Use of 5-Methoxy-2-Aminoindane (“MEAI”) in a Method for Treating Cocaine Addiction

Abstract

The present disclosure relates to a method of treating cocaine intoxication by administering 5-methoxy-2-aminoindane or a salt thereof in a therapeutically effective amount to a subject in need thereof. The present disclosure also relates to a method of treating cocaine intoxication by administering 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof and an N-acylethanolamine or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to a subject in need thereof.

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority to U.S. Provisional Patent Application 63 / 365,627, filed Jun. 1, 2022, the entire content of which is incorporated herein by reference.

[0002] Field of the disclosure In some embodiments, the present invention relates to a method of treating cocaine addiction by administering a therapeutically effective amount of 5-methoxy-2-aminoindane (“MEAI”). In certain other embodiments, the treatment method includes administering MEAI in combination with an N-acylethanolamine, such as palmitoylethanolamide (“PEA”).

Background Art

[0003] Background of the disclosure Cocaine enhances the activity of monoamine neurotransmitters (dopamine, norepinephrine, serotonin) in the central and peripheral nervous systems by blocking the presynaptic reuptake pumps (transporters) of these neurotransmitters. The major synaptic effects of cocaine are the release of dopamine from synaptic vesicles and the blockade of dopamine reuptake, resulting in enhanced dopaminergic neurotransmission. Thus, cocaine addiction is referred to as a disorder of the brain's dopamine reward system. Cocaine also has a second action of blocking voltage-dependent membrane sodium ion channels. This action explains the local anesthetic effect and may contribute to cardiac arrhythmias. https: / / www.sciencedirect.com / topics / agricultural-and-biological-sciences / cocaine#:~:text=The%20major%20synaptic%20effect%20of,the%20brain's%20dopamine%20reward%20system.

[0004] In 2017, it was estimated that approximately 0.9% of the world's population suffered from drug use (excluding alcohol) disorders. The global prevalence trend is shown in the graph. At the national level, this prevalence ranged from 0.4% to 3.5%. The highest prevalence was in the United States, where in 2017, approximately 1 in 30 people had drug use disorders. Looking at these trends by age, globally, adults in their 20s are most likely to have drug use disorders, with over 2% (1 in 50) of those aged 20 - 29 having drug use disorders. In the United States, in 2017, 8 - 9% of adults in the early 20s had drug use disorders. This is a rate of 1 in 11 or 1 in 12. It is estimated that globally, approximately 71 million people had drug use disorders in 2017. The main groups of illicit drugs used in international statistics are opioids, cocaine, amphetamines, and cannabis. https: / / ourworldindata.org / illicit-drug-use

[0005] Compounds derived from 2 - aminoindane have been shown to selectively bind to the dopamine D3 receptor. U.S. Patent No. 5,708,018 discloses several 2 - aminoindane derivatives, and the hypothesis is presented that these 2 - aminoindane derivatives are useful in the treatment of CNS disorders related to the dopamine D3 receptor. One such compound is 5 - methoxy - 2 - aminoindane ("MEAI").

[0006] N-acylethanolamine (NAE) is a lipid-derived signaling molecule. N-acylethanolamine (NAE) is formed by the binding of one of several acyl groups to the nitrogen atom in ethanolamine. Examples of N-acylethanolamine include anandamide (amide of arachidonic acid (20:4 omega-6) and ethanolamine), N-palmitoylethanolamine (amide of palmitic acid (16:0) and ethanolamine), N-oleoylethanolamine (amide of oleic acid (oleic acid (18:1) and ethanolamine), N-stearoylethanolamine (amide of stearic acid (18:0) and ethanolamine) and N-docosahexaenoylethanolamine (amide of docosahexaenoic acid (22:6) and ethanolamine).

[0007] Palmitoylethanolamide (PEA, also known as N-(2-hydroxyethyl)hexadecanamide, hydroxyethyl palmitamide, palmidrol, N-palmitoylethanolamine and palmitylethanolamine) is an endogenous fatty acid amide and belongs to a class of nuclear factor agonists. PEA has been demonstrated to bind to receptors in the cell nucleus (nuclear receptors) and exert various biological functions related to chronic pain and inflammation. Studies have shown that PEA interacts with different non-CB1 / CB2 receptors, suggesting that PEA utilizes a unique "parallel" endocannabinoid signaling system. This concept has been further supported by increasing 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 are due to its affinity for PPAR (especially PPAR-α and PPAR-γ). PEA has been shown to have an affinity for the cannabinoid-like G-coupled receptors GPR55 and GPR119 as well as the transient receptor potential vanilloid type 1 receptor (TRPV1). PEA has been shown to have anti-inflammatory, antinociceptive, neuroprotective and antiepileptic properties.

Summary of the Invention

[0008] Summary of the disclosure In some embodiments, a method of treating cocaine addiction, comprising administering to a subject in need thereof a therapeutically acceptable amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof, thereby treating cocaine addiction, is provided.

[0009] In certain embodiments, the 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is administered as a daily dose of about 25 mg to about 100 mg. In other embodiments, the 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is administered as a daily dose of about 21 mg to about 84 mg. In yet other embodiments, the 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is administered as a daily dose of about 21 mg to about 100 mg, about 25 mg to about 90 mg, about 30 mg to about 80 mg, about 40 mg to about 70 mg or about 50 mg to about 60 mg.

[0010] In some embodiments, the daily dose is administered as a single dose or divided doses more than once. In other embodiments, the 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is administered twice daily.

[0011] In other embodiments, the therapeutically effective amount of 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof comprises about 0.36 mg to about 1.4 mg / kg body weight / day, about 0.5 mg to about 1.3 mg / kg body weight / day, about 0.6 mg to about 1.2 mg / kg body weight / day, about 0.7 mg to about 1.1 mg / kg body weight / day or about 0.8 mg to about 1.0 mg / kg body weight / day.

[0012] In certain embodiments, the cocaine addiction is withdrawal symptoms after cocaine withdrawal.

[0013] In some embodiments, the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and / or excipient. In certain embodiments, the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, solution, stock solution, suspension or syrup.

[0014] In other embodiments, the pharmaceutical composition is a composition in unit dosage form. In certain embodiments, the amount of 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof in the unit dosage form is about 21 mg to about 100 mg, about 25 mg to about 90 mg, about 30 mg to about 80 mg, about 40 mg to about 70 mg or about 50 mg to about 60 mg. In certain embodiments, the amount of said 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is about 50 mg.

[0015] In some embodiments, administration of the pharmaceutical composition is by oral administration, sublingual administration, buccal administration, intravaginal administration, rectal administration, parenteral administration, transdermal administration, or administration by inhalation. In certain embodiments, parenteral administration is intravenous administration, intramuscular administration or subcutaneous administration.

[0016] In some embodiments, treating cocaine addiction attenuates the craving for cocaine.

[0017] Other embodiments relate to the use of a pharmaceutical composition comprising 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof for treating cocaine addiction as described in any of the foregoing embodiments.

[0018] In some embodiments, a method of reducing the likelihood of recurrence of cocaine addiction, the method comprising administering to a subject in need thereof a therapeutically acceptable amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof, thereby reducing the likelihood of recurrence of cocaine addiction.

[0019] In certain embodiments, 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is administered as a daily dose of about 25 mg to about 100 mg. In other embodiments, 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is administered as a daily dose of about 21 mg to about 84 mg. In still other embodiments, 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is administered as a daily dose of about 21 mg to about 100 mg, about 25 mg to about 90 mg, about 30 mg to about 80 mg, about 40 mg to about 70 mg, or about 50 mg to about 60 mg.

[0020] In some embodiments, the daily dose is administered as a single dose or as divided doses more than once. In other embodiments, 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is administered twice daily.

[0021] In other embodiments, the therapeutically effective amount of 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof includes about 0.36 mg to about 1.4 mg / kg body weight / day, about 0.5 mg to about 1.3 mg / kg body weight / day, about 0.6 mg to about 1.2 mg / kg body weight / day, about 0.7 mg to about 1.1 mg / kg body weight / day, or about 0.8 mg to about 1.0 mg / kg body weight / day.

[0022] In certain embodiments, the cocaine intoxication is withdrawal symptoms after cocaine withdrawal.

[0023] In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient. In certain embodiments, the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, solution, stock solution, suspension, or syrup.

[0024] In other embodiments, the pharmaceutical composition is a unit dosage form composition. In certain embodiments, the amount of 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof in the unit dosage form is about 21 mg to about 100 mg, about 25 mg to about 90 mg, about 30 mg to about 80 mg, about 40 mg to about 70 mg, or about 50 mg to about 60 mg. In certain embodiments, the amount of the 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is about 50 mg.

[0025] In some embodiments, the administration of the pharmaceutical composition is by oral administration, sublingual administration, buccal administration, intravaginal administration, rectal administration, parenteral administration, transdermal administration, or administration by inhalation. In certain embodiments, parenteral administration is intravenous administration, intramuscular administration, or subcutaneous administration.

[0026] Other embodiments relate to the use of a pharmaceutical composition comprising 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof for reducing the likelihood of relapse of cocaine addiction as described in claims 18-32.

[0027] In some embodiments, there is provided a method of treating cocaine addiction, comprising administering to a subject in need thereof a therapeutically acceptable amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof and an N-acylethanolamine or a pharmaceutically acceptable salt thereof, thereby treating cocaine addiction.

[0028] In certain embodiments, 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is administered as a daily dose of about 25 mg to about 100 mg. In other embodiments, 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is administered as a daily dose of about 21 mg to about 84 mg. In still other embodiments, 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is administered as a daily dose of about 21 mg to about 100 mg, about 25 mg to about 90 mg, about 30 mg to about 80 mg, about 40 mg to about 70 mg, or about 50 mg to about 60 mg.

[0029] In some embodiments, the daily dose is administered as a single dose or as divided doses more than once. In other embodiments, 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is administered twice daily.

[0030] In other embodiments, the therapeutically effective amount of 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof includes from about 0.36 mg to about 1.4 mg / kg body weight / day, from about 0.5 mg to about 1.3 mg / kg body weight / day, from about 0.6 mg to about 1.2 mg / kg body weight / day, from about 0.7 mg to about 1.1 mg / kg body weight / day, or from about 0.8 mg to about 1.0 mg / kg body weight / day.

[0031] In certain embodiments, cocaine addiction is a withdrawal symptom after cocaine withdrawal.

[0032] In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient. In certain embodiments, the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, solution, stock solution, suspension or syrup.

[0033] In other embodiments, the pharmaceutical composition is a unit dosage form composition. In certain embodiments, the amount of 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof in the unit dosage form is from about 21 mg to about 100 mg, from about 25 mg to about 90 mg, from about 30 mg to about 80 mg, from about 40 mg to about 70 mg, or from about 50 mg to about 60 mg. In certain embodiments, the amount of the 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is about 50 mg.

[0034] In some embodiments, administration of the pharmaceutical composition is by oral administration, sublingual administration, buccal administration, intravaginal administration, rectal administration, parenteral administration, transdermal administration, or administration by inhalation. In certain embodiments, parenteral administration is intravenous administration, intramuscular administration or subcutaneous administration.

[0035] In some embodiments, the N-acylethanolamine is palmitoylethanolamide or a pharmaceutically acceptable salt thereof. In certain embodiments, the N-acylethanolamine or a pharmaceutically acceptable salt thereof is administered as a daily dose of about 200 mg to about 1800 mg, about 250 mg to about 1550 mg, about 300 mg to about 1200 mg, about 350 mg to about 950 mg, about 400 mg to about 700 mg, about 450 mg to about 600 mg, or about 500 mg to about 550 mg.

[0036] In some embodiments, treating cocaine addiction attenuates the craving for cocaine.

[0037] Other embodiments relate to the use of a pharmaceutical composition comprising 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof and palmitoylethanolamide or a pharmaceutically acceptable salt thereof for treating cocaine addiction as described in any of the foregoing embodiments.

[0038] In some embodiments, a method of reducing the likelihood of recurrence of cocaine addiction, comprising administering to a subject in need thereof a therapeutically acceptable amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof, thereby reducing the likelihood of recurrence of cocaine addiction.

[0039] In certain embodiments, 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is administered as a daily dose of about 25 mg to about 100 mg. In other embodiments, 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is administered as a daily dose of about 21 mg to about 84 mg. In yet other embodiments, 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is administered as a daily dose of about 21 mg to about 100 mg, about 25 mg to about 90 mg, about 30 mg to about 80 mg, about 40 mg to about 70 mg, or about 50 mg to about 60 mg.

[0040] In some embodiments, the daily dose is administered as a single dose or divided doses more than once. In other embodiments, 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is administered twice daily.

[0041] In other embodiments, the therapeutically effective amount of 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof includes from about 0.36 mg to about 1.4 mg / kg body weight / day, from about 0.5 mg to about 1.3 mg / kg body weight / day, from about 0.6 mg to about 1.2 mg / kg body weight / day, from about 0.7 mg to about 1.1 mg / kg body weight / day or from about 0.8 mg to about 1.0 mg / kg body weight / day.

[0042] In certain embodiments, the cocaine addiction is withdrawal symptoms after cocaine withdrawal.

[0043] In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient. In certain embodiments, the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, solution, stock solution, suspension or syrup.

[0044] In other embodiments, the pharmaceutical composition is a unit dosage form composition. In certain embodiments, the amount of 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof in the unit dosage form is from about 21 mg to about 100 mg, from about 25 mg to about 90 mg, from about 30 mg to about 80 mg, from about 40 mg to about 70 mg or from about 50 mg to about 60 mg. In certain embodiments, the amount of the 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof is about 50 mg.

[0045] In some embodiments, the administration of the pharmaceutical composition is by oral administration, sublingual administration, buccal administration, intravaginal administration, rectal administration, parenteral administration, transdermal administration, or administration by inhalation. In certain embodiments, parenteral administration is intravenous administration, intramuscular administration or subcutaneous administration.

[0046] In some embodiments, the N-acylethanolamine is palmitoylethanolamide or a pharmaceutically acceptable salt thereof. In certain embodiments, the N-acylethanolamine or a pharmaceutically acceptable salt thereof is administered as a daily dose of about 200 mg to about 1800 mg, about 250 mg to about 1550 mg, about 300 mg to about 1200 mg, about 350 mg to about 950 mg, about 400 mg to about 700 mg, about 450 mg to about 600 mg, or about 500 mg to about 550 mg.

[0047] Other embodiments relate to the use of a pharmaceutical composition comprising 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof and an N-acylethanolamine or a pharmaceutically acceptable salt thereof for reducing the likelihood of relapse of cocaine addiction as claimed in claims 53 to 69. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] The foregoing summary, as well as the following detailed description of the disclosure, will be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the disclosure, the accompanying drawings show some, but not all, alternative embodiments. However, it should be understood that the disclosure is not limited to the exact arrangements and instrumentalities shown. These figures, which are incorporated herein and constitute a part of this specification, serve to explain the principles of the disclosure.

[0049]

Figure 1

[0050]

Figure 2

[0051] DETAILED DESCRIPTION OF THE DISCLOSURE In some embodiments, the present invention relates to cocaine addiction, and more particularly, but not exclusively, to a method of treating cocaine addiction, comprising administering to a subject in need thereof a therapeutically effective amount of MEAI or a pharmaceutically acceptable salt thereof. In other embodiments, the present disclosure provides a method of reducing the likelihood of relapse of cocaine addiction, comprising administering to a subject in need thereof a therapeutically acceptable amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof.

[0052] The present disclosure provides a method of treating cocaine addiction, comprising administering to a subject in need thereof a therapeutically effective amount of MEAI or a physiologically acceptable salt thereof, and an N-acylethanolamine or a pharmaceutically acceptable salt thereof. In other embodiments, the present disclosure provides a method of reducing the likelihood of relapse of cocaine addiction, comprising administering to a subject in need thereof a therapeutically acceptable amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindane or a pharmaceutically acceptable salt thereof and an N-acylethanolamine or a physiologically acceptable salt thereof. In some embodiments, the N-acylethanolamine is PEA.

[0053] Definitions: "Isomer" means a compound that has the same number and type of atoms, and thus the same molecular weight, but differs with respect to the arrangement or configuration of the atoms in space.

[0054] "Stereoisomers" or "optical isomers" mean stable isomers that have at least one chiral atom or restricted rotation that gives rise to a perpendicular plane of asymmetry (e.g., certain biphenyls, allenes, 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 give rise to stereoisomerism, the present disclosure contemplates stereoisomers and mixtures thereof. The compounds of the present disclosure and their salts contain chiral carbon atoms and can thus exist as single stereoisomers, racemates, and mixtures of enantiomers and diastereomers. Typically, such compounds are 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 detailed below, the individual stereoisomers of the compounds can be separated or resolved, such as by separation or recrystallization, chromatographic techniques, use of chiral separating agents, or direct separation of enantiomers on a chiral chromatography column, following synthesis from an optically active starting material containing the desired chiral center or following conversion of a mixture of enantiomeric products to a mixture of diastereomers. Specific stereochemical starting compounds are commercially available or are prepared by the methods described below and separated by techniques well known in the art.

[0055] It is well known in the art that the biological and pharmacological activities of a compound are sensitive to the compound's stereochemistry. Thus, for example, enantiomers often exhibit significantly different biological activities, including differences in pharmacokinetic properties such as metabolism, protein binding, etc., and pharmacological properties such as the type of activity exhibited, the degree of activity, toxicity, etc. Accordingly, one of ordinary skill in the art would understand that if one enantiomer is enriched or separated from the other enantiomer, it may be more active or exhibit beneficial effects. Further, one of ordinary skill in the art would know methods for separating, enriching, or selectively preparing the enantiomers of the compounds of the present disclosure from the knowledge of the present disclosure and the prior art.

[0056] Thus, while racemic drugs can be used, they are often less effective than administering the drug as a pure enantiomer in the same amount. In fact, in some cases, one of the enantiomers may be pharmacologically inactive and function only as a diluent. For example, ibuprofen was previously administered as a racemate, but only the S-isomer of ibuprofen has been shown to be effective as an anti-inflammatory agent (however, in the case of ibuprofen, the R-isomer is inactive but is converted to the S-isomer in vivo, so the rate of action of the racemic drug is inferior to that of the pure S-isomer). Further, the pharmacological activities of enantiomers may have different biological activities. For example, S-penicillamine is a therapeutic agent for chronic arthritis, while R-penicillamine is toxic. In fact, some purified enantiomers are more advantageous than the racemate, as reported that the transdermal penetration rate of the purified individual isomers is 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 the (S)-isomer and the (R)-isomer. In other embodiments, provided herein are mixtures of compounds in which the individual compounds of the mixture predominantly exist in the (S)-isomer or (R)-isomer configuration. For example, the mixture of compounds 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 more. In other embodiments, the mixture of compounds has an (S)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to about 99.5%, greater than about 99% to about 99.5%, or more. In other embodiments, the mixture of compounds 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 more. In some other embodiments, the mixture of compounds 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 more.

[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 can be prepared by using resolution methods well known to those skilled in the art following the preparation of a racemic mixture. These resolution methods are exemplified as follows: (1) attaching a 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 salts using an optically active resolving agent; or (3) directly separating a mixture of optical enantiomers on a chiral chromatography 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, methods of crystallizing the compound as a chiral salt complex, methods of crystallizing the compound in a chiral solvent, etc. Stereoisomers can also be obtained from stereoisomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthesis methods.

[0059] Thus, if one enantiomer is more pharmacologically active, less toxic, or has more favorable pharmacokinetics than the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially. By doing so, the patient being treated is exposed to a lower total dose of the drug and a lower dose of the potentially toxic enantiomer or an inhibitor of the other enantiomer.

[0060] As used herein, the nomenclature of compounds containing organic compounds can be given using common names, IUPAC, IUBMB, or CAS recommendations regarding nomenclature. Those skilled in the art can readily confirm the structure of a compound by using the naming rules to systematically reduce the compound structure or by using commercially available software such as TM (Cambridgesoft Corporation, U.S.A.) to give a name. The chemical names were generated using PerkinElmer ChemDraw® Professional version 17.

[0061] The compounds of the present disclosure may contain one or more chiral centers and / or double bonds and thus 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 by the symbols "R" or "S" depending on the arrangement of the substituents around the stereogenic carbon atoms. The present disclosure encompasses the various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. A mixture of enantiomers or diastereomers may be designated as "(±)" in the nomenclature, but those skilled in the art will recognize that the structure may implicitly indicate a chiral center. In some embodiments, the enantiomers or stereoisomers may be provided substantially free of the corresponding enantiomers.

[0062] In one aspect, the present invention 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.

[0063] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a mixture of MEAI or a salt thereof and at least one N-acylethanolamine or a salt thereof, wherein the molar ratio between MEAI and N-acylethanolamine is from about 1:0.2 to about 1:2000.

[0064] As used herein, the term "pharmaceutical composition" means a preparation of an active agent described herein and other chemical components such as physiologically suitable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism. The expression "pharmaceutically acceptable carrier" as used herein means a carrier, excipient or diluent that does not cause significant irritation to the organism and does not impair the biological activity and properties of the administered compound. Adjuvants are also included in these expressions.

[0065] As used herein, the term "excipient" means an inert substance added to a pharmaceutical composition to facilitate the administration of the active ingredient. By way of example, but not limitation, excipients include calcium carbonate, calcium phosphate, various sugars and various types of starches, cellulose derivatives, gelatin, oils such as vegetable or fish oil, and polyethylene glycol.

[0066] As used herein, the term "carrier" means a diluent, adjuvant, excipient or vehicle with which a compound is administered. Such pharmaceutical carriers can be sterile liquids such as water or oil. Aqueous solutions of water or aqueous solutions of saline, dextrose and glycerol are preferably employed as carriers, especially in the case of injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences", 18th Edition, by E. W. Martin.

[0067] As used herein, the expression "pharmaceutically acceptable" means molecular entities and compositions that are physiologically tolerable and do not normally produce allergic or similar untoward reactions when administered to an individual. Preferably, particularly when the formulation is for use in humans, the term "pharmaceutically acceptable" can mean approved by a regulatory agency (such as the U.S. Food and Drug Administration) or listed in a generally recognized pharmacopoeia (such as the U.S. Pharmacopoeia) for use in animals.

[0068] As used herein, the term "N-acylethanolamine" generally refers to a type of fatty acid amide, a lipid-derived signaling molecule formed by the attachment of one of several acyl groups to the ethanolamine nitrogen atom. Conceptually, these amides are formed by the release of one molecule of water from a fatty acid and ethanolamine, but in known biological synthesis, specific phospholipase D is used to cleave the phospholipid unit from N-acylphosphatidylethanolamine. The suffixes -amine and -amide in these names each refer to the single nitrogen atom in ethanolamine that links the compounds. The reason ethanolamine is called "amine" is that the free terminal nitrogen in its subunit is regarded as such, and it is called "amide" when considered to be linked to the adjacent carbonyl group of the acyl subunit. The names of these compounds may be denoted as either "amide" or "amine" in this application. The term "ethanolamine" is used in its general sense and means to include monoethanolamine, diethanolamine, triethanolamine, and mixtures thereof.

[0069] As used herein, the term "derivative" means a compound whose core structure is the same as or closely resembles an N-acylethanolamine compound, but has chemical or physical modifications such as different or additional side groups.

[0070] As used herein, the term "salt" means any form of the active ingredient in which the active ingredient is in ionic form, either bound to a counterion (cation or anion) or in solution. This includes complexes of the active ingredient with other molecules or ions, particularly complexes complexed by ionic interactions. Pharmaceutically acceptable salts are known to those skilled in the art.

[0071] In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is from about 1:0.2 to about 1:5. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is from about 1:0.22 to about 1:4.5, from about 1:0.25 to about 1:4, from about 1:0.28 to about 1:3.5, from about 1:0.33 to about 1:3, from about 1:0.4 to about 1:2.5, from about 1:0.5 to about 1:2 or about 1:1. Each possibility represents a separate embodiment of the invention.

[0072] In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is from about 1:15 to about 1:1800. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is from about 1:16 to about 1:1700, from about 1:17 to about 1:1600, from about 1:18 to about 1:1500, from about 1:19 to about 1:1400, from about 1:20 to about 1:1300, from about 1:21 to about 1:1200, from about 1:22 to about 1:1100, from about 1:23 to about 1:1000, from about 1:24 to about 1:900, from about 1:15 to about 1:800, from about 1:16 to about 1:700, from about 1:17 to about 1:600, from about 1:18 to about 1:500, from about 1:19 to about 1:490, from about 1:20 to about 1:480, from about 1:21 to about 1:470 or from about 1:22 to about 1:460. Each possibility represents a separate embodiment of the invention. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is from about 1:25 to about 1:450. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is from about 1:10 to about 1:500, from about 1:15 to about 1:450, from about 1:20 to about 1:400, from about 1:25 to about 1:350, from about 1:30 to about 1:300, from about 1:35 to about 1:250, from about 1:40 to about 1:200 or from about 1:45 to about 1:150. Each possibility represents a separate embodiment of the invention. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is from about 1:50 to about 1:100. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:10. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:20. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:30. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:40. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:50. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:60. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:70.In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:80. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:90. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:100. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:110. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:120. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:130. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:140. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:150. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:160. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:170. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:180. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:190. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:200. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is at least about 1:10, at least about 1:20, at least about 1:30, at least about 1:40, at least about 1:50, at least about 1:60, at least about 1:70, at least about 1:80, at least about 1:90 or at least about 1:100. Each possibility represents a separate embodiment of the invention.

[0073] In certain embodiments, the pharmaceutical composition comprises from about 0.5 mg to 10 mg of MEAI or a salt thereof. In certain embodiments, the pharmaceutical composition comprises from about 1 mg to 9.5 mg, from about 1.5 mg to 9 mg, from about 2 mg to 8.5 mg, from about 2.5 mg to 8 mg, from about 3 mg to 7.5 mg, from about 3.5 mg to 7 mg, from about 4 mg to 6.5 mg, from about 4.5 mg to 6 mg, or from about 5 mg to 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 invention. In certain embodiments, the pharmaceutical composition comprises less than about 0.5 mg, less than about 1 mg, less than about 1.5 mg, less than about 2 mg, less than about 2.5 mg, less than about 3 mg, less than about 3.5 mg, less than about 4 mg, less than about 4.5 mg, less than about 5 mg, less than about 5.5 mg, less than about 6 mg, less than about 6.5 mg, less than about 7 mg, less than about 7.5 mg, less than about 8 mg, less than about 8.5 mg, less than about 9 mg, less than about 9.5 mg, or about 10 mg of MEAI or a salt thereof. Each possibility represents a separate embodiment of the invention. In certain embodiments, the pharmaceutical composition comprises from about 0.5 mg to about 1 mg, from about 0.5 mg to about 1.5 mg, from about 0.5 mg to about 2 mg, from about 0.5 mg to about 2.5 mg, from about 0.5 mg to about 3 mg, from about 0.5 mg to about 3.5 mg, from about 0.5 mg to about 4 mg, from about 0.5 mg to about 4.5 mg, from about 0.5 mg to about 5 mg, from about 0.5 mg to about 5.5 mg, from about 0.5 mg to about 6 mg, from about 0.5 mg to about 6.5 mg, from about 0.5 mg to about 7 mg, from about 0.5 mg to about 7.5 mg, from about 0.5 mg to about 8 mg, from about 0.5 mg to about 8.5 mg, from about 0.5 mg to about 9 mg, or from about 0.5 mg to about 9.5 mg of MEAI or a salt thereof. Each possibility represents a separate embodiment of the invention.

[0074] In certain embodiments, the pharmaceutical composition comprises from about 200 mg to 1800 mg of N-acylethanolamine or a salt thereof. In certain embodiments, the pharmaceutical composition comprises from about 250 mg to 1550 mg, from about 300 mg to 1200 mg, from about 350 mg to 950 mg, from about 400 mg to 700 mg, from about 450 mg to 600 mg, or from about 500 mg to 550 mg of N-acylethanolamine or a salt thereof. Each possibility represents a separate embodiment of the invention. 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 1650 mg, at least about 1700 mg, at least about 1750 mg, or at least about 1800 mg of N-acylethanolamine or a salt thereof.In certain embodiments, the pharmaceutical composition comprises from about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg or about 1800 mg of an N-acylethanolamine or a salt thereof. Each possibility represents a separate embodiment of the invention.

[0075] In certain embodiments, the N-acylethanolamine is N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoyl isopropylamide, oleoylethanolamine (OEA), palmitoyl isopropylamide (PIA), or a salt thereof, or a combination thereof. Each possibility represents a separate embodiment of the invention. In certain embodiments, the N-acylethanolamine is PEA or a salt thereof. In certain embodiments, the N-acylethanolamine consists of PEA or a salt thereof. In certain embodiments, the N-acylethanolamine consists of PEA.

[0076] In certain embodiments, the pharmaceutical composition is formulated for systemic administration. In certain embodiments, the pharmaceutical composition is formulated for oral administration, buccal 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, buccal administration, nasal administration or sublingual administration. Each possibility represents a separate embodiment of the invention. In certain embodiments, the pharmaceutical composition is formulated for oral administration. In certain embodiments, the pharmaceutical composition is formulated for buccal administration. In certain embodiments, the pharmaceutical composition is formulated for nasal administration. In certain embodiments, the pharmaceutical composition is formulated for sublingual administration.

[0077] Techniques for the formulation and administration of drugs are well known in the art and are described, for example, in “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa. The pharmaceutical compositions of the invention can be manufactured by processes well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

[0078] For oral administration, the pharmaceutical composition can be readily formulated by combining the active compound with a pharmaceutically acceptable carrier well-known in the art. Such carriers enable the formulation of the pharmaceutical composition as tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, etc. for oral ingestion by a patient. Pharmacological preparations for oral use can be made using solid excipients, and optionally, the resulting mixture is ground and, if desired, appropriate auxiliaries are added, and then the mixture of granules is processed to obtain cores for tablets or dragees. Suitable excipients include, in particular, fillers such as sugars including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hydroxypropylmethyl-cellulose and sodium carboxymethyl cellulose; and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). Optionally, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts such as sodium alginate may be added.

[0079] The term "oral administration" means any administration method by which the active agent can be administered by swallowing, chewing, sucking or drinking an oral dosage form. Examples of solid dosage forms include conventional tablets, multilayer tablets, capsules, caplets, etc., which do not substantially release the drug in the mouth or oral cavity.

[0080] The cores of dragees are provided with a suitable coating. For this purpose, a concentrated sugar solution which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solution and suitable organic solvents or solvent mixtures can be used. Dyes or pigments can be added to the tablets or the coatings of dragees for identification or to characterize different combinations of the dosage of the active compound.

[0081] Orally administrable pharmaceutical compositions include hard or soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules can 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 can be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin or liquid polyethylene glycol. Additionally, a stabilizer may be added. All formulations for oral administration must be in a dosage suitable for the selected route of administration. In the case of buccal and sublingual administration, the composition can take the form of tablets or lozenges formulated by conventional methods or in an adhesive carrier. Alternatively, the active ingredient may be in the form of a powder for constitution with a suitable vehicle, such as a sterile pyrogen-free aqueous solution, before use.

[0082] Pharmaceutical compositions suitable for use in connection with the present invention include compositions containing the active ingredient in an amount effective to achieve the intended purpose. More specifically, a "therapeutically effective amount" means an amount of the active ingredient effective to prevent, alleviate or improve the symptoms or side effects of a disease or disorder, or to extend the survival period of the subject being treated. Determination of a therapeutically effective amount is well within the ability of those skilled in the art, especially in light of the detailed disclosure provided herein. More specifically, a "therapeutically effective amount of a mixture" means an amount of at least two active ingredients, each of which may not independently be a therapeutically effective amount, or both of which may not be therapeutically effective amounts, but the mixture is nevertheless effective to prevent, alleviate or improve the symptoms or side effects of a disease or disorder, or to extend the survival of the subject being treated. As used herein, the term "mixture" means a non-covalent combination of two molecules.

[0083] For any formulation used in the methods of the present invention, the dosage or therapeutically effective amount can first be estimated from in vitro, in vivo, and cell culture assays. For example, in animal models, dosages can be formulated to achieve the desired concentration or titer. Such information can be used to more accurately determine useful dosages in humans. The dosage of each compound of the required combination depends on several factors, such as the method of administration, the disease being treated, the severity of the disease, whether the disease is being treated or prevented, the age, weight, and health status of the person being treated, etc. Furthermore, pharmacogenomic (the effect of genotype on the pharmacokinetics, pharmacodynamics profile, or efficacy profile of a therapeutic agent) information regarding a particular patient may affect the dosage used. Continuous daily administration may not be required, and the treatment regimen may require periods during which the agent is not administered, or treatment may be administered as needed during acute exacerbation periods. Dosage escalation may or may not be required, and depending on the treatment regimen, a reduction in the dosage of the medication may be necessary. The toxicity and therapeutic efficacy of the active ingredients described herein can be measured by standard pharmaceutical procedures in vitro, in cell culture, or in experimental animals. The data obtained from these in vitro and cell culture assays and animal tests can be used to formulate the dosage range for use in humans. The dosage can vary depending on the dosage form used and the route of administration used. The exact formulation, route of administration, and dosage can be selected by an individual physician taking into account the patient's condition (see, e.g., Fingl, E. et al. (1975), “The Pharmacological Basis of Therapeutics,” Ch. 1, p. 1). Depending on the severity and responsiveness of the condition being treated, administration can be a single or multiple administrations over the course of treatment, which can last from several days to several weeks, or until cure is achieved or a reduction in the disease state is achieved.

[0084] In another aspect, the present invention further provides dosage units comprising or consisting of the above pharmaceutical composition.

[0085] In certain embodiments, the dosage unit comprises the pharmaceutical composition. In certain embodiments, the dosage unit consists of the pharmaceutical composition. In certain embodiments, the dosage unit is formulated as a gel, powder, or spray. In certain embodiments, the dosage unit is formulated as a gel. In certain embodiments, the dosage unit is formulated as a powder. In certain embodiments, the dosage unit is formulated as a spray.

[0086] The present invention further provides, in another aspect, the pharmaceutical composition or dosage unit for use in a method of preventing or treating a condition that is susceptible to prevention or treatment by at least one MEAI.

[0087] As used herein, the term "treating" includes, but is not limited to, any one or more of suppressing, ameliorating, inhibiting, attenuating, blocking, suppressing, reducing, delaying, stopping, alleviating, or preventing one or more symptoms or side effects of a disease or condition of the present invention.

[0088] The term "acute" means a condition that follows a severe course over a relatively short period.

[0089] As used herein, the term "chronic" means that the duration of a disease or condition of the present invention is weeks, months, or in some cases, years. The intensity of the disease or condition can vary depending on various conditions such as the patient's age, temperature, season, type of disease, etc.

[0090] As used herein, the term "about" when used in relation to a value, a plurality of 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, plurality of 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".

[0091] The terms "comprises", "comprising", "includes", "including", "having" and their conjugates mean "including but not limited to...".

[0092] The term "consisting of..." means "including and limited to...".

[0093] The term "consisting essentially of..." means that a composition, method or microcapsule may contain additional components, steps and / or parts, but only if the additional components, steps and / or parts do not substantially change the basic and novel properties of the required composition, method or structure.

[0094] As used herein, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "compound" or "at least one compound" can include a plurality of compounds including mixtures thereof.

[0095] Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine LD 50 (50% lethal dose of the population) and ED 50 (therapeutically effective dose for 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, and can be expressed as the ratio of LD 50 / ED 50 . Compositions showing a large therapeutic index are preferred.

[0096] Data obtained from cell culture assays or animal tests can be used when formulating in the dosage range for use in humans. Therapeutically effective doses achieved in one animal model can be converted for use in another animal, including humans, using conversion factors known in the art (see, for example, Freireich et al., Cancer Chemother. Reports 50(4):219 - 244 (1966) and the following table regarding equivalent surface area dosing factors).

Table 1

[0097] The dosage of such compounds preferably lies within the range of circulating concentrations that have little or no toxicity and include an ED 50 This dosage can vary within this range depending on the dosage form used and the route of administration utilized. Generally, the therapeutically effective amount can vary depending on the age, condition, and sex of the subject and the severity of the subject's medical condition. The dosage is determined by a physician and can be adjusted as needed in accordance with the observed therapeutic effect.

[0098] One of ordinary skill in the art will recognize that both in vivo and in vitro tests using appropriate, well - known, and generally accepted cell and / or animal models can predict the ability of a test compound to treat or prevent a given disorder.

[0099] One of ordinary skill in the art will further recognize that human clinical trials, including first - in - human dosage range and efficacy testing in healthy patients and / or patients suffering from a given disorder, can be completed according to methods well - known in the clinical and medical arts.

[0100] Although the present invention has been described with reference to specific embodiments, it will be understood by those skilled in the art that various changes can be made and equivalents can be substituted without departing from the scope of the present invention. Furthermore, many changes can be made to adapt a particular situation or material to the teachings of the present invention without departing from its scope. Accordingly, the present invention is not intended to be limited to the specific embodiments disclosed, but is intended to cover all embodiments falling within the scope of the appended claims.

[0101] The following examples are presented to more fully illustrate some embodiments of the present invention. However, these should in no way be construed as limiting the broad scope of the present invention.

Example

[0102] Example 1: Description of MEAI as an Anti-Reward / Addiction-Like Agent To examine the anti-reward effect of MEAI, rats in the conditioned place preference (CPP) model were used to find a dose that does not cause reward or intoxication. In this model, if a drug is rewarding, the rats will show a preference for spending time in the compartment where the drug was administered on each conditioning day. If MEAI is a non-rewarding agent, the rats are expected not to prefer the compartment associated with MEAI.

[0103] Two groups were tested: one group was administered MEAI (at four different doses), and the second group was administered cocaine on each conditioning day. Additionally, a portion of the rats administered cocaine were treated with MEAI on the test day to determine whether MEAI has a therapeutic-like effect.

[0104] In the CPP assay, rats were trained to associate a reward with an environmental cue. Two groups of rats were allowed to freely move from a striped compartment to a smooth compartment in a closed arena for 20 minutes during a 3-day baseline period. Time was measured to determine which compartment the rats spent more time in (i.e., preferred). Baseline data were determined as the average time spent in each compartment. After the baseline period, a 5-day training period was established where rats were injected with saline (I.P.) in the morning and placed in the preferred compartment for 20 minutes. Four hours after the saline injection, cocaine (15 mg / kg I.P.) or MEAI (4 doses; 20 mg / kg, 10 mg / kg, 5 mg / kg, and 2.5 mg / kg I.P.) was injected and the rats were placed in the less preferred compartment for 20 minutes. On day 6, a CPP test was performed (similar to the baseline period) to examine whether MEAI produced a reward-like effect similar to cocaine. The duration spent in each compartment was calculated as the difference (in seconds) between the baseline time and the test time as described above.

[0105] Description of MEAI as an anti-reward / anti-drug-like agent In the first part of this study, it was examined whether administration of four different doses of MEAI affected the reward.

[0106] The test was started with MEAI at 20 mg / kg. At this dose, 65.7% of the rats showed side effects such as restlessness, aggression, piloerection, tremors, low posture, diarrhea, and secretion of "vaginal plugs". Rats administered this dose showed a short time (seconds) in a non-preferred location indicating low reward. Due to such side effects, it was decided to test MEAI at a low dose rather than a high dose. Therefore, the next dose tested was 10 mg / kg of MEAI. Side effects such as restlessness, aggression, piloerection, tremors, low posture, diarrhea, and secretion of "vaginal plugs" were observed in 51% of the rats administered this dose. Although not statistically significant compared to the 20 mg / kg dose, there was a tendency for symptoms to improve. At this dose, the time spent in the non-preferred location was longer, indicating a rewarding effect. Based on these results, 5 mg / kg and 2.5 mg / kg were selected as the next two doses. Side effects were shown in 20.2% of the rats at the 5 mg / kg dose and in 21.4% of the rats at the 2.5 mg / kg dose, and the side effects were restlessness, diarrhea, and secretion of "vaginal plugs". At these two doses, the time spent in the non-preferred location was negative, indicating a counter-rewarding effect. Overall, the most negative average value was at the 5 mg / kg dose, so it was decided to test the effectiveness of this dose as a treatment for cocaine preference in rats.

[0107] Figure 1 shows the results of the CPP assay. The Y-axis indicates the time spent in the less preferred compartment during the baseline test. Behavioral data were analyzed by ordinary one-way analysis of variance. Data are represented as mean ± SEM, and a p-value of ****p < 0.0001 was considered significant. n = 5 - 14 rats / group

[0108] Testing of MEAI as a treatment for cocaine preference in rats Based on previous results, since there was a satisfactory anti-reward effect, 5 mg / kg of MEAI was selected as the treatment dose. Twelve rats were conditioned with cocaine (15 mg / kg), and on the test day, MEAI (5 mg / kg i.p.) was injected, and then they were allowed to wait in the home cage for 10 minutes. Next, the treated rats were placed in the central compartment of the arena for the test. The results were variable. That is, there were rats showing preference for the non-preferred compartment (negative values) and rats still preferring the baseline preferred compartment (positive values). The K-cluster test was used to determine whether two different groups within the group could be statistically significantly separated.

[0109] The two groups were divided as values less than 100 seconds (MEAI A) and values greater than 100 seconds (MEAI B) in the non-preferred compartment. Next, the high dose (10 mg / kg i.p.) was considered, and it was decided to investigate whether the high dose (10 mg / kg i.p.) was a more effective treatment option. As can be seen in Figure 2, 5 mg / kg of MEAI resulted in better results in reducing the reward. The Y-axis in Figure 2 represents the time spent in the less preferred compartment during the baseline test. The behavioral data were analyzed by ordinary one-way analysis of variance. The data are presented as mean ± SEM, and a probability value of *p < 0.001 was considered significant. n = 5 - 12 rats / group

[0110] Using the K-cluster method, the MEAI (5 mg / kg) values were divided into two different groups. MEAI A represents values less than 100 (seconds), and MEAI B represents values greater than 100 (seconds).

[0111] Many features and advantages of the present disclosure are apparent from the detailed description, and thus, it is intended that the appended claims cover all such features and advantages of the present disclosure that fall within the true spirit and scope of the present disclosure. Further, since numerous modifications and variations will readily occur to those skilled in the art, it is not desired to limit the present disclosure to the exact structures and operations illustrated and described, and thus, reliance can be placed on all suitable modifications and equivalents that fall within the scope of the present disclosure.

[0112] Furthermore, those skilled in the art will understand that the inventive concept underlying the present disclosure can be readily used as a basis for designing other structures, methods, and systems for carrying out some of the objectives of the present disclosure. Accordingly, the claims are not to be regarded as limited by the foregoing description or examples.

Claims

1. A pharmaceutical composition for treating cocaine addiction, comprising a therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition for reducing the likelihood of relapse of cocaine addiction, comprising a therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition for treating cocaine addiction, comprising a therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of N-acylethanolamine or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition for reducing the likelihood of relapse of cocaine addiction, comprising a therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of N-acylethanolamine or a pharmaceutically acceptable salt thereof.

5. 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof a) 25 mg to 100 mg; b) 21 mg to 84 mg; c) 21 mg to 100 mg; d) 25 mg to 90 mg; e) 30 mg to 80 mg; f) 40 mg to 70 mg; or g) 50mg to 60mg A pharmaceutical composition according to any one of claims 1 to 4, formulated for administration as a daily dose.

6. The pharmaceutical composition according to claim 5, wherein the daily dose is formulated for single administration or for more than one divided dose.

7. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is formulated for administration twice a day.

8. A therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof a) 0.36 mg / kg body weight / day to 1.4 mg / kg body weight / day; b)0.5mg / kg body weight / day to 1.3mg / kg body weight / day; c) 0.6 mg / kg body weight / day to 1.2 mg / kg body weight / day; d) 0.7 mg / kg body weight / day to 1.1 mg / kg body weight / day; or e) A pharmaceutical composition according to any one of claims 1 to 4, comprising 0.8 mg / kg body weight / day to 1.0 mg / kg body weight / day.

9. To treat cocaine addiction or reduce the likelihood of relapse of cocaine addiction, a) Treating withdrawal symptoms after cocaine withdrawal; b) to reduce cravings for cocaine; or c) Reduce the reward effect induced by cocaine. The pharmaceutical composition according to any one of claims 1 to 4.

10. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a stock solution, a suspension, or a syrup.

12. The pharmaceutical composition is a composition in unit dosage form; The amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof in a unit dosage form is a) 25 mg to 100 mg; b) 21 mg to 84 mg; c) 21 mg to 100 mg; d) 25 mg to 90 mg; e) 30 mg to 80 mg; f) 40 mg to 70 mg; g) 50 mg to 60 mg; or The method according to claim 11, wherein the amount is 50 mg.

13. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is formulated for oral administration, sublingual administration, buccal administration, vaginal administration, rectal administration, non-enteral administration, transdermal administration, or administration by inhalation.

14. The pharmaceutical composition according to claim 13, wherein the non-enteral administration is intravenous, intramuscular, or subcutaneous administration.

15. The pharmaceutical composition according to claim 3 or 4, wherein the N-acylethanolamine is N-palmitoylethanolamine or a pharmaceutically acceptable salt thereof.

16. N-acylethanolamine or a pharmaceutically acceptable salt thereof a) 200 mg to 1800 mg; b) 250 mg to 1550 mg; c) 300 mg to 1200 mg; d) 350 mg to 950 mg; e) 400 mg to 700 mg; f) 450 mg to 600 mg; or g) 500mg to 550mg A pharmaceutical composition according to claim 3 or 4, formulated for administration as a daily dose.

17. The molar ratio between 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof is a)1:0.2～1:2000； b) 1:0.2 to 1:5; or c)1:15～1:1800 The pharmaceutical composition according to claim 3 or 4.

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