Composition containing 5-methoxy-2-aminoindan for the treatment of depression

Abstract

The present invention relates to a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier and / or additive, and its use in a method for treating depression, comprising administering the composition in a therapeutically effective amount to a subject in need.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application 63 / 492,837 filed March 29, 2023, and incorporates its contents in whole herein by reference.

[0002] Field of Invention The present invention relates to compositions and methods for the treatment of depression. The present invention provides pharmaceutical compositions comprising 5-methoxy-2-aminoindan ("MEAI") or a pharmaceutically acceptable salt thereof, and methods for using the same in the treatment of depression. [Background technology]

[0003] Background of the Invention Depression, or major depressive disorder (MDD), is one of the most incapacitating medical disorders, with a lifetime prevalence of approximately 17% (Kessler et al., Arch Gen Psychiatry. 62(6):593-602 (2005)). It often appears early in life, can follow a chronic course, and adversely affects the prognosis of other medical conditions such as coronary artery disease, diabetes, and osteoporosis.

[0004] Depression is characterized by a depressed mood and a markedly reduced interest in or pleasure of activity. Other symptoms include significant weight loss or gain, decreased or increased appetite, insomnia or hypersomnia, psychomotor agitation or stagnation, fatigue or lethargy, feelings of worthlessness or excessive or inappropriate guilt, difficulty thinking or concentrating, recurring thoughts about death, suicidal ideation or attempts. A variety of physical symptoms may also be present. While depressed feelings are common, especially after experiencing failure in life, a depressive disorder is not diagnosed until symptoms reach a threshold and persist for at least two weeks. The severity of depression can range from mild to very severe. Most are incidental, but can be recurrent or chronic. Some people have only one episode and fully return to pre-illness functioning. However, more than 50 percent of people who initially experience a single major depressive episode eventually develop another episode.

[0005] Depression is more common in women than in men. The point prevalence of unipolar depressive episodes is estimated at 1.9% in men and 3.2% in women, with 5.8% of men and 9.5% of women experiencing a depressive episode during a 12-month period. These prevalences vary across populations and may be higher in some populations. A World Health Organization study reported that depression is a leading cause of years living with disability and the fourth leading cause of disability-adjusted life. Disability-adjusted life is the reduction in an individual's productive life and is an index that takes into account premature death (Murray et al., Lancet. 349(9063):1436-1442 (1997)).

[0006] Unfortunately, current drug therapies for treating depression take weeks to months to achieve maximum effectiveness, during which time patients continue to suffer from symptoms and remain at risk of self-harm and damage to their personal and professional lives. In fact, the several-week delay in the onset of action of traditional antidepressants is recognized as a major limitation, particularly leading to a significant morbidity and high risk of suicidal behavior during the first nine days of antidepressant initiation (Jick et al., Jama. 292(3):338-343 (2004)). [Overview of the project] [Problems that the invention aims to solve]

[0007] Therefore, there remains an unmet need to provide effective and rapid treatment for post-administration depression.

[0008] Compounds derived from 2-aminoindanes have been shown to selectively bind to dopamine D3 receptors. U.S. Patent 5,708,018 discloses several 2-aminoindane derivatives and hypothesizes that these derivatives may be useful in treating CNS disorders associated with dopamine D3 receptors. One such compound is 5-methoxy-2-aminoindane ("MEAI"), whose chemical formula is: [ka] That is the case.

[0009] N-acylethanolamines (NAEs) are lipid-derived signaling molecules. They are formed when one of several types of acyl groups is bonded to the nitrogen atom of ethanolamine. Examples of N-acylethanolamines include anandamide (amide of arachidonic acid (20:4 omega-6) and ethanolamine), N-palmitoylethanolamine (amide of palmitic acid (16:0) and ethanolamine), N-oleoylethanolamine (amide of oleic acid (18:1) and ethanolamine), N-stearoylethanolamine (amide of stearic acid (18:0) and ethanolamine), and N-docosahexaenoylethanolamine (amide of docosahexaenoic acid (22:6) and ethanolamine).

[0010] The term "N-acylethanolamine" as used herein generally refers to a type of fatty acid amide, a lipid-derived signaling molecule formed when one of several types of acyl groups is bonded to the nitrogen atom of ethanolamine. These amides can be formed from a fatty acid and ethanolamine with the release of one molecule of water, although known biosynthesis uses specific phospholipase D to cleave the phospholipid unit from N-acylphosphatidylethanolamine. The suffixes -amine and -amide in these names refer to the single nitrogen atom of ethanolamine that binds the compound, respectively: in ethanolamine, it is referred to as "amine" because it is considered the free terminal nitrogen in its subunit, and as "amide" when it is considered to be bonded to the adjacent carbonyl group of the acyl subunit. The names of these compounds may appear as "amide" or "amine" herein, and the meaning is equivalent. The term "ethanolamine" is used in a general sense and includes mono-ethanolamine, di-ethanolamine, tri-ethanolamine, and mixtures thereof.

[0011] Palmitoylethanolamide (PEA, also known as N-(2-hydroxyethyl)hexadecanamide; hydroxyethylpalmitamide; palmidol; N-palmitoylethanolamine; and palmitylethanolamide) is an endogenous fatty acid amide belonging to the class of nuclear factor agonists. The chemical structure of PEA is: [ka] It is. PEA has been shown to bind to receptors in the cell nucleus (nuclear receptors) and exert various biological functions related to chronic pain and inflammation. There are studies indicating that PEA interacts with different non-CB1 / CB2 receptors, suggesting that PEA utilizes a unique "parallel" endocannabinoid signaling system. This concept is further supported by increasing evidence that PEA production and inactivation can occur independently of AEA and 2-AG production and inactivation. Most of the biological effects of PEA on cells are obtained through its affinity for PPAR (especially PPAR-alpha and PPAR-gamma). PEA has an affinity for the cannabinoid-like G-coupled receptors GPR55 and GPR119 as well as the transient receptor potential vanilloid type 1 receptor (TRPV1). PEA has been shown to have anti-inflammatory, antinociceptive, neuroprotective, and antiepileptic properties.

Means for Solving the Problems

[0012] Summary of the Invention The present invention provides a pharmaceutical composition comprising MEAI or a pharmaceutically acceptable salt thereof. The present invention also provides a pharmaceutical composition comprising a combination of MEAI or a salt thereof and N-acylethanolamine or a salt thereof. In certain embodiments, the N-acylethanolamine or a salt thereof is PEA or a salt thereof. In certain embodiments, these compositions contain a pharmaceutical dosage and can be used in various ways. In particular, the present invention provides a method for preventing and / or treating depression.

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

[0014] In one embodiment, the molar ratio of MEAI to N-acylethanolamine is approximately 1:0.2 to approximately 1:5. In another embodiment, the molar ratio of MEAI to N-acylethanolamine is approximately 1:0.22 to approximately 1:4.5, approximately 1:0.25 to approximately 1:4, approximately 1:0.28 to approximately 1:3.5, approximately 1:0.33 to approximately 1:3, approximately 1:0.4 to approximately 1:2.5, approximately 1:0.5 to approximately 1:2, or approximately 1:1. Each possibility represents another aspect of the present invention. In any of the above embodiments, N-acylethanolamine is PEA or a salt thereof.

[0015] In one embodiment, the molar ratio of MEAI to N-acylethanolamine is approximately 1:15 to approximately 1:1000. In another embodiment, the molar ratio of MEAI to N-acylethanolamine is approximately 1:16 to approximately 1:900, approximately 1:17 to approximately 1:800, approximately 1:18 to approximately 1:700, approximately 1:19 to approximately 1:600, approximately 1:20 to approximately 1:500, approximately 1:21 to approximately 1:480, or approximately 1:22 to approximately 1:460. Each possibility represents another aspect of the present invention. In another embodiment, the molar ratio of MEAI to N-acylethanolamine is approximately 1:25 to approximately 1:450. In some embodiments, the molar ratio of MEAI to N-acylethanolamine is approximately 1:10 to 1:500, 1:15 to 1:450, 1:20 to 1:400, 1:25 to 1:350, 1:30 to 1:300, 1:35 to 1:250, 1:40 to 1:200, or 1:45 to 1:150. Each possibility represents another aspect of the present invention. In some embodiments, the molar ratio of MEAI to N-acylethanolamine is approximately 1:50 to 1:100. In some embodiments, the molar ratio of MEAI to N-acylethanolamine is approximately 1:10. In some embodiments, the molar ratio of MEAI to N-acylethanolamine is approximately 1:20. In some embodiments, the molar ratio of MEAI to N-acylethanolamine is approximately 1:30. In one embodiment, the molar ratio of MEAI to N-acylethanolamine is approximately 1:40. In another embodiment, the molar ratio of MEAI to N-acylethanolamine is approximately 1:50. In another embodiment, the molar ratio of MEAI to N-acylethanolamine is approximately 1:60. In another embodiment, the molar ratio of MEAI to N-acylethanolamine is approximately 1:70. In another embodiment, the molar ratio of MEAI to N-acylethanolamine is approximately 1:80. In another embodiment, the molar ratio of MEAI to N-acylethanolamine is approximately 1:90. In another embodiment, the molar ratio of MEAI to N-acylethanolamine is approximately 1:100. In another embodiment, the molar ratio of MEAI to N-acylethanolamine is approximately 1:110. In another embodiment, the molar ratio of MEAI to N-acylethanolamine is approximately 1:120.In certain embodiments, the molar ratio of MEAI to N-acylethanolamine is about 1:130. In certain embodiments, the molar ratio of MEAI to N-acylethanolamine is about 1:140. In certain embodiments, the molar ratio of MEAI to N-acylethanolamine is about 1:150. In certain embodiments, the molar ratio of MEAI to N-acylethanolamine is about 1:160. In certain embodiments, the molar ratio of MEAI to N-acylethanolamine is about 1:170. In certain embodiments, the molar ratio of MEAI to N-acylethanolamine is about 1:180. In certain embodiments, the molar ratio of MEAI to N-acylethanolamine is about 1:190. In certain embodiments, the molar ratio of MEAI to N-acylethanolamine is about 1:200. In certain embodiments, the molar ratio of MEAI to 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 aspect of the invention. In any of the above embodiments, the N-acylethanolamine is PEA or a salt thereof.

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

[0017] In one embodiment, the pharmaceutical composition contains about 200 to 1800 mg of N-acylethanolamine or a salt thereof. In another embodiment, the pharmaceutical composition contains about 250 mg, about 500 mg, about 750 mg, about 1000 mg, or about 1500 mg of N-acylethanolamine or a salt thereof. Each possibility represents another aspect of the present invention. In any of the above embodiments, N-acylethanolamine is PEA or a salt thereof.

[0018] In one embodiment, 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 another aspect of the present invention. In one embodiment, the N-acylethanolamine is PEA or a salt thereof. In one embodiment, the N-acylethanolamine consists of PEA or a salt thereof. In one embodiment, the N-acylethanolamine consists of PEA.

[0019] In one embodiment, the pharmaceutical composition is formulated for systemic administration. In another embodiment, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalation, topical, rectal, vaginal, non-enteral, intravenous, intramuscular, or subcutaneous administration. In another embodiment, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. Each possibility represents another aspect of the present invention. In another embodiment, the pharmaceutical composition is formulated for oral administration. In another embodiment, the pharmaceutical composition is formulated for oral mucosal administration. In another embodiment, the pharmaceutical composition is formulated for nasal administration. In yet another embodiment, the pharmaceutical composition is formulated for sublingual administration.

[0020] The present invention further provides, in one embodiment, a dosage unit comprising or consisting of the above-mentioned pharmaceutical composition.

[0021] In one embodiment, the dosage unit comprises the above-mentioned pharmaceutical composition. In another embodiment, the dosage unit consists of the above-mentioned pharmaceutical composition. In another embodiment, the dosage unit is formulated as a gel, powder, or spray. In another embodiment, the dosage unit is formulated as a gel. In another embodiment, the dosage unit is formulated as a powder. In another embodiment, the dosage unit is formulated as a spray.

[0022] In one embodiment, N-acylethanolamine enhances the therapeutic efficacy of MEAI compared to the same pharmaceutical composition without N-acylethanolamine. In another embodiment, N-acylethanolamine reduces the required therapeutic dose of MEAI compared to the same pharmaceutical composition without N-acylethanolamine. In another embodiment, N-acylethanolamine broadens the therapeutic range of MEAI compared to the same pharmaceutical composition without N-acylethanolamine.

[0023] In one embodiment, the present invention relates to a pharmaceutical composition comprising MEAI or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier and / or additive. In one embodiment, the present invention relates to a pharmaceutical composition comprising MEAI or a salt thereof, and N-acylethanolamine or a salt thereof, and at least one pharmaceutically acceptable carrier and / or additive. In one embodiment, N-acylethanolamine is PEA or a salt thereof.

[0024] In one embodiment, the pharmaceutical composition comprises a unit dose of MEAI or a pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition is a solid composition. In yet another embodiment, the pharmaceutical composition is a liquid composition. In yet another embodiment, the pharmaceutical composition is packaged as a single unit dose or multiple single unit doses.

[0025] In one embodiment, the unit dosage form contains about 20 mg to about 60 mg of MEAI or a pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition is formulated for oral administration.

[0026] In other embodiments, the present invention relates to a method for treating depression, comprising administering a pharmaceutical composition containing a therapeutically effective amount of MEAI or a pharmaceutically acceptable salt thereof to a subject in need, thereby treating the condition. In other embodiments, the present invention relates to a method for treating depression, comprising administering a therapeutically effective amount of MEAI or a salt thereof and N-acylethanolamine or a salt thereof to a subject in need, thereby treating the condition. In one embodiment, the administered pharmaceutical composition contains a unit dose of MEAI or a pharmaceutically acceptable salt thereof in the range of about 20 to about 60 mg, for example, about 20 mg of MEAI or about 60 mg of MEAI. In one embodiment, the administered pharmaceutical composition contains a unit dose of N-acylethanolamine or a pharmaceutically acceptable salt thereof in the range of about 200 to about 1800 mg, for example, about 200 mg of N-acylethanolamine or about 1800 mg of N-acylethanolamine. In one embodiment, MEAI or a pharmaceutically acceptable salt thereof is administered in doses in the range of about 0.2 mg / kg to 5.0 mg / kg body weight of MEAI. In one embodiment, N-acylethanolamine or a pharmaceutically acceptable salt thereof is administered in doses ranging from approximately 2.5 mg / kg to 36.0 mg / kg body weight of N-acylethanolamine. In one embodiment, N-acylethanolamine or a pharmaceutically acceptable salt thereof is PEA.

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

[0028] In certain embodiments, in the method of the present invention, the pharmaceutical composition is a unit dosage form composition. In other embodiments, the amount of MEAI or a pharmaceutically acceptable salt thereof in the unit dosage form ranges from about 20 mg to about 60 mg. In certain embodiments, the pharmaceutical composition is administered orally. In certain embodiments, the pharmaceutical composition containing MEAI or a pharmaceutically acceptable salt thereof is administered daily. In certain embodiments, the method reduces depression, for example, measured by a change in the BDI-II total score, for example, by at least 1 to 10 points, for example, by at least 10 points. In certain embodiments, the method reduces depression, measured by a standardized mean difference of at least 0.2 in the BDI-II total score, for example, at least about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, or more, for example, a change of at least 0.5.

[0029] Further embodiments and full scope of application of the present invention will become apparent from the detailed description shown below. However, the detailed description describes preferred embodiments of the present invention, and various changes and modifications within the spirit and scope of the present invention will be apparent to those skilled in the art from this detailed description, and are shown only as examples.

Mode for Carrying Out the Invention

[0030] Detailed description of the invention Definition: When ranges of values are recited, it is intended to include each value and subrange within the range. For example, "C1-C6 alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 、and C 5-6 alkyl.

[0031] "Isomers" are compounds that have the same number and types of atoms, and therefore the same molecular weight, but differ in the arrangement or configuration of atoms in space.

[0032] A “stereoisomer” or “optical isomer” is a stable isomer that has at least one chiral atom or bound rotation that gives rise to a perpendicular chiral plane (e.g., certain biphenyl, allene, and spiro compounds) and is capable of rotating plane-polarized light. Due to the chiral centers and other chemical structures present in the compounds of the present invention that can give rise to stereoisomerism, the present invention intends stereoisomers and mixtures thereof. The compounds of the present invention and their salts contain a chiral carbon atom and therefore can exist as single stereoisomers, racemates, and mixtures of enantiomers and diastereomers. Typically, such compounds are prepared as racemic mixtures. However, if desired, such compounds may be prepared or isolated as pure stereoisomers, i.e., individual enantiomers or diastereomers, or stereoisomer-enriched mixtures. As further detailed below, individual stereoisomers of a compound are produced by synthesis from optically active starting materials containing the desired chiral center, or by a mixture of enantiomer products followed by separation or resolution, e.g., conversion to a diastereomer mixture followed by separation or recrystallization, chromatographic techniques, the use of chiral resolving agents, or direct separation of enantiomers on a chiral chromatography column. Starting compounds with specific stereochemistrys are commercially available or produced by the methods described below and resolution by techniques well known in the art.

[0033] It is well known in the art that the biological and pharmacological activity of a compound is sensitive to its stereochemistry. Therefore, for example, enantiomers often exhibit remarkably different biological activities, including differences in pharmacokinetic properties such as metabolism and protein binding, as well as pharmacological properties such as the type, degree, and toxicity of the activity they exhibit. Thus, those skilled in the art will recognize that one enantiomer may be more active or exhibit beneficial effects when concentrated relative to or separated from another enantiomer. Furthermore, how to separate, enrich, or selectively produce enantiomers of the compounds of the present invention will be understood by those skilled in the art from the knowledge of this disclosure and the prior art.

[0034] Therefore, while racemates of drugs may be used, they are often less effective than equivalent amounts of enantiomerically pure drugs; in fact, in some cases, one enantiomer may be pharmacologically inactive and act only as a diluent. For example, ibuprofen was previously administered as a racemate, but only the S-isomer of ibuprofen has been shown to be effective as an anti-inflammatory agent (however, in the case of ibuprofen, the R-isomer is inactive but is converted to the S-isomer in vivo, and therefore the rapid activity of the racemic drug is lower than that of the pure S-isomer). Furthermore, the pharmacological activity of enantiomers can have different biological activities. For example, S-penicillamine is a therapeutic agent for chronic arthritis, while R-penicillamine is toxic. In fact, some purified enantiomers have advantages over racemates, as it has been reported that the purified individual isomers have a faster transdermal penetration rate compared to the racemic mixture. See U.S. Patents 5,114,946 and 4,818,541.

[0035] In one embodiment, the compound is a racemic mixture of (S)- and (R)-isomers. In another embodiment, a mixture of compounds is provided, wherein the individual compounds of the mixture are primarily in (S)- or (R)-isomer configurations. For example, the compound mixture has an excess of 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 (S)-enantiomers. In other embodiments, the compound mixture has an excess of (S)-enantiomers of approximately 55% to over 99.5%, approximately 60% to over 99.5%, approximately 65% ​​to over 99.5%, approximately 70% to over 99.5%, approximately 75% to over 99.5%, approximately 80% to over 99.5%, approximately 85% to over 99.5%, approximately 90% to over 99.5%, approximately 95% to over 99.5%, approximately 96% to over 99.5%, approximately 97% to over 99.5%, approximately 98% to over 99.5%, approximately 99% to over 99.5%, or more. In other embodiments, the compound mixture has a (R)-enantiomer purity of 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 higher. In one other embodiment, the compound mixture has an excess of (R)-enantiomers of approximately 55% to over 99.5%, approximately 60% to over 99.5%, approximately 65% ​​to over 99.5%, approximately 70% to over 99.5%, approximately 75% to over 99.5%, approximately 80% to over 99.5%, approximately 85% to over 99.5%, approximately 90% to over 99.5%, approximately 95% to over 99.5%, approximately 96% to over 99.5%, approximately 97% to over 99.5%, approximately 98% to over 99.5%, approximately 99% to over 99.5%, or more.

[0036] The individual stereoisomers of the compounds of the present invention can be produced by synthesis from commercially available starting materials containing asymmetric or stereocenters, or by separation methods well known to those skilled in the art, which follow the production of racemic mixtures. These separation methods are exemplified by (1) binding of the enantiomer mixture to a chiral auxiliary, separation of the resulting diastereomer mixture by recrystallization or chromatography and liberation of an optically pure product from the auxiliary; (2) salt formation using an optically active resolving agent; or (3) direct separation of the optical enantiomer mixture on a chiral chromatography column. Stereoisomer mixtures can also be separated into component stereoisomers by well known methods such as chiral phase gas chromatography, chiral phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Stereoisomers can also be obtained from stereoisomerically pure intermediates, reagents, and catalysts by well known asymmetric synthesis methods.

[0037] Therefore, if one enantiomer is pharmacologically more active, less toxic, or has a more favorable metabolic disposition than the other, administering that enantiomer preferentially is therapeutically more beneficial. In this way, the total dose of the drug to which the patient is exposed during treatment is low, and the dose of the enantiomer that may be toxic or inhibit the other enantiomer is low.

[0038] The nomenclature of compounds, including organic compounds, used herein may be given using common names, IUPAC, IUBMB, or CAS nomenclature recommendations. Those skilled in the art can, if given a nominal name, use a systematic classification of compound structures or CHEMDRAW to determine the structure of the compound. TM This can be easily verified using commercially available software such as that from Cambridgesoft Corporation (USA). The chemical name is PerkinElmer ChemDraw. (登録商標) Created using Professional, version 17.

[0039] The compounds of the present invention may contain one or more chiral centers and / or double bonds, and therefore may exist as stereoisomers such as geometric isomers, enantiomers, or diastereomers. The term “stereoisomer,” as used herein, consists of all geometric isomers, enantiomers, or diastereomers. These compounds may be designated by the symbol “R” or “S” depending on the arrangement of substituents around the stereogenic carbon atom. The present invention encompasses various stereoisomers and mixtures thereof of these compounds. Stereoiomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers are designated “(±)” in nomenclature, but those skilled in the art will recognize that the structure may implicitly indicate a chiral center. In some embodiments, an enantiomer or stereoisomer may be provided without substantially a corresponding enantiomer.

[0040] In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of MEAI or a salt thereof. In another embodiment, the present invention provides 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 one embodiment, at least one N-acylethanolamine or a salt thereof comprises PEA or a salt thereof. In one embodiment, MEAI or a salt thereof and at least one N-acylethanolamine or a salt thereof exist in one combination. In one embodiment, MEAI or a salt thereof and at least one N-acylethanolamine or a salt thereof are packaged in separate units within a kit, for example, in vials.

[0041] In another embodiment, the present invention provides 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 of MEAI to N-acylethanolamine is about 1:0.2 to about 1:1000. In one embodiment, at least one N-acylethanolamine or a salt thereof comprises PEA or a salt thereof.

[0042] As used herein, "pharmaceutical composition" refers to a preparation of the activator described herein and other chemical components such as physiologically appropriate carriers and additives. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to a living organism. As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier, additive, or diluent that does not cause significant irritation to a living organism and does not inhibit the biological activity and properties of the administered compound. Adjuvants are included under these terms.

[0043] As used herein, the term "additive" refers to an inert substance added to a pharmaceutical composition to further enhance the administration of the active ingredient. Examples of additives include, but are not limited to, calcium carbonate, povidone K-30, crospovidone, silicon dioxide, magnesium stearate, calcium phosphate, various types of sugars and starches, cellulose derivatives, gelatin, oils such as vegetable oil or fish oil, and polyethylene glycol.

[0044] The term "carrier" as used herein refers to a diluent, adjuvant, additive, or medium through which a compound is administered. Such pharmaceutical carriers may be sterile liquids such as water and oil. Water or aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably used as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin, 18th Edition.

[0045] The term "unit dose" as used herein refers to the fixed amount, or unit, of a compound in a composition that is administered to or ingested by a subject.

[0046] As used herein, the term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically acceptable and, when administered to an individual, do not typically produce allergic or similar toxicity. Preferably, and especially when the formulation is used in humans, the term "pharmaceutically acceptable" may mean that it is listed in a pharmacopoeia (e.g., the United States Pharmacopeia) that is approved by a regulatory authority (e.g., the U.S. Food and Drug Administration) or that is generally recognized for use in animals.

[0047] The term "derivative" as used herein refers to a compound whose core structure is the same as or closely mimics that of a 2-aminoindan or N-acylethanolamine compound, but which has different or additional chemical or physical modifications.

[0048] The term "salt" as used herein refers to any form of the active ingredient, assuming it is in ionic form and is bound to a counterion (cation or anion) or present in solution. This also includes complexes of the active ingredient with other molecules and ions, particularly complexes formed by ionic interactions.

[0049] As used herein, the term “pharmaceutically acceptable salt” typically refers to a charged species of a parent compound and its counterion used to modify the solubility characteristics of the parent compound and / or to reduce any significant irritation to an organism caused by the parent compound, without inhibiting the biological activity and properties of the compound being administered.

[0050] In one embodiment of the present invention, a pharmaceutically acceptable salt of the compound described herein may be an acid addition salt comprising, optionally, 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 counterion derived from a selected acid that forms the 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 a drug and one equivalent or more of an acid.

[0052] Acid addition salts can include a wide variety of organic and inorganic acids, including, but not limited to, hydrochloric acid (which yields hydrochloric acid addition salts), hydrobromic acid (which yields hydrobromic acid addition salts), acetic acid (which yields acetic acid addition salts), ascorbic acid (which yields ascorbic acid addition salts), benzenesulfonic acid (which yields besylate addition salts), camphorsulfonic acid (which yields camphorsulfonic acid addition salts), citric acid (which yields citrate addition salts), maleic acid (which yields maleic acid addition salts), malic acid (which yields malic acid addition salts), methanesulfonic acid (which yields methanesulfonic acid (mesylate) addition salts), naphthalenesulfonic acid (which yields naphthalenesulfonic acid addition salts), oxalic acid (which yields oxalic acid addition salts), phosphoric acid (which yields phosphate addition salts), toluenesulfonic acid (which yields p-toluenesulfonic acid addition salts), succinic acid (which yields succinic acid addition salts), sulfuric acid (which yields sulfuric acid addition salts), tartaric acid (which yields tartaric acid addition salts), and trifluoroacetic acid (which yields trifluoroacetic acid addition salts). Each of these acid addition salts can be a single or polyaddition salt, and these terms are defined herein.

[0053] In one embodiment, a pharmaceutically acceptable salt of the compound described herein may be a base addition salt, optionally comprising at least one group of the compound in its anionic form in combination with at least one counterion (i.e., cation) that forms the pharmaceutically acceptable salt. Examples of suitable cations include, but are not limited to, metal cations of sodium, potassium, magnesium, and calcium or ammonium.

[0054] Each of these base addition salts can be a single or multiple addition salt, and these terms are defined herein.

[0055] Depending on the stoichiometric ratio of the basic or acidic charged group (e.g., an amine group) in the compound and the counterion in the salt, an acid or base addition salt can be a single addition salt or a polyaddition salt.

[0056] The term "single addition salt" used here refers to a salt in which the stoichiometric ratio of the counterion to the charged form of the compound is 1:1, such that the addition salt contains 1 molar equivalent of the counterion for every 1 molar equivalent of the compound.

[0057] The term "multiple addition salt" used here refers to a salt in which the stoichiometric ratio of counterions to the charged form of the compound is greater than 1:1, such as 2:1, 3:1, 4:1, etc., so that the addition salt contains 2 or more molar equivalents of counterions per molar equivalent of the compound.

[0058] Furthermore, in any of the embodiments described herein, each of the compounds described herein may include a salt thereof, and may be in the form of a solvate or hydrate thereof.

[0059] The term "solvate" refers to a complex formed by a solute (the 2-aminoindan derivative described herein) and a solvent, in which the solvent does not interfere with the biological activity of the solute, and which has a variable stoichiometric range (e.g., 2, 3, 4, 5, 6, etc.).

[0060] The term "hydrate" refers to a solvate, as defined above, in which the solvent is water.

[0061] In one embodiment, the pharmaceutical composition comprises a unit dose of about 20 to about 60 mg of MEAI or a pharmaceutically acceptable salt thereof. In another embodiment, 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 of MEAI or a pharmaceutically acceptable salt thereof. In another embodiment, 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 of MEAI or a pharmaceutically acceptable salt thereof. Each possibility represents another aspect of the present invention. In another embodiment, 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 of MEAI or a pharmaceutically acceptable salt thereof. Each possibility represents another aspect of the present invention.

[0062] In one embodiment, the pharmaceutical composition comprises a unit dose of MEAI or a pharmaceutically acceptable salt thereof in an amount 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. In one embodiment, the pharmaceutical composition comprises a unit dose of 20 mg of MEAI or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition comprises a unit dose of 60 mg of MEAI or a pharmaceutically acceptable salt thereof. Each possibility represents another aspect of the present invention.

[0063] In one embodiment, the pharmaceutical composition contains MEAI or a pharmaceutically acceptable salt thereof in a concentration sufficient to provide the patient with a dose of about 0.2 mg / kg to about 5 mg / kg body weight. In another embodiment, the pharmaceutical composition contains MEAI or a pharmaceutically acceptable salt thereof in a concentration sufficient to provide the 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 one embodiment, the pharmaceutical composition contains MEAI or a pharmaceutically acceptable salt thereof in a concentration sufficient to provide the 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 body weight. Each possibility represents another aspect of the present invention. In one embodiment, the pharmaceutical composition contains MEAI or a pharmaceutically acceptable salt thereof in a concentration sufficient to provide the 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 body weight. Each possibility represents another aspect of the present invention. In one embodiment, the pharmaceutical composition contains MEAI or a pharmaceutically acceptable salt thereof in a concentration sufficient to provide the 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 another aspect of the present invention.

[0064] In one embodiment, the pharmaceutical composition containing MEAI also contains about 200 to 1800 mg of N-acylethanolamine or a salt thereof. In another embodiment, the pharmaceutical composition contains about 250 to 1550 mg, about 300 to 1200 mg, about 350 to 950 mg, about 400 to 700 mg, about 450 to 600 mg, or about 500 to 550 mg of N-acylethanolamine or a salt thereof. Each possibility represents another aspect of the present invention. In another embodiment, the pharmaceutical composition contains 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 It contains 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 of N-acylethanolamine or a salt thereof. In one embodiment, the pharmaceutical composition contains about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, 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 of N-acylethanolamine or a salt thereof. Each possibility represents another aspect of the present invention.

[0065] In one embodiment, the pharmaceutical composition comprising MEAI also comprises a concentration of N-acylethanolamine or a 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 36 mg / kg body weight. In one embodiment, the pharmaceutical composition contains N-acylethanolamine or a pharmaceutically acceptable salt thereof in a concentration sufficient to provide the patient with a dose of approximately 2.5 to approximately 5 mg / kg, approximately 5 mg / kg to approximately 7.5 mg / kg, approximately 7.5 mg / kg to approximately 10 mg / kg, approximately 10 mg / kg to approximately 12.5 mg / kg, approximately 12.5 mg / kg to approximately 15 mg / kg, approximately 15 mg / kg to approximately 17.5 mg / kg, approximately 17.5 mg / kg to approximately 20 mg / kg, approximately 20 mg / kg to approximately 22.5 mg / kg, approximately 22.5 mg / kg to approximately 25 mg / kg, approximately 25 mg / kg to approximately 27.5 mg / kg, approximately 27.5 mg / kg to approximately 30 mg / kg, approximately 30 mg / kg to approximately 32.5 mg / kg, and approximately 32.5 mg / kg to approximately 36 mg / kg body weight. In one embodiment, the pharmaceutical composition contains a concentration of N-acylethanolamine or a 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 body weight of N-acylethanolamine or a salt thereof. Each possibility represents another aspect of the present invention. In one embodiment, the pharmaceutical composition contains a concentration of N-acylethanolamine or a 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 body weight of N-acylethanolamine or a salt thereof. Each possibility represents another aspect of the present invention.In one embodiment, the pharmaceutical composition contains N-acylethanolamine or a pharmaceutically acceptable salt thereof in a concentration sufficient to provide a patient with a dose of N-acylethanolamine or a salt thereof equivalent to 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 of N-acylethanolamine or a salt thereof. Each possibility represents a different aspect of the present invention.

[0066] In one embodiment, 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 another aspect of the present invention. In one embodiment, the N-acylethanolamine is PEA or a salt thereof. In one embodiment, the N-acylethanolamine consists of PEA or a salt thereof. In one embodiment, the N-acylethanolamine consists of PEA.

[0067] In one embodiment, the pharmaceutical composition is formulated for systemic administration. In another embodiment, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalation, topical, rectal, vaginal, non-enteral, intravenous, intramuscular, or subcutaneous administration. In another embodiment, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. Each possibility represents another aspect of the present invention. In another embodiment, the pharmaceutical composition is formulated for oral administration. In another embodiment, the pharmaceutical composition is formulated for oral mucosal administration. In another embodiment, the pharmaceutical composition is formulated for nasal administration. In yet another embodiment, the pharmaceutical composition is formulated for sublingual administration.

[0068] Techniques for the formulation and administration of drugs are well known in the art and can be found, for example, in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa. The pharmaceutical compositions of the present invention may be produced by methods well known in the art, for example, by conventional mixing, dissolution, granulation, sugar-coated tablet production, elutriation, emulsification, encapsulation, capture, or freeze-drying methods.

[0069] For oral administration, pharmaceutical compositions can be readily formulated by combining an active compound with a pharmaceutically acceptable carrier well known in the art. Such carriers allow the pharmaceutical composition to be formulated into tablets, pills, coated tablets, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral intake by the patient. Pharmacological formulations for oral use can be prepared using solid additives, and the resulting mixture may be crushed, and after the addition of suitable adjuvants as desired, the granular mixture may be processed to obtain tablets or coated tablet cores. Suitable additives include fillers such as sugars containing lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, and sodium carbomethylcellulose; and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or sodium alginate salts thereof may be added.

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

[0071] The sugar-coated tablet core is provided with a suitable coating. For this purpose, a concentrated sugar solution may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol, titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or sugar-coated tablet coating for identification or characterization of various combinations of active compound doses.

[0072] Pharmaceutical compositions for oral administration include hard or soft-sealed capsules made from gelatin and a plasticizer such as glycerol or sorbitol. The capsules may contain an active ingredient mixed with a bulking agent such as lactose, a binder such as starch, a lubricant such as talc or magnesium stearate, and optionally, a stabilizer. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Further stabilizers may be added. Oral formulations may be in doses suitable for the chosen route of administration. For buccal and sublingual administration, the composition may take the form of tablets or lozenges formulated in conventional methods or on an adhesive carrier. Alternatively, the active ingredient may be in powder form for mixing with a suitable medium, e.g., a sterile, pyrogen-free, water-based solution, before use.

[0073] Pharmaceutical compositions suitable for use in the context of the present invention include compositions in which the active ingredient is contained in an amount effective for achieving the intended purpose. More specifically, “therapeutic amount” means an amount of the active ingredient effective in preventing, reducing, or improving the symptoms or side effects of a disease or disorder, or in extending the survival of the subject being treated. Determining the therapeutic amount is well within the capabilities of those skilled in the art, particularly in light of the detailed disclosure provided herein. More specifically, “therapeutic mixture” means an amount of at least two active ingredients, where each of the active ingredients may not be therapeutically effective individually, or both active ingredients may not be therapeutically effective, but the mixture is nevertheless effective in preventing, reducing, or improving the symptoms or side effects of a disease or disorder, or in extending the survival of the subject being treated. As used herein, “mixture” means a non-covalent combination of two molecules.

[0074] For any formulation in the methods of the present invention, the dose or therapeutically effective dose is initially estimated by in vitro, in vivo, and cell culture assays. For example, a certain dose can be formulated in an animal model to achieve a desired concentration or potency. Using such information, a more precise determination of an effective dose in humans can be made. The dose of the claimed composition depends on several factors, including the method of administration, the disease being treated, the severity of the disease, whether the disease is being treated or prevented, and the age, weight, and health of the person being treated. Furthermore, pharmacogenomics information (the influence of genotype on pharmacokinetics, pharmacodynamics, or therapeutic efficacy profiles) for a particular patient may influence the dose used. Continuous daily dosing may not be necessary; a treatment regimen may require drug-free cycles, or treatment may be administered on an as-needed basis during periods of acute disease exacerbation. Dose escalation may or may not be necessary; a treatment regimen may require a decrease in the drug therapy dose. The toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard formulation procedures in vitro, in cell culture, or in experimental animals. Data obtained from these in vitro and cell culture assays and animal studies can be used to formulate the range of dosages for use in humans. Dosages may vary depending on the dosage form and route of administration used. The exact formulation, route of administration, and dosage may be individually selected by the physician in light of the patient's condition (see, for example, Fingl, E. et al. (1975), "The Pharmacological Basis of Therapeutics," Ch. 1, p. 1). Depending on the severity and responsiveness of the condition being treated, medication may be administered once or multiple times, and the treatment process may continue for several days to several weeks, or until a cure or reduction of the disease state is achieved.

[0075] In another embodiment, the present invention provides a dosage unit comprising or consisting of the above-mentioned pharmaceutical composition.

[0076] In one embodiment, the dosage unit comprises the above-mentioned pharmaceutical composition. In another embodiment, the dosage unit consists of the above-mentioned pharmaceutical composition. In another embodiment, the dosage unit is formulated as a gel, powder, or spray. In another embodiment, the dosage unit is formulated as a gel. In another embodiment, the dosage unit is formulated as a powder. In another embodiment, the dosage unit is formulated as a spray.

[0077] In other embodiments, the present invention provides the above-mentioned pharmaceutical compositions or dosage units for use in methods for preventing or treating depression.

[0078] In one embodiment, the present invention provides a method for reducing depression, measured by the standardized mean difference of the change in the total BDI-II score of a control group. See, for example, Beck et al., “Beck Depression Inventory-II”, American Psychological Association, 1996. In one embodiment, the present invention provides a method for reducing depression in a control group, measured by a conversion of the total BDI-II score, for example, by at least 1 to 10 points, for example, at least 10 points. In one embodiment, the reduction in depression is measured, for example, over a two-week period, and compared to the score before the start of treatment, by at least 1 point, for example, preferably at least 10 points. The BDI-II score represents the sum of 21 depressive symptoms, including, for example, grief, guilt, anger, and indecisiveness, which the control group self-rates on a scale of 0 to 3. For the grief symptom, a score of 0 indicates “not feeling sad,” and a score of 3 indicates “unbearably sad and unhappy.” A total score of 0–13 across 21 symptoms indicates no depression or very mild depression, 14–19 indicates mild depression, 20–28 indicates moderate depression, and 29–63 indicates severe depression. In one embodiment, the present invention provides a method for reducing depression in a subject, measured by a change of at least 5 points in the BDI-II total score over a two-week period. In one embodiment, the present invention provides a method for reducing depression in a subject, measured by a change of at least 3 points in the BDI-II total score over a two-week period. In one embodiment, the present invention provides a method for reducing depression in a subject, measured by a change of approximately 3–20 points, 5–20 points, or 10–20 points in the BDI-II total score over a two-week period.

[0079] The standardized mean difference in the change in the BDI-II total score can be calculated using the following formula:

[0080]

number

[0081] In Equation 1, SMD, or d, represents the standardized mean difference, and M BDI,1 This represents the average BDI-II score change for the first group, M BDI,2 The d-value represents the mean BDI-II score change of the second group, SD1 represents the standard deviation of the mean BDI-II score change of the first group, and SD2 represents the standard deviation of the mean BDI-II score change of the second group. A d-value of 0.2 or greater represents a small effect, a d-value of 0.5 or greater represents a moderate effect, and a d-value of 0.8 or greater represents a large effect (Cohen, J. Statistical Power Analysis for the Behavioral Science. 2nd ed. Hillsdale, NJ: Lawrence Erlbaum; 1988).

[0082] In one embodiment, the first group may be the experimental group under study. In one embodiment, the experimental group under study may be administered the pharmaceutical composition described herein. In one embodiment, the second group may be the control group under study.

[0083] Patients with clinical depression generally exhibit an average BDI-II score of 30 points at the start of a two-week period, with a standard deviation of 10 points for the average BDI-II score. For example, the experimental group may show an average BDI-II score change of -10 after two weeks (e.g., an average BDI-II score of 30 at the start of the two-week period and 20 after two weeks), while the control group may show an average BDI-II score change of -5 after two weeks (e.g., an average BDI-II score of 30 to 25). According to Equation 1, the d value in this example is 0.5, which may represent a moderate effect of the treatment on the experimental group compared to the control group. A clinical response to the treatment can be represented by an improvement of 50% or more in the average BDI-II score after two weeks. "Improvement in average BDI-II score" can be understood as a decrease in the average BDI-II score. Clinical remission can be represented by a mean BDI-II score of 13 or less and a mean BDI-II score improvement of 50% or more after a two-week period, indicating that the person is not depressed or has only mild depression.

[0084] In one embodiment, the present invention provides a method for reducing depression, comprising administering a pharmaceutical composition containing a therapeutically effective amount of MEAI or a pharmaceutically acceptable salt thereof to a subject in need thereof. In one embodiment, the pharmaceutical composition contains a unit dose in the range of about 20 mg to about 60 mg of MEAI or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition contains 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 of MEAI or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition contains 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 of MEAI or a pharmaceutically acceptable salt thereof. Each possibility represents another aspect of the present invention. In one embodiment, the pharmaceutical composition comprises a unit dose of MEAI or a pharmaceutically acceptable salt thereof 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. Each possibility represents another aspect of the present invention.

[0085] In one embodiment, the present invention provides a method for reducing depression, comprising administering to a subject in need of such reduction a pharmaceutical composition containing a therapeutically effective amount of MEAI or a pharmaceutically acceptable salt thereof, in doses of about 0.2 mg / kg to 5.0 mg / kg body weight of MEAI. In one embodiment, the therapeutically effective amount is administered at a frequency or duration sufficient to reduce depression, for example, by measuring the BDI-II score, for example, by a change of at least one point in the BDI-II score. In one embodiment, the subject is administered doses of 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, and about 3.0 mg / kg to about 3. MEAI or a pharmaceutically acceptable salt of 5 mg / kg, approximately 3.5 mg / kg to approximately 4.0 mg / kg, approximately 4.0 mg / kg to approximately 4.5 mg / kg, or approximately 4.5 mg / kg to approximately 5.0 mg / kg body weight. In one embodiment, a subject is administered MEAI or a pharmaceutically acceptable salt of approximately 0.2 mg / kg, approximately 0.5 mg / kg, approximately 1.0 mg / kg, approximately 1.5 mg / kg, approximately 2.0 mg / kg, approximately 2.5 mg / kg, approximately 3.0 mg / kg, approximately 3.5 mg / kg, approximately 4.0 mg / kg, approximately 4.5 mg / kg, or approximately 5.0 mg / kg body weight. Each possibility represents another aspect of the present invention. In one embodiment, the subject is administered a dose of MEAI or a pharmaceutically acceptable salt thereof of approximately 0.2 mg / kg, less than approximately 0.5 mg / kg, less than approximately 1.0 mg / kg, less than approximately 1.5 mg / kg, less than approximately 2.0 mg / kg, less than approximately 2.5 mg / kg, less than approximately 3.0 mg / kg, less than approximately 3.5 mg / kg, less than approximately 4.0 mg / kg, less than approximately 4.5 mg / kg, or approximately 5.0 mg / kg body weight. Each possibility represents another aspect of the present invention.In one embodiment, the subject is administered a dose of MEAI or a pharmaceutically acceptable salt thereof of approximately 0.2 mg / kg to approximately 0.5 mg / kg, approximately 0.2 mg / kg to approximately 1.0 mg / kg, approximately 0.2 mg / kg to approximately 1.5 mg / kg, approximately 0.2 mg / kg to approximately 2.0 mg / kg, approximately 0.2 mg / kg to approximately 2.5 mg / kg, approximately 0.2 mg / kg to approximately 3.0 mg / kg, approximately 0.2 mg / kg to approximately 3.5 mg / kg, approximately 0.2 mg / kg to approximately 4.0 mg / kg, approximately 0.2 mg / kg to approximately 4.5 mg / kg, or approximately 0.2 mg / kg to approximately 5.0 mg / kg body weight. Each possibility represents another aspect of the present invention.

[0086] In one embodiment, the present invention provides a method for reducing depression, comprising administering to a subject in need of such reduction a pharmaceutical composition containing, for example, one of the above-mentioned doses or concentrations, N-acylethanolamine or a pharmaceutically acceptable salt thereof, and also containing N-acylethanolamine or a pharmaceutically acceptable salt thereof. In one embodiment, the therapeutic dose is administered at a frequency or duration sufficient to reduce depression, for example, by measuring, for example, a BDI-II score, for example, a change of at least one point in the BDI-II score. In one embodiment, the pharmaceutical composition contains 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 of N-acylethanolamine or a salt thereof. Each possibility represents another aspect of the present invention. In one embodiment, the pharmaceutical composition contains at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, at least about 400 mg, 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 It contains 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 of N-acylethanolamine or a salt thereof.In one embodiment, the pharmaceutical composition contains about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, 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 of N-acylethanolamine or a salt thereof. Each possibility represents another aspect of the present invention. In the above embodiment, N-acylethanolamine or a salt thereof may include PEA or a salt thereof.

[0087] In one embodiment, the pharmaceutical composition contains N-acylethanolamine or a pharmaceutically acceptable salt thereof in a concentration sufficient to provide a patient with a dose of about 2.5 mg / kg to about 36 mg / kg body weight. In one embodiment, the pharmaceutical composition contains N-acylethanolamine or a pharmaceutically acceptable salt thereof in a concentration sufficient to provide the patient with a dose of approximately 2.5 to approximately 5 mg / kg, approximately 5 mg / kg to approximately 7.5 mg / kg, approximately 7.5 mg / kg to approximately 10 mg / kg, approximately 10 mg / kg to approximately 12.5 mg / kg, approximately 12.5 mg / kg to approximately 15 mg / kg, approximately 15 mg / kg to approximately 17.5 mg / kg, approximately 17.5 mg / kg to approximately 20 mg / kg, approximately 20 mg / kg to approximately 22.5 mg / kg, approximately 22.5 mg / kg to approximately 25 mg / kg, approximately 25 mg / kg to approximately 27.5 mg / kg, approximately 27.5 mg / kg to approximately 30 mg / kg, approximately 30 mg / kg to approximately 32.5 mg / kg, and approximately 32.5 mg / kg to approximately 36 mg / kg body weight. In one embodiment, the pharmaceutical composition contains N-acylethanolamine or a pharmaceutically acceptable salt thereof in a concentration sufficient to provide the 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 32.5 mg / kg, or about 36 mg / kg body weight. Each possibility represents another aspect of the present invention. In one embodiment, the pharmaceutical composition contains N-acylethanolamine or a pharmaceutically acceptable salt thereof in a concentration sufficient to provide the 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 32.5 mg / kg, or about 36 mg / kg body weight. Each possibility represents another aspect of the present invention.In one embodiment, the pharmaceutical composition contains an N-acylethanolamine or a pharmaceutically acceptable salt thereof in a concentration sufficient to provide the patient with a dose of approximately 2.5 mg / kg to approximately 5 mg / kg, approximately 2.5 mg / kg to approximately 7.5 mg / kg, approximately 2.5 mg / kg to approximately 10 mg / kg, approximately 2.5 mg to approximately 12.5 mg / kg, approximately 2.5 mg / kg to approximately 15 mg / kg, approximately 2.5 mg / kg to approximately 17.5 mg / kg, approximately 2.5 mg / kg to approximately 20 mg / kg, approximately 2.5 mg / kg to approximately 22.5 mg / kg, approximately 2.5 mg / kg to approximately 25 mg / kg, approximately 2.5 mg / kg to approximately 27.5 mg / kg, approximately 2.5 mg / kg to approximately 30 mg / kg, approximately 2.5 mg / kg to approximately 32.5 mg / kg, or approximately 2.5 mg / kg to approximately 36 mg / kg body weight. Each possibility represents another aspect of the present invention. In the above embodiment, N-acylethanolamine or a salt thereof may include PEA or a salt thereof.

[0088] In one embodiment, the pharmaceutical composition is formulated for systemic administration. In another embodiment, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalation, topical, rectal, vaginal, non-enteral, intravenous, intramuscular, or subcutaneous administration. In another embodiment, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. Each possibility represents another aspect of the present invention. In another embodiment, the pharmaceutical composition is formulated for oral administration. In another embodiment, the pharmaceutical composition is formulated for oral mucosal administration. In another embodiment, the pharmaceutical composition is formulated for nasal administration. In yet another embodiment, the pharmaceutical composition is formulated for sublingual administration.

[0089] In one embodiment, the pharmaceutical composition is administered orally. In one embodiment, the pharmaceutical composition containing MEAI or a pharmaceutically acceptable salt thereof is administered daily. In one embodiment, the administered pharmaceutical composition contains a unit dose of MEAI or a pharmaceutically acceptable salt thereof of 1 to 400 mg, for example, 20 to 60 mg. In one embodiment, the administered pharmaceutical composition contains a unit dose of 20 mg of MEAI or a pharmaceutically acceptable salt thereof. In one embodiment, the administered pharmaceutical composition contains a unit dose of 60 mg of MEAI or a pharmaceutically acceptable salt thereof.

[0090] The term “treatment” as used herein includes, but is not limited to, any one or more of the following: suppression, improvement, inhibition, attenuation, blockage, inhibition, suggestion, delay, cessation, mitigation, or prevention of one or more symptoms or side effects of the disease or condition of the present invention.

[0091] The term "acute" refers to a condition that is severe but has a relatively short duration.

[0092] As used herein, the term “chronic” means that the duration of the disease or condition in this invention is several weeks, months, or possibly years. The severity of the disease or condition may be distinguished by various factors such as the patient’s age, temperature, season, and type of disease.

[0093] In relation to one value, multiple values, or a range of values ​​defined by minimum and maximum values, the term "approximately" as used herein means a value that is 10% lower and / or higher than the corresponding value, multiple values, or range of values. For example, the term "approximately 1" means "0.9 to 1.1", the term "approximately 1 or 2" means "0.9 to 1.1 or 1.8 to 2.2", and the term "approximately 1 to approximately 2" means "0.9 to 2.2".

[0094] The terms "include," "include," "incorporate," "contain," and "possess," as well as their conjugations, all mean "to include, but not to limit."

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

[0096] The term “essentially consisting of” means that the composition, method, or microcapsule may include further components, processes, and / or parts, provided that such further components, processes, and / or parts do not substantially alter the basis and novel features of the claimed composition, method, or structure.

[0097] As used here, the singular form includes plural references unless otherwise clearly indicated by the context. For example, the term “compound” or “at least one compound” includes multiple compounds, including mixtures thereof.

[0098] Toxicity and therapeutic efficacy are, for example, LD 50 (Lethal dose in 50% of the population) and ED 50 The therapeutic dose (effective dose for 50% of the population) can be determined by standard formulation procedures in cell culture or experimental animals. The dose ratio between toxicity and therapeutic effect is the therapeutic index, or ratio LD50. 50 / ED 50 It can be expressed as follows. Compositions with a large therapeutic index are preferred.

[0099] Values ​​obtained from cell culture assays or animal studies can be used to formulate dosage ranges for human use. The therapeutically effective dose achieved in one animal model can be converted to use in other animals, including humans, using conversion factors known in this field (see, for example, Freireich et al., Cancer Chemother. Reports 50(4):219 244 (1966) and the following Table for Equivalent Surface Area Dosage Factors). [Table 1]

[0100] The dosage of such compounds is preferably ED 50It contains and is within a range of circulating concentrations that are of little or no toxicity. The dosage may vary within this range depending on the dosage form used and the route of administration. In general, the therapeutically effective dose may vary depending on the age, condition, and sex of the subject, as well as the severity of the subject's medical condition. The dosage is determined by the physician and may be adjusted as needed to match the observed therapeutic effect.

[0101] Those skilled in the art will recognize that both in vivo and in vitro studies using appropriate, known, and generally accepted cell and / or animal models predict the ability of a compound to treat or prevent a certain disorder.

[0102] Those skilled in the art will further recognize that human clinical trials, including first-in-human, dose-range and efficacy studies, and studies involving healthy subjects and / or those with certain disabilities, can be conducted in accordance with methods well known in the clinical and medical fields.

[0103] While the present invention is described with reference to certain embodiments, those skilled in the art will understand that various modifications can be made and equivalents can be substituted without departing from the spirit of the invention. Furthermore, many modifications can be made to the teachings of the present invention to suit specific situations or materials without departing from their scope. Therefore, although the present invention is not implemented in any specific embodiment disclosed, it is intended to include all embodiments that fall within the scope of the appended claims. [Examples]

[0104] Herein, with reference to the following examples, a non-limiting embodiment of the present invention will be described in conjunction with the above.

[0105] Example 1: Testing and Evaluation Subjects in the experimental group will be administered a pharmaceutical composition containing a unit dose of 20 mg or 60 mg of MEAI or a pharmaceutically acceptable salt thereof daily. Subjects in the control group will be administered a placebo daily, containing the same additives but without the active ingredient. The daily dose will be administered to subjects approximately 0.5 to 1 hour after a meal. Adverse effects and any changes in vital signs will be evaluated in subjects in both the experimental and control groups after administration of the pharmaceutical composition. Subjects in both the experimental and control groups will be evaluated on days 5, 10, and 17±1 after the first dose to determine the change in depressive symptoms compared to day 0 (pre-administration). Depressive symptoms will be assessed using the Beck Depression Inventory-II (BDI-II) and monitored for the presence of symptoms, particularly grief, guilt, suicidal ideation, loss of interest, and changes in sleep and appetite, over a two-week period (see, e.g., Beck et al., “Beck Depression Inventory-II”, American Psychological Association, 1996). The response to each symptom (e.g., guilt) is scored from 0 to 3, where 0 represents no symptoms and 3 represents the most severe symptoms. The responses to all symptoms are added together. The mean total BDI-II score and the standard deviation of the mean BDI-II score are evaluated in both the experimental and control groups on days 5, 10, and 17± days after the first dose. The change in the mean total score from before administration to days 5, 10, and 17±1 is evaluated in both the experimental and control groups. The standardized mean difference score is evaluated at each time interval from before administration to day 5, before administration to day 10, and before administration to day 17±1.

[0106] Example 2: Testing and Evaluation Subjects in the experimental group will be administered daily a pharmaceutical composition containing a unit dose of 20 mg or 60 mg of MEAI or a pharmaceutically acceptable salt thereof and 200 mg or 1800 mg of at least one N-acylethanolamine or a pharmaceutically acceptable salt thereof. Subjects in the control group will be administered daily a placebo containing the same additives but without the active ingredient. The daily dose will be administered to subjects approximately 0.5 to 1 hour after a meal. Adverse effects and any changes in vital signs in subjects in both the experimental and control groups will be evaluated after administration of the pharmaceutical composition. Subjects in both the experimental and control groups will be evaluated on days 5, 10, and 17±1 after the first dose to determine the change in depressive symptoms compared to day 0 (pre-administration). Depressive symptoms will be assessed using the Beck Depression Inventory-II (BDI-II) over a two-week period, monitoring for the presence of symptoms, particularly grief, guilt, suicidal ideation, loss of interest, and changes in sleep and appetite (see, e.g., Beck et al., “Beck Depression Inventory-II”, American Psychological Association, 1996). Responses for each symptom (e.g., guilt) will be scored from 0 to 3, with 0 representing no symptoms and 3 representing the most severe symptoms, and the responses for all symptoms will be added together. The mean total BDI-II score and the standard deviation of the mean BDI-II score will be assessed in both the experimental and control groups at 5, 10, and 17± days after the first dose. The change in the mean total score from pre-medication to 5, 10, and 17±1 days will be assessed in both the experimental and control groups. Standardized mean difference scores will be assessed at each time interval: 5, 10, and 17±1 days from pre-medication.

[0107] Many of the features and advantages of the present invention are evident from the detailed specification, and therefore, all such features and advantages covered by the appended claims are intended to fall within the true spirit and scope of the invention. Furthermore, since many modifications and variations are readily available to those skilled in the art, it is not desirable to limit the invention to the exact configuration and operation described and written, and therefore, all suitable modifications and equivalents are expected to fall within the scope of the invention.

[0108] Furthermore, it will be apparent to those skilled in the art that the fundamental concepts of this disclosure can be readily used as a basis for designing other structures, methods, and systems to carry out the invention for several purposes. Accordingly, the claims should not be considered to be limited to the prior description or examples.

Claims

1. A method for treating depression, comprising administering a therapeutically effective amount of 5-methoxy-2-aminoindan ("MEAI") or a pharmaceutically acceptable salt thereof to a subject in need thereof.

2. The method of claim 1, wherein the subject requiring it is administered a therapeutically effective dose of MEAI for a period sufficient to treat depression, as measured by a decrease in the BDI-II score.

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

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

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

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

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

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

9. The method according to any one of claims 1 to 8, wherein the subject requiring it is administered a therapeutically effective amount of MEAI or a pharmaceutically acceptable salt thereof at a concentration in the range of 0.2 mg / kg to 5.0 mg / kg body weight.

10. The method according to any one of claims 1 to 9, wherein a therapeutically effective amount of MEAI is formulated as a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and / or additive.

11. The method according to any one of claims 1 to 10, wherein a therapeutically effective amount of MEAI is formulated as a free-flowing powder, tablet, capsule, lozenge, liquid, liquid concentrate, or syrup.

12. The method according to any one of claims 1 to 11, wherein a therapeutically effective dose of MEAI is administered orally.

13. The method according to any one of claims 1 to 12, wherein a therapeutically effective dose of MEAI is administered daily.

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

15. The method of claim 14, wherein the reduction in the total BDI-II score is at least 10 points.

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

17. A method for 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 N-acylethanolamine or a pharmaceutically acceptable salt thereof.

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

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

20. The method according to any one of claims 17 to 19, wherein the subject requiring it is administered a single unit dose or multiple single unit doses of a therapeutically effective amount of MEAI and a therapeutically effective amount of N-acylethanolamine.

21. The method according to any one of claims 17 to 20, wherein a therapeutically effective amount of MEAI and a therapeutically effective amount of N-acylethanolamine are administered as a solid composition.

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

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

24. The method according to any one of claims 17 to 23, wherein the subject requiring it is administered a therapeutically effective amount of MEAI or a pharmaceutically acceptable salt thereof at a concentration in the range of 0.2 mg / kg to 5.0 mg / kg body weight.

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

26. The method of claim 25, wherein a single composition or a simultaneous or sequential composition further comprises at least one pharmaceutically acceptable carrier and / or additive.

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

28. The method according to any one of claims 17 to 27, wherein a therapeutically effective amount of N-acylethanolamine or a pharmaceutically acceptable salt thereof comprises N-acylethanolamine in an amount of about 2.5 mg / kg to 36 mg / kg per body weight of the subject requiring it.

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

30. The method according to any one of claims 17 to 29, wherein a therapeutically effective amount of MEAI or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of N-acylethanolamine or a pharmaceutically acceptable salt thereof are administered daily.

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

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

33. The method of claim 32, wherein the reduction in the total BDI-II score is at least 10 points.

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

35. The method according to 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 N-acylethanolamine is PEA or a pharmaceutically acceptable salt thereof.

37. A composition for use in the manufacture of a pharmaceutical for treating or improving depression in a subject requiring treatment, comprising 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 additive.

38. A 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 a plurality of single unit doses.

40. A composition for use according to any one of claims 37 to 39, wherein the composition is a solid-state composition.

41. A composition for use according to any one of claims 37 to 39, wherein the composition is in liquid form.

42. A 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. A 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. A 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 requiring it.

45. A composition for use according to any one of claims 37 to 44, wherein the composition is formulated as a free-flowing powder, tablets, capsules, lozenges, liquids, liquid concentrates, or syrups.

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

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

48. A 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 pharmaceutical for treating or improving depression in a subject requiring treatment, comprising a therapeutically effective amount of 5-methoxy-2-aminoindan ("MEAI") or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of N-acylethanolamine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier and / or additive.

50. A composition for use of claim 49, wherein the composition is a unit dosage form composition.

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

52. A composition for use according to any one of claims 49 to 51, wherein the composition is a solid-state composition.

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

54. A 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. A 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. A 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 requiring it.

57. A composition for use according to any one of claims 49 to 56, wherein the composition is formulated as a free-flowing powder, tablets, capsules, lozenges, liquids, liquid concentrates, or syrups.

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

59. A 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. A composition for use according to any one of claims 49 to 59, wherein the composition comprises N-acylethanolamine or a pharmaceutically acceptable salt thereof in an amount of about 2.5 mg / kg to 36 mg / kg per body weight of an object requiring it.

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

63. A composition for use in the treatment or improvement of depression, comprising a composition for a subject requiring treatment, the composition comprising 5-methoxy-2-aminoindan ("MEAI") or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier and / or additive.

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

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

66. A composition for use according to any one of claims 63 to 65, wherein the composition is a solid-state composition.

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

68. A 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. A 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. A 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 requiring it.

71. A composition for use according to any one of claims 63 to 70, wherein the composition is formulated as a free-flowing powder, tablets, capsules, lozenges, liquids, liquid concentrates, or syrups.

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

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

74. A 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 a composition for a subject requiring treatment, the composition comprising 5-methoxy-2-aminoindan ("MEAI") or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of N-acylethanolamine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier and / or additive.

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

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

78. A composition for use according to any one of claims 75 to 77, wherein the composition is a solid-state composition.

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

80. A 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. A 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. A 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 requiring it.

83. A composition for use according to any one of claims 75 to 82, wherein the composition is formulated as a free-flowing powder, tablets, capsules, lozenges, liquids, liquid concentrates, or syrups.

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

85. A 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. A composition for use according to any one of claims 75 to 85, wherein the composition comprises N-acylethanolamine or a pharmaceutically acceptable salt thereof in an amount of about 2.5 mg / kg to 36 mg / kg per body weight of the subject requiring it.

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

Images