 1 :500, about 1 :21 to about 1 :480, or about 1 :22 to about

[0020] 1 :460. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is between about 1 :25 to about 1 :450. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is between about 1 :10 to about 1 :500, about 1 :15 to about 1 :450, about 1 :20 to about 1 :400, about 1 :25 to about 1 :350, about 1 :30 to about 1 :300, about 1 :35 to about 1 :250, about 1 :40 to about 1 :200, or about 1 :45 to about 1 :150. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the molar ratio between the MEAI and the N- acylethanolamine is between about 1 :50 to about 1 :100. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :10. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :20. In certain embodiments, the molar ratio between the MEAI and the N- acylethanolamine is about 1 :30. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :40. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :50. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :60. In certain embodiments, the molar ratio between the MEAI and the N- acylethanolamine is about 1 :70. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :80. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :90. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :100. In certain embodiments, the molar ratio between the MEAI and the N- acylethanolamine is about 1 :110. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :120. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :130. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :140. In certain embodiments, the molar ratio between the MEAI and the N- acylethanolamine is about 1 :150. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :160. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :170. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :180. In certain embodiments, the molar ratio between the MEAI and the N- acylethanolamine is about 1 :190. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :200. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is at least about 1 :10, at least about 1 :20, at least about 1 :30, at least about 1 :40, at least about 1 :50, at least about 1 :60, at least about 1 :70, at least about 1 :80, at least about 1 :90, or at least about 1 :100. 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.

[0021]

[0016] In certain embodiments, the pharmaceutical composition comprises a unit dose of about 20 to about 60 mg MEAI or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises a unit dose of about 25 mg, about 45 mg, or about 60 mg MEAI or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises a concentration of MEAI or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 0.2 mg / kg to 5.0 mg / kg body weight. Each possibility represents a separate embodiment of the present disclosure.

[0022]

[0017] In certain embodiments, the pharmaceutical composition comprises about 200-1800 mg N-acylethanolamine or a salt thereof. In certain embodiments, the pharmaceutical composition comprises about 250 mg, about 500 mg, about 750 mg, about 1000 mg or about 1500 mg N-acylethanolamine or a salt thereof. 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.

[0023]

[0018] 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 combination thereof. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the N-acylethanolamine is PEA or a salt thereof. In certain embodiments, the N-acylethanolamine consists of PEA or a salt thereof. In certain embodiments, the N-acylethanolamine consists of PEA.

[0024]

[0019] 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, inh alation al, 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.

[0025]

[0020] The present disclosure further provides, in some embodiments, a dosage unit comprising or consisting of the pharmaceutical composition described above.

[0026]

[0021] In certain embodiments, the dosage unit comprises the pharmaceutical composition described above. In certain embodiments, the dosage unit consisting of the pharmaceutical composition described above. 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 gel. In certain embodiments, the dosage unit is formulated as a powder. In certain embodiments, the dosage unit is formulated as a spray.

[0027]

[0022] In certain embodiments, the N-acylethanolamine increases the therapeutic potency of the MEAI compared to the same pharmaceutical composition without the N- acylethanolamine. In certain embodiments, the N-acylethanolamine decreases the required therapeutic dosage of the MEAI compared to the same pharmaceutical composition without the N-acylethanolamine. In certain embodiments, the N- acylethanolamine expands the therapeutic window of the MEAI compared to the same pharmaceutical composition without the N-acylethanolamine.

[0028]

[0023] In some embodiments, the present disclosure is directed to a pharmaceutical composition comprising MEAI, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier and / or excipient. In some embodiments, the present disclosure is directed to a pharmaceutical composition comprising MEAI, or a salt thereof, and an N-acylethanolamine, or a salt thereof, and at least one pharmaceutically acceptable carrier and / or excipient. In some embodiments, the N-acylethanolamine is PEA or a salt thereof.

[0029]

[0024] In some embodiments, the pharmaceutical composition comprises a unit dose of MEAI or a pharmaceutically acceptable salt thereof. In other embodiments, the pharmaceutical composition is a solid form composition. In still other embodiments, the pharmaceutical composition is a liquid form composition. In additional embodiments, the pharmaceutical composition is packaged as a single unit dose or as a plurality of single unit doses.

[0030]

[0025] In some embodiments, the unit dosage form comprises from about 20 mg to about 60 mg of MEAI or a pharmaceutically acceptable salt thereof. In some other embodiments, the pharmaceutical composition is formulated for oral administration.

[0031]

[0026] In other embodiments, the disclosure is directed to a method of treating depression, comprising administrating to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising MEAI, or a pharmaceutically acceptable salt thereof, thereby treating the condition. In other embodiments, the disclosure is directed to a method of treating depression, comprising administering to a subject in need thereof a therapeutically effective amount of MEAI, or a salt thereof, and an N-acylethanolamine, or a salt thereof, thereby treating the condition. In some embodiments, the administered pharmaceutical composition comprises a unit dose ranging from about 20 to about 60 mg of MEAI or a pharmaceutically acceptable salt thereof, e.g., about 20 mg MEAI or about 60 mg MEAI. In some embodiments, the administered pharmaceutical composition comprises a unit dose ranging from about 200 to about 1800 mg N-acylethanolamine or a pharmaceutically acceptable salt thereof, e.g., about 200 mg N-acylethanolamine or about 1800 mg N-acylethanolamine. In some embodiments, MEAI, or pharmaceutically acceptable salt thereof, is administered at a dose ranging from about 0.2 mg / kg to 5.0 mg / kg body weight MEAL In some embodiments, the N-acylethanolamine, or pharmaceutically acceptable salt thereof, is administered at a dose ranging from about 2.5 mg / kg to 36.0 mg / kg body weight N-acylethanolamine. In some embodiments, the N-acylethanolamine, or pharmaceutically acceptable salt thereof, is PEA.

[0032]

[0027] In further embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient. In other embodiments, the pharmaceutical composition is a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, or a syrup.

[0033]

[0028] In some embodiments, in the methods of the disclosure the pharmaceutical composition is a unit dosage form composition. In other embodiments, the amount of MEAI, or pharmaceutically acceptable salt thereof, in the unit dosage form ranges from about 20 mg to about 60 mg. In some embodiments, the pharmaceutical composition is administered orally. In some embodiments, the pharmaceutical composition comprising MEAI or pharmaceutically acceptable salt thereof is administered daily. In some embodiments, the method reduces depression, e.g., as measured by change in a BDI-II total score, e.g., by at least 1-10 points, e.g., by at least ten points. In some embodiments, the method reduces depression as measured by a standardized mean difference of at least 0.2 in a BDI-II total score, e.g., a change of at least about 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, or more e.g., by at least 0.5.

[0034]

[0029] Further embodiments and the full scope of applicability of the present disclosure will become apparent from the detailed description given hereinafter. However, the detailed description, while indicating preferred embodiments of the disclosure, is given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.

[0035] Detailed Description of the Disclosure

[0036] Definitions:

[0037]

[0030] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-Ce alkyl” is intended to encompass Ci , C2, C3, C4, C5, Ce, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0038]

[0031] “Isomers” means compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms in space.

[0032] “Stereoisomer” or “optical isomer” mean a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structure exist in the compounds of the disclosure which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof. The compounds of the disclosure and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As discussed in more detail below, individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well-known in the art.

[0039]

[0033] It is well-known in the art that the biological and pharmacological activity of a compound is sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like. Thus, one skilled in the art will appreciate that one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer. Additionally, one skilled in the art would know how to separate, enrich, or selectively prepare the enantiomers of the compounds of the disclosure from this disclosure and the knowledge of the prior art.

[0040]

[0034] Thus, although the racemic form of drug may be used, it is often less effective than administering an equal amount of enantiomerically pure drug; indeed, in some cases, one enantiomer may be pharmacologically inactive and would merely serve as a simple diluent. For example, although ibuprofen had been previously administered as a racemate, it has been shown that only the S-isomer of ibuprofen is effective as an anti-inflammatory agent (in the case of ibuprofen, however, although the R-isomer is inactive, it is converted in vivo to the S-isomer, thus, the rapidity of action of the racemic form of the drug is less than that of the pure S-isomer). Furthermore, the pharmacological activities of enantiomers may have distinct biological activity. For example, S-penicillamine is a therapeutic agent for chronic arthritis, while R- penicillamine is toxic. Indeed, some purified enantiomers have advantages over the racemates, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to the racemic mixture. See U.S. Pat. Nos. 5,114,946 and 4,818,541.

[0041]

[0035] In some embodiments, the compound is a racemic mixture of (S)- and (R)- isomers. In other embodiments, provided herein is a mixture of compounds wherein individual compounds of the mixture exist predominately in an (S)- or (R)-isomeric configuration. For example, the compound mixture has an (S)-enantiomeric excess of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more. In other embodiments, the compound mixture has an (S)- enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about

[0042] 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about

[0043] 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about

[0044] 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more. In other embodiments, the compound mixture has an (R)-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more. In some other embodiments, the compound mixture has an (R)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5% or more.

[0036] Individual stereoisomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by: (1 ) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary; (2) salt formation employing an optically active resolving agent; or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0045]

[0037] Thus, if one enantiomer is pharmacologically more active, less toxic, or has a preferred disposition in the body than the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially. In this way, the patient undergoing treatment would be exposed to a lower total dose of the drug and to a lower dose of an enantiomer that is possibly toxic or an inhibitor of the other enantiomer.

[0046]

[0038] As used herein, nomenclature for compounds including organic compounds, can be given using common names, IUPAC, IUBMB, or CAS recommendations for nomenclature. One of skill in the art can readily ascertain the structure of a compound if given a name, either by systemic reduction of compound structure using naming conventions, or by commercially available software, such as CHEMDRAW™ (Cambridgesoft Corporation, U.S.A.). Chemical names were generated using PerkinElmer ChemDraw® Professional, version 17.

[0047]

[0039] The compounds of the disclosure may contain one or more chiral centers and / or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term “stereoisomers” when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbol “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. In some embodiments, an enantiomer or stereoisomer may be provided substantially free of the corresponding enantiomer.

[0048]

[0040] The present disclosure provides, in one aspect, a pharmaceutical composition comprising a therapeutically-effective amount of MEAI or a salt thereof. The present disclosure provides, in another aspect, a pharmaceutical composition comprising a therapeutically-effective amount of MEAI or a salt thereof and at least one N-acylethanolamine or a salt thereof. In some embodiments, the at least one N- acylethanolamine or a salt thereof comprises PEA or a salt thereof. In some embodiments, the MEAI or a salt thereof and at least one N-acylethanolamine or a salt thereof are present in a single combination. In some embodiments, the MEAI 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.

[0049]

[0041] The present disclosure provides, in another aspect, a pharmaceutical composition comprising a therapeutically-effective amount of MEAI or a salt thereof and at least one N-acylethanolamine or a salt thereof, wherein the molar ratio between the MEAI and the N-acylethanolamine is between about 1 :0.2 to about 1 :1000. In some embodiments, the at least one N-acylethanolamine or a salt thereof comprises PEA or a salt thereof.

[0050]

[0042] As used herein, a "pharmaceutical composition" refers to a preparation of the active agents described herein with other chemical components such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism. As used herein, 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.

[0051]

[0043] 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.

[0044] The term "carrier" as used herein refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin, 18th Edition.

[0052]

[0045] 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.

[0053]

[0046] 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).

[0054]

[0047] The term "derivative" as used herein means a compound whose core structure is the same as, or closely resembles that of 2-aminoindan or an N- acylethanolamine compound, but which has a chemical or physical modification, such as different or additional side groups.

[0055]

[0048] 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.

[0056]

[0049] As used herein, the phrase “pharmaceutically acceptable salt” refers to a charged species of the parent compound and its counter-ion, which is typically used to modify the solubility characteristics of the parent compound and / or to reduce any significant irritation to an organism by the parent compound, while not abrogating the biological activity and properties of the administered compound.

[0057]

[0050] In some embodiments of the present disclosure, a pharmaceutically acceptable salt of the compounds described herein may optionally 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.

[0051] The acid addition salts of the compounds described herein may therefore be complexes formed between one or more basic groups of the drug and one or more equivalents of an acid.

[0058]

[0052] The acid addition salts may include a variety of organic and inorganic acids, such as, but not limited to, hydrochloric acid which affords a hydrochloric acid addition salt, hydrobromic acid which affords a hydrobromic acid addition salt, acetic acid which affords an acetic acid addition salt, ascorbic acid which affords an ascorbic acid addition salt, benzenesulfonic acid which affords a besylate addition salt, camphorsulfonic acid which affords a camphorsulfonic acid addition salt, citric acid which affords a citric acid addition salt, maleic acid which affords a maleic acid addition salt, malic acid which affords a malic acid addition salt, methanesulfonic acid which affords a methanesulfonic acid (mesylate) addition salt, naphthalenesulfonic acid which affords a naphthalenesulfonic acid addition salt, oxalic acid which affords an oxalic acid addition salt, 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.

[0059]

[0053] In some embodiments, a pharmaceutically acceptable salt of the compounds described 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.

[0060]

[0054] Each of these base addition salts can be either a mono-addition salt or a poly-addition salt, as these terms are defined herein.

[0061]

[0055] 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.

[0062]

[0056] 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

[0063] 1 :1 , such that the addition salt includes one molar equivalent of the counter-ion per one molar equivalent of the compound.

[0057] 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.

[0064]

[0058] Further, in any one of the embodiments described herein, each of the compounds described herein, including the salts thereof, may be in a form of a solvate or a hydrate thereof.

[0065]

[0059] 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.

[0066]

[0060] The term “hydrate” refers to a solvate, as defined hereinabove, where the solvent is water.

[0067]

[0061] In certain embodiments, the pharmaceutical composition comprises a unit dose of about 20 to about 60 mg MEAI or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises a unit dose of about 25 to about 55 mg, about 30 to about 50 mg, about 35 to about 45 mg, or about 35 to about 40 mg MEAI or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises a unit dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg MEAI or a pharmaceutically acceptable salt thereof. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the pharmaceutical composition comprises a unit dose of about 20 mg, less than about 25 mg, less than about 30 mg, less than about 35 mg, less than about 40 mg, less than about 45 mg, less than about 50 mg, less than about 55 mg, or about 60 mg MEAI or a pharmaceutically acceptable salt thereof. Each possibility represents a separate embodiment of the present disclosure.

[0068]

[0062] In certain embodiments, the pharmaceutical composition comprises a unit dose of about 20 mg to about 25 mg, about 20 mg to about 30 mg, about 20 mg to about 35 mg, about 20 mg to about 40 mg, about 20 mg to about 45 mg, about 20 mg to about 50 mg, about 20 mg to about 55 mg, or about 20 mg to about 60 mg MEAI or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises a unit dose of 20 mg MEAI or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises a unit dose of 60 mg MEAI or a pharmaceutically acceptable salt thereof. Each possibility represents a separate embodiment of the present disclosure.

[0069]

[0063] In some embodiments, the pharmaceutical composition comprises a concentration of MEAI or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 0.2 mg / kg to about 5 mg / kg body weight. In certain embodiments, the pharmaceutical composition comprises a concentration of MEAI 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, or about 4.5 mg / kg to about 5.0 mg / kg body weight. In certain embodiments, the pharmaceutical composition comprises a concentration of MEAI 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 MEAI 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, 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 MEAI 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, or about 0.2 mg / kg to about 5.0 mg / kg body weight. Each possibility represents a separate embodiment of the present disclosure.

[0070]

[0064] In certain embodiments, a pharmaceutical composition comprising MEAI also comprises about 200-1800 mg N-acylethanolamine 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 1 100 mg, at least about 1 150 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.

[0071]

[0065] In some embodiments, the pharmaceutical composition comprising MEAI also comprises a concentration of N-acylethanolamine or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of the N-acylethanolamine or a salt thereof of about 2.5 mg / kg to about 36 mg / kg body weight. In certain embodiments, the pharmaceutical composition comprises a concentration of N-acylethanolamine or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 2.5 to about 5 mg / kg, about 5 mg / kg to about 7.5 mg / kg, about 7.5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 12.5 mg / kg, about 12.5 mg / kg to about 15 mg / kg, about 15 mg / kg to about 17.5 mg / kg, about 17.5 mg / kg to about 20 mg / kg, about 20 mg / kg to about 22.5 mg / kg, about 22.5 mg / kg to about 25 mg / kg, about 25 mg / kg to about 27.5 mg / kg, about 27.5 mg / kg to about 30 mg / kg, about 30 mg / kg to about 32.5 mg / kg, about 32.5 mg / kg to about 36 mg / kg body weight. In certain embodiments, the pharmaceutical composition comprises a concentration of N-acylethanolamine or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of N- acylethanolamine or a salt thereof of about 2.5 mg / kg, about 5 mg / kg, about 7.5 mg / kg, about 10 mg / kg, about 12.5 mg / kg, about 15 mg / kg, about 17.5 mg / kg, about 20 mg / kg, about 22.5 mg / kg, about 25 mg / kg, about 27.5 mg / kg, about 30 mg / kg, about 32.5 mg / kg, or about 36 mg / kg bodyweight. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the pharmaceutical composition comprises a concentration of N-acylethanolamine or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of N-acylethanolamine or a salt thereof of about 2.5 mg / kg, less than about 2.5 mg / kg, less than about 5 mg / kg, less than about 7.5 mg / kg, less than about 10 mg / kg, less than about 12.5 mg / kg, less than about 15 mg / kg, less than about 17.5 mg / kg, less than about 20 mg / kg, less than about 22.5 mg / kg, less than about 25 mg / kg, less than about 27.5 mg / kg, less than about 30 mg / kg, less than about 32.5 mg / kg, or about 36 mg / kg bodyweight. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the pharmaceutical composition comprises a concentration of N- acylethanolamine or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of N-acylethanolamine or a salt thereof of about 2.5 mg / kg to about 5 mg / kg, about 2.5 mg / kg to about 7.5 mg / kg, about 2.5 mg / kg to about 10 mg / kg, about 2.5 mg to about 12.5 mg / kg, about 2.5 mg / kg to about 15 mg / kg, about 2.5 mg / kg to about 17.5 mg / kg, about 2.5 mg / kg to about 20 mg / kg, about 2.5 mg / kg to about 22.5 mg / kg, about 2.5 mg / kg to about 25 mg / kg, about 2.5 mg / kg to about 27.5 mg / kg, about 2.5 mg / kg to about 30 mg / kg, about 2.5 mg / kg to about 32.5 mg / kg, or about 2.5 mg / kg to about 36 mg / kg body weight. Each possibility represents a separate embodiment of the present disclosure.

[0072]

[0066] 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 combination thereof. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the N-acylethanolamine is PEA or a salt thereof. In certain embodiments, the N-acylethanolamine consists of PEA or a salt thereof. In certain embodiments, the N-acylethanolamine consists of PEA.

[0073]

[0067] 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, inh alation al, 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.

[0074]

[0068] Techniques for formulation and administration of drugs 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.

[0075]

[0069] For oral administration, the pharmaceutical composition can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the pharmaceutical composition to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient. Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries as desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, and sodium carbomethylcellulose; and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, may be added.

[0076]

[0070] The term "oral administration" refers to any method of administration in which an active agent can be administered by swallowing, chewing, sucking, or drinking an oral dosage form. Examples of solid dosage forms include conventional tablets, multi-layer tablets, capsules, caplets, etc., which do not substantially release the drug in the mouth or in the oral cavity.

[0077]

[0071] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0078]

[0072] 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.

[0079]

[0073] Pharmaceutical compositions suitable for use in the context of the present disclosure include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a "therapeutically effective amount" means an amount of active ingredients effective to prevent, alleviate, or ameliorate symptoms or side effects of a disease or disorder, or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. More specifically, a "therapeutically effective amount of a mixture" means an amount of at least two active ingredients, wherein each one of the active ingredients independently may not be in a therapeutically effective amount or wherein both of the active ingredients may not be in a therapeutically effective amount, the mixture is nevertheless effective to prevent, alleviate, or ameliorate symptoms or side effects of a disease or disorder, or prolong the survival of the subject being treated. The term "mixture" as used herein refers to a non-covalent combination of two molecules.

[0080]

[0074] For any preparation used in the methods of the present disclosure, the dosage or the therapeutically effective amount can be estimated initially from in vitro, in vivo and cell culture assays. For example, a dose can be formulated in animal models to achieve a desired concentration or titer. Such information can be used to determine useful doses more accurately in humans. The dosage of the claimed compositions depends on several factors, including: the administration method, the disease to be treated, the severity of the disease, whether the disease is to be treated or prevented, and the age, weight, and health of the person to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular patient may affect dosage used. Continuous daily dosing may not be required; a therapeutic regimen may require cycles, during which time a drug is not administered, or therapy may be provided on an as-needed basis during periods of acute disease worsening. Dosage escalation may or may not be required; a therapeutic regimen may require reduction in medication dosage. Toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, in cell cultures or experimental animals. The data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition (See, e.g., Fingl, E. et al. (1975), "The Pharmacological Basis of Therapeutics," Ch. 1 , p. 1). Depending on the severity and responsiveness of the condition to be treated, dosing can be of a single or a plurality of administrations, with course of treatment lasting from several days to several weeks, or until cure is affected or diminution of the disease state is achieved.

[0081]

[0075] The present disclosure further provides, in another aspect, a dosage unit comprising or consisting of the pharmaceutical composition described above.

[0082]

[0076] In certain embodiments, the dosage unit comprises the pharmaceutical composition described above. In certain embodiments, the dosage unit consisting of the pharmaceutical composition described above. 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 gel. In certain embodiments, the dosage unit is formulated as a powder. In certain embodiments, the dosage unit is formulated as a spray.

[0083]

[0077] The present disclosure further provides, in another aspect, a pharmaceutical composition or a dosage unit as described above for use in a method for preventing or treating depression.

[0084]

[0078] In some embodiments, the present disclosure provides a method of reducing depression as measured by a standardized mean difference for a change in a BDI-II total score of a group of subjects. See Beck Depression Inventory (BDI-II), e.g., Beck et al., “Beck Depression Inventory-H”, American Psychological Association, 1996. In some embodiments, the present disclosure provides a method of reducing depression in a subject as measured by change in a BDI-II total score, e.g., by at least 1 -10 points, e.g., by at least ten points. In some embodiments, the reduction in depression is by at least one point, e.g., preferably by at least ten points, e.g., as measured over a two-week period as compared to the score prior to the start of treatment. The BDI-II score indicates a sum of 21 depression symptoms including, for example, sadness, guilt, anger, and indecisiveness, where a subject self-evaluates a score from 0 to 3. A score of 0 for the sadness symptom would indicate “I do not feel sad” whereas a score of 3 would indicate “I am so sad and unhappy that I can’t stand it.” Total scores for the 21 symptoms ranging from 0-13 indicate none or minimal depression, 14-19 indicate mild depression, 20-28 indicate moderate depression, and 29-63 indicates severe depression. In some embodiments, the present disclosure provides a method that reduces depression in a subject as measured by a change in a BDI-II total score by at least five points over a two-week period. In some embodiments, the present disclosure provides a method that reduces depression in a subject as measured by a change in a BDI-II total score by at least three points over a two-week period. In some embodiments, the present disclosure provides a method that reduces depression in a subject as measured by a change in a BDI-II total score by about three to twenty points, five to twenty points, or ten to twenty points over a two-week period.

[0085]

[0079] A standardized mean difference for a change in a BDI-II total score may be calculated by the following equation:

[0086]

[0080] (Equation 1)

[0087]

[0081] In Equation 1 , SMD, or d, represents the standardized mean difference, MBDI 1represents a mean BDI-II score change for a first group, MBDI 2represents a mean BDI-II score change for a second group, SD1represents a standard deviation of the mean BDI-II score change for the first group, and SD2represents a standard deviation of the mean BDI-II score change for the second group. A d value of greater than or equal to 0.2 represents a small effect, a d value of greater than or equal to 0.5 represents a moderate effect, and a d value greater than or equal to 0.8 represents a large effect (Cohen, J. Statistical Power Analysis for the Behavioral Science. 2nded. Hillsdale, NJ: Lawrence Erlbaum; 1988).

[0082] In some embodiments, the first group may be an experimental group of subjects. In some embodiments, the experimental group of subjects may receive a pharmaceutical composition as described in the present disclosure. In some embodiments, the second group may be a control group of subjects.

[0088]

[0083] Patients with clinical depression may generally exhibit a mean BDI-II score of 30 points at the beginning of the two-week period and a standard deviation of the mean BDI-II score may be 10 points. As an example, an experimental group of subjects may exhibit a mean BDI-II score change after a two-week period of -10 (e.g., mean BDI- II score of 30 at the beginning of the two-week period and 20 after the two-week period), and a control group of subjects may exhibit a mean BDI-II score change after a two- week period of -5 (e.g., mean BDI-II score of 30 to 25). According to Equation 1 , the d value for this example is equal to 0.5, which may represent a moderate effect of the treatment to the experimental group of subjects compared to the control group of subjects. A clinical response to a treatment may be represented by a greater than or equal to 50% improvement in a mean BDI-II score after a two-week period. “Improvement in a mean BDI-II score” may be understood as a decrease in a mean BDI-II score. A clinical remission may be represented by a mean BDI-II score of less than or equal to 13, indicating none or minimal depression, and a greater than or equal to 50% improvement in a mean BDI-II score after a two-week period.

[0089]

[0084] In some embodiments, the present disclosure provides a method of reducing depression, comprising administrating to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising MEAI, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a unit dose ranging from about 20 mg to about 60 mg of MEAI or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises a unit dose of about 25 mg to about 55 mg, about 30 mg to about 50 mg, about 35 mg to about 45 mg, or about 35 mg to about 40 mg MEAI or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises a unit dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg MEAI or a pharmaceutically acceptable salt thereof. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the pharmaceutical composition comprises a unit dose of about 20 mg, less than about 25 mg, less than about 30 mg, less than about 35 mg, less than about 40 mg, less than about 45 mg, less than about 50 mg, less than about 55 mg, or about 60 mg MEAI or a pharmaceutically acceptable salt thereof. Each possibility represents a separate embodiment of the present disclosure.

[0090]

[0085] In some embodiments, the present disclosure provides a method of reducing depression, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising MEAI, or a pharmaceutically acceptable salt thereof, at a dose of about 0.2 mg / kg to 5.0 mg / kg body weight MEAI. In some embodiments, the therapeutically effective amount is administered at a frequency or for a duration of time sufficient to reduce depression, e.g., as measured by a change in BDI-II score, e.g., by at least 1 point on the BDI-II score. In some embodiments, the subject is administered about 0.2 mg / kg to about 1 .0 mg / kg, about 1 .0 mg / kg to about 1 .5 mg / kg, about 1 .5 mg / kg 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 3.0 mg / kg to about 3. 5 mg / kg, about 3.5 mg / kg to about 4.0 mg / kg, about 4.0 mg / kg to about 4.5 mg / kg, or about 4.5 mg / kg to about 5.0 mg / kg body weight MEAI or pharmaceutically acceptable salt thereof. In certain embodiments, the subject is administered 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 MEAI or pharmaceutically acceptable salt thereof. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the subject is administered a dose of about 0.2 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, or about 5.0 mg / kg body weight of MEAI or pharmaceutically acceptable salt thereof. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the subject is administered 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 / kg 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, or about 0.2 mg / kg to about 5.0 mg / kg body weight of MEAI or pharmaceutically acceptable salt thereof. Each possibility represents a separate embodiment of the present disclosure.

[0091]

[0086] In some embodiments, the present disclosure provides a method of reducing depression, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising MEAI, or a pharmaceutically acceptable salt thereof, e.g., at one of the dosages or concentrations listed above, and also comprising an N-acylethanolamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is administered at a frequency or for a duration of time sufficient to reduce depression, e.g., as measured by a change in BDI-II score, e.g., by at least 1 point on the BDI-II score. 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 1 100 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 the embodiments above, the N-acylethanolamine or a salt thereof may comprise PEA or a salt thereof.

[0092]

[0087] In some embodiments, the pharmaceutical composition comprises a concentration of N-acylethanolamine or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 2.5 mg / kg to about 36 mg / kg body weight. In certain embodiments, the pharmaceutical composition comprises a concentration of N-acylethanolamine or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 2.5 to about 5 mg / kg, about 5 mg / kg to about 7.5 mg / kg, about 7.5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 12.5 mg / kg, about 12.5 mg / kg to about 15 mg / kg, about 15 mg / kg to about 17.5 mg / kg, about

[0093] 17.5 mg / kg to about 20 mg / kg, about 20 mg / kg to about 22.5 mg / kg, about 22.5 mg / kg to about 25 mg / kg, about 25 mg / kg to about 27.5 mg / kg, about 27.5 mg / kg to about 30 mg / kg, about 30 mg / kg to about 32.5 mg / kg, about 32.5 mg / kg to about 36 mg / kg body weight. In certain embodiments, the pharmaceutical composition comprises a concentration of N-acylethanolamine or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 2.5 mg / kg, about 5 mg / kg, about 7.5 mg / kg, about 10 mg / kg, about 12.5 mg / kg, about 15 mg / kg, about 17.5 mg / kg, about 20 mg / kg, about 22.5 mg / kg, about 25 mg / kg, about 27.5 mg / kg, about 30 mg / kg, about

[0094] 32.5 mg / kg, or about 36 mg / kg bodyweight. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the pharmaceutical composition comprises a concentration of N-acylethanolamine or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 2.5 mg / kg, less than about 2.5 mg / kg, less than about 5 mg / kg, less than about 7.5 mg / kg, less than about 10 mg / kg, less than about 12.5 mg / kg, less than about 15 mg / kg, less than about 17.5 mg / kg, less than about 20 mg / kg, less than about 22.5 mg / kg, less than about 25 mg / kg, less than about 27.5 mg / kg, less than about 30 mg / kg, less than about

[0095] 32.5 mg / kg, or about 36 mg / kg bodyweight. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the pharmaceutical composition comprises a concentration of N-acylethanolamine or pharmaceutically acceptable salt thereof sufficient to provide a patient with a dose of about 2.5 mg / kg to about 5 mg / kg, about 2.5 mg / kg to about 7.5 mg / kg, about 2.5 mg / kg to about 10 mg / kg, about 2.5 mg to about 12.5 mg / kg, about 2.5 mg / kg to about 15 mg / kg, about 2.5 mg / kg to about 17.5 mg / kg, about 2.5 mg / kg to about 20 mg / kg, about 2.5 mg / kg to about 22.5 mg / kg, about 2.5 mg / kg to about 25 mg / kg, about 2.5 mg / kg to about 27.5 mg / kg, about

[0096] 2.5 mg / kg to about 30 mg / kg, about 2.5 mg / kg to about 32.5 mg / kg, or about 2.5 mg / kg to about 36 mg / kg body weight. Each possibility represents a separate embodiment of the present disclosure. In the embodiments above, the N-acylethanolamine or a salt thereof may comprise PEA or a salt thereof.

[0097]

[0088] 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, inh alation al, 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.

[0098]

[0089] In some embodiments, the pharmaceutical composition is administered orally. In some embodiments, the pharmaceutical composition comprising MEAI or pharmaceutically acceptable salt thereof is administered daily. In some embodiments, the administered pharmaceutical composition comprises a unit dose of 1-400 mg, e.g., 20-60 mg, MEAI or a pharmaceutically acceptable salt thereof. In some embodiments, the administered pharmaceutical composition comprises a unit dose of 20 mg MEAI or a pharmaceutically acceptable salt thereof. In some embodiments, the administered pharmaceutical composition comprises a unit dose of 60 mg MEAI or a pharmaceutically acceptable salt thereof.

[0099]

[0090] 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 one or more symptoms or side effects of the diseases or conditions of the disclosure.

[0100]

[0091] The term "acute" refers to a condition with a relatively short, severe course.

[0101]

[0092] 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 differentiate according to various conditions such as patient age, temperature, season, type of disease, etc.

[0102]

[0093] 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

[0103] 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".

[0104]

[0094] The terms "comprises", "comprising", "includes", "including", "having" and their conjugates mean "including but not limited to."

[0105]

[0095] The term "consisting of" means "including and limited to".

[0096] The term "consisting essentially of" means that the composition, method or microcapsules may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

[0106]

[0097] 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.

[0107]

[0098] Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD5o (the dose lethal to 50% of the population) and the ED5o (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.

[0108]

[0099] 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).

[0109] Table 1. Equivalent Surface Area Dosage Factors.

[0110]

[0100] The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with 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.

[0101] One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0111]

[0102] One skilled in the art will further recognize that human clinical trials including first-in-human, dose ranging and efficacy trials, in healthy patients and / or those suffering from a given disorder, may be completed according to methods well known in the clinical and medical arts.

[0112]

[0103] 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.

[0113] Examples

[0114]

[0104] Reference is now made to the following example, which together with the above descriptions illustrate some embodiments of the present disclosure in a nonlimiting fashion.

[0115] Example 1 : Tests and Evaluations

[0116]

[0105] Subjects of an experimental group receive daily doses of a pharmaceutical composition comprising MEAI, or pharmaceutically acceptable salt thereof at a unit dose of 20 mg or 60 mg. Subjects of a control group receive daily doses of a placebo with the same excipients but with no active ingredient. The daily doses are administered to subjects at approximately 0.5 to 1 hour after a meal. Subjects of both the experimental and control group are evaluated for adverse effects and any changes to vital signs after administration of the pharmaceutical composition. On days 5, 10, and

[0117] 17+ / - 1 after the initial dose, subjects of both the experimental and control group are evaluated to determine changes in depression symptoms compared to day 0 (predosing). Depression symptoms are assessed using the Beck Depression Inventory (BDI-II) to monitor the presence of symptoms including, among others, sadness, guilt, suicidal thoughts, loss of interest, and changes in sleep and appetite over a two-week period (see, e.g., Beck et al., “Beck Depression Inventory-H”, American Psychological Association, 1996). A response for each symptom (e.g., guilt) is scored from 0 to 3, with 0 representing the absence of the symptom and 3 representing the most severe symptom, and the responses for all symptoms assessed are added. On days 5, 10, and 17 + / - after the initial dose, a mean total BDI-II score, and a standard deviation of the mean BDI-II score is evaluated for the both experimental and the control group. A change in the mean total score from the pre-dosing to Day 5, to Day 10, and to Day 17+ / -1 is evaluated for the experimental group and the control group. A standardized mean difference score is evaluated for each time interval of pre-dosing to Day 5, predosing to Day 10, and pre-dosing to Day 17 + / -1.

[0118] Example 2: Tests and Evaluations

[0119]

[0106] Subjects of an experimental group receive daily doses of a pharmaceutical composition comprising MEAI, or pharmaceutically acceptable salt thereof at a unit dose of 20 mg or 60 mg and 200 mg or 1800 mg of at least one N-acylethanolamine, or pharmaceutically acceptable salt thereof. Subjects of a control group receive daily doses of a placebo with the same excipients but with no active ingredient. The daily doses are administered to subjects at approximately 0.5 to 1 hour after a meal. Subjects of both the experimental and control group are evaluated for adverse effects and any changes to vital signs after administration of the pharmaceutical composition. On days 5, 10, and 17+ / - 1 after the initial dose, subjects of both the experimental and control group are evaluated to determine changes in depression symptoms compared to day 0 (pre-dosing). Depression symptoms are assessed using the Beck Depression Inventory (BDI-II) to monitor the presence of symptoms including, among others, sadness, guilt, suicidal thoughts, loss of interest, and changes in sleep and appetite over a two-week period (see, e.g., Beck et al., “Beck Depression Inventory-H”, American Psychological Association, 1996). A response for each symptom (e.g., guilt) is scored from 0 to 3, with 0 representing the absence of the symptom and 3 representing the most severe symptom, and the responses for all symptoms assessed are added. On days 5, 10, and 17 + / - after the initial dose, a mean total BDI-II score, and a standard deviation of the mean BDI-II score is evaluated for the both experimental and the control group. A change in the mean total score from the pre-dosing to Day 5, to Day 10, and to Day

[0120] 17+ / -1 is evaluated for the experimental group and the control group. A standardized mean difference score is evaluated for each time interval of pre-dosing to Day 5, predosing to Day 10, and pre-dosing to Day 17 + / -1.

[0121]

[0107] The many features and advantages of the present disclosure are apparent from the detailed specification, and thus it is intended by the appended claims to cover all such features and advantages of the present disclosure that fall within the true spirit and scope of the present disclosure. Further, since numerous modifications and variations will readily occur to those skilled in the art, it is not desired to limit the present disclosure to the exact construction and operation illustrated and described and accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the present disclosure.

[0108] Moreover, those skilled in the art will appreciate that the conception upon which this disclosure is based may readily be used as a basis for designing other structures, methods, and systems for carrying out the several purposes of the present disclosure. Accordingly, the claims are not to be considered as limited by the foregoing description or examples.

Claims

WHAT IS CLAIMED IS:1 . A method of treating depression, comprising administering to a subject in need thereof a therapeutically effective amount of 5-methoxy-2-aminoindan (“MEAI”), or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the subject in need thereof is administered a therapeutically effective amount of MEAI for a period of time sufficient to treat depression, as measured by a reduction in a BDI-II score.

3. The method of claim 1 or 2, wherein the therapeutically effective amount of MEAI is administered as a unit dose.

4. The method of claim 3, wherein the subject is administered a single unit dose or a plurality of single unit doses of the therapeutically effective amount of MEAI.

5. The method of any one of claims 1 to 4, wherein the therapeutically effective amount of MEAI is administered as a solid form composition.

6. The method of any one of claims 1 to 4, wherein the therapeutically effective amount of MEAI is administered as a liquid form composition.

7. The method of any one of claims 1 to 6, wherein the therapeutically effective amount of MEAI, or pharmaceutically acceptable salt thereof, is administered to the subject in need thereof as a unit dose ranging from 20 mg to 60 mg.

8. The method of any one of claims 1 to 6, wherein the therapeutically effective amount of MEAI, or pharmaceutically acceptable salt thereof, is administered to the subject in need thereof as a unit dose of about 20 mg or about 60 mg.

9. The method of any one of claims 1 to 8, wherein the subject in need thereof is administered a therapeutically effective amount of MEAI, or pharmaceutically acceptable salt thereof, at a concentration ranging from 0.2 mg / kg to 5.0 mg / kg body weight.10.The method of any one of claims 1 to 9, wherein the therapeutically effective amount of MEAI is formulated as a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and / or excipient.1 1 .The method of any one of claims 1 to 10, wherein the therapeutically effective amount of MEAI is formulated as a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, or a syrup.

12. The method of any one of claims 1 to 1 1 , wherein the therapeutically effective amount of MEAI is administered orally.

13. The method of any one of claims 1 to 12, wherein the therapeutically effective amount of MEAI is administered daily.

14. The method of any one of claims 1 to 13, wherein the therapeutically effective amount of MEAI is administered at a frequency or for a duration of time sufficient to achieve a reduction in a BDI-II total score.

15. The method of claim 14, wherein the reduction in the BDI-II total score is a reduction of at least ten points.

16. The method of any one of claims 1 to 15, wherein the therapeutically effective amount of MEAI is administered at a frequency or for a duration of time sufficient to achieve a standardized mean difference of at least 0.5 in a BDI-II total score.

17. A method of treating depression, comprising administering to a subject in need thereof a therapeutically effective amount of 5-methoxy-2-aminoindan (“MEAI”), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an N-acylethanolamine, or a pharmaceutically acceptable salt thereof.

18. The method of claim 17, wherein the subject in need thereof is administered a therapeutically effective amount of MEAI, or pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an N-acylethanolamine, or pharmaceutically acceptable salt thereof, for a period of time sufficient to treat depression, as measured by a reduction in a BDI-II score.

19. The method of claim 17 or 18, wherein the therapeutically effective amount of MEAI and the therapeutically effective amount of N-acylethanolamine are administered as a unit dose.

20. The method of any one of claims 17 to 19, wherein the subject in need thereof is administered a single unit dose or a plurality of single unit doses of the therapeutically effective amount of MEAI and the therapeutically effective amount of N-acylethanolamine.21 .The method of any one of claims 17 to 20, wherein the therapeutically effective amount of MEAI and the therapeutically effective amount of N-acylethanolamine are administered as a solid form composition.

22. The method of any one of claims 17 to 20, wherein the therapeutically effective amount of MEAI and the therapeutically effective amount of N-acylethanolamine are administered as a liquid form composition.

23. The method of any one of claims 17 to 22, wherein the therapeutically effective amount of MEAI is administered as a unit dose ranging from 20 mg to 60.

24. The method of any one of claims 17 to 23, wherein the subject in need thereof is administered a therapeutically effective amount of MEAI, or pharmaceuticallyacceptable salt thereof, at a concentration ranging from 0.2 mg / kg to 5.0 mg / kg body weight.

25. The method of any one of claims 17 to 24, wherein the therapeutically effective amount of MEAI, or a pharmaceutically acceptable salt thereof, and the therapeutically effective amount of N-acylethanolamine, or a pharmaceutically acceptable salt thereof, are administered in a single composition or in simultaneous or sequential compositions.

26. The method of claim 25, wherein the single composition, simultaneous, or sequential compositions further comprise at least one pharmaceutically acceptable carrier and / or excipient.

27. The method of any one of claims 17 to 26, wherein the therapeutically effective amount of N-acylethanolamine, or pharmaceutically acceptable salt thereof, comprises about 200 to 1800 mg of N-acylethanolamine, or a pharmaceutically acceptable salt thereof.

28. The method of any one of claims 17 to 27, wherein the therapeutically effective amount of N-acylethanolamine, or pharmaceutically acceptable salt thereof, comprises about 2.5 mg / kg to 36 mg / kg of N-acylethanolamine per bodyweight of the subject in need thereof.

29. The method of any one of claims 17 to 28, wherein the therapeutically effective amount of MEAI, or pharmaceutically acceptable salt thereof, and the therapeutically effective amount of N-acylethanolamine, or pharmaceutically acceptable salt thereof, are administered orally.

30. The method of any one of claims 17 to 29, wherein the therapeutically effective amount of MEAI, or pharmaceutically acceptable salt thereof, and the therapeutically effective amount of N-acylethanolamine, or pharmaceutically acceptable salt thereof, are administered daily.31 .The method of any one of claims 17 to 30, wherein the therapeutically effective amount of MEAI, or pharmaceutically acceptable salt thereof, and the therapeutically effective amount of N-acylethanolamine, or pharmaceutically acceptable salt thereof, are formulated as a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, or a syrup.

32. The method of any one of claims 17 to 31 , wherein the therapeutically effective amount of MEAI, or pharmaceutically acceptable salt thereof, and the therapeutically effective amount of N-acylethanolamine, or pharmaceutically acceptable salt thereof,are administered at a frequency or for a duration of time sufficient to achieve a reduction in a BDI-II total score.

33. The method of claim 32, wherein the reduction in the BDI-II total score is a reduction of at least ten points.

34. The method of any one of claims 17 to 33, wherein the therapeutically effective amount of MEAI, or pharmaceutically acceptable salt thereof, and the therapeutically effective amount of N-acylethanolamine, or pharmaceutically acceptable salt thereof, are administered at a frequency or for a duration of time sufficient to achieve a standardized mean difference of at least 0.5 in a BDI-II total score.

35. The method of any one of claims 17 to 34, wherein the N-acylethanolamine is selected from N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA) , and pharmaceutically acceptable salts thereof.

36. The method of claim 35, wherein the N-acylethanolamine is PEA or a pharmaceutically acceptable salt thereof.

37. A composition for use in the manufacture of a medicament for treating or improving depression in a subject in need thereof, wherein the composition comprises a therapeutically effective amount of 5-methoxy-2-aminoindan (“MEAI”), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier and / or excipient.

38. The composition for use according to claim 37, wherein the composition is a unit dosage form composition.

39. The composition for use according to claim 38, wherein the composition is packaged as a single unit dose or as a plurality of single unit doses.

40. The composition for use according to any one of claims 37 to 39, wherein the composition is a solid form composition.41 .The composition for use according to any one of claims 37 to 39, wherein the composition is a liquid form composition.

42. The composition for use according to any one of claims 37 to 41 , wherein the composition comprises 20 mg to 60 mg of MEAI or a pharmaceutically acceptable salt thereof.

43. The composition for use according to any one of claims 37 to 41 , wherein the composition comprises about 20 mg or about 60 mg of MEAI or a pharmaceutically acceptable salt thereof.

44. The composition for use according to any one of claims 37 to 43, wherein the composition comprises 0.2 mg / kg to 5.0 mg / kg of MEAI, or a pharmaceutically acceptable salt thereof, per body weight of the subject in need thereof.

45. The composition for use according to any one of claims 37 to 44, wherein the composition is formulated as a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, or a syrup.

46. The composition for use according to any one of claims 37 to 45, wherein the composition is formulated for oral administration.

47. The composition for use according to any one of claims 37 to 46 wherein the composition further comprises an N-acylethanolamine, or a pharmaceutically acceptable salt thereof.

48. The composition for use according to claim 47, wherein the N-acylethanolamine is selected from N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA) , and pharmaceutically acceptable salts thereof.

49. A composition for use in the manufacture of a medicament for treating or improving depression in a subject in need thereof, wherein the composition comprises a therapeutically effective amount of 5-methoxy-2-aminoindan (“MEAI”), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an N-acylethanolamine, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier and / or excipient.

50. The composition for use according to claim 49, wherein the composition is a unit dosage form composition.51 .The composition for use according to claim 50, wherein the composition is packaged as a single unit dose or as a plurality of single unit doses.

52. The composition for use according to any one of claims 49 to 51 , wherein the composition is a solid form composition.

53. The composition for use according to any one of claims 49 to 51 , wherein the composition is a liquid form composition.

54. The composition for use according to any one of claims 49 to 53, wherein the composition comprises 20 mg to 60 mg of MEAI or a pharmaceutically acceptable salt thereof.

55. The composition for use according to any one of claims 49 to 53, wherein the composition comprises about 20 mg or about 60 mg of MEAI or a pharmaceutically acceptable salt thereof.

56. The composition for use according to any one of claims 49 to 55, wherein the composition comprises 0.2 mg / kg to 5.0 mg / kg of MEAI, or a pharmaceutically acceptable salt thereof, per body weight of the subject in need thereof.

57. The composition for use according to any one of claims 49 to 56, wherein the composition is formulated as a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, or a syrup.

58. The composition for use according to any one of claims 49 to 57, wherein the composition is formulated for oral administration.

59. The composition for use according to any one of claims 49 to 58, wherein the composition comprises about 200 to 1800 mg of N-acylethanolamine, or a pharmaceutically acceptable salt thereof.

60. The composition for use according to any one of claims 49 to 59, wherein the composition comprises about 2.5 mg / kg to 36 mg / kg of N-acylethanolamine, or a pharmaceutically acceptable salt thereof, per bodyweight of the subject in need thereof.61 .The composition for use according to any one of claims 49 to 60, wherein the N- acylethanolamine is selected from N-palmitoylethanolamine (PEA), Me- palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), and pharmaceutically acceptable salts thereof.

62. The composition for use according to any one of claims 49 to 61 , wherein the N- acylethanolamine is PEA or a pharmaceutically acceptable salt thereof.

63. A composition for use in the treatment or improvement of depression comprising to a subject in need thereof the composition, wherein the composition comprises 5- methoxy-2-aminoindan (“MEAI”), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier and / or excipient.

64. The composition for use according to claim 63, wherein the composition is a unit dosage form composition.

65. The composition for use according to claim 64, wherein the composition is packaged as a single unit dose or as a plurality of single unit doses.

66. The composition for use according to any one of claims 63 to 65, wherein the composition is a solid form composition.

67. The composition for use according to any one of claims 63 to 65, wherein the composition is a liquid form composition.

68. The composition for use according to any one of claims 63 to 67, wherein the composition comprises 20 mg to 60 mg of MEAI or a pharmaceutically acceptable salt thereof.

69. The composition for use according to any one of claims 63 to 67, wherein the composition comprises about 20 mg or about 60 mg of MEAI or a pharmaceutically acceptable salt thereof.

70. The composition for use according to any one of claims 63 to 69, wherein the composition comprises 0.2 mg / kg to 5.0 mg / kg of MEAI, or a pharmaceutically acceptable salt thereof, per body weight of the subject in need thereof.71 .The composition for use according to any one of claims 63 to 70, wherein the composition is formulated as a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, or a syrup.

72. The composition for use according to any one of claims 63 to 71 , wherein the composition is formulated for oral administration.

73. The composition for use according to any one of claims 63 to 72, wherein the composition further comprises an N-acylethanolamine, or a pharmaceutically acceptable salt thereof.

74. The composition for use according to claim 73, wherein the N-acylethanolamine is selected from N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA) , and pharmaceutically acceptable salts thereof.

75. A composition for use in the treatment or improvement of depression comprising to a subject in need thereof the composition, wherein the composition comprises 5- methoxy-2-aminoindan (“MEAI”), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an N-acylethanolamine, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier and / or excipient.

76. The composition for use according to claim 75, wherein the composition is a unit dosage form composition.

77. The composition for use according to claim 76, wherein the composition is packaged as a single unit dose or as a plurality of single unit doses.

78. The composition for use according to any one of claims 75 to 77, wherein the composition is a solid form composition.

79. The composition for use according to any one of claims 75 to 77, wherein the composition is a liquid form composition.

80. The composition for use according to any one of claims 75 to 79, wherein the composition comprises 20 mg to 60 mg of MEAI or a pharmaceutically acceptable salt thereof.81 .The composition for use according to any one of claims 75 to 79, wherein the composition comprises about 20 mg or about 60 mg of MEAI or a pharmaceutically acceptable salt thereof.

82. The composition for use according to any one of claims 75 to 81 , wherein the composition comprises 0.2 mg / kg to 5.0 mg / kg of MEAI, or a pharmaceutically acceptable salt thereof, per body weight of the subject in need thereof.

83. The composition for use according to any one of claims 75 to 82, wherein the composition is formulated as a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, or a syrup.

84. The composition for use according to any one of claims 75 to 83, wherein the composition is formulated for oral administration.

85. The composition for use according to any one of claims 75 to 84, wherein the composition comprises about 200 to 1800 mg of N-acylethanolamine, or a pharmaceutically acceptable salt thereof.

86. The composition for use according to any one of claims 75 to 85, wherein the composition comprises about 2.5 mg / kg to 36 mg / kg of N-acylethanolamine, or pharmaceutically acceptable salt thereof, per body weight of the subject in need thereof.

87. The composition for use according to any one of claims 75 to 86, wherein the N- acylethanolamine is selected from N-palmitoylethanolamine (PEA), Me- palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), and pharmaceutically acceptable salts thereof.

88. The composition for use according to any one of claims 75 to 87, wherein the N- acylethanolamine is PEA or a pharmaceutically acceptable salt thereof.

Images