Compositions Comprising MEAI and N-Acylethanolamines and Uses Thereof

Abstract

The present disclosure relates to pharmaceutical compositions comprising 5-methoxy-2-aminoindan or a salt thereof, and an N-acylethanolamine or a salt thereof, and at least one pharma- ceutically acceptable carrier and / or excipient, and their use in methods of modulating impulsive behavior by administering a therapeutically effective amount of said compositions to a subject in need thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 317,257, filed March 7, 2022, the contents of which are incorporated herein by reference.

[0002] Field of Disclosure 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 of their use in a variety of indications treatable with MEAI. [Background technology]

[0003] Background of the disclosure Binging or binge behavior is uncontrolled excessive behavior, such as indulging in various activities such as eating, drinking, drugs, sweets, shopping, sex, etc. All types of impulsivity are now recognized as ways of dealing with negative emotions that are neither rational nor healthy.

[0004] Impulse disorders are characterized by feelings of helplessness, secrecy, shame, and social isolation. Occasional indulgences become a real problem when subjects feel the need to be alone and not moderate, or schedule urges around (or instead of) work and social obligations. Compulsive eating (binge eating) is now the most common eating disorder in adults, compulsive shopping disorder ("shopping addiction") is on the rise, and compulsive drinking (binge drinking) is widespread.

[0005] The causes of all types of compulsive behavior can be grouped into three categories: psychological, chemical and sociocultural.

[0006] The most common psychological causes of impulsivity are anxiety, stress and depression. Impulsivity is often simply a way to numb unhappy feelings, but it can also be a symptom of an undiagnosed mental disorder. For example, depression can cause low self-esteem, body dissatisfaction, poor impulse control and difficulty controlling emotions, all of which can trigger impulses. Naturally, the pain and guilt that follows an impulse can trigger depression, which can trigger another impulse, and so on.

[0007] Alcohol is one of the most dangerous psychoactive substances, popular and commonly used, but whose excessive and uncontrolled consumption can lead to impulsive behavior. Alcohol is consumed for several reasons, including to quench thirst, to warm or cool the drinker's body, for taste, and because alcoholic beverages are associated with other aspects of life, such as food and friendships. The psychological effects of alcohol contribute to some of these reasons.

[0008] Many people with alcoholism are sometimes able to control their drinking and have only a few drinks. At other times, they may start out intending to have only two or three drinks, but after the first drink they lose control and end up drinking much more than they would like to. Often this takes the form of compulsion or "binge drinking."

[0009] Alcohol consumption is a growing problem worldwide and some believe it has already overtaken tobacco in overall health and social care costs. Excessive and / or prolonged alcohol consumption can have undesirable physiological and psychological effects, including short-term effects such as gastric irritation, anxiety disorders and other states of agitation, and longer-term effects such as cirrhosis, fatty liver disease, cardiomyopathy and dementia. Alcohol consumption can lead to intoxication, with serious consequences such as accidents and uncontrollable violent behaviour, and associated medical complications.

[0010] Compounds derived from 2-aminoindan have been shown to selectively bind to dopamine D3 receptors. US Patent No. 5,708,018 discloses several 2-aminoindan derivatives and the hypothesis that these 2-aminoindan derivatives may be useful in treating central nervous system (CNS) disorders associated with dopamine D3 receptors. One such compound is 5-methoxy-2-aminoindan ("MEAI"). The chemical structure of MEAI is: [ka] It is.

[0011] N-Acylethanolamines (NAEs) are lipid-derived signaling molecules. They are formed when one of several types of acyl groups is attached to the nitrogen atom of ethanolamine. Examples of N-acylethanolamines include anandamide (the amide of arachidonic acid (20:4 omega-6) and ethanolamine), N-palmitoylethanolamine (the amide of palmitic acid (16:0) and ethanolamine), N-oleoylethanolamine (the amide of oleic acid (18:1) and ethanolamine), N-stearoylethanolamine (the amide of stearic acid (18:0) and ethanolamine), and N-docosahexaenoylethanolamine (the amide of docosahexaenoic acid (22:6) and ethanolamine).

[0012] Palmitoylethanolamide (PEA, also known as N-(2-hydroxyethyl)hexadecanamide; hydroxyethyl palmitamide; palmidrol; N-palmitoylethanolamine; and palmitylethanolamide) is an endogenous fatty acid amide and belongs to the class of nuclear factor agonists. The chemical structure of PEA is: [ka] PEA has been shown to bind to receptors located within the cell nucleus (nuclear receptors) and exert a variety of biological functions related to chronic pain and inflammation. Studies have shown that PEA interacts with another non-CB1 / CB2 receptor, suggesting that PEA utilizes a unique "parallel" endocannabinoid signaling system. This concept is further supported by growing evidence that the production and inactivation of PEA can occur independently of the production and inactivation of AEA and 2-AG. Many of the biological effects of PEA on cells can be attributed to its affinity for PPARs (particularly PPAR-alpha and PPAR-gamma). PEA has been shown to have 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 anticonvulsant properties. Summary of the Invention

[0013] Disclosure Summary The present disclosure provides pharmaceutical compositions comprising MEAI or its salt and N-acylethanolamine or its salt combination.In some embodiments, these combinations comprise specific molar ratios and / or dosages between each active agent and can be used in various ways.In particular, the present disclosure provides methods for preventing and / or treating various conditions that respond to MEAI treatment, such as drinking, including alcoholism, eating, smoking, shopping or sexual activity.

[0014] In one embodiment, 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 the N-acylethanolamine is between about 1:0.2 and about 1:2000.

[0015] 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 possible value represents a separate embodiment of the disclosure.

[0016] In certain embodiments, the pharmaceutical composition comprises about 0.5-10 mg of 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 of MEAI or a salt thereof. Each possible value represents a separate embodiment of the disclosure.

[0017] In certain embodiments, the pharmaceutical composition comprises about 200-1800 mg of the N-acylethanolamine or a salt thereof. In certain embodiments, the pharmaceutical composition comprises about 250 mg, about 500 mg, about 750 mg, about 1000 mg, or about 1500 mg of the N-acylethanolamine or a salt thereof. Each possible amount represents a separate embodiment of the disclosure.

[0018] In certain embodiments, the N-acylethanolamine is selected from the group consisting of N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, 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, the N-acylethanolamine is PEA or its salt. In certain embodiments, the N-acylethanolamine consists of PEA or its salt. In certain embodiments, the N-acylethanolamine consists of PEA.

[0019] In certain embodiments, the pharmaceutical composition is formulated for systemic administration. In certain embodiments, the pharmaceutical composition is formulated for oral administration, oral mucosal administration, nasal administration, sublingual administration, inhalation administration, topical administration, rectal administration, vaginal administration, parenteral administration, intravenous administration, intramuscular administration, or subcutaneous administration. In certain embodiments, the pharmaceutical composition is formulated for oral administration, oral mucosal administration, nasal administration, 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.

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

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

[0022] In certain embodiments, the N-acylethanolamine increases the therapeutic effect of MEAI compared to the same pharmaceutical composition without the N-acylethanolamine. In certain embodiments, the N-acylethanolamine reduces the required therapeutic dose of MEAI compared to the same pharmaceutical composition without the N-acylethanolamine. In certain embodiments, the N-acylethanolamine reduces at least one side effect of MEAI compared to the same pharmaceutical composition without the N-acylethanolamine. In certain embodiments, the N-acylethanolamine expands the therapeutic window of MEAI compared to the same pharmaceutical composition without the N-acylethanolamine. In certain embodiments, the PEA or a salt thereof increases the therapeutic effect of THC or a salt thereof compared to the same pharmaceutical composition without the PEA or a salt thereof. In certain embodiments, the PEA or a salt thereof reduces the required therapeutic dose of THC or a salt thereof compared to the same pharmaceutical composition without the PEA or a salt thereof. In certain embodiments, the PEA or a salt thereof reduces at least one side effect of THC or a salt thereof compared to the same pharmaceutical composition without the PEA or a salt thereof. In certain embodiments, the PEA or a salt thereof increases the therapeutic window of THC or a salt thereof compared to the same pharmaceutical composition without the PEA or a salt thereof.

[0023] 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.

[0024] In certain embodiments of the above method, MEAI and N-acylethanolamine administration is repeated three times a day. In certain embodiments of the above method, MEAI and N-acylethanolamine administration is repeated twice a day. In certain embodiments of the above method, MEAI and N-acylethanolamine administration is repeated once a day. In certain embodiments of the above method, MEAI and N-acylethanolamine administration is repeated once every two days. In certain embodiments of the above method, MEAI and N-acylethanolamine administration is repeated once every three days.

[0025] In some embodiments, the present disclosure is directed to a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a salt thereof, and an N-acylethanolamine or a salt thereof, and at least one pharma- ceutically acceptable carrier and / or excipient.

[0026] In some embodiments, the pharmaceutical composition is a unit dosage form composition. In other embodiments, the pharmaceutical composition is a solid unit dosage form composition. In yet other embodiments, the pharmaceutical composition is a liquid unit dosage form composition. In further embodiments, the pharmaceutical composition is packaged as a single unit dose or as a plurality of single unit doses.

[0027] In some embodiments, the unit dosage form contains between 30 mg and 130 mg of 5-methoxy-2-aminoindan.In some other embodiments, the pharmaceutical composition is formulated for oral administration.

[0028] In other embodiments, the present disclosure is directed to a method for regulating impulsive behavior, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or its salt and N-acylethanolamine or its salt, thereby regulating impulsive behavior.In some embodiments, impulsive behavior is related to drinking, eating, smoking, shopping or sexual activity.In other embodiments, impulsive behavior is impulsive drinking.

[0029] In further embodiments, the pharmaceutical composition further comprises at least one pharma- ceutically acceptable carrier and / or excipient.In other embodiments, the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, liquid concentrate, or syrup.

[0030] In some embodiments, in the method of the present disclosure, the pharmaceutical composition is a unit dosage form composition.In other embodiments, the amount of 5-methoxy-2-aminoindan in the unit dosage form ranges from 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.

[0031] Further embodiments and the full scope of applicability of the present disclosure will become apparent from the detailed description set forth below. However, the detailed description and specific examples (while indicating preferred embodiments of the disclosure) are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. [Brief description of the drawings]

[0032] Brief explanation of the figure The foregoing summary and the following detailed description of the present disclosure can be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the present disclosure, the accompanying drawings show some, but not all, alternative embodiments. It should be understood, however, that the present disclosure is not limited to the precise arrangements and instrumentalities shown. These drawings, which are incorporated in and constitute a part of this specification, serve to explain the principles of the present disclosure.

[0033] [Figure 1] Figure 1 shows food intake as the mean fold change + / - SEM for each group relative to baseline (i.e., food intake measured before MEAI treatment) and statistical analysis was performed using Student's T-test for each group vs. control; *p<0.05, ***p<0.001 for mice in cycle 1 (Figure 1A) and cycle 2 (Figure 1B).

[0034] [Diagram 2] Figures 2A and 2B show the alcohol intake of mice in the intermittent access to 20% alcohol in two-bottle choice (IA2BC) model. Results for cycle 1 (Figure 2A) and cycle 2 (Figure 2B) are shown as mean ± SEM of alcohol intake (g / kg / 24 h) from day 1 to day 47 / 50 of intake. Statistical analysis used two-way ANOVA followed by Bonferroni post-hoc test for multiple comparisons, only for days 6 / 7 of treatment (*p<0.05; **p<0.01; ***p<0.001).

[0035] [Diagram 3] Figure 3 shows alcohol intake before and after treatment. Results for cycle 1 are shown in Figure 3A and for cycle 2 in Figure 3B. Results are shown as mean ± SEM of alcohol intake (g / kg / 24h). Statistical analysis consisted of two-way ANOVA (repeated measures) followed by Bonferroni post-hoc test to compare replicate means by row (**p<0.01; ***p<0.001).

[0036] [Figure 4]Figure 4 shows the fold change in alcohol intake on drinking days over 6-7 days of MEAI / PEA treatment relative to baseline alcohol intake before treatment for each group. Results are shown as mean fold change + SEM. Mean fold change is for all drinking days combined. Statistical analysis was performed using Student's T-test (*p<0.05).

[0037] [Diagram 5] Figure 5 shows water intake in mice in the intermittent access to 20% alcohol in two-bottle choice (IA2BC) model. Results from cycle 1 (Figure 5A) and cycle 2 (Figure 5B) are shown as the mean ± SEM of water intake (g / kg / 24h) from day 1 to day 47 / 50 of intake.

[0038] [Figure 6] Figure 6 shows the mean alcohol preference [alcohol intake g / kg / 24 h / (total fluid intake g / kg / 24 h)] for cycle 1 (Figure 6A) and cycle 2 (Figure 6B). Results are presented as mean ± SEM. Results are presented as mean ± SEM. Statistical analysis was performed by two-way ANOVA followed by Bonferroni post-hoc test for multiple comparisons (*p<0.05; **p<0.01).

[0039] [Figure 7] Figure 7 shows the alcohol intake of mice in the intermittent access to 20% alcohol in two-bottle choice (IA2BC) model. Results for cycle 1 (Figure 7A) and cycle 2 (Figure 7B) are shown as the mean ± SEM of alcohol intake (g / kg / 24 h) from day 22 (6 intake days before treatment) to day 47 / 50 (6 / 7 intake days after treatment).

[0040] [Figure 8] 8A and 8B show the mean alcohol intake during cycle 1 and cycle 2 on the six drinking days during MEAI treatment.

[0041] [Figure 9]9A and 9B show results shown as mean + / - SEM for alcohol intake (g / kg / 24 h) for cycle 1 and cycle groups. Statistical analysis was by two-way ANOVA followed by Bonferroni post-hoc test for multiple comparisons (*p<0.05; **p<0.01; ***p<0.001).

[0042] [Figure 10] Figure 10 shows the fold change in alcohol intake on the 6 drinking days of MEAI treatment relative to the amount of alcohol consumed before MEAI treatment in the cycle 1 group. Results are shown as the mean fold change ± SEM. Figure 10A shows the mean fold change on each of the 6 drinking days. Figure 10B shows the mean fold change across all drinking days combined. Statistical analysis for cycle 1 was performed using paired Student's T-test.

[0043] [Figure 11] Figure 11 shows the fold change in alcohol intake on the 6 MEAI-treated drinking days relative to the amount consumed before MEAI treatment in the cycle 1 group. Results are shown as fold change ± SEM. Figure 11A shows the mean fold change on each of the 6 drinking days. Figure 11B shows the mean fold change across all drinking days combined. Statistical analysis for cycle 2 was performed using one-way repeated measures ANOVA (repeated measures) followed by Bonferroni post-hoc tests with all mean values ​​compared by row (*p<0.05; **p<0.01; ***p<0.005). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] Detailed Description of the Disclosure The present disclosure, in some embodiments thereof, relates to impulsive behavior, and more particularly, but not exclusively, to compositions and methods for the modulation of impulsive behavior, such as compulsive drinking.

[0045] The terms "impulse", "impulse behavior", "impulse disorder", "impulsive" and "impulsive behavior" as used herein are interchangeable and refer to uncontrolled excessive behaviors, such as indulging in various activities, such as eating, drinking, smoking, drug use, shopping, and sexual activity. Impulsive behaviors include episodes of intense, short-term overuse and overconsumption of food, alcohol, smoking articles, drugs, sweets, sexual intercourse, and the like. Impulsive behaviors are compulsive in style, intensity, addictiveness, history, motivation, and difficulty to control and modify. As used herein, "compulsive behavior" refers to impulsive behaviors that are often influenced by subconscious desires and motivations, and actions and behaviors that have a predictable pattern that are strong, uncontrollable, and difficult to attenuate.

[0046] The subject who needs to regulate impulsive behavior is generally a subject who regularly, for example, more than once a week, or occasionally or less frequently, for example, once or twice a year, experiences episodes of excessive consumption of impulsive objects (e.g., food, alcohol, smoking, drug use, sweets, sexual activity, shopping, etc.), depending on the severity of the impulse.For example, blackout drinkers who experience blackouts even when drinking only twice a year are defined herein as subjects who need to regulate their impulsive drinking.The determination of subjects who need to regulate their impulsive behavior can be made in some cases according to national or international standards, or by acceptable evaluation by medical professionals (e.g., physicians, psychologists, cognitive therapists, social workers, nutritionists, etc., depending on the impulse disorder).

[0047] In some embodiments of any of the present disclosure, the impulsive behavior is associated with drinking, smoking, eating, shopping, and / or sexual activity.

[0048] The phrase "impulse drinking" or "impulse drinking disorder" as used herein is determined according to national or international definitions defined by regulatory authorities, for example, along with the definition of impulse drinking used by the National Health Service (NHS) and the Office for National Statistics in the United Kingdom (UK), and corresponding departments, departments and / or agencies in other countries. The definition of impulse drinking used by the NHS and the Office for National Statistics is drinking more than twice the low-risk drinking guidelines in a single drinking occasion, which recommends that men should not regularly drink more than the low-risk guidelines of 3-4 units of alcohol (equivalent to a pint and a half of 4% beer (approximately 852 ml)) and women should not drink more than 2-3 units of alcohol (equivalent to a 175 ml glass of wine). "Regularly" means drinking every day or most days of the week.

[0049] In some embodiments, the methods provided herein are for reducing drinking in a non-impulsive subject, e.g., who desires to control drinking in certain situations (e.g., during particular events or at certain times).

[0050] In its broadest sense, "controlling impulse drinking" refers to controlling excessive and uncontrollable consumption of alcoholic beverages. Controlling impulse drinking involves reducing the amount of alcohol consumed in one drinking occasion and / or reducing the number of drinking occasions.

[0051] In the context of embodiments of the present disclosure, impulse drinking control relates to providing feelings of satisfaction, satiety, or fulfillment that discourages impulse drinking. Impulse drinking control as practiced in embodiments of the present disclosure affects true harm reduction utility by discouraging impulse drinking in a manner that is easy to implement (by drinking alcohol) and harmless to the drinker (pending toxicological validation).

[0052] Definition: When a range of values ​​is listed, it is intended to encompass each value and subrange within that range. For example, "C1-C6 alkyl" refers to C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, 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 is intended to be encompassed.

[0053] "Isomers" means compounds having the same number and kinds of atoms, and therefore the same molecular weight, but differing with regard to the arrangement or configuration of the atoms in space.

[0054] "Stereoisomer" or "optical isomer" refers to a stable isomer that has at least one chiral atom or is restricted in rotation to produce a perpendicular asymmetric plane (e.g., certain biphenyl, allene, and spiro compounds) and can rotate plane-polarized light. Since the compounds of the present disclosure have asymmetric centers and other chemical structures that can produce stereoisomers, the present disclosure contemplates stereoisomers and mixtures thereof. The compounds of the present disclosure and their salts contain asymmetric carbon atoms and therefore can exist as single stereoisomers, racemates, and mixtures of enantiomers and diastereomers. In general, such compounds can be prepared as racemic mixtures. However, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As described in more detail below, individual stereoisomers of the compounds can be prepared by synthesis from optically active starting materials containing the desired chiral center, or by preparation of 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, the use of chiral resolving agents, or direct separation of the enantiomers on a chiral chromatographic column. Starting compounds of particular stereochemistry are either commercially available or are prepared by the methods described below and resolved by techniques well known in the art.

[0055] It is well known in the art that the biological and pharmacological activity of a compound is sensitive to the stereochemistry of the compound.Therefore, for example, enantiomers often exhibit significantly different biological activities, including differences in pharmacokinetic properties, including metabolism, protein binding, etc., and differences in pharmacological properties, including the type of activity exhibited, the degree of activity, toxicity, etc. Thus, those skilled in the art understand that one enantiomer may be more active or exhibit beneficial effects when enriched with respect to the other enantiomer or separated from the other enantiomer.Furthermore, those skilled in the art know how to separate, enrich, or selectively prepare the enantiomers of the compounds of the present disclosure from the knowledge of this disclosure and the prior art.

[0056] Thus, although a racemic drug can be used, it is often less effective than administering an equal amount of the enantiomerically pure drug; in fact, in some cases, one enantiomer may be pharmacologically inactive and merely function 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, so that the racemic drug acts less quickly than the pure S-isomer). Furthermore, the pharmacological activity of the enantiomers may have different biological activities. For example, S-penicillamine is a treatment for chronic arthritis, while R-penicillamine is toxic. In fact, some purified enantiomers have advantages over the racemates, as the rate of percutaneous penetration of the purified individual isomers has been reported to be faster than that of the racemic mixture. See U.S. Patent Nos. 5,114,946 and 4,818,541.

[0057] In some embodiments, the compound is a racemic mixture of (S) and (R) isomers.In other embodiments, provided herein is a mixture of compounds, in which each compound of the mixture is predominantly present in (S) or (R) isomeric configuration.For example, the compound mixture has an (S) enantiomeric excess of greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, greater than about 99%, greater than about 99.5%, or greater. 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 97% to about 99.5%, greater than about 98% to about 99.5%, greater than about 99% to about 99.5%, or greater than about 99.5%. In other embodiments, the compound mixture has an (R) enantiomeric purity of greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, greater than about 99%, greater than about 99.5%, or greater. 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 about 99.5%, greater than about 99% to about 99.5%, or greater.

[0058] Individual stereoisomers of the compounds of the present disclosure can be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) attaching the mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography, and liberating the optically pure product from the auxiliary; (2) forming a salt with an optically active resolving agent; or (3) directly separating the mixture of optical enantiomers on a chiral chromatographic column. Stereoisomeric mixtures can also be resolved into the constituent stereoisomers by well-known methods such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthesis methods.

[0059] Therefore, it may be therapeutically beneficial to administer one enantiomer preferentially if it is more pharmacologically active, less toxic, or has more favorable pharmacokinetic properties than the other enantiomer, in which case the treated patient will receive a lower total dose of drug and a lower dose of the enantiomer that may be toxic or an inhibitor of the other enantiomer.

[0060] As used herein, nomenclature for compounds, including organic compounds, may be given using common names, IUPAC, IUBMB, or CAS nomenclature recommendations. Those skilled in the art will appreciate the systematic abbreviation of compound structures using naming conventions, or the CHEMDRAW nomenclature. TM The structures of named compounds can be readily verified by commercially available software such as PerkinElmer ChemDraw (Cambridgesoft Corporation, USA). (登録商標) Created using Professional, version 17.

[0061] The compounds of the present disclosure may contain one or more chiral centers and / or double bonds, and therefore exist as stereoisomers, such as geometric isomers, enantiomers, or diastereomers. As used herein, the term "stereoisomer" consists of all geometric isomers, enantiomers, or diastereomers. These compounds may be designated with the symbols "R" or "S" depending on the arrangement of the substituents around the stereogenic 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 may be designated "(±)" in the nomenclature, but one of skill in the art will recognize that the structure may implicitly indicate a chiral center. In some embodiments, an enantiomer or stereoisomer may be provided substantially free of the corresponding enantiomer.

[0062] The present disclosure provides, in certain embodiments, 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.

[0063] 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 the N-acylethanolamine is between about 1:0.2 and about 1:2000.

[0064] As used herein, "pharmaceutical composition" refers to a preparation of an active agent described herein and other chemical components, such as physiologically suitable carriers and additives. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism. As used herein, the phrase "pharmaceutical acceptable carrier" refers to a carrier, additive or diluent that is not significantly irritating to an organism and does not impair the biological activity and properties of the compound to be administered. Adjuvants are included in these terms.

[0065] The term "additive" as used herein refers to the inactive substance added to pharmaceutical composition to further facilitate the administration of active ingredient.The examples of additives include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, oil such as vegetable oil or fish oil, and polyethylene glycol.

[0066] 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 saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin, 18th Edition.

[0067] The phrase "pharmaceutical acceptable" as used herein refers to molecular entities and compositions that are physiologically acceptable and generally do not cause allergic or similar toxicity when administered to an individual.Preferably, and particularly when the formulation is used in humans, the term "pharmaceutical acceptable" can mean approved by a regulatory agency (e.g., the U.S. Food and Drug Administration) or listed in a generally accepted pharmacopoeia (e.g., the U.S. Pharmacopoeia) for use in animals.

[0068] As used herein, the phrase "pharmaceutically acceptable salts" refers to charged species of the parent compound and its counterion, which are generally used to modify the solubility characteristics of the parent compound and / or to reduce significant irritation to an organism by the parent compound, while not destroying the biological activity and properties of the administered compound.

[0069] In the context of some embodiments of the present disclosure, a pharma- ceutically acceptable salt of a compound described herein may be an acid addition salt that optionally comprises at least one basic (e.g., amine) group of a compound in positively charged form (e.g., ammonium ion) in combination with at least one counterion derived from a selected acid to form a pharma- ceutically acceptable salt.

[0070] Thus, the acid addition salts of the compounds described herein may be complexes formed between one or more basic groups of the drug and one or more equivalents of an acid.

[0071] Acid addition salts include, but are not limited to, various organic and inorganic acids such as hydrochloric acid which produces a hydrochloric acid addition salt, hydrobromic acid which produces a hydrobromic acid addition salt, acetic acid which produces an acetic acid addition salt, ascorbic acid which produces an ascorbic acid addition salt, benzenesulfonic acid which produces a besylic acid addition salt, camphorsulfonic acid which produces a camphorsulfonic acid addition salt, citric acid which produces a citric acid addition salt, maleic acid which produces a maleic acid addition salt, malic acid which produces a malic acid addition salt, methanesulfonic acid which produces a methanesulfonic acid (mesylate) addition salt, naphthalenesulfonic acid which produces a naphthalenesulfonic acid addition salt, oxalic acid which produces an oxalic acid addition salt, phosphoric acid which produces a phosphoric acid addition salt, toluenesulfonic acid which produces a p-toluenesulfonic acid addition salt, succinic acid which produces a succinic acid addition salt, sulfuric acid which produces a sulfuric acid addition salt, tartaric acid which produces a tartrate addition salt, and trifluoroacetic acid which produces a trifluoroacetic acid addition salt. Each of these acid addition salts can be either mono- or poly-addition salts, as these terms are defined herein.

[0072] In the context of some of the present embodiments, a pharma- ceutically acceptable salt of a compound described herein may be, optionally, a base addition salt consisting of at least one group of the compound in an anionic form, in combination with at least one counterion (i.e., cation) to form a pharma- ceutically acceptable salt. Examples of suitable cations include, but are not limited to, metal cations of metals such as sodium, potassium, magnesium, and calcium or ammonium.

[0073] Each of these base addition salts may be either a mono- or poly-addition salt, as these terms are defined herein.

[0074] Depending on the stoichiometric ratio of basic or acidic charged groups in the compound (eg, amine groups) and the counterions in the salt, acid or base addition salts can be either mono- or poly-addition salts.

[0075] As used herein, the phrase "mono-addition salt" refers to a salt in which the stoichiometric ratio of counterion to the charged form of the compound is 1:1, such that the addition salt contains one molar equivalent of counterion per molar equivalent of compound.

[0076] As used herein, the phrase "polyaddition salt" refers to a salt in which the stoichiometric ratio of counterion to charged form of the compound is greater than 1:1, e.g., 2:1, 3:1, 4:1, etc., such that the addition salt contains 2 or more molar equivalents of counterion per molar equivalent of compound.

[0077] Furthermore, in any one of the embodiments described herein, each of the compounds described herein, including the salts thereof, may be in the form of a solvate or hydrate thereof.

[0078] The term "solvate" refers to a stoichiometrically variable complex (e.g., di-, tri-, tetra-, penta-, hexa-, etc.) formed by a solute (a 2-aminoindan derivative as described herein) and a solvent, whereby the solvent does not interfere with the biological activity of the solute.

[0079] The term "hydrate" refers to a solvate, as defined herein above, wherein the solvent is water.

[0080] The term "N-acylethanolamine" as used herein generally refers to a type of fatty acid amide, a lipid-derived signaling molecule formed when any of several types of acyl groups are attached to the nitrogen atom of ethanolamine. Although these amides can conceptually be formed from fatty acids and ethanolamine with the release of one molecule of water, known biological synthesis employs specific phospholipase D to cleave the phospholipid unit from N-acylphosphatidylethanolamine. The suffixes -amine and -amide in these names each refer to the single nitrogen atom of ethanolamine that links the compound: the "amine" in ethanolamine because it is considered the free terminal nitrogen in that subunit, while the "amide" is referred to when it is considered to be attached to the adjacent carbonyl group of the acyl subunit. The names of these compounds may be written as either "amide" or "amine" in this application. The term "ethanolamine" is used in a generic sense and is meant to include monoethanolamine, diethanolamine, triethanolamine, and mixtures thereof.

[0081] The term "derivative" as used herein means a compound whose core structure is identical to or closely resembles an N-acylethanolamine compound, but has chemical or physical modifications, such as different or additional side groups.

[0082] As used herein, the term "salt" refers to any form of an active ingredient in which the active ingredient is in ionic form, associated with a counterion (cation or anion), or in solution. It also includes complexes of the active ingredient with other molecules and ions, particularly complexes that are complexed through ionic interactions.

[0083] 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, between about 1:0.25 and about 1:4, between about 1:0.28 and about 1:3.5, between about 1:0.33 and about 1:3, between about 1:0.4 and about 1:2.5, between about 1:0.5 and about 1:2, or about 1:1. Each possibility represents a separate embodiment of the disclosure.

[0084] In certain embodiments, the molar ratio between MEAI and N-acylethanolamines is between about 1:15 and about 1:1800. In certain embodiments, the molar ratio between MEAI and N-acylethanolamines is between about 1:16 and about 1:1700, between about 1:17 and about 1:1600, between about 1:18 and about 1:1500, between about 1:19 and about 1:1400, between about 1:20 and about 1:1300, between about 1:21 and about 1:1200, between about 1:22 and about 1:1100, between about 1:1300 and about 1:1400, between about 1:1500 and about 1:1600, between about 1:17 and about 1:1800, between about 1:19 and about 1:1500, between about 1:1800 and about 1:1900, between about 1:20 and about 1:1300, between about 1:21 and about 1:1200, between about 1:22 and about 1:1100, between about 1:1300 and about 1:1400, between about 1:1500 and about 1:1600, between about 1:17 and about 1:18 ... Between about 1:23 and about 1:1000, between about 1:24 and about 1:900, between about 1:15 and about 1:800, between about 1:16 and about 1:700, between about 1:17 and about 1:600, between about 1:18 and about 1:500, between about 1:19 and about 1:490, between about 1:20 and about 1:480, between about 1:21 and about 1:470, or between about 1:22 and 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 between about 1:25 and about 1:450. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is between about 1:10 and about 1:500, between about 1:15 and about 1:450, between about 1:20 and about 1:400, between about 1:25 and about 1:350, between about 1:30 and about 1:300, between about 1:35 and about 1:250, between about 1:40 and about 1:200, or between about 1:45 and about 1:150. Each possibility represents a separate embodiment of the disclosure. 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 1:10. 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 disclosure.

[0085] In certain embodiments, the pharmaceutical composition comprises about 0.5-10 mg of MEAI or a salt thereof. In certain embodiments, the pharmaceutical composition comprises about 1-9.5 mg, about 1.5-9 mg, about 2-8.5 mg, about 2.5-8 mg, about 3-7.5 mg, about 3.5-7 mg, about 4-6.5 mg, about 4.5-6 mg, or about 5-5.5 mg of MEAI or a salt thereof. In certain embodiments, the pharmaceutical composition comprises about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg of MEAI or a salt thereof. Each possibility represents a separate embodiment of the 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 less than about 10 mg of MEAI or a salt thereof, with each possibility representing a separate embodiment of the 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 of MEAI or a salt thereof. Each possibility represents a separate embodiment of the disclosure.

[0086] In certain embodiments, the pharmaceutical composition comprises about 200-1800 mg of the N-acylethanolamine or a salt thereof. In certain embodiments, the pharmaceutical composition comprises about 250-1550 mg, about 300-1200 mg, about 350-950 mg, about 400-700 mg, about 450-600 mg, or about 500-550 mg of the N-acylethanolamine or a salt thereof. Each possibility represents a separate embodiment of the 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, 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 1700 mg, at least about 1800 mg, at least about 1900 mg, at least about 2000 mg, at least about 2100 mg, at least about 2200 mg, at least about 2300 mg, at least about 2400 mg, at least about 250 mg, at least about 2600 mg, at least about 2700 mg, at least about 2800 mg, at least about 2900 mg, at least about 3000 mg, at least about 3100 mg, at least about 3200 mg, at least about 3300 mg, at least about 3400 mg, at least about 350 mg, at least about 3600 mg, at least about 37 mg, at least about 1650 mg, at least about 1700 mg, at least about 1750 mg or at least about 1800 mg of the N-acylethanolamine or 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, 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. mg of N-acylethanolamine or salt thereof. Each possibility represents a separate embodiment of the present disclosure.

[0087] In certain embodiments, the N-acylethanolamine is selected from the group consisting of N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, 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, the N-acylethanolamine is PEA or its salt. In certain embodiments, the N-acylethanolamine consists of PEA or its salt. In certain embodiments, the N-acylethanolamine consists of PEA.

[0088] In certain embodiments, the pharmaceutical composition is formulated for systemic administration. In certain embodiments, the pharmaceutical composition is formulated for oral administration, oral mucosal administration, nasal administration, sublingual administration, inhalation administration, topical administration, rectal administration, vaginal administration, parenteral administration, intravenous administration, intramuscular administration, or subcutaneous administration. In certain embodiments, the pharmaceutical composition is formulated for oral administration, oral mucosal administration, nasal administration, 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.

[0089] Techniques for formulation and administration of pharmaceutical agents 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 manufactured by processes well known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.

[0090] For oral administration, pharmaceutical compositions can be easily formulated by combining the active compounds with pharma- ceutically acceptable carriers well known in the art. Such carriers allow the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by patients. Oral pharmacological preparations can be prepared by grinding the mixture obtained with solid additives, optionally adding suitable auxiliary agents, and then processing the mixture of granules to obtain tablets or dragee cores. Suitable additives are, in particular, sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, and sodium carbomethylcellulose; and / or fillers, such as physiologically acceptable polymers, such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0091] The term "oral administration" refers to any method of administration in which an active agent can be administered by swallowing, chewing, sucking, or drinking an oral dosage form. Examples of solid dosage forms include conventional tablets, multi-layer tablets, capsules, caplets, etc., which do not substantially release the drug in the mouth or oral cavity.

[0092] The dragee core is provided with a suitable coating.For this purpose, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and concentrated sugar solutions that may optionally contain suitable organic solvents or solvent mixtures can be used.Dyes or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of doses of active compounds.

[0093] Orally usable pharmaceutical compositions include hard or soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. The capsules may contain the active ingredient mixed with a filler 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 oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added. In addition, stabilizers may also be added. All preparations for oral administration should be in a dosage suitable for the chosen route of administration. For buccal and sublingual administration, the compositions may take the form of tablets or lozenges formulated in a conventional manner, or in the form of an adhesive carrier. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, for example, a sterile, pyrogen-free aqueous solution, before use.

[0094] Pharmaceutical compositions suitable for use in the context of the present disclosure include compositions in which the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a "therapeutically effective amount" refers to an amount of active ingredients effective to prevent, reduce, or ameliorate symptoms or side effects of a disease or disorder, or to prolong the survival of a subject being treated. Determination of a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein. More specifically, a "therapeutically effective amount of a mixture" refers to an amount of at least two active ingredients, where each of the active ingredients may not be an independently therapeutically effective amount, or both of the active ingredients may not be therapeutically effective amounts, and the mixture is nevertheless effective to prevent, reduce, or ameliorate symptoms or side effects of a disease or disorder, or to prolong the survival of a subject being treated. As used herein, the term "mixture" refers to a non-covalent association of two molecules.

[0095] For any formulation used in the disclosed method, the dosage or therapeutically effective amount can be estimated initially from in vitro, in vivo and cell culture assays. For example, doses can be calculated in animal models to achieve a desired concentration or potency. Such information can be used to more accurately determine useful doses in humans. The dosage of each compound of the claimed combination 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. In addition, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic, or efficacy profile of a therapeutic agent) information about a particular patient can affect the dosage used. Continuous daily administration may not be necessary; the treatment regimen may require drug-free cycles or treatment may be provided appropriately during acute disease exacerbations. Dosage increases may or may not be necessary; the treatment regimen may require dosage reductions. Toxicity and therapeutic effects of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, cell cultures, or experimental animals. The data obtained from these in vitro and cell culture assays and animal studies can be used in formulating various dosages for use in humans. Dosages may vary depending on the dosage form used and the route of administration utilized. The exact formulation, route of administration, and dosage can be selected by the individual physician in view 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, single or multiple doses can be administered, and treatment can continue for several days to several weeks, or until a cure is achieved or a diminution of the disease state is achieved.

[0096] The present disclosure further provides, in another aspect, a dosage unit comprising or consisting of the above pharmaceutical composition.

[0097] In certain embodiments, the dosage unit comprises the pharmaceutical composition described above. In certain embodiments, the dosage unit consists of the pharmaceutical composition described above. In certain embodiments, the dosage unit is formulated as a gel, a powder or a spray. In certain embodiments, the dosage unit is formulated as a gel. In certain embodiments, the dosage unit is formulated as a powder. In certain embodiments, the dosage unit is formulated as a spray.

[0098] The present disclosure further provides, in another aspect, a pharmaceutical composition or dosage unit as described above for use in a method for preventing or treating a condition preventable or treatable by at least one MEAI.

[0099] The term "treating" as used herein includes, but is not limited to, any one or more of eliminating, ameliorating, inhibiting, attenuating, blocking, suppressing, reducing, slowing, halting, relieving, or preventing one or more symptoms or side effects of a disease or condition of the disclosure.

[0100] "Acute" refers to a condition involving a severe course of a relatively short duration.

[0101] The term "chronic" as used herein means that the disease or condition of the present disclosure may last for weeks, months, or years. The intensity of the disease or symptoms may vary depending on various conditions, such as, for example, the age of the patient, temperature, season, type of illness, etc.

[0102] As used herein, the term "about" when used in connection with a value, values, or a range of values ​​defined by a minimum and a maximum value, means a value that is 10% lower and / or higher than the corresponding value, values, or range of values. For example, the expression "about 1" means "0.9 to 1.1", the expression "about 1 or 2" means "0.9 to 1.1 or 1.8 to 2.2", and the expression "about 1 to about 2" means "0.9 to 2.2".

[0103] The words "including," "having," and similar terms mean "including, but not limited to."

[0104] The term "consisting of" means "including and limited to."

[0105] The term "consisting essentially of" means that the composition, method, or microcapsule may include additional components, steps, and / or moieties, but only if the additional components, steps, and / or moieties do not materially alter the basic and novel characteristics of the claimed composition, method, or structure.

[0106] As used herein, the singular forms, "a," "an," and similar forms include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" can include a plurality of compounds, including mixtures thereof.

[0107] Toxicity and therapeutic efficacy can be measured, for example, by LD 50 (a dose that is lethal to 50% of the population) and ED 50 The dose that is therapeutically effective in 50% of the population can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 Compositions that exhibit large therapeutic indices are desirable.

[0108] The data obtained from cell culture assays or animal studies can be used in calculating various dosage ranges for use in humans. Therapeutically effective doses achieved in one animal model can be converted for use in other animals, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Reports 50(4):219 244 (1966) and the table of equivalent surface area dosage factors below). [Table 1]

[0109] The dosage of such compounds is preferably within the range of ED 50 The blood concentration range includes 0.1 to 0.5 mg / kg / day, and has little or no toxicity. The dosage can vary within this range depending on the dosage form used and the route of administration used. In general, the therapeutically effective amount can vary depending on the age, condition, and sex of the subject, and the severity of the medical condition of the subject. The dosage can be determined by a physician and can be adjusted accordingly to the observed treatment effect.

[0110] Those skilled in the art will recognize that both in vivo and in vitro tests using appropriate, known and generally accepted cellular and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0111] One of skill in the art will further recognize that human clinical trials, including first-in-human, dose-ranging and efficacy studies, in healthy subjects and / or patients suffering from a given disorder can be completed according to methods well known in the clinical and medical arts.

[0112] Although the present disclosure has been described with reference to specific embodiments, those skilled in the art will recognize that various changes can be made and equivalents substituted without departing from the scope of the present disclosure. In addition, many modifications can be made to adapt a particular situation or material to the teachings of the present disclosure without departing from its scope. Therefore, it is not intended that the disclosure be limited to the particular embodiments disclosed, but the disclosure is intended to include all embodiments falling within the scope of the appended claims.

[0113] The following examples are presented to more fully illustrate some embodiments of the present disclosure, but they should in no way be construed as limiting the broad scope of the disclosure. EXAMPLES

[0114] Example 1: Evaluation of the efficacy of MEAI and PEA on compulsive drinking in mice Drinking alcohol and alcoholism are a growing problem worldwide and some believe they have already overtaken tobacco in overall health and social care costs.Excessive and / or prolonged alcohol use can have undesirable physiological and psychological effects, including short-term effects such as gastric irritation, anxiety disorders and other agitated states, and longer-term effects such as cirrhosis, fatty liver disease, cardiomyopathy and dementia.

[0115] MEAI (5-methoxy-2-aminoindan or 5-MeO-AI) is a derivative of 2-aminoindan and is useful as an impulse control or impulse reliever that provides feelings of satisfaction, satiety or satiability and regulates (e.g., inhibits) impulsive behaviors such as impulse drinking. Administering an effective amount of an impulse control agent to a subject, alone or in combination with an alcoholic beverage, is expected to reduce the amount of alcohol consumed in impulse drinking and prevent many of the adverse effects associated with excessive drinking. This is particularly relevant for severe intoxication that can lead to serious consequences such as accidents and uncontrollable violent behavior, associated medical complications, as well as short-term effects such as gastric irritation, anxiety disorders and other agitated states.

[0116] The objective of this study was to evaluate the effectiveness of MEAI in suppressing impulse drinking in mice, in combination with palmitoylethanolamide (PEA), at several MEAI doses.

[0117] The principle of the test is based on the intermittent access to 20% alcohol in two-bottle choice (IA2BC) model in mice. During the test period, mice were provided with two bottles: one bottle of water and another bottle of 20% ethanol solution, which were removed after 24 h and replaced with another bottle of water for another 24 h. In total, mice were provided with 20% ethanol for 24 h, three times a week, for 7–8 weeks (21–22 drinking days).

[0118] Alcohol intake was measured (by measuring pre- and post-drinking weights) after each 24-h alcohol exposure. After 4 weeks of intermittent 20% alcohol intake, mice were assigned to groups according to alcohol intake, resulting in balanced groups. To examine the effect of treatment on reducing alcohol intake, mice were treated daily with test article or vehicle during weeks 6-7 / 8.

[0119] Vehicle and test formulations were prepared as shown in Table 2. [Table 2]

[0120] Preparation of formulations: Vehicle 1: Prepared from water for injection.

[0121] Vehicle 2: A solution was prepared from Ethanol for Injection: Kolliphor: Water (1:1:18 respectively).

[0122] Test Article 1 (MEAI): Supplied as a powder and dissolved by dilution several-fold with Vehicle 1 according to Table 2.

[0123] Test Article 2 (PEA): Supplied as a powder and dissolved at 5 mg / mL with Vehicle 2 according to Table 2.

[0124] Experimental model: Animals: C57BL / 6 mice, female, 7-8 weeks old at the start of the study (Envigo RMS Ltd., Israel). The minimum and maximum initial body weights in each group did not exceed ±20% of the group mean body weight.

[0125] Animal handling was performed in accordance with the guidelines of the National Institutes of Health (NIH) and the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC). In this study, mice were housed in 36.5 × 20.7 × 13 cm filtered cages (up to 5 mice per cage) with a stainless steel top mesh providing pelleted food and drinking water in plastic bottles; bedding: steam-sterilized clean rice husk (Envigo, Teklad, Laboratory grade, Sani-chips). Bedding was changed along with the cages at least once a week.

[0126] Mice were fed a commercial rodent diet (Teklad Certified Global 18% Protein Diet, Envigo cat# 2018SC) ad libitum and had free access to sterilized, acidified drinking water (pH 2.5–3.5) provided by the municipality.

[0127] Mice were housed under standard laboratory conditions, fully air-conditioned and filtered (HEPA F6 / 6), with an ample supply of fresh air (minimum 15 air changes / hour). Mice were housed in a climate-controlled environment with temperatures ranging from 18 to 24°C and relative humidity ranging from 30 to 70%, with a reversed 12-h light / 12-h dark cycle (6 pm / 6 am).

[0128] Animals were assigned to cages randomly on the day of receipt or according to body weight, if necessary.

[0129] Mice were examined by the attending veterinarian (AV) prior to the start of the experimental phase to ensure their suitability for the study. Animals were inspected daily for signs of morbidity or mortality.

[0130] Experimental design and conditions: No pain medication was administered as this may have interfered with the study.

[0131] Animals that lost 10% of their initial body weight were provided with wet food on the bottom of their cage, given saline subcutaneous injections (SC) as needed, and weighed daily.

[0132] Animals found in a moribund state and those exhibiting severe and persistent pain and enduring signs of distress were humanely euthanized as detailed in the ethical committee approval. Animals exhibiting a weight loss of more than 20% from the first weight measurement or more than 10% from the value immediately preceding each successive daily weight measurement were also humanely euthanized.

[0133] The date of first administration was defined as "day 1," and the date of end of administration was defined as "day 50" for cycle 1 and "day 52" for cycle 2.

[0134] The study was conducted in two cycles. In the first cycle there were five groups, four groups were treated with MEAI at a high concentration and a control group was treated with water for injection - Vehicle 1. In cycle 2, three more groups of mice were treated with a combination of MEAI+PEA (a high dilution of MEAI), another group of PEA+Vehicle 1 treated mice, and another group with Vehicle 2 containing the vehicle for PEA (1:1:18 ethanol:Kolliphor:water).

[0135] In both cycles, mice were given only alcohol (three times per week) for the first 5 weeks to establish the IA2BC model and compulsive drinking. During the final 2 weeks, in addition to the every-other-day alcohol treatment, mice were administered the test article / vehicle (MEAI, PEA) daily to examine its effect on alcohol drinking. Administration occurred immediately before (15–30 min) drinking. An additional 5 12-week-old mice were not treated with alcohol and served as naïve mice for histological controls.

[0136] Each test article and vehicle formulation was administered to 9 or 5 mice per group according to Table 3. The study timeline was performed according to Table 4. [Table 3] [Table 4]

[0137] Testing and Evaluation: Morbidity and mortality checks were performed daily. Animals sacrificed during the study were considered to have died during the study for the purposes of interpreting the results. If death occurred before the scheduled end of the study, gross pathology evaluation was performed as close as possible to the time of death. Time of death was recorded as accurately as possible.

[0138] Body weights were recorded on arrival, before the start of the study, three times weekly thereafter, and at the end of the study.

[0139] Animals were observed for clinical signs from day 1 and then three times weekly until the termination of the study. Observations recorded any abnormalities including changes in local injection sites, skin, hair, eyes, mucous membranes, respiratory tract, occurrence of secretions and excretions (e.g., diarrhea), and autonomic activity (e.g., lacrimation, salivation, piloerection, pupil size, abnormal breathing patterns). Also included were changes in gait, posture, and response to handling, bizarre behavior, tremors, convulsions, sleep, and coma. All observed abnormalities, signs of toxicity, moribundity, and deaths prior to termination were recorded.

[0140] The animals were fed twice before the first dose (when drinking alcohol and when not drinking alcohol), during each drinking period (six times in total), and before the end (when not drinking alcohol).

[0141] Food intake was recorded for each cage for 18 ± 2 h. Calculated food intake was determined based on the weight of food offered in the hopper and the remaining unused food.

[0142] Alcohol and water intake of animals was recorded per cage for 24±2 h starting on day 1 and then three times weekly until the end of the study.

[0143] At the end of the study, five mice from groups 1–10 (two from groups 6F and 7F) were sampled (approximately 0.5 mL) from the submandibular vein and sacrificed according to the ethical committee approval. Blood was collected in K3-EDTA tubes. Plasma was separated and stored at (-60°C)–(-90°C) for future bioanalytical evaluation. After terminal bleeding, the brains, kidneys, and livers of the same five mice from each group were dissected and flash-frozen for future bioanalytical evaluation (in groups 6F and 7F, only two mice were sampled for future bioanalytical evaluation).

[0144] Organs were harvested from the remaining animals in each group and fixed in buffered 4% formaldehyde for future histological evaluation (liver, kidney, heart, pancreas, brain, spleen, lung, and thyroid).

[0145] Numerical results were expressed as means and standard deviations or standard errors. Whenever applicable, descriptive statistics and between-group comparisons of data 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.

[0146] Body weight (BW) was monitored every other day for all animals in all groups. Two-way ANOVA showed that there was no significant change in BW in all groups compared to the control groups (1F in cycle 1, 6F and 7F in cycle 2) except for group 4F (MEAI interim administration), which was significantly lower than the control group only during day 40 of cycle 1 (*p<0.05).

[0147] For gross pathology examination, animals were evaluated for macroscopic findings. Pathological findings (lightening and / or enlargement) detected in the liver, kidney, heart and spleen were observed in all groups, including the vehicle-treated groups (groups 1F, 6F and 7F). All groups were alcohol-treated, suggesting that these were most likely related to alcohol consumption and not MEAI treatment.

[0148] Furthermore, white spots were observed in organs such as the pancreas (see Appendix Figure 8), liver, and peritoneum, subcutaneous tissue, and adipose tissue in mice from groups 9F and 10F in cycle 2, but not in cycle 1. These white spots may be accumulations of PEA.

[0149] result The results showed that MEAI treatment significantly reduced alcohol consumption in a dose-dependent manner, and PEA treatment had an additive effect at low doses of MEAI. There were no significant differences in the body weight of the animals, and food intake was not affected by MEAI treatment.

[0150] During the study, four deaths were observed in animals in the high-dose treatment group, but it is important to consider that these animals were treated with MEAI after a long period of alcohol consumption. Evidence that alcohol consumption is harmful can be found in the gross pathology analysis, with macroscopic findings mainly in the liver, kidneys, heart and spleen in all groups, including the control group.

[0151] Based on these findings, we can conclude that MEAI had an inhibitory effect on alcohol drinking in mice in the IA2BC model, and PEA at a low dose of MEAI ameliorated this effect.

[0152] For gross pathology examination, animals were evaluated for macroscopic findings. Pathological findings (lightening and / or enlargement) detected in the liver, kidney, heart and spleen were observed in all groups, including the vehicle-treated groups (Groups 1F, 6F and 7F). All groups were alcohol-treated, suggesting that these were most likely related to alcohol consumption and not MEAI treatment.

[0153] In addition, white spots were observed in organs such as the pancreas, liver, and peritoneum, subcutaneous tissue, and adipose tissue in mice from groups 9F and 10F in cycle 2, but not in cycle 1. These white spots may be accumulations of PEA.

[0154] Feeding Amount: Food intake per mouse per cage was monitored for 24 hours during the drinking period by weighing food before and after 24 hours. Food intake was measured throughout all MEAI treatment days in both cycles. The mean value for each group on each feeding day was calculated for each animal as a fold change from baseline (i.e., food intake measured before MEAI treatment). Statistical analysis was performed by comparing the fold change values ​​of each MEAI / PEA treatment group with the vehicle group (1F / 6F / 7F).

[0155] As shown in Figure 1A, in cycle 1, all groups showed increased food intake compared to their own baseline (fold change >1.0). The fold change in the 3F group (MEAI 40 mg / kg) was significantly lower compared to the control 1F group (MEAI 0) (*p<0.05). The fold change in the 4F group (MEAI 60 mg / kg) was lower than the control but not significant. The 2F groups (MEAI 20 mg / kg) and 5F groups (MEAI 100 mg / kg) were similar to the control 1F group.

[0156] In cycle 2, none of the groups had a significant change in food intake compared to their own baseline except for the control 7F group (MEAI / PEA 0 / 25 mg / kg), which had a 22% decrease in food intake to 0.78 ± 0.03 times, see Figure 1B. The other groups had no change compared to their own baseline levels, but showed significantly higher food intake compared to the 7F group (group 8F MEAI / PEA 20 / 25 mg / kg, ***p<0.001; groups 9F and 10F MEAI / PEA 60 / 25 mg / kg and 100 / 25 mg / kg, *p<0.05).

[0157] Drinking: Intermittent access to 20% alcohol in two-bottle choice (IA2BC) model in mice. Mice were given 20% ethanol 24 hours a day, 3 times a week for 5 weeks (15 drinking days), and alcohol intake was measured by body weight. After 5 weeks, mice were divided into groups according to alcohol intake, and the effect of MEAI / PEA treatment on alcohol intake reduction was examined. Mice were administered vehicle / MEAI / PEA daily between days 36-48 of cycle 1 and between days 36-51 of cycle 2. Figures 3A and 3B show that alcohol intake during the 6 / 7 days of treatment was significantly reduced in treated vs. control mice in a dose-dependent manner in both cycles. Further graphs summarizing the alcohol intake results are shown in Figures 7A and 7B, Figures 8A and 8B, and Figures 9A and 9B (alcohol intake during MEAI treatment), and Figures 10A and 10B, and Figures 11A and 11B (fold change in alcohol intake). Statistical analysis was performed using two-way analysis of variance with Bonferroni post-hoc test for multiple comparisons (*p<0.05; **p<0.01; ***p<0.001).

[0158] The mean intake before and during treatment was compared between groups. Figure 4 shows the mean alcohol intake on the 6 drinking days before MEAI treatment for each group (white bars) versus the mean alcohol intake on the 6 drinking days during MEAI treatment for each group (blue bars). In cycle 1, treatment with MEAI at 40 mg / kg and above significantly reduced alcohol intake compared to before treatment (***p<0.01; ***p<0.001). In cycle 2, dual treatment with MEAI at 20 mg / kg and above plus 25 mg / kg PEA significantly reduced alcohol intake compared to before treatment (***p<0.01, ***p<0.001).

[0159] The average intake before and during treatment was compared for each group. Figure 3 shows the average alcohol intake for each group on the 6 drinking days before MEAI treatment (white bars) versus the average alcohol intake for each group on the 6 drinking days during MEAI treatment (blue bars). In cycle 1 (Figure 3A), MEAI treatment at 40 mg / kg or higher significantly reduced alcohol intake compared to before treatment (***p<0.01; ***p<0.001). In cycle 2 (Figure 3B), dual treatment with MEAI at 20 mg / kg or higher plus 25 mg / kg PEA significantly reduced alcohol intake compared to before treatment (***p<0.01, ***p<0.001).

[0160] The additive effect of PEA was tested by comparing alcohol intake 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 alcohol intake from its own baseline before treatment was compared for the 6-7 drinking days treated with MEAI / PEA. The results in Figure 5 show that MEAI co-treatment at the lower doses of 20 mg / kg and 60 mg / kg significantly reduced alcohol intake compared to the same doses of MEAI alone without PEA (*p<0.05). The highest dose of 100 mg / kg MEAI reduced alcohol intake after PEA administration, but did not reach statistical significance.

[0161] The additive effect of PEA was tested by comparing alcohol intake 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 alcohol intake from its own baseline before treatment was compared for the 6-7 drinking days treated with MEAI / PEA. The results in Figure 4 show that MEAI co-treatment at the lower doses of 20 mg / kg and 60 mg / kg significantly reduced alcohol intake compared to the same doses of MEAI alone without PEA (*p<0.05). The highest dose of 100 mg / kg MEAI reduced alcohol intake after PEA administration, but did not reach statistical significance.

[0162] Water intake: Water intake during alcohol treatment was monitored three times a week for 5 weeks. The effect of MEAI / PEA treatment on water intake was examined. Mice were treated daily with vehicle / MEAI / PEA between days 36-48 in cycle 1 and between days 36-51 in cycle 2. Figure 5 shows that water intake increased during MEAI treatment in both cycles. In cycle 2 (Figure 5B), water intake increased in a dose-dependent manner and was inversely correlated with alcohol intake, which was decreased in a dose-dependent manner.

[0163] Alcohol preference Mean alcohol preference was defined and assessed as the ratio of alcohol weight (g / kg / 24 h) divided by the total weight of water and alcohol consumed by the animals (g / kg / 24 h). As shown in Figures 6A and 6B, alcohol preference was dose-dependently decreased after MEAI and MEAI / PEA treatment compared to the control group. In both cycles, the decrease was statistically significant at the highest dose (100 mg / kg MEAI; 100 / 25 mg / kg MEAI / PEA), suggesting that the decrease in alcohol consumption was associated with an increase in water intake.

[0164] conclusion The effect of MEAI in combination with palmitoylethanolamide (PEA) at several MEAI doses to reduce alcohol consumption in mice with intermittent access to 20% alcohol in a two-bottle choice setting (IA2BC) was evaluated. Mice were provided with a 20% alcohol solution for 24 h, 3 times a week for 7 weeks, and were treated with MEAI or MEAI / PEA daily during the final 2 weeks of alcohol treatment. Alcohol consumption was measured by weighing the alcohol bottle before and after drinking, and water intake was measured in parallel. In addition, food intake (24 h) was measured before, during, and after MEAI / PEA treatment during the drinking days.

[0165] Results showed that MEAI treatment significantly reduced alcohol consumption in treated animals in a dose-dependent manner, and PEA treatment had an additive effect at low doses of MEAI.Furthermore, MEAI treatment inversely increased water intake in both cycles, which resulted in a dose-dependent decrease in alcohol preference (as a percentage of total water).

[0166] There were no significant differences in the body weight of the animals and food consumption was not affected by MEAI treatment.

[0167] During the study, four deaths were observed in animals from the high-dose treatment group, but it is important to consider that these animals were treated with MEAI after a long period of alcohol consumption. Supporting evidence that alcohol consumption is harmful can be found in the gross pathology analysis, with macroscopic findings in all groups, including the control group, mainly in the liver, kidneys, heart and spleen.

[0168] Based on the above findings, under the present test conditions, MEAI exhibited the effect of suppressing alcohol drinking in mice in the IA2BC model, and PEA, starting from a low dose of MEAI, ameliorated this effect.

[0169] The many features and advantages of the present disclosure will be apparent from the detailed specification, and it is, therefore, intended by the appended claims to cover all such features and advantages of the present disclosure that are within the true spirit and scope of the present disclosure. Further, since numerous modifications and variations will readily occur to those skilled in the art, it is not desired to limit the disclosure to the exact construction and operation shown and described, and therefore, all suitable modifications and equivalents may be utilized that are within the scope of the present disclosure.

[0170] Moreover, those skilled in the art will appreciate that the conception on which this disclosure is based may be readily utilized as a basis for the designing of other structures, methods and systems for carrying out the several purposes of the present disclosure. Accordingly, the claims are not to be deemed limited by the foregoing description or examples.

Claims

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

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

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

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

5. The pharmaceutical composition according to claim 1, 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 claim 1, wherein the pharmaceutical composition comprises 30 mg to 130 mg of MEAI or a salt thereof.

7. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises 70 mg of MEAI or a salt thereof.

8. The pharmaceutical composition according to claim 1, wherein MEAI or a salt thereof and N-acylethanolamine or a salt thereof are present in a molar ratio of 1:0.2 to 1:2000.

9. A pharmaceutical composition, a) 200 mg to 1800 mg of N-acylethanolamine or its salt; b) 250 mg to 1550 mg of N-acylethanolamine or its salt; c) 300 mg to 1200 mg of N-acylethanolamine or a salt thereof; d) 350 mg to 950 mg of N-acylethanolamine or its salt; e) 400 mg to 700 mg of N-acylethanolamine or a salt thereof; or f) 450 mg to 600 mg of N-acylethanolamine or its salt A pharmaceutical composition according to claim 1, comprising:

10. A pharmaceutical composition, a) 50 mg of N-acylethanolamine or a salt thereof; b) 100 mg of N-acylethanolamine or a salt thereof; c) 150 mg of N-acylethanolamine or a salt thereof; d) 200 mg of N-acylethanolamine or a salt thereof; e) 250 mg of N-acylethanolamine or a salt thereof; f) 400 mg of N-acylethanolamine or its salt; g) 500 mg of N-acylethanolamine or its salt; h) 750 mg of N-acylethanolamine or a salt thereof; i) 800 mg of N-acylethanolamine or a salt thereof; j) 1000 mg of N-acylethanolamine or a salt thereof; or k) 1500 mg of N-acylethanolamine or its salt A pharmaceutical composition according to claim 1, comprising:

11. The pharmaceutical composition according to claim 1, wherein the N-acylethanolamine or a salt thereof is selected from the group consisting of N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), and any combination thereof.

12. The pharmaceutical composition according to claim 1, wherein the N-acylethanolamine or its salt is N-palmitoylethanolamine (PEA).

13. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is formulated for oral administration, oral mucosal administration, nasal administration, sublingual administration, inhalation administration, topical administration, rectal administration, vaginal administration, non-enteral administration, intravenous administration, intramuscular administration, or subcutaneous administration.

14. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is formulated for oral administration.

15. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is formulated for administration once a day, twice a day, or three times a day.

16. A pharmaceutical agent for regulating impulsive behavior, comprising 5-methoxy-2-aminoindan (MEAI) or a salt thereof and N-acylethanolamine or a salt thereof.

17. The pharmacopoeia according to claim 16, wherein the impulsive behavior is related to drinking, eating, smoking, shopping, or sexual activity.

18. The pharmaceutical product according to claim 16, wherein the impulsive behavior is impulsive drinking.

19. The pharmaceutical product according to claim 16, further comprising at least one pharmaceutically acceptable carrier and / or additive.

20. The pharmaceutical product according to claim 16, which is a free-flowing powder, tablet, capsule, lozenge, liquid, liquid concentrate, or syrup.

21. The pharmaceutical composition according to claim 16, which is a unit dosage form composition.

22. The pharmaceutical product according to claim 16, comprising 30 mg to 130 mg of MEAI or a salt thereof.

23. The pharmaceutical product according to claim 16, comprising 70 mg of MEAI or a salt thereof.

24. The pharmaceutical product according to claim 16, wherein MEAI or a salt thereof and N-acylethanolamine or a salt thereof are present in a molar ratio of 1:0.2 to 1:2000.

25. a) 200 mg to 1800 mg of N-acylethanolamine or a salt thereof; b) 250 mg to 1550 mg of N-acylethanolamine or its salt; c) 300 mg to 1200 mg of N-acylethanolamine or a salt thereof; d) 350 mg to 950 mg of N-acylethanolamine or its salt; e) 400 mg to 700 mg of N-acylethanolamine or a salt thereof; or f) 450 mg to 600 mg of N-acylethanolamine or its salt The pharmaceutical product according to claim 16, including the above.

26. a) 50 mg of N-acylethanolamine or a salt thereof; b) 100 mg of N-acylethanolamine or a salt thereof; c) 150 mg of N-acylethanolamine or a salt thereof; d) 200 mg of N-acylethanolamine or a salt thereof; e) 250 mg of N-acylethanolamine or a salt thereof; f) 400 mg of N-acylethanolamine or its salt; g) 500 mg of N-acylethanolamine or its salt; h) 750 mg of N-acylethanolamine or a salt thereof; i) 800 mg of N-acylethanolamine or a salt thereof; j) 1000 mg of N-acylethanolamine or a salt thereof; or k) 1500 mg of N-acylethanolamine or its salt The pharmaceutical product according to claim 16, including the above.

27. ​​The pharmaceutical product according to claim 16, wherein the N-acylethanolamine or a salt thereof is selected from the group consisting of N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA), and any combination thereof.

28. The pharmaceutical product according to claim 16, wherein the N-acylethanolamine or its salt is N-palmitoylethanolamine (PEA).

29. The pharmaceutical product according to claim 16, formulated for oral administration, oral mucosal administration, nasal administration, sublingual administration, inhalation administration, local administration, rectal administration, vaginal administration, non-enteral administration, intravenous administration, intramuscular administration, or subcutaneous administration.

30. The pharmaceutical product according to claim 16, formulated for oral administration.

31. The pharmaceutical product according to claim 16, which is formulated for administration once a day, twice a day, or three times a day.

32. A pharmaceutical agent for increasing the palatability of water intake compared to alcohol intake, or for increasing the amount of water intake, comprising 5-methoxy-2-aminoindan (MEAI) or a salt thereof and N-acylethanolamine or a salt thereof.

33. A pharmaceutical agent for increasing the palatability of water intake compared to alcohol intake, or for increasing the amount of water intake, comprising 5-methoxy-2-aminoindan (MEAI) or a salt thereof.

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