Compositions comprising meai and n-acyl ethanoamines and uses thereof

Abstract

The present disclosure relates to pharmaceutical compositions comprising 5-methoxy-2-aminoindane, or a salt thereof, and N-acyl ethanolamine, or a salt thereof, and at least one pharmaceutically acceptable carrier and / or excipient, and their use in methods of modulating uncontrolled behavior by administering to a subject in need thereof a therapeutically effective amount of the composition.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 317,257, filed on March 7, 2022, the contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to compositions and methods for enhancing the therapeutic effect and / or reducing the side effects of 5-methoxy-2-aminoindan ("MEAI"). The present disclosure provides pharmaceutical compositions comprising MEAI and N-acylethanolamines such as palmitoylethanolamide ("PEA"), and methods for using them to treat a variety of indications that can be treated with MEAI. Background Art

[0004] Binging or binge behavior is an uncontrolled excessive indulgence in a variety of activities such as eating, drinking, drugs, sweets, shopping, sex, etc. It is now recognized that all types of bingeing are irrational or unhealthy ways to deal with negative emotions.

[0005] Conservation disorders are characterized by feelings of powerlessness, secrecy, shame, and social isolation. Once the subject feels that the indulgence needs to be kept in private, or that it needs to be arranged during (or in lieu of) work and social obligations, occasional overindulgence can become a real problem. Binge eating is now the most common eating disorder in adults, compulsive shopping disorder ("shopaholics") is increasing, and binge drinking is prevalent.

[0006] The causes of any type of uncontrolled behavior can be divided into three categories: psychological, chemical, and sociocultural.

[0007] The most common psychological causes of bingeing are anxiety, stress, and depression. While bingeing is often just a way to numb unpleasant emotions, it can also be a symptom of an undiagnosed mental disorder. For example, depression can lead to low self-esteem, body dissatisfaction, poor impulse control, and difficulty managing emotions—all of which can trigger bingeing. Of course, the pain and guilt that follows a binge can trigger depression, which can trigger another binge, and so on.

[0008] Alcohol is one of the most popular, commonly used, yet dangerous psychoactive substances and can lead to uncontrolled behaviour if consumed in excessive, uncontrolled amounts. Drinking is done for a number of reasons, including to quench thirst, to warm or cool the drinker, for taste, and because of the association of alcoholic beverages with other aspects of life, such as food and friendship. The psychological effects of alcohol contribute to some of these reasons.

[0009] Many people with alcohol dependence find that sometimes they can control their intake and only have a few drinks. At other times, even if their initial intention was to have only a few drinks, once they have their first drink, they lose control and drink much more than they intended. This often takes the form of binge or "bender drinking."

[0010] Alcohol use is a growing problem worldwide, with some suggesting that it may already surpass tobacco in terms of overall health and social care costs. Excessive and / or chronic alcohol use may have a number of undesirable physiological and psychological effects, including short-term effects such as gastric irritation, anxiety disorders and other excitable states, and long-term effects such as cirrhosis, fatty liver disease, cardiomyopathy and dementia. Alcohol use may lead to intoxication, which in turn can have serious consequences such as accidents and uncontrolled violent behaviour with subsequent medical complications.

[0011] Compounds derived from 2-aminoindan have been shown to selectively bind to dopamine D3 receptors. U.S. Pat. No. 5,708,018 discloses certain 2-aminoindan derivatives and hypothesizes that these 2-aminoindan derivatives may be used to treat CNS disorders associated with dopamine D3 receptors. One such compound is 5-methoxy-2-aminoindan ("MEAI"). The chemical structure of MEAI is:

[0012]

[0013] N-acylethanolamines (NAEs) are lipid-derived signaling molecules. They are formed when one of several acyl groups is attached to the nitrogen atom of ethanolamine. Examples of N-acylethanolamines include anandamide (amide of arachidonic acid (20:4ω-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).

[0014] Palmitoylethanolamide (PEA, also known as N-(2-hydroxyethyl) hexadecanoamide; hydroxyethyl palmitamide; palmitoyl (palmidrol); N-palmitoylethanolamine; and palmitylethanolamide) is an endogenous fatty acid amide that belongs to the class of nuclear factor agonists. The chemical structure of PEA is: PEA has been shown to bind to receptors in the cell nucleus (nuclear receptors) and to exert a variety of biological functions associated with chronic pain and inflammation. Studies have shown that PEA interacts with different non-CB1 / CB2 receptors, suggesting that PEA utilizes a unique "parallel" endocannabinoid signaling system. Increasing evidence further supports the concept that the production and inactivation of PEA can occur independently of the production and inactivation of AEA and 2-AG. Most of the biological effects of PEA on cells can be attributed to its affinity for PPARs (specifically PPAR-α and PPAR-γ). PEA has been shown to have affinity for the cannabinoid-like G-coupled receptors GPR55 and GPR119 and the transient receptor potential vanilloid type 1 receptor (TRPV1). PEA has been shown to have anti-inflammatory, anti-nociceptive, neuroprotective, and anticonvulsant properties. Summary of the invention

[0015] The present disclosure provides a pharmaceutical composition comprising a combination of MEAI or a salt thereof and N-acylethanolamine or a salt thereof. In some embodiments, these combinations include a specific molar ratio between the corresponding active agent and / or dosage, and can be used in a variety of methods. Specifically, the present disclosure provides a method for preventing and / or treating a variety of conditions in response to MEAI treatment, such as drinking (including alcoholism), eating, smoking, shopping or sexual behavior.

[0016] In one aspect, the present disclosure provides a pharmaceutical composition comprising a mixture 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 between MEAI and N-acylethanolamine is between about 1:0.2 and about 1:2000.

[0017] In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is between about 1:0.2 and about 1:5. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is between about 1:0.5 and about 1:2. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is between about 1:15 and about 1:1800. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is between about 1:25 and about 1:450. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is between about 1:50 and about 1:100. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:50. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:100. Each possibility represents a separate embodiment of the present disclosure.

[0018] In certain embodiments, the pharmaceutical composition comprises about 0.5-10 mg MEAI or a salt thereof. In certain embodiments, the pharmaceutical composition comprises about 1 mg, about 2.5 mg, about 5 mg, or about 10 mg MEAI or a salt thereof. Each possibility represents a separate embodiment of the present disclosure.

[0019] In certain embodiments, the pharmaceutical composition comprises about 200-1800 mg N-acylethanolamine or its salt. In certain embodiments, the pharmaceutical composition comprises about 250 mg, about 500 mg, about 750 mg, about 1000 mg or about 1500 mg N-acylethanolamine or its salt. Each possibility represents a separate embodiment of the present disclosure.

[0020] In certain embodiments, N-acylethanolamine is selected from the group consisting of N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexylamide, palmitoylbutyramide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), its salt and any combination thereof. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, N-acylethanolamine is PEA or its salt. In certain embodiments, N-acylethanolamine consists of PEA or its salt. In certain embodiments, N-acylethanolamine consists of PEA.

[0021] In certain embodiments, the pharmaceutical composition is formulated for systemic administration. In certain embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalation, topical, rectal, vaginal, parenteral, intravenous, intramuscular or subcutaneous administration. In certain embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal or sublingual administration. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the pharmaceutical composition is formulated for oral administration. In certain embodiments, the pharmaceutical composition is formulated for oral mucosal administration. In certain embodiments, the pharmaceutical composition is formulated for nasal administration. In certain embodiments, the pharmaceutical composition is formulated for sublingual administration.

[0022] In another aspect, the present disclosure further provides a dosage unit comprising or consisting of the above-mentioned pharmaceutical composition.

[0023] In certain embodiments, the dosage unit comprises the above-mentioned pharmaceutical composition. In certain embodiments, the dosage unit consists of the above-mentioned pharmaceutical composition. In certain embodiments, the dosage unit is formulated as a gel, powder or spray. In certain embodiments, the dosage unit is formulated as a gel. In certain embodiments, the dosage unit is formulated as a powder. In certain embodiments, the dosage unit is formulated as a spray.

[0024] In certain embodiments, compared with the same pharmaceutical composition without N-acylethanolamine, N-acylethanolamine increases the therapeutic efficacy of MEAI. In certain embodiments, compared with the same pharmaceutical composition without N-acylethanolamine, N-acylethanolamine reduces the required therapeutic dose of MEAI. In certain embodiments, compared with the same pharmaceutical composition without N-acylethanolamine, N-acylethanolamine reduces at least one side effect of MEAI. In certain embodiments, compared with the same pharmaceutical composition without N-acylethanolamine, N-acylethanolamine prolongs the therapeutic window of MEAI. In certain embodiments, compared with the same pharmaceutical composition without PEA or its salt, PEA or its salt increases the therapeutic efficacy of THC or its salt. In certain embodiments, compared with the same pharmaceutical composition without PEA or its salt, PEA or its salt reduces the required therapeutic dose of THC or its salt. In certain embodiments, compared with the same pharmaceutical composition without PEA or its salt, PEA or its salt reduces at least one side effect of THC or its salt. In certain embodiments, compared with the same pharmaceutical composition without PEA or its salt, PEA or its salt prolongs the therapeutic window of THC or its salt.

[0025] In certain embodiments of the above methods, the MEAI and the N-acylethanolamine are contained in the same pharmaceutical composition. In certain embodiments of the above methods, the MEAI and the N-acylethanolamine are contained in different pharmaceutical compositions.

[0026] In certain embodiments of the above methods, the administration of MEAI and N-acylethanolamines is repeated three times a day. In certain embodiments of the above methods, the administration of MEAI and N-acylethanolamines is repeated twice a day. In certain embodiments of the above methods, the administration of MEAI and N-acylethanolamines is repeated once a day. In certain embodiments of the above methods, the administration of MEAI and N-acylethanolamines is repeated every two days. In certain embodiments of the above methods, the administration of MEAI and N-acylethanolamines is repeated every three days.

[0027] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a salt thereof and N-acylethanolamine or a salt thereof and at least one pharmaceutically acceptable carrier and / or excipient.

[0028] In some embodiments, the pharmaceutical composition is a unit dosage composition. In other embodiments, the pharmaceutical composition is a solid unit dosage composition. In yet other embodiments, the pharmaceutical composition is a liquid unit dosage composition. In other embodiments, the pharmaceutical composition is packaged as a single unit dose or as multiple single unit doses.

[0029] In some embodiments, the unit dosage form comprises 30 mg to 130 mg of 5-methoxy-2-aminoindan.In some other embodiments, the pharmaceutical composition is formulated for oral administration.

[0030] In other embodiments, the present disclosure relates to a method of regulating uncontrolled behavior, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a salt thereof and N-acylethanolamine or a salt thereof, thereby regulating uncontrolled behavior. In some embodiments, the uncontrolled behavior is related to drinking, eating, smoking, shopping, or sexual behavior. In other embodiments, the uncontrolled behavior is binge drinking.

[0031] In further embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.In other embodiments, the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, liquid concentrate or syrup.

[0032] In some embodiments, the pharmaceutical composition in the methods of the present disclosure is a unit dosage composition. In other embodiments, the amount of 5-methoxy-2-aminoindan in the unit dosage form is about 30 mg to about 130 mg. In certain embodiments, the amount of 5-methoxy-2-aminoindan is about 70 mg. In some embodiments, the pharmaceutical composition is administered orally.

[0033] Further embodiments and the full scope of applicability of the present disclosure will become apparent from the detailed description given below. However, while indicating preferred embodiments of the present disclosure, the detailed description and specific examples are given by way of illustration only, because various changes and modifications within the spirit and scope of the present disclosure will be apparent to those skilled in the art from the detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] When read in conjunction with the accompanying drawings, the foregoing summary of the present disclosure and the following detailed description will be better understood. To illustrate the present disclosure, the accompanying drawings illustrate some but not all alternative embodiments. However, it should be understood that the present disclosure is not limited to the precise arrangements and means shown. These figures are incorporated into and constitute a part of the specification and help explain the principles of the present disclosure.

[0035] Figure 1 shows the mean fold change + / - SEM of food consumption relative to baseline (i.e., food consumption measured before MEAI treatment) for each group, with statistical analysis performed using Student's T-test for each group vs. the control group; for cycle 1 ( Figure 1A ) and period 2( Figure 1B ) of mice, *p<0.05, ***p<0.001.

[0036] Figure 2A and 2B Alcohol consumption in mice given intermittent 20% alcohol in the two-bottle choice (IA2BC) model is shown. Figure 2A ) and period 2( Figure 2B ) are presented as mean (g / kg / 24h) ± SEM of alcohol consumption from day 1 of consumption until day 47 / 50. Statistical analysis was performed only on day 6 / 7 of treatment using two-way ANOVA followed by Bonferroni post hoc test for multiple comparisons (*p<0.05; **p<0.01; ***p<0.001).

[0037] Figure 3 shows alcohol consumption before and after treatment. Figure 3A The results for cycle 1 are shown, and Figure 3B Results for period 2 are shown. Results are presented as mean values ​​of alcohol consumption (g / kg / 24h) ± SEM. Statistical analysis was performed using two-way ANOVA (repeated measures), followed by comparison of replicate means row by row by Bonferroni post hoc test. (**p<0.01; ***p<0.001).

[0038] Figure 4 The fold change of each group's consumption during the 6-7 drinking days of MEAI / PEA treatment relative to their own baseline consumption before treatment is shown. Results are presented as the mean + SEM of the fold change. The mean fold change for all drinking days is summed. Statistical analysis was performed using Student's T-test (*p<0.05).

[0039] FIG5 shows water consumption in mice given intermittent 20% alcohol in the two-bottle choice (IA2BC) model. Figure 5A ) and period 2( Figure 5B ) are expressed as mean (g / kg / 24h) ± SEM of water consumption from day 1 until day 47 / 50 of consumption.

[0040] Figure 6 shows that cycle 1 ( Fig. 6A ) and period 2( Figure 6B ) average alcohol preference [alcohol consumption g / kg / 24h / (total fluid consumption g / kg / 24h). Results are presented as mean ± SEM. Statistical analysis was performed using two-way ANOVA followed by Bonferroni post hoc test for multiple comparisons (*p<0.05; **p<0.01).

[0041] FIG. 7 shows the alcohol consumption of mice given intermittent 20% alcohol in the two-bottle choice (IA2BC) model. Fig. 7A ) and period 2( Figure 7B ) are expressed as mean (g / kg / 24h) ± SEM of alcohol consumption from day 22 (6 consumption days before treatment) until day 47 / 50 (6 / 7 consumption days of treatment).

[0042] Fig. 8A and 8B Shown are mean alcohol consumption during period 1 and period 2 over the 6 drinking days during MEAI treatment.

[0043] Fig.9A and 9B Results are shown for mean (g / kg / 24h) + / - SEM of alcohol consumption for period 1 and period groups. Statistical analysis was performed using two-way ANOVA followed by Bonferroni post hoc test for multiple comparisons (*p<0.05; **p<0.01; ***p<0.001).

[0044] Figure 10 shows the fold change between alcohol consumption during the 6 drinking days treated with MEAI and self-consumption before MEAI treatment in the period 1 group. Results are presented as mean ± SEM of fold change. Fig. 10A The mean fold change for each of the 6 drinking days is shown. Fig. 10B The mean fold change for all drinking days combined is shown. Statistical analysis for period 1 was performed using paired Student's T-test.

[0045] Figure 11 shows the fold change between alcohol consumption during the 6 drinking days treated with MEAI and self-consumption before MEAI treatment in the period 1 group. Results are presented as mean ± SEM of fold change. Fig.11A The mean fold change for each of the 6 drinking days is shown. Fig. 11B The mean fold change for all drinking days combined is shown. Statistical analysis for cycle 2 was performed using one-way repeated measures ANOVA (repeated measures), followed by Bonferroni post hoc tests to compare all means row by row (*p<0.05; **p<0.01; ***p<0.005). DETAILED DESCRIPTION

[0046] The present disclosure, in some embodiments thereof, relates to binge behavior, and more particularly, but not exclusively, to compositions and methods for modulating binge behavior, such as binge drinking.

[0047] As used herein, the terms "binge," "binge behavior," "binge disorder," "bingeing," and "bingeing behavior" are interchangeable and relate to uncontrolled excessive indulgence in various activities such as eating, drinking, smoking, drugs, shopping, sexual behavior. Binge behavior includes intensive, short episodes of overuse and overconsumption of food, alcohol, tobacco products, drugs, sweets, sex, etc. Binge behavior is compulsive in style, intensity, habit, history, motivation, and difficulty of control and remediation. As used herein, "compulsive behavior" refers to driven behavior that is often influenced by subconscious desires and motivations, as well as intense, uncontrollable, difficult to tame behavior and behavior with predictable patterns.

[0048] Subjects who need to adjust uncontrolled behavior are usually subjects who experience the onset of excessive consumption of uncontrolled objects (such as food, alcohol, smoking, drug abuse, sweets, sex, shopping, etc.), which either occur regularly, such as more than once a week, or occasionally, or even rarely, such as once or twice a year, depending on the severity of uncontrolled. For example, even if they drink twice a year, they will experience blackouts. The subjects who need to adjust binge drinking are defined as subjects in this article. In some cases, it can be determined according to national or international standards, or by acceptable assessments of health professionals (such as doctors, psychologists, cognitive therapists, social workers, nutritionists, etc., depending on uncontrolled disorders) that need to adjust uncontrolled behavior.

[0049] In any of some embodiments of the present disclosure, the intemperate behavior is related to drinking, smoking, eating, shopping, and / or sexual behavior.

[0050] As used herein, the phrase "binge drinking" or "binge drinking disorder" is determined according to national or international definitions defined by regulatory agencies, for example, according to the United Kingdom (UK) National Health Service (NHS) and the Office for National Statistics and other national corresponding service systems, bureaus and / or authoritative bodies to the definition of binge drinking. The definition of binge drinking used by the NHS and the Office for National Statistics describes it as drinking more than twice the low-risk drinking guidelines in a single drinking session, wherein the guidelines recommend that people should not regularly drink more than the low-risk guidelines, i.e., 3-4 units of alcohol for men (equivalent to a pint and a half of 4% beer (about 852mL)) and 2-3 units of alcohol for women (equivalent to a glass of 175mL wine). "Regularly" refers to drinking most of the time every day or week.

[0051] In some embodiments, the methods provided herein are used to reduce alcohol consumption in non-abstinent subjects who wish to control their alcohol consumption, for example, under certain circumstances (eg, during a particular event or time point).

[0052] The term "binge drinking regulation" refers broadly to controlling excessive, uncontrolled consumption of alcoholic beverages. Regulating binge drinking involves reducing the amount of alcohol consumed in a single drinking session and / or reducing the number of drinking sessions.

[0053] In the context of the embodiments of the present disclosure, binge drinking regulation involves imparting a sense of satisfaction, satiety, or contentedness that prevents binge drinking. Binge drinking regulation as practiced in the embodiments of the present disclosure achieves true harm reduction utility by preventing binge drinking in a manner that is easy to implement (by drinking) and harmless to the drinker (pending toxicological validation).

[0054] definition

[0055] When a numerical range is listed, it is intended to include every value and subrange within that range. For example, "C1-C6 alkyl" is intended to include 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.

[0056] "Isomers" are compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ in the arrangement or configuration of the atoms in space.

[0057] "Stereoisomer" or "optical isomer" refers to a stable isomer that has at least one chiral atom or restricted rotation to produce a perpendicular asymmetric plane (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane polarized light. Due to the presence of asymmetric centers and other chemical structures in the compounds of the present disclosure that may produce stereoisomerism, the present disclosure contemplates stereoisomers and mixtures thereof. The compounds of the present disclosure and their salts include asymmetric carbon atoms and therefore can exist as single stereoisomers, racemates, and mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as racemic mixtures. However, if desired, such compounds can be prepared or separated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As discussed in more detail below, individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral center or by preparing a mixture of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of a chiral resolving agent or direct separation of the enantiomers on a chiral chromatographic column. Starting compounds of specific stereochemistry are either commercially available or prepared by the methods described below and resolved by techniques well known in the art.

[0058] It is well known in the art that the biological and pharmacological activities of compounds are sensitive to the stereochemistry of the compound. Thus, for example, enantiomers typically exhibit significantly different biological activities, including differences in pharmacokinetic properties (including metabolism, protein binding, etc.) and pharmacological properties (including differences in the type of activity displayed, degree of activity, toxicity, etc.). Thus, those skilled in the art will understand that when one enantiomer is enriched relative to the other enantiomer or separated from the other enantiomer, it may be more active or may exhibit a beneficial effect. In addition, those skilled in the art will know how to separate, enrich or selectively prepare the enantiomers of the disclosed compounds from the knowledge of the present disclosure and the prior art.

[0059] Therefore, although the drug can be used in racemic form, its effect is usually not as good as administering an equal amount of enantiomerically pure drug; in fact, in some cases, one enantiomer may be pharmacologically inactive and can only serve as a simple diluent. For example, although ibuprofen has been administered as a racemate before, studies have shown that only the S-isomer of ibuprofen can be effectively used as an anti-inflammatory agent (however, in the case of ibuprofen, although the R-isomer is inactive, it is converted to the S-isomer in the body, so the racemic form of the drug has a slower rate of action than the pure S-isomer). In addition, the pharmacological activity of the enantiomers may have different biological activities. For example, S-penicillamine is a drug for treating chronic arthritis, while R-penicillamine is toxic. In fact, some purified enantiomers have advantages over racemates, and purified individual isomers are reported to have faster transdermal penetration rates than racemic mixtures. See U.S. Patent Nos. 5,114,946 and 4,818,541.

[0060] In some embodiments, the compound is a racemic mixture of (S)- and (R)-isomers. In other embodiments, provided herein are mixtures of compounds wherein the individual compounds of the mixture exist predominantly in the (S)- or (R)-isomer configuration. For example, the compound mixture has an (S)-enantiomeric excess greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more. In other embodiments, the compound mixture has an (S)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more. In other embodiments, the compound mixture has an (R)-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more. In some other embodiments, the compound mixture has an (R)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more.

[0061] Individual stereoisomers of the disclosed compounds may be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by preparing a racemic mixture followed by resolution methods known to those of ordinary skill in the art. Examples of such resolution methods include: (1) attaching the enantiomeric mixture to a chiral auxiliary, separating the resulting diastereomeric mixture by recrystallization or chromatography, and releasing the optically pure product from the auxiliary; (2) forming salts using an optically active resolving agent; or (3) directly separating a mixture of optical enantiomers on a chiral chromatographic column. Stereoisomeric mixtures may also be resolved into their component stereoisomers by known methods, such as chiral gas chromatography, chiral high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers may also be obtained from stereoisomerically pure intermediates, reagents, and catalysts by known asymmetric synthetic methods.

[0062] Thus, if one enantiomer is pharmacologically more active, less toxic, or has a more favorable distribution in the body than the other enantiomer, then it would be therapeutically beneficial to preferentially administer that enantiomer, so that the treated patient would be exposed to a lower total dose of the drug and a lower dose of the potentially toxic enantiomer or other enantiomer inhibitors.

[0063] As used herein, the nomenclature of chemical compounds, including organic compounds, may be given using common names, IUPAC, IUBMB or CAS nomenclature suggestions. If a name is given, one skilled in the art will either systematically reduce the compound structure using the naming convention or by commercially available software such as CHEMDRAW TM The structures of the compounds can be easily determined using the PerkinElmer Professional, version 17.

[0064] Compounds of the present disclosure may contain one or more chiral centers and / or double bonds, and therefore exist in the form of stereoisomers such as geometric isomers, enantiomers or diastereomers. The term "stereoisomer" used herein consists of all geometric isomers, enantiomers or diastereomers. These compounds can be represented by the symbol "R" or "S", depending on the configuration of the substituents around the stereoisomeric carbon atom. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. A mixture of enantiomers or diastereomers can be represented as "(±)" in the nomenclature, but those skilled in the art will recognize that the structure can implicitly represent a chiral center. In some embodiments, an enantiomer or stereoisomer substantially free of the corresponding enantiomer can be provided.

[0065] In one aspect, the present disclosure provides a pharmaceutical composition comprising a mixture of a therapeutically effective amount of MEAI or a salt thereof and at least one N-acylethanolamine or a salt thereof.

[0066] In another aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a mixture of MEAI or a salt thereof and at least one N-acylethanolamine or a salt thereof, wherein the molar ratio between MEAI and N-acylethanolamine is between about 1:0.2 and about 1:2000.

[0067] As used herein, "pharmaceutical composition" refers to a preparation of an active agent described herein with other chemical components, such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism. As used herein, the phrase "pharmaceutically acceptable carrier" refers to a carrier, excipient or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. These phrases include adjuvants.

[0068] The term "excipient" as used herein refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of an active ingredient. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and starch types, cellulose derivatives, gelatin, oils (e.g., vegetable oils or fish oils), and polyethylene glycols.

[0069] The term "carrier" as used herein refers to a diluent, adjuvant, excipient or vehicle with which a compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils. 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.

[0070] As used herein, the phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce allergic or similar toxicity when administered to an individual. Preferably, and particularly in the case of formulations for use in humans, the term "pharmaceutically acceptable" may mean approved by a regulatory agency (e.g., the U.S. Food and Drug Administration) or listed in a recognized pharmacopoeia for use in animals (e.g., the U.S. Pharmacopeia).

[0071] As used herein, the phrase "pharmaceutically acceptable salts" refers to charged species of a parent compound and its counterions which are typically used to alter the solubility characteristics of the parent compound and / or reduce any significant irritation of the parent compound to an organism, while not abrogating the biological activity and properties of the administered compound.

[0072] In the context of some embodiments of the present disclosure, pharmaceutically acceptable salts of the compounds described herein may optionally be acid addition salts comprising a positively charged form (e.g., an ammonium ion) of at least one basic (e.g., amine) group of the compound, in combination with at least one counterion derived from the selected acid to form a pharmaceutically acceptable salt.

[0073] An acid addition salt of a compound described herein may thus be a complex formed between one or more basic groups of the drug and one or more equivalent acids.

[0074] Acid addition salts can include various organic and inorganic acids such as, but not limited to, hydrochloric acid to provide hydrochloric acid addition salts, hydrobromic acid to provide hydrobromic acid addition salts, acetic acid to provide acetic acid addition salts, ascorbic acid to provide ascorbic acid addition salts, benzenesulfonic acid to provide benzenesulfonate addition salts, camphorsulfonic acid to provide camphorsulfonic acid addition salts, citric acid to provide citric acid addition salts, maleic acid to provide maleic acid addition salts, malic acid to provide malic acid addition salts, methanesulfonic acid to provide methanesulfonic acid (mesylate) addition salts, naphthalenesulfonic acid to provide naphthalenesulfonic acid addition salts, oxalic acid to provide oxalic acid addition salts, phosphoric acid to provide phosphoric acid addition salts, toluenesulfonic acid to provide p-toluenesulfonic acid addition salts, succinic acid to provide succinic acid addition salts, sulfuric acid to provide sulfuric acid addition salts, tartaric acid to provide tartaric acid addition salts, and trifluoroacetic acid to provide trifluoroacetic acid addition salts. Each of these acid addition salts can be a mono-addition salt or a poly-addition salt, as those terms are defined herein.

[0075] In the context of some embodiments of the present disclosure, a pharmaceutically acceptable salt of a compound described herein may optionally be a base addition salt comprising an anionic form of at least one group of the compound in combination with at least one counterion (i.e., a cation) to form a pharmaceutically acceptable salt. Examples of suitable cations include metal cations of metals such as, but not limited to, sodium, potassium, magnesium, and calcium, or ammonium.

[0076] Each of these base addition salts may be a mono-addition salt or a multiple-addition salt as defined herein.

[0077] Acid or base addition salts can be mono- or poly-addition salts, depending on the stoichiometric ratio between the basic or acidic charged groups (eg amine groups) in the compound and the counterions in the salt.

[0078] As used herein, the phrase "mono-addition salt" refers to a salt wherein the stoichiometric ratio between the counterion and the charged form of the compound is 1:1, ie, the addition salt contains one molar equivalent of the counterion for every one molar equivalent of the compound.

[0079] As used herein, the phrase "multiple addition salt" refers to salts wherein the stoichiometric ratio between the counterion and the charged form of the compound is greater than 1:1, e.g., 2:1, 3:1, 4:1, etc., i.e., the addition salt contains two or more molar equivalents of the counterion for every one molar equivalent of the compound.

[0080] Furthermore, in any of the embodiments described herein, each compound described herein, including salts thereof, may be in the form of a solvate or a hydrate thereof.

[0081] The term "solvate" refers to a complex of variable stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, etc.) formed by a solute (a 2-aminoindan derivative described herein) and a solvent, wherein the solvent does not interfere with the biological activity of the solute.

[0082] The term "hydrate" refers to a solvate as described above wherein the solvent is water.

[0083] As used herein, the term "N-acylethanolamine" generally refers to a fatty acid amide, a lipid-derived signaling molecule formed when one of several types of acyl groups is attached to the nitrogen atom of ethanolamine. These amides can conceptually be formed from fatty acids and ethanolamine releasing a water molecule, but the known biosynthesis uses a specific phospholipase D to cleave the phospholipid unit from the N-acylphosphatidylethanolamine. The suffixes -amine and -amide in these names both refer to the single nitrogen atom of the ethanolamine that holds the compound together: in ethanolamine it is called "amine" because it is considered to be the free terminal nitrogen in that subunit, while when it is considered to be attached to the adjacent carbonyl group of the acyl subunit, it is called "amide". In this application, the names of these compounds may be accompanied by "amide" or "amine". The term "ethanolamine" is used in a general sense, meaning to include monoethanolamine, diethanolamine, triethanolamine and mixtures thereof.

[0084] As used herein, the term "derivative" refers to a compound whose core structure is the same as or very similar to the N-acylethanolamine compound, but has chemical or physical modifications, such as different or additional side groups.

[0085] The term "salt" as used herein refers to any form of the active ingredient, wherein the active ingredient is in ionic form and is combined with a counterion (cation or anion) or in solution. This also includes complexes of the active ingredient with other molecules and ions, especially complexes complexed by ionic interactions.

[0086] In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is between about 1:0.2 and about 1:5. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is between about 1:0.22 and about 1:4.5, about 1:0.25 and about 1:4, about 1:0.28 and about 1:3.5, about 1:0.33 and about 1:3, about 1:0.4 and about 1:2.5, about 1:0.5 and about 1:2, or about 1:1. Each possibility represents a separate embodiment of the present disclosure.

[0087] In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is between about 1:15 and about 1:1800. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:16 to about 1:1700, about 1:17 to about 1:1600, about 1:18 to about 1:1500, about 1:19 to about 1:1400, about 1:20 to about 1:1300, about 1:21 to about 1:1200, about 1:22 to about 1:1100, about 1:23 to about 1:1000, about 1:24 to about 1:900, about 1:15 to about 1:800, about 1:16 to about 1:700, about 1:17 to about 1:600, about 1.18 to about 1:500, about 1:19 to about 1:490, about 1:20 to about 1:480, about 1:21 to about 1:470, or about 1:22 to about 1:460. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:25 to about 1:450. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:10 to about 1:500, about 1:15 to about 1:450, about 1:20 to about 1:400, about 1:25 to about 1:350, about 1:30 to about 1:300, about 1:35 to about 1:250, about 1:40 to about 1:200 or about 1:45 to about 1:150. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:50 to about 1:100. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:10. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:20. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:30. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:40. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:50. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:60. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:70. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:80. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:90. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:100. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:110. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:120. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:130.In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:140. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:150. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:160. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:170. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:180. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:190. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:200. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is at least about 1:10, at least about 1:20, at least about 1:30, at least about 1:40, at least about 1:50, at least about 1:60, at least about 1:70, at least about 1:80, at least about 1:90, or at least about 1: 100. Each possibility represents a separate embodiment of the present disclosure.

[0088] In certain embodiments, pharmaceutical composition comprises about 0.5-10mg MEAI or its salt.In certain embodiments, pharmaceutical composition comprises about 1-9.5mg, about 1.5-9mg, about 2-8.5mg, about 2.5-8mg, about 3-7.5mg, about 3.5-7mg, about 4-6.5mg, about 4.5-6mg or about 5-5.5mg MEAI or its salt.In certain embodiments, pharmaceutical composition comprises about 0.5mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3mg, about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg or about 10mg MEAI or its salt.Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the pharmaceutical composition comprises less than about 0.5 mg, less than about 1 mg, less than about 1.5 mg, less than about 2 mg, less than about 2.5 mg, less than about 3 mg, less than about 3.5 mg, less than about 4 mg, less than about 4.5 mg, less than about 5 mg, less than about 5.5 mg, less than about 6 mg, less than about 6.5 mg, less than about 7 mg, less than about 7.5 mg, less than about 8 mg, less than about 8.5 mg, less than about 9 mg, less than about 9.5 mg or about 10 mg of MEAI or its salt. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the pharmaceutical composition comprises about 0.5 mg to about 1 mg, about 0.5 mg to about 1.5 mg, about 0.5 mg to about 2 mg, about 0.5 mg to about 2.5 mg, about 0.5 mg to about 3 mg, about 0.5 mg to about 3.5 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 4.5 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 5.5 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 6.5 mg, about 0.5 mg to about 7 mg, about 0.5 mg to about 7.5 mg, about 0.5 mg to about 8 mg, about 0.5 mg to about 8.5 mg, about 0.5 mg to about 9 mg, or about 0.5 mg to about 9.5 mg MEAI or a salt thereof. Each possibility represents a separate embodiment of the present disclosure.

[0089] In certain embodiments, the pharmaceutical composition comprises about 200-1800 mg N-acylethanolamine or its salt. In certain embodiments, the pharmaceutical composition comprises about 250-1550 mg, about 300-1200 mg, about 350-950 mg, about 400-700 mg, about 450-600 mg or about 500-550 mg N-acylethanolamine or its salt. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the pharmaceutical composition comprises at least about 50 mg, at least about 100 mg, at least about 150 mg, 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 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 certain embodiments, the pharmaceutical composition comprises about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, or about 1800 mg. N-acylethanolamine or a salt thereof. Each possibility represents a separate embodiment of the present disclosure.

[0090] In certain embodiments, N-acylethanolamine is selected from the group consisting of N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexylamide, palmitoylbutyramide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), its salt and any combination thereof. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, N-acylethanolamine is PEA or its salt. In certain embodiments, N-acylethanolamine consists of PEA or its salt. In certain embodiments, N-acylethanolamine consists of PEA.

[0091] In certain embodiments, the pharmaceutical composition is formulated for systemic administration. In certain embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalation, topical, rectal, vaginal, parenteral, intravenous, intramuscular or subcutaneous administration. In certain embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal or sublingual administration. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the pharmaceutical composition is formulated for oral administration. In certain embodiments, the pharmaceutical composition is formulated for oral mucosal administration. In certain embodiments, the pharmaceutical composition is formulated for nasal administration. In certain embodiments, the pharmaceutical composition is formulated for sublingual administration.

[0092] Techniques for 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 disclosure can be prepared by methods well known in the art, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating or lyophilizing processes.

[0093] For oral administration, pharmaceutical compositions can be easily formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art. Such carriers enable pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by patients. Pharmacological preparations for oral use can be prepared as follows: using solid excipients, optionally grinding the resulting mixture, and processing the mixture of particles (after adding suitable adjuvants as needed) to obtain tablets or dragee cores. Suitable excipients are particularly fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose products such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethyl-cellulose and sodium carboxymethylcellulose; and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If necessary, disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or its salts such as sodium alginate can be added.

[0094] The term "oral administration" refers to any method of administration of an active agent by swallowing, chewing, sucking or drinking an oral dosage form. Examples of solid dosage forms include conventional tablets, multilayer tablets, capsules, caplets, etc., which do not substantially release the drug in the mouth or oral cavity.

[0095] The dragee cores may be provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talcum powder, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablet or dragee coatings for identification or characterization of different combinations of active compound dosages.

[0096] Orally usable pharmaceutical compositions include hard or soft sealed capsules made of gelatin and plasticizers (such as glycerol or sorbitol). Capsules can contain active ingredients mixed with the following materials: fillers such as lactose, adhesives such as starch, lubricants such as talcum powder or magnesium stearate and optional stabilizers. In soft capsules, the active ingredient can be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers can be added. All formulations for oral administration should be dosages suitable for selected routes of administration. For oral and sublingual administration, the composition can take the form of tablets or lozenges prepared in a conventional manner or in a viscous carrier. Alternatively, the active ingredient can be in powder form, so that it can be constructed with a suitable vehicle (such as a sterile, pyrogen-free water-based solution) before use.

[0097] Pharmaceutical compositions suitable for use in the context of the present disclosure include compositions containing active ingredients in an amount effective to achieve the intended purpose. More specifically, a "therapeutically effective amount" refers to an amount of active ingredients that effectively prevents, alleviates or improves the symptoms or side effects of a disease or disorder, or prolongs the survival of a subject. The determination of a therapeutically effective amount is entirely within the capabilities of those skilled in the art, particularly in light of the detailed disclosure provided herein. More specifically, a "therapeutically effective amount of a mixture" refers to the amount of at least two active ingredients, each of which may independently not be in a therapeutically effective amount, or both of which may not be in a therapeutically effective amount, but the mixture is still effective in preventing, alleviating or improving the symptoms or side effects of a disease or disorder, or prolonging the survival of a subject. The term "mixture" as used herein refers to a non-covalent combination of two molecules.

[0098] For any formulation used in the disclosed methods, the dosage or therapeutically effective amount can be preliminarily assessed from in vitro, in vivo and cell culture assays. For example, the dosage can be formulated in an animal model to achieve the desired concentration or titer. This information can be used to more accurately determine useful dosages for humans. The dosage of each compound in the claimed combination depends on several factors, including: the method of administration, the disease to be treated, the severity of the disease, whether the disease is to be treated or prevented, and the age, weight and health of the person to be treated. In addition, pharmacogenomic (the effect of genotype on the pharmacokinetics, pharmacodynamics or efficacy characteristics of therapeutic drugs) information about a particular patient may affect the dosage used. Continuous daily administration may not be required; the treatment regimen may require cycles during which no administration is given, or treatment may be provided as needed during acute disease exacerbations. Dose increases may or may not be required; the treatment regimen may require a reduction in the dose of the drug. The toxicity and efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, cell culture or experimental animals. The data obtained from these in vitro and cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The dosage may vary depending on the dosage form and route of administration employed. The exact formulation, route of administration and dosage can be selected by the individual physician according to the patient's condition (see, e.g., Fingl, E. et al. (1975), "The Pharmacological Basis of Therapeutics", Chapter 1, page 1). Depending on the severity and responsiveness of the condition to be treated, administration can be single or multiple administrations, and the course of treatment can last from a few days to a few weeks, or until a cure is achieved or the disease state is alleviated.

[0099] In another aspect, the present disclosure further provides a dosage unit comprising or consisting of the above-mentioned pharmaceutical composition.

[0100] In certain embodiments, the dosage unit comprises the above-mentioned pharmaceutical composition. In certain embodiments, the dosage unit consists of the above-mentioned pharmaceutical composition. In certain embodiments, the dosage unit is formulated as a gel, powder or spray. In certain embodiments, the dosage unit is formulated as a gel. In certain embodiments, the dosage unit is formulated as a powder. In certain embodiments, the dosage unit is formulated as a spray.

[0101] In another aspect, the present disclosure further provides a pharmaceutical composition or dosage unit as described above for use in a method of preventing or treating a disorder that can be prevented or treated by at least one MEAI.

[0102] As used herein, the term "treat" includes, but is not limited to, one or more of the following: eliminating, ameliorating, inhibiting, attenuating, blocking, suppressing, reducing, delaying, stopping, alleviating or preventing one or more symptoms or side effects of a disease or disorder of the present disclosure.

[0103] The term "acute" refers to a relatively short-lived, severe illness.

[0104] The term "chronic" as used herein means that the duration of the disease or condition of the present disclosure may be weeks, months, or even years. The intensity of the disease or condition may vary depending on various conditions such as patient age, temperature, season, disease type, etc.

[0105] The term "about" as used herein is related to a value, multiple values, or a range of values ​​defined by a minimum and maximum value, and refers to a value that is 10% lower and / or higher than the corresponding value, multiple values, or range of values. For example, the phrase "about 1" means "0.9 to 1.1", the phrase "about 1 or 2" means "0.9 to 1.1 or 1.8 to 2.2", and the phrase "about 1 to about 2" means "0.9% to 2.2".

[0106] The terms "comprises / comprising", "includes / including", and "having" and their variations mean "including but not limited to".

[0107] The term "consisting of" means "including and limited to."

[0108] The term "consisting essentially of" means that the composition, method or microcapsule may include additional ingredients, steps and / or parts, but these additional ingredients, steps and / or parts do not materially change the basic and novel characteristics of the claimed composition, method or structure.

[0109] As used herein, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0110] Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell culture or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD 50 / ED 50 Compositions that exhibit large therapeutic indices are preferred.

[0111] The data obtained from cell culture assays or animal studies can be used to formulate dosage ranges for humans. Using conversion factors known in the art, a therapeutically effective dose obtained in an animal model can be converted to a dosage for another animal, including humans (see, e.g., Freireich et al., Cancer Chemother. Reports 50(4):219-244 (1966) and the equivalent surface area dose factors in the following table).

[0112] Table 1. Equivalent surface area dose factors.

[0113]

[0114] The dosage of such compounds is preferably within the range of ED including little or no toxicity. 50 The dosage may vary within this range, depending on the dosage form used and the route of administration used. In general, the therapeutically effective amount may vary depending on the age, condition and gender of the subject and the severity of the subject's condition. The dosage may be determined by the physician and adjusted, if necessary, to accommodate the observed therapeutic effect.

[0115] Those skilled in the art will recognize that both in vivo and in vitro assays using appropriate, known and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0116] Those skilled in the art will further recognize that human clinical trials, including first-in-human trials, dose ranging and efficacy trials, in healthy patients and / or patients with a given disorder can be accomplished according to methods well known in the clinical and medical arts.

[0117] Although the present disclosure has been described with reference to certain embodiments, it will be appreciated by those skilled in the art that various changes may be made and equivalent methods may be substituted without departing from the scope of the present disclosure. In addition, many modifications may be made to adapt specific circumstances or materials to the teachings of the present disclosure without departing from the scope of the present disclosure. Therefore, the present disclosure is not limited to the specific embodiments disclosed, but the present disclosure will include all embodiments falling within the scope of the appended claims.

[0118] In order to more fully illustrate some embodiments of the present disclosure, the following examples are given. However, they should in no way be construed as limiting the broad scope of the present disclosure.

[0119] Example

[0120] Example 1: Evaluation of the efficacy of MEAI and PEA in binge drinking in mice

[0121] Problem drinking and alcohol abuse are increasing worldwide and are believed to outweigh tobacco in terms of overall health and social care costs. Excessive and / or chronic alcohol use can have a number of undesirable physiological and psychological effects, including short-term effects such as gastric irritation, anxiety disorders and other excitable states, and long-term effects such as cirrhosis, fatty liver disease, cardiomyopathy and dementia.

[0122] MEAI (5-methoxy-2-aminoindan or 5-MeO-AI) is a derivative of 2-aminoindan that can be used as an overindulgence modifier or overindulgence reliever to produce a sense of satisfaction, satiety or contentment, and to modulate (e.g., prevent) overindulgence such as binge drinking. Administration of an effective amount of an overindulgence modifier to a subject, either alone or in combination with an alcoholic beverage, is expected to reduce alcohol consumption during binge drinking and prevent many of the adverse effects associated with excessive drinking. This is particularly relevant to short-term effects, such as severe intoxication leading to serious consequences (e.g., accidents and uncontrolled violent behavior), and subsequent medical complications, as well as gastric irritation, anxiety disorders, and other excitable states.

[0123] The aim of this study was to evaluate the efficacy of MEAI at several MEAI doses and in combination with palmitoylethanolamide (PEA) in reducing binge drinking in mice.

[0124] The principle of the study is based on the intermittent intake of 20% alcohol in mice in the two-bottle choice (IA2BC) model. Throughout the study, the mice were provided with two bottles: one bottle of water and the other bottle of 20% ethanol solution, which was removed after 24 hours and replaced with another bottle of water for another 24 hours. In total, the mice consumed 20% ethanol for 24 hours three times a week for seven or eight weeks (21-22 alcohol consumption days).

[0125] Alcohol consumption was measured after each 24-hour alcohol exposure (by weighing the alcohol bottles before and after exposure). After four weeks of intermittent 20% alcohol intake, mice were divided into different groups based on their alcohol consumption to achieve balanced groups. To examine the efficacy of treatment in reducing alcohol consumption, mice were treated with the test item or vehicle daily during weeks 6-7 / 8.

[0126] Vehicle and test formulations were prepared as shown in Table 2.

[0127] Table 2: Test items and vehicle formulation*

[0128]

[0129] "F" means female; "Gr" means group; "No." means number

[0130] Recipe preparation:

[0131] Vehicle 1: Prepared with water for injection.

[0132] Vehicle 2: A solution was prepared from ethanol:Kolliphor:water for injection (1:1:18 respectively).

[0133] Test Item 1 (MEAI): Supplied in powder form and dissolved using Vehicle 1 at various dilutions according to Table 2.

[0134] Test Item 2 (PEA): Supplied in powder form and dissolved using Vehicle 2 according to Table 2 at a concentration of 5 mg / mL.

[0135] Experimental model:

[0136] Animals: C57BL / 6 mice, female, 7-8 weeks at the start of the study (Envigo RMS Ltd., Israel). The minimum and maximum initial body weights of each group did not exceed ±20% of the group mean body weight.

[0137] Animal handling was performed in accordance with the guidelines of the National Institutes of Health (NIH) and AAALAC International. In this study, mice were housed in filtered cages (maximum 5 per cage) with dimensions of 36.5 x 20.7 x 13 cm, with a stainless steel grid on the top to facilitate feeding of pelleted food and drinking water in plastic bottles; bedding: steam-sterilized clean rice husks (Envigo, Teklad, laboratory grade, Sani-chips). The bedding material was changed at least once a week along with the cages.

[0138] Mice had free access to a commercial rodent diet (Teklad Certified Global 18% Protein Diet, Envigo Catalog #2018SC). Mice had free access to sterilized and acidified drinking water (pH between 2.5 and 3.5) obtained from a municipal water supply.

[0139] Mice were housed under standard laboratory conditions with air conditioning and filtration (HEPA F6 / 6) and adequate fresh air supply (at least 15 air changes / hour). Mice were housed in a climate-controlled environment. The temperature range was 18-24°C and the relative humidity range was 30-70% with a reversed 12-hour light and 12-hour dark cycle (6 pm / 6 am).

[0140] Animals were randomly assigned to cages or allocated according to body weight on the day of receipt.

[0141] Before the start of the experimental period, mice were examined by the attending veterinarian (AV) to determine their suitability for the study. Animals were checked daily for signs of morbidity or mortality.

[0142] Experimental design and conditions:

[0143] Taking pain medications may interfere with the study, so no pain medications were used.

[0144] Animals that lost 10% of their initial body weight received wet food on the bottom of their cages and were injected subcutaneously with normal saline as needed and were weighed daily.

[0145] Animals in a moribund state and animals showing signs of severe prolonged pain and persistent severe prolonged distress were humanely euthanized according to details approved by the ethics committee. Animals that had lost more than 20% of their body weight compared to their initial body weight determination or more than 10% of their body weight compared to the last consecutive daily measurement were also humanely euthanized.

[0146] The first dosing day was designated "Day 1" and the end days were "Day 50" (Cycle 1) and Day 52 (Cycle 2).

[0147] The study was conducted in two cycles. The first cycle included five groups: four of them were treated with high concentrations of MEAI, and the control group was treated with "water for injection" - vehicle 1. In the second cycle, three more groups were treated with a combination of MEAI + PEA (increasing dilutions of MEAI), another group was treated with PEA + vehicle 1, and another group was treated with vehicle 2 containing a solvent for PEA (ethanol: Kolliphor: water 1:1:18).

[0148] In both cycles, mice received only alcohol (three times per week) for the first five weeks to establish the IA2BC model and binge drinking. During the final two weeks, mice were dosed with the test item / vehicle (MEAI, PEA) daily in addition to alcohol treatment every other day to examine its effect on alcohol consumption. Dosing was performed before the addition of alcohol (15-30 minutes). An additional five mice aged 12 weeks were not treated with alcohol and served as a first-line histological control. Mouse.

[0149] Each test item and vehicle formulation was administered to 9 or 5 mice per group according to Table 3. The study schedule was conducted according to Table 4.

[0150] Table 3: Group allocation

[0151]

[0152]

[0153] Table 4: Study Timeline*

[0154]

[0155] #Terminate cycle 1 on day 50. Terminate cycle 2 on day 52.

[0156] Testing and Evaluation:

[0157] Check for morbidity and mortality daily. Animals sacrificed during the study are considered dead animals for study results. If death occurs before the study is scheduled to end, gross pathology assessment should be performed as close to the time of death as possible. Record the time of death as accurately as possible.

[0158] Body weight was recorded upon arrival, before the start of the study, three times per week thereafter, and at the end of the study.

[0159] Animals were observed for clinical signs starting on day 1 and three times a week thereafter until the study was terminated. Any abnormalities, such as changes in the local injection site, skin, hair, eyes, mucous membranes, respiration, the occurrence of secretions and excretions (such as diarrhea), and autonomic activity (such as tearing, salivation, piloerection, pupil size, abnormal breathing pattern) were observed and recorded. Changes in gait, posture, and response to handling, such as the occurrence of strange behavior, tremors, convulsions, sleep, and coma were also included. All observed abnormalities, signs of intoxication, moribund states, and pre-terminal deaths were recorded.

[0160] Animals were fed twice before the first dosing (during alcohol addition and during the period without alcohol addition), each time alcohol was added during the dosing period (six times in total), and before termination (without alcohol addition).

[0161] Food consumption was recorded for each cage for 18 ± 2 hours. Food consumption (calculated value) was determined based on the provided diet placed in the hopper and the remaining unused diet weighed.

[0162] Alcohol and water consumption of each cage was recorded for 24 ± 2 h starting on day 1 and three times a week thereafter until the end of the study.

[0163] At the time of termination, about 0.5 mL of blood was taken from the submandibular vein of 5 animals (2 animals in 6F and 7F groups) from groups 1-10 and killed according to regulations according to the approval of the ethics committee. Blood was collected in K3-EDTA tubes. Plasma was separated and stored at a temperature of (-60°C) to (-90°C) for future bioanalysis evaluation. After the bleeding was terminated, the brain, kidney and liver of the same 5 mice in each group were cut open and quickly frozen for future bioanalysis evaluation (only 2 mice were taken out in 6F and 7F groups for future bioanalysis evaluation).

[0164] Organs from the remaining animals in each group were harvested and fixed in 4% buffered formaldehyde for possible future histological evaluation (liver, kidney, heart, pancreas, brain, spleen, lung, and thyroid).

[0165] Numerical results are given as mean and standard deviation or standard error. Where applicable, descriptive statistics and comparisons between groups were performed using appropriate statistical analysis programs (e.g., GraphPad Prism version 5.02 for Windows, GraphPad Software, San Diego California USA). A probability of 5% (p ≤ 0.05) was considered statistically significant.

[0166] The body weight (BW) of all animals in all groups was monitored every other day. Two-way ANOVA showed that the body weight of all groups did not change significantly compared with the control group (1F in cycle 1, 6F and 7F in cycle 2), except for group 4F (MEAI medium dose), which was significantly lower than the control group only on day 40 of cycle 1 (*p<0.05).

[0167] Animals were evaluated for macroscopic findings during macroscopic pathology examination. Pathological findings (bright color and / or enlargement) detected in the liver, kidney, heart, and spleen were observed in all groups including vehicle treatment (Groups 1F, 6F, and 7F). All groups were treated with alcohol, suggesting that these were most likely related to alcohol consumption and not to MEAI treatment.

[0168] In addition, white spots were found in the pancreas (see Figure 8 in the Appendix), liver, peritoneum and other organs, subcutaneous and adipose tissues of mice in the 9F and 10F groups in cycle 2, but not in cycle 1. These white spots may be the accumulation of PEA.

[0169] result:

[0170] Results showed that MEAI treatment had a significant dose-dependent effect in reducing alcohol consumption in treated animals, while PEA treatment had an additive effect at lower MEAI doses. There were no significant differences in the body weight of the animals, and food consumption was not affected by MEAI treatment.

[0171] During the study, four deaths were observed in the high-dose treatment group, but it must be considered that these animals were treated with MEAI after prolonged alcohol consumption. Supporting evidence for the deleterious effects of alcohol consumption can be found in the macroscopic pathological analysis, which showed macroscopic findings in the majority of the liver, kidneys, heart, and spleen in all groups, including the control group.

[0172] Based on the above findings, it can be concluded that MEAI exhibited an inhibitory effect on alcohol consumption in mice in the IA2BC model, and PEA ameliorated this effect at a lower MEAI dose.

[0173] Animals were evaluated for macroscopic findings during macroscopic pathological examination. Pathological findings (bright color and / or enlargement) detected in liver, kidney, heart and spleen were observed in all groups including vehicle treatment (groups 1F, 6F and 7F). Alcohol treatment was used in all groups, indicating that these were most likely related to drinking and were not related to MEAI treatment.

[0174] In addition, white spots were found in the pancreas, liver, and peritoneal, subcutaneous, and adipose tissues of mice in the 9F and 10F groups in cycle 2, but not in cycle 1. These white spots may be the accumulation of PEA.

[0175] Food consumption:

[0176] During the alcohol addition period, the food consumption of each mouse in each individual cage was monitored for 24 hours by measuring the weight of food before and after 24 hours. During all MEAI treatment days in two cycles, food consumption was measured. The mean value of each group on each consumption day was calculated as the fold change of each animal compared to the baseline (i.e., the food consumption measured before MEAI treatment). The fold change value of each MEAI / PEA treatment group was compared with the vehicle group (1F / 6F / 7F) and statistically analyzed.

[0177] like Figure 1A As shown, during cycle 1, all groups had an increase in food consumption compared to their baseline (>1.0 fold change). The fold change of group 3F (MEAI 40 mg / kg) was significantly lower than that of control group 1F (MEAI 0) (*p<0.05). The fold change of group 4F (MEAI 60 mg / kg) was lower than that of the control group, but not significantly. Group 2F (MEAI 20 mg / kg) and group 5F (MEAI 100 mg / kg) were similar to control group 1F.

[0178] In cycle 2, except for the control group 7F (MEAI / PEA 0 / 25 mg / kg), the food consumption of other groups did not change compared with their baseline, and the food consumption of the control group decreased by 22% to 0.78±0.03 times. Figure 1B The other groups that did not change from their own baseline levels had a significant increase in food consumption compared to Group 7F (Group 8F MEAI / PEA 20 / 25 mg / kg, ***p<0.001; Group 9F and Group 10F MEAI / PEA 60 / 25 mg / kg and 100 / 25 mg / kg, *p<0.05).

[0179] Alcohol consumption:

[0180] Mice were given intermittent 20% alcohol in a two-bottle choice (IA2BC) model. Mice were given 20% ethanol three times a week for 24 hours for five weeks (15 alcohol consumption days), and alcohol consumption was measured by weight. After 5 weeks, mice were grouped according to their alcohol consumption, and the effect of MEAI / PEA treatment in reducing alcohol consumption was examined. Mice were treated with vehicle / MEAI / PEA every day on days 36-48 of cycle 1 and days 36-51 of cycle 2. Figure 3A and 3B The results show that during the 6 / 7 day treatment period, alcohol consumption was significantly reduced in the treated mice in a dose-dependent manner compared to the control group in both cycles. Other graphs summarizing the alcohol consumption results are shown in Fig. 7A and 7B, 8A and 8B, 9A and 9B (alcohol consumption during MEAI treatment), and Fig. 10A and 10B , 11A and 11B (fold change in alcohol consumption). Statistical analysis was performed only on days 6 / 7 of treatment using two-way ANOVA followed by Bonferroni post hoc test for multiple comparisons (*p<0.05; **p<0.01; ***p<0.001).

[0181] The mean consumption before treatment was compared with the mean consumption during treatment in each group. Figure 4 The mean of alcohol consumption on the six drinking days before MEAI treatment for each group (white bars) is shown, compared with the mean of alcohol consumption on the six drinking days during MEAI treatment for each group (blue bars). In cycle 1, alcohol consumption was significantly reduced after treatment with 40 mg / kg and higher doses of MEAI compared with pre-treatment consumption (**p<0.01; ***p<0.001). In cycle 2, alcohol consumption was significantly reduced after dual treatment with 20 mg / kg and higher doses of MEAI plus 25 mg / kg PEA compared with pre-treatment consumption (**p<0.01, ***p<0.001).

[0182] The mean consumption before treatment was compared with the mean consumption during treatment for each group. Figure 3 shows the mean of each group’s alcohol consumption on the six drinking days before MEAI treatment (white bars) compared with the mean of each group’s consumption on the six drinking days during MEAI treatment (blue bars). Figure 3A ), alcohol consumption was significantly reduced after treatment with MEAI 40 mg / kg and higher compared with pre-treatment consumption (**p<0.01; ***p<0.001). Figure 3B ), dual treatment with 20 mg / kg and higher doses of MEAI plus 25 mg / kg PEA resulted in a significant reduction in alcohol consumption compared with pre-treatment consumption (**p<0.01, ***p<0.001).

[0183] The additive effect of PEA was tested by comparing alcohol consumption in groups treated with the same dose of MEAI (20 / 60 / 100 mg / kg) with or without PEA (25 mg / kg). The fold change in consumption during 6-7 drinking days treated with MEAI / PEA was compared for each group compared to its own baseline consumption before treatment. The results in Figure 5 show that at the lower doses of 20 and 60 mg / kg MEAI, alcohol consumption was significantly reduced with the combined treatment compared to mice treated with MEAI alone at the same dose without PEA (*p<0.05). At the highest dose of 100 mg / kg MEAI, alcohol consumption was reduced after the addition of PEA, but it did not reach statistical significance.

[0184] The additive effect of PEA was tested by comparing alcohol consumption in groups treated with the same dose of MEAI (20 / 60 / 100 mg / kg) with or without PEA (25 mg / kg). The fold change in consumption during 6-7 drinking days with MEAI / PEA treatment was compared for each group compared to its own baseline consumption before treatment. Figure 4 Results in the study showed that at the lower doses of 20 and 60 mg / kg MEAI, the combined treatment significantly reduced alcohol consumption compared to mice treated with MEAI alone at the same dose without PEA (*p<0.05). At the highest dose of 100 mg / kg MEAI, there was a reduction in alcohol consumption after the addition of PEA, but it did not reach statistical significance.

[0185] Water consumption:

[0186] During alcohol treatment, water consumption was monitored three times a week for five weeks. The effect of MEAI / PEA treatment on water consumption was examined. Mice were treated daily with vehicle / MEAI / PEA on days 36-48 of cycle 1 and days 36-51 of cycle 2. Figure 5 shows that water consumption increased during MEAI treatment in both cycles. Figure 5B ), water consumption increased in a dose-dependent manner and was negatively correlated with alcohol consumption, which decreased in a dose-dependent manner.

[0187] Alcohol Preference:

[0188] Mean alcohol preference was assessed and was defined as the ratio of the weight of alcohol (g / kg / 24h) divided by the total weight of water and alcohol consumed by the animal (g / kg / 24h). Fig. 6A and 6BAs shown, alcohol preference was reduced in a dose-dependent manner after MEAI and MEAI / PEA treatment compared with the control group. The reduction was statistically significant at the highest dose (100 mg / kg MEAI; 100 / 25 mg / kg MEAI / PEA) in both cycles, indicating that the reduction in alcohol consumption was associated with an increase in water consumption.

[0189] in conclusion:

[0190] The efficacy of MEAI in reducing alcohol consumption in mice was evaluated at several MEAI doses and in combination with palmitoylethanolamide (PEA) in a two-bottle choice (IA2BC) model of intermittent 20% alcohol ingestion. Mice were provided with a 20% alcohol solution for 24 h, three times per week for 7 weeks and treated with MEAI or MEAI / PEA daily during the last two weeks of alcohol treatment. Alcohol consumption was measured by weighing the alcohol bottle before and after; water consumption was also measured. In addition, food consumption (within 24 h) was measured on alcohol-added days before, during, and after MEAI / PEA treatment.

[0191] Results showed that MEAI treatment had a significant dose-dependent effect in reducing alcohol consumption in treated animals, with PEA treatment having an additive effect at lower MEAI doses. In addition, in an inverse correlation, water consumption increased during both cycles of MEAI treatment, and thus, alcohol preference (as a percentage of total fluid) was also reduced in a dose-dependent manner.

[0192] There were no significant differences in the body weight of the animals, and food consumption was not affected by MEAI treatment.

[0193] During the study, four deaths were observed in the high-dose treatment group, but it must be considered that these animals were treated with MEAI after prolonged alcohol consumption. Supporting evidence for the deleterious effects of alcohol consumption can be found in the macroscopic pathological analysis, which showed macroscopic findings in the majority of the liver, kidneys, heart, and spleen in all groups, including the control group.

[0194] Based on the above findings and under the conditions of this study, MEAI showed an inhibitory effect on alcohol consumption in mice in the IA2BC model, and PEA ameliorated this effect starting from a low MEAI dose.

[0195] The many features and advantages of the present disclosure are apparent from the detailed description, and thus the appended claims are intended to cover all such features and advantages of the present disclosure that fall within the true spirit and scope of the present disclosure. Furthermore, since numerous modifications and variations will readily occur to those skilled in the art, it is not desired to limit the present disclosure to the exact construction and operation shown and described, and therefore all suitable modifications and equivalents may be employed, which are within the scope of the present disclosure.

[0196] Furthermore, those skilled in the art will appreciate that the concepts upon which the present disclosure is based can be readily used as a basis for designing other structures, methods and systems to achieve the several purposes of the present disclosure.Accordingly, the claims should not be considered limited to the foregoing description or embodiments.

Claims

1. A pharmaceutical composition comprising 5-methoxy-2-aminoindan or a salt thereof and N-acylethanolamine or a salt thereof, and at least one pharmaceutically acceptable carrier and / or excipient.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a unit dosage composition.

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is a solid unit dosage form composition.

4. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is a liquid unit dosage composition.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is packaged as a single unit dose or as a plurality of single unit doses.

6. The pharmaceutical composition according to any one of claims 2 to 5, wherein the unit dosage form comprises 30 mg to 130 mg of 5-methoxy-2-aminoindan.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition is formulated for oral administration.

8. A method for regulating uncontrolled behavior, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a salt thereof and N-acylethanolamine or a salt thereof, thereby regulating the uncontrolled behavior.

9. The method of claim 8, wherein the intemperate behavior is related to drinking, eating, smoking, shopping or sexual behavior.

10. The method of claim 8 or 9, wherein the intemperate behavior is binge drinking.

11. The method according to any one of claims 8 to 10, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

12. The method according to any one of claims 8 to 11, wherein the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, liquid concentrate or syrup.

13. The method according to any one of claims 8 to 12, wherein the pharmaceutical composition is a unit dosage composition.

14. The method of claim 13, wherein the amount of 5-methoxy-2-aminoindan in the unit dosage form is from about 30 mg to about 130 mg.

15. The method of claim 14, wherein the amount of 5-methoxy-2-aminoindan is about 70 mg.

16. The method according to any one of claims 8 to 15, wherein the pharmaceutical composition is administered orally.

17. Use of the pharmaceutical composition of any one of claims 1 to 7 for regulating uncontrolled behavior.

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