Use of 5-methoxy-2-aminoindane ("MEAI") in method for treating cocaine addiction

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 365,627, filed on June 1, 2022, the contents of which are hereby incorporated by reference. Technical Field

[0003] In some embodiments, the present invention relates to a method of treating cocaine addiction by administering a therapeutically effective amount of 5-methoxy-2-aminoindan ("MEAI"). In certain other embodiments, the method of treatment comprises administering MEAI in combination with an N-acylethanolamine, such as palmitoylethanolamide ("PEA"). Background of the Invention

[0005] Cocaine enhances the activity of monoamine neurotransmitters (dopamine, norepinephrine and serotonin) in the central and peripheral nervous systems by blocking the presynaptic reuptake pumps (transporters) of monoamine neurotransmitters. The main synaptic effect of cocaine is to release dopamine from synaptic vesicles and block dopamine reuptake, thereby leading to enhanced dopaminergic neurotransmission. Therefore, cocaine addiction is called a disease of the brain dopamine reward system. Cocaine also has a second effect of blocking voltage-gated membrane sodium ion channels. This effect explains its local anesthetic effect and may cause arrhythmias.

[0006] https: / / www.sciencedirect.com / topics / agricultural-and-biological-sciences / cocaine#:~:text=The%20major%20synaptic%20effect%20of,the%20brai n′s%20dopamine%20reward%20system.

[0007] It is estimated that in 2017, approximately 0.9% of the global population had a drug use (excluding alcohol) disorder. Prevalence trends around the world are shown in the chart. At a country level, this prevalence ranges from 0.4% to 3.5%. The highest prevalence is in the United States, where approximately 1 in 30 people were addicted to drugs in 2017. When these trends are broken down by age, we see that adults in their 20s are most likely to have a drug use disorder globally; among people aged 20-29, more than 2% (1 in 50) have a drug use disorder. In 2017, 8%-9% of adults in their early 20s in the United States had a drug use disorder; that's about 1 in 11 or 1 in 12. It is estimated that approximately 71 million people worldwide had a drug use disorder in 2017. The main groups of illicit drugs used in international statistics are opioids, cocaine, amphetamines, and cannabis.

[0008] https: / / ourworldindata.org / illicit-drug-use

[0009] Compounds derived from 2-aminoindan have been shown to selectively bind to dopamine D3 receptors. U.S. Pat. No. 5,708,018 discloses certain 2-aminoindan derivatives and hypothesizes that these 2-aminoindan derivatives may be useful in treating CNS disorders associated with dopamine D3 receptors. One such compound is 5-methoxy-2-aminoindan ("MEAI").

[0010] 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 (amide of arachidonic acid (20:4ω-6) and ethanolamine), N-palmitoylethanolamine (amide of palmitic acid (16:0) and ethanolamine), N-oleoylethanolamine (amide of oleic acid (18:1) and ethanolamine), N-stearoylethanolamine (amide of stearic acid (18:0) and ethanolamine), and N-docosahexaenoylethanolamine (amide of docosahexaenoic acid (22:6) and ethanolamine).

[0011] Palmitoylethanolamide (PEA, also known as N-(2-hydroxyethyl) palmitamide; hydroxyethyl palmitamide; palmitamideethanol; N-palmitoylethanolamine; and palmitylethanolamide) is an endogenous fatty acid amide that belongs to the class of nuclear factor agonists. PEA has been shown to bind to receptors in the cell nucleus (nuclear receptors) and exert a variety of biological functions associated with chronic pain and inflammation. Studies have shown that PEA interacts with different non-CB1 / CB2 receptors, indicating that PEA utilizes a unique "parallel" endocannabinoid signaling system. Increasing evidence further supports the concept that PEA production and inactivation can occur independently of AEA and 2-AG production and inactivation. The various biological effects of PEA on cells can be attributed to its affinity for PPARs (particularly PPAR-α and PPAR-γ). PEA has been shown to have affinity for cannabinoid-like G-coupled receptors GPR55 and GPR119 and transient receptor potential vanilloid type 1 receptor (TRPV1). PEA has been shown to have anti-inflammatory, anti-nociceptive, neuroprotective, and anticonvulsant properties. Summary of the invention

[0012] In some embodiments, a method for treating cocaine addiction is provided, the method comprising administering to a subject in need thereof a therapeutically acceptable amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof, thereby treating cocaine addiction.

[0013] In certain embodiments, 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 25 to about 100 mg. In other embodiments, 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 21 to about 84 mg. In still other embodiments, 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 21 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

[0014] In some embodiments, the daily dose is administered in a single dose or in more than one divided dose. In other embodiments, 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered twice a day.

[0015] In other embodiments, the therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof comprises about 0.36 to about 1.4 mg / kg body weight / day, about 0.5 to about 1.3 mg / kg body weight / day, about 0.6 to about 1.2 mg / kg body weight / day, about 0.7 to about 1.1 mg / kg body weight / day, or about 0.8 to about 1.0 mg / kg body weight / day.

[0016] In certain embodiments, cocaine addiction is withdrawal symptoms following cocaine abstinence.

[0017] In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient. In specific embodiments, the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, liquid concentrate, suspension or syrup.

[0018] In other embodiments, the pharmaceutical composition is a unit dosage composition. In certain embodiments, the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof in a unit dosage form is about 21 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg. In a specific embodiment, the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is about 50 mg.

[0019] In some embodiments, administration of the pharmaceutical composition is oral, sublingual, buccal, vaginal, rectal, parenteral, transdermal, or by inhalation. In certain embodiments, parenteral administration is intravenous, intramuscular, or subcutaneous administration.

[0020] In some embodiments, treating cocaine addiction reduces craving for cocaine.

[0021] Other embodiments relate to the use of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof according to any one of the preceding embodiments for treating cocaine addiction.

[0022] In some embodiments, a method for reducing the likelihood of relapse of cocaine addiction is provided, the method comprising administering to a subject in need thereof a therapeutically acceptable amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof, thereby reducing the likelihood of relapse of cocaine addiction.

[0023] In certain embodiments, 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 25 to about 100 mg. In other embodiments, 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 21 to about 84 mg. In still other embodiments, 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 21 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

[0024] In some embodiments, the daily dose is administered in a single dose or in more than one divided dose. In other embodiments, 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered twice a day.

[0025] In other embodiments, the therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof comprises about 0.36 to about 1.4 mg / kg body weight / day, about 0.5 to about 1.3 mg / kg body weight / day, about 0.6 to about 1.2 mg / kg body weight / day, about 0.7 to about 1.1 mg / kg body weight / day, or about 0.8 to about 1.0 mg / kg body weight / day.

[0026] In certain embodiments, cocaine addiction is withdrawal symptoms following cocaine abstinence.

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

[0028] In other embodiments, the pharmaceutical composition is a unit dosage composition. In certain embodiments, the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof in a unit dosage form is about 21 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg. In a specific embodiment, the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is about 50 mg.

[0029] In some embodiments, administration of the pharmaceutical composition is oral, sublingual, buccal, vaginal, rectal, parenteral, transdermal, or by inhalation. In certain embodiments, parenteral administration is intravenous, intramuscular, or subcutaneous administration.

[0030] Other embodiments relate to the use of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof according to claims 18-32 for reducing the likelihood of relapse in cocaine addiction.

[0031] In some embodiments, a method for treating cocaine addiction is provided, the method comprising administering to a subject in need thereof a therapeutically acceptable amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof, thereby treating cocaine addiction.

[0032] In certain embodiments, 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 25 to about 100 mg. In other embodiments, 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 21 to about 84 mg. In still other embodiments, 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 21 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

[0033] In some embodiments, the daily dose is administered in a single dose or in more than one divided dose. In other embodiments, 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered twice a day.

[0034] In other embodiments, the therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof comprises about 0.36 to about 1.4 mg / kg body weight / day, about 0.5 to about 1.3 mg / kg body weight / day, about 0.6 to about 1.2 mg / kg body weight / day, about 0.7 to about 1.1 mg / kg body weight / day, or about 0.8 to about 1.0 mg / kg body weight / day.

[0035] In certain embodiments, cocaine addiction is withdrawal symptoms following cocaine abstinence.

[0036] In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient. In specific embodiments, the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, liquid concentrate, suspension or syrup.

[0037] In other embodiments, the pharmaceutical composition is a unit dosage composition. In certain embodiments, the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof in a unit dosage form is about 21 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg. In a specific embodiment, the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is about 50 mg.

[0038] In some embodiments, administration of the pharmaceutical composition is oral, sublingual, buccal, vaginal, rectal, parenteral, transdermal, or by inhalation. In certain embodiments, parenteral administration is intravenous, intramuscular, or subcutaneous administration.

[0039] In some embodiments, the N-acylethanolamine is palmitoylethanolamide or a pharmaceutically acceptable salt thereof. In specific embodiments, the N-acylethanolamine or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 200 to about 1800 mg, about 250 to about 1550 mg, about 300 to about 1200 mg, about 350 to about 950 mg, about 400 to about 700 mg, about 450 to about 600 mg, or about 500 to about 550 mg.

[0040] In some embodiments, treating cocaine addiction reduces craving for cocaine.

[0041] Other embodiments relate to the use of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof and palmitoylethanolamide or a pharmaceutically acceptable salt thereof according to any one of the preceding embodiments for the treatment of cocaine addiction.

[0042] In some embodiments, a method for reducing the likelihood of relapse of cocaine addiction is provided, the method comprising administering to a subject in need thereof a therapeutically acceptable amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof, thereby reducing the likelihood of relapse of cocaine addiction.

[0043] In certain embodiments, 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 25 to about 100 mg. In other embodiments, 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 21 to about 84 mg. In still other embodiments, 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 21 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

[0044] In some embodiments, the daily dose is administered in a single dose or in more than one divided dose. In other embodiments, 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered twice a day.

[0045] In other embodiments, the therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof comprises about 0.36 to about 1.4 mg / kg body weight / day, about 0.5 to about 1.3 mg / kg body weight / day, about 0.6 to about 1.2 mg / kg body weight / day, about 0.7 to about 1.1 mg / kg body weight / day, or about 0.8 to about 1.0 mg / kg body weight / day.

[0046] In certain embodiments, cocaine addiction is withdrawal symptoms following cocaine abstinence.

[0047] In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient. In specific embodiments, the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, liquid concentrate, suspension or syrup.

[0048] In other embodiments, the pharmaceutical composition is a unit dosage composition. In certain embodiments, the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof in a unit dosage form is about 21 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg. In a specific embodiment, the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is about 50 mg.

[0049] In some embodiments, administration of the pharmaceutical composition is oral, sublingual, buccal, vaginal, rectal, parenteral, transdermal, or by inhalation. In certain embodiments, parenteral administration is intravenous, intramuscular, or subcutaneous administration.

[0050] In some embodiments, the N-acylethanolamine is palmitoylethanolamide or a pharmaceutically acceptable salt thereof. In specific embodiments, the N-acylethanolamine or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 200 to about 1800 mg, about 250 to about 1550 mg, about 300 to about 1200 mg, about 350 to about 950 mg, about 400 to about 700 mg, about 450 to about 600 mg, or about 500 to about 550 mg.

[0051] Other embodiments relate to the use of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof according to claims 53-69 for reducing the likelihood of relapse in cocaine addiction. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] When read in conjunction with the accompanying drawings, the foregoing summary of the invention and the following detailed description of the present disclosure will be better understood. For the purpose of illustrating the present disclosure, the accompanying drawings show some but not all alternative embodiments. However, it should be understood that the present disclosure is not limited to the precise arrangements and means shown. These drawings, which are incorporated into and constitute a part of this specification, help explain the principles of the present disclosure.

[0053] Figure 1 Data from a conditioned place preference ("CPP") assay are shown, with the Y axis representing the time spent in the less preferred compartment during the baseline test. Behavioral data were analyzed using ordinary one-way ANOVA. Data are presented as mean ± SEM and are considered**** A probability value of p < 0.0001 was significant.

[0054] Figure 2 Data from the CPP assay are shown, with the Y axis representing the time spent in the less preferred compartment during the baseline test. Behavioral data were analyzed using ordinary one-way ANOVA. Data are presented as mean ± SEM and are considered * The probability value of p<0.001 was significant. MEAI (5 mg / kg) values ​​were assigned to two different groups using K-Cluster method. MEAI A represents values ​​below 100 (seconds) and MEAI B represents values ​​above 100 (seconds). DETAILED DESCRIPTION

[0055] In some embodiments, the present invention relates to cocaine addiction, and more particularly, but not exclusively, to a method for treating cocaine addiction, the method 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 for reducing the likelihood of relapse in cocaine addiction, the method comprising administering to a subject in need thereof a therapeutically acceptable amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof.

[0056] The present disclosure also provides a method for treating cocaine addiction, the method comprising administering a therapeutically effective amount of MEAI or a physiologically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof to a subject in need thereof. In other embodiments, the present disclosure provides a method for reducing the likelihood of relapse of cocaine addiction, the method comprising administering a therapeutically acceptable amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a physiologically acceptable salt thereof to a subject in need thereof. In some embodiments, N-acylethanolamine is PEA.

[0057] definition:

[0058] "Isomers" means compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ in the arrangement or configuration of the atoms in space.

[0059] "Stereoisomer" or "optical isomer" means a stable isomer that has at least one chiral atom or restricted rotation to produce a vertical asymmetric plane (e.g., some biphenyls, allenes, and spiro compounds) and can rotate plane polarized light. Because there are asymmetric centers and other chemical structures that can cause stereoisomerism in the compounds of the present disclosure, 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 as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as racemic mixtures. However, if desired, such compounds can be prepared or separated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As discussed in more detail below, individual stereoisomers of a compound are prepared by synthesizing or preparing a mixture of enantiomeric products from optically active starting materials containing the desired chiral center, followed by separation or resolution, such as conversion into a mixture of diastereomers, followed by separation or recrystallization, chromatographic techniques, use of a chiral resolving agent, or direct separation of the enantiomers on a chiral chromatographic column. Starting compounds of particular stereochemistry are either commercially available or prepared by the methods described below and resolved by techniques well known in the art.

[0060] It is well known in the art that the biological and pharmacological activities of compounds are sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit significantly different biological activities, including differences in pharmacokinetic properties, including metabolism, protein binding, etc., and pharmacological properties, including the type of activity displayed, degree of activity, toxicity, etc. Therefore, it will be understood by those skilled in the art that one enantiomer may be more active or may exhibit a beneficial effect when enriched relative to another enantiomer or when separated from another enantiomer. In addition, those skilled in the art will know how to separate, enrich, or selectively prepare enantiomers of compounds of the present disclosure based on the knowledge of the present disclosure and the prior art.

[0061] Therefore, although the racemic form of the drug can be used, it is generally not as effective as administering an equal amount of enantiomerically pure drug; in fact, in some cases, one enantiomer may be pharmacologically inactive and will only act as a simple diluent. For example, although ibuprofen was previously administered as a racemate, it has been shown that only the S-isomer of ibuprofen is effective as an anti-inflammatory agent (however, in the case of ibuprofen, although the R-isomer is inactive, it is converted into the S-isomer in vivo, and therefore, the racemic form of the drug has a lower action rate than the pure S-isomer). In addition, the pharmacological activity of enantiomers can have different biological activities. For example, S-penicillamine is a therapeutic agent for chronic arthritis, while R-penicillamine is toxic. In fact, some purified enantiomers are superior to racemates because it has been reported that purified individual isomers have faster transdermal penetration rates compared to racemic mixtures. See U.S. Patent Nos. 5,114,946 and 4,818,541.

[0062] In some embodiments, the compound is a racemic mixture of (S)- and (R)-isomers. In other embodiments, provided herein are mixtures of compounds wherein the individual compounds of the mixture exist primarily as (S)- or (R)-isomer configurations. For example, the compound mixture has an (S)-enantiomeric excess greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more. In other embodiments, the compound mixture has an (S)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more. In other embodiments, the compound mixture has an (R)-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more. In some other embodiments, the compound mixture has an (R)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more.

[0063] Individual stereoisomers of the compounds of the present disclosure can be prepared synthetically from commercially available starting materials containing asymmetric centers or stereocenters, or by preparing racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These resolution methods are exemplified by: (1) attaching a mixture of enantiomers to a chiral auxiliary, separating the resulting diastereomeric mixture by recrystallization or chromatography, and releasing the optically pure product from the auxiliary; (2) forming salts using an optically active resolving agent; or (3) directly separating a mixture of optical enantiomers on a chiral chromatographic column. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods such as chiral gas chromatography, chiral high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereoisomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthesis methods.

[0064] Thus, if one enantiomer is pharmacologically more active, less toxic, or has a preferred disposition in vivo than the other enantiomer, it would be therapeutically more beneficial to preferentially administer that enantiomer. In this manner, the patient being treated would be exposed to a lower total dose of the drug and a lower dose of the potentially toxic enantiomer or other enantiomer inhibitors.

[0065] As used herein, the nomenclature of compounds, including organic compounds, may be given using common names, IUPAC, IUBMB or CAS recommended nomenclature. If a name is given, one skilled in the art will either systematically reduce the compound structure by using the naming convention or by using commercially available software such as CHEMDRAW TM The structures of the compounds were easily determined using the PerkinElmer Professional, version 17.

[0066] 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. The term "stereoisomer" when used herein is composed of all geometric isomers, enantiomers or diastereomers. These compounds can be represented by the symbol "R" or "S", depending on the configuration of the substituents around the stereocarbon isomeric atoms. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. A mixture of enantiomers or diastereomers can be referred to as "(±)" in nomenclature, but the technician will be aware that the structure can implicitly indicate a chiral center. In some embodiments, an enantiomer or stereoisomer substantially free of the corresponding enantiomer can be provided.

[0067] In one aspect, the present invention provides a pharmaceutical composition comprising a mixture of a therapeutically effective amount of MEAI or a salt thereof and at least one N-acylethanolamine or a salt thereof.

[0068] In another aspect, the present invention provides a pharmaceutical composition comprising a mixture of a therapeutically effective amount of MEAI or a salt thereof and at least one N-acylethanolamine or a salt thereof, wherein the molar ratio between MEAI and N-acylethanolamine is about 1:0.2 to about 1:2000.

[0069] As used herein, "pharmaceutical composition" refers to a preparation of an active agent as described herein with other chemical components such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism. As used herein, the phrase "pharmaceutically acceptable carrier" refers to a carrier, excipient or diluent that does not significantly irritate an organism and does not abrogate the biological activity and properties of the administered compound. These phrases include adjuvants.

[0070] The term "excipient" as used herein refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of an active ingredient. Examples of excipients include, without limitation, calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, oils such as vegetable oils or fish oils, and polyethylene glycols.

[0071] The term "carrier" as used herein refers to a diluent, adjuvant, excipient or vehicle with which a compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils. Water or aqueous solutions, saline solutions and aqueous dextrose and glycerol solutions are preferably used as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin, 18th edition.

[0072] The phrase "pharmaceutically acceptable" as used herein refers to molecular entities and compositions that are physiologically tolerable and typically do not produce allergic or similar toxicity when administered to an individual. Preferably, and particularly in the case of formulations for human use, the term "pharmaceutically acceptable" may refer to being approved by a regulatory agency (e.g., the U.S. Food and Drug Administration) or listed in a generally recognized pharmacopoeia for use in animals (e.g., the U.S. Pharmacopeia).

[0073] The term "N-acylethanolamine" as used herein generally refers to a class of fatty acid amides, i.e., lipid-derived signaling molecules, which are formed when one of several types of acyl groups is attached to the nitrogen atom of ethanolamine. These amides can conceptually be formed from fatty acids and ethanolamine, while releasing a water molecule, but known biological synthesis uses a specific phospholipase D to cleave phospholipid units from N-acylphosphatidylethanolamine. The suffixes -amine and -amide in these names each refer to a single nitrogen atom of ethanolamine that connects the compounds together: in ethanolamine, it is referred to as "amine" because it is considered to be a free terminal nitrogen in the subunit, and when it is considered to be bound to the adjacent carbonyl group of the acyl subunit, it is referred to as "amide". In this application, the names of these compounds may appear simultaneously with "amide" or "amine". The term "ethanolamine" is used in a general sense and is intended to include monoethanolamine, diethanolamine, triethanolamine and mixtures thereof.

[0074] As used herein, the term "derivative" means a compound whose core structure is identical or very similar to N-acylethanolamine, but which has chemical or physical modifications, such as different or additional side groups.

[0075] The term "salt" as used herein refers to any form of the active ingredient, wherein the active ingredient is in ionic form and coupled to a counterion (cation or anion) or in solution. This also includes complexes of the active ingredient with other molecules and ions, particularly complexes complexed by ionic interactions. Pharmaceutically acceptable salts are known to those of ordinary skill in the art.

[0076] 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 present invention.

[0077] 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 present invention. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:25 to about 1:450. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:10 to about 1:500, about 1:15 to about 1:450, about 1:20 to about 1:400, about 1:25 to about 1:350, about 1:30 to about 1:300, about 1:35 to about 1:250, about 1:40 to about 1:200, or about 1:45 to about 1:150. Each possibility represents a separate embodiment of the present invention. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:50 to about 1:100. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:10. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:20. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:30. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:40. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:50. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:60. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:70. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:80. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:90. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:100. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:110. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:120. In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:130.In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:140.

[0078] In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:150.

[0079] In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:160.

[0080] In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:170.

[0081] In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:180.

[0082] In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:190.

[0083] In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is about 1:200.

[0084] In certain embodiments, the molar ratio between MEAI and N-acylethanolamine is at least about 1:10, at least about 1:20, at least about 1:30, at least about 1:40, at least about 1:50, at least about 1:60, at least about 1:70, at least about 1:80, at least about 1:90, or at least about 1: 100. Each possibility represents a separate embodiment of the present invention.

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

[0086] In certain embodiments, the pharmaceutical composition comprises about 200-1800 mg N-acylethanolamine or its salt. In certain embodiments, the pharmaceutical composition comprises about 250-1550 mg, about 300-1200 mg, about 350-950 mg, about 400-700 mg, about 450-600 mg or about 500-550 mg N-acylethanolamine or its salt. Each possibility represents a separate embodiment of the present 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, to At least about 950 mg, at least about 1000 mg, at least about 1050 mg, at least about 1100 mg, at least about 1150 mg, at least about 1200 mg, at least about 1250 mg, at least about 1300 mg, at least about 1350 mg, at least about 1400 mg, at least about 1450 mg, at least about 1500 mg, at least about 1550 mg, at least about 1600 mg, at least about 1650 mg, at least about 1700 mg, at least about 1750 mg or at least about 1800 mg of N-acylethanolamine or a salt thereof. In certain embodiments, the pharmaceutical composition comprises about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, or about 1800 mg of N-acylethanolamine or a salt thereof. Each possibility represents a separate embodiment of the present invention.

[0087] In certain embodiments, N-acylethanolamine is N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexylamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA) or its salt or any combination thereof. Each possibility represents a separate embodiment of the present invention. In certain embodiments, N-acylethanolamine is PEA or its salt. In certain embodiments, N-acylethanolamine consists of PEA or its salt. In certain embodiments, N-acylethanolamine consists of PEA.

[0088] In certain embodiments, the pharmaceutical composition is formulated for systemic administration. In certain embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalation, topical, rectal, vaginal, parenteral, intravenous, intramuscular or subcutaneous administration. In certain embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal or sublingual administration. Each possibility represents a separate embodiment of the present invention. 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 pharmaceuticals are well known in the art and can be found, for example, in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa. The pharmaceutical compositions of the present invention can be manufactured by methods well known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, embedding or lyophilizing processes.

[0090] For oral administration, pharmaceutical compositions can be easily formulated by combining the active compound with a pharmaceutically acceptable carrier well known in the art. Such carriers enable pharmaceutical compositions to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by patients. Oral pharmaceutical preparations can be prepared as follows: using solid excipients, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable adjuvants as needed to obtain tablets or dragee cores. Suitable excipients are particularly fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose and sodium carboxymethylcellulose; and / or physiologically acceptable polymers such as polyvinyl pyrrolidone (PVP). If necessary, disintegrants such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, can be added.

[0091] The term "oral administration" refers to any method of administration in 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 in the oral cavity.

[0092] The dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol, titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings to identify or characterize the different combinations of active compound dosages.

[0093] Pharmaceutical compositions that can be used orally include hard or soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Capsules can contain active ingredients mixed with: fillers such as lactose, adhesives such as starch, lubricants such as talc or magnesium stearate and optionally stabilizers. In soft capsules, active ingredients can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers can be added. The dosage of all preparations for oral administration should be suitable for the selected route of administration. For buccal and sublingual administration, the composition can take the form of tablets or lozenges prepared in a conventional manner or in a viscous carrier. Alternatively, the active ingredient can be in the form of a powder reconstructed with a suitable vehicle (e.g., sterile pyrogen-free water-based solution) before use.

[0094] Pharmaceutical compositions suitable for use in the context of the present invention include compositions comprising active ingredients in an amount effective to achieve the intended purpose. More specifically, a "therapeutically effective amount" means the amount of an active ingredient that effectively prevents, alleviates or improves the symptoms or side effects of a disease or disorder, or prolongs the survival of a treated subject. The determination of a therapeutically effective amount is entirely 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" means the amount of at least two active ingredients, each of which may not be in a therapeutically effective amount independently, or both of which may not be in a therapeutically effective amount, but the mixture effectively prevents, alleviates or improves the symptoms or side effects of a disease or disorder, or prolongs the survival of a treated subject. The term "mixture" as used herein refers to a non-covalent combination of two molecules.

[0095] For any formulation used in the method of the present invention, the dosage or therapeutically effective amount can be initially estimated by in vitro, in vivo and cell culture assays. For example, the dosage can be formulated in an animal model to achieve the desired concentration or titer. This information can be used to more accurately determine useful doses in humans. The dosage of each compound of the combination claimed depends on several factors, including: the method of administration, the disease to be treated, the severity of the disease, whether the disease is to be treated or prevented, and the age, weight and health of the person to be treated. In addition, pharmacogenomics (the effect of genotype on the pharmacokinetics, pharmacodynamics or efficacy characteristics of the therapeutic agent) information about a specific patient can affect the dosage used. Continuous daily administration may not be required; the treatment regimen may require a period during which the drug is not administered, or treatment may be provided as needed during acute disease exacerbations. Dose escalation may or may not be required; the treatment regimen may require a reduction in drug dosage. The toxicity and therapeutic efficacy of the active ingredients described herein can be determined in vitro, in cell culture or in experimental animals by standard pharmaceutical procedures. The data obtained from these in vitro and cell culture assays and animal studies can be used to formulate a dosage range for human use. The dosage can vary depending on the dosage form adopted and the route of administration utilized. The exact formulation, route of administration and dosage can be selected by the individual physician according to the patient's condition (see, e.g., Fingl, E. et al. (1975), "The Pharmacological Basis of Therapeutics," Chapter 1, page 1). Depending on the severity and responsiveness of the condition to be treated, administration may be single or multiple administrations, with courses lasting from several days to several weeks, or until a cure is achieved or a diminution of the disease state is achieved.

[0096] In another aspect, the present invention further provides 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, 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.

[0098] In another aspect, the present invention further provides a pharmaceutical composition or dosage unit as described above for use in a method for preventing or treating a condition amenable to prevention or treatment by at least one MEAI.

[0099] The term "treat" as used herein includes, but is not limited to, any one or more of the following: eliminating, ameliorating, inhibiting, attenuating, blocking, suppressing, reducing, delaying, stopping, alleviating or preventing one or more symptoms or side effects of a disease or disorder of the present invention.

[0100] The term "acute" refers to a disorder that has a relatively short, severe course.

[0101] As used herein, the term "chronic" means that the length of time of a disease or condition of the present invention may be weeks, months, or possibly years. The intensity of a disease or condition may vary depending on various conditions such as patient age, temperature, season, disease type, etc.

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

[0103] The terms "comprises", "comprising", "include", "including", "having" and their enumerations 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 ingredients, steps and / or parts, but the additional ingredients, steps and / or parts do not materially change the basic and novel characteristics of the claimed composition, method or structure.

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

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

[0108] The data obtained from cell culture assays or animal studies can be used to formulate a dosage range for human use. The therapeutically effective dose achieved in an animal model can be converted to another animal (including humans) using conversion factors known in the art (see, e.g., Freirichich et al., Cancer Chemother. Reports 50 (4): 219-244 (1966) and the equivalent surface area dose factors in the following table).

[0109] Table 2. Equivalent surface area dose factors.

[0110]

[0111] The dosage of such compounds is preferably within the range of ED with little or no toxicity. 50 The dosage may vary within this range depending on the dosage form employed and the route of administration utilized. Generally, the therapeutically effective amount may vary with the age, condition, and sex of the subject and the severity of the subject's medical condition. The dosage may be determined by a physician and adjusted as necessary to accommodate the observed therapeutic effect.

[0112] Those skilled in the art will appreciate that both in vivo and in vitro assays using appropriate, known and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0113] Those skilled in the art will further appreciate that human clinical trials (including first-in-human, dose-ranging and efficacy trials) in healthy patients and / or patients suffering from a given disorder can be performed according to methods well known in the clinical and medical arts.

[0114] Although the present invention has been described with reference to specific embodiments, it will be appreciated by those skilled in the art that various changes may be made and may be replaced with equivalents without departing from the scope of the present invention. In addition, many modifications may be made to adapt specific situations or materials to the teachings of the present invention without departing from the scope of the present invention. Therefore, it is contemplated that the present invention is not limited to the disclosed specific embodiments, but that the present invention will include all embodiments falling within the scope of the appended claims.

[0115] The following examples are presented to more fully illustrate some embodiments of the present invention. However, the examples should in no way be construed as limiting the broad scope of the present invention.

[0116] Example 1: Elucidation of MEAI as an anti-reward / addiction-like agent

[0117] To investigate the anti-rewarding effects of MEAI, we used rats in the conditioned place preference (CPP) model to find a dose that would not induce reward and addiction. In this model, if the drug has a rewarding effect, the rats will show a preference for spending time in the compartment that received the drug on each conditioning day. If the MEAI is a non-rewarding agent, it would be expected that the rats would not show a preference for the compartment associated with the MEAI.

[0118] Two groups were tested: one group received MEAI (at four different doses), while the second group received cocaine on each conditioning day. Additionally, some of the rats that received cocaine were treated with MEAI on the test day to determine if MEAI had a treatment-like effect.

[0119] In CPP determination, rats learn to associate rewards with environmental cues. Two groups of rats experience a baseline period of three days, during which each rat is allowed to move freely from a striped compartment to a smooth compartment in a closed activity area within 20 minutes. Time measurement is performed to determine in which compartment rats spend more time (i.e., preference). Baseline data is determined as the average duration spent in each compartment. After the baseline period, a 5-day training period is performed, in which rats are injected with saline (intraperitoneally) in the morning and are placed in the compartment of preference for 20 minutes. Four hours after saline injection, cocaine (15mg / kg, intraperitoneal) or MEAI (4 doses; 20, 10, 5 and 2.5mg / kg, intraperitoneal) is injected, and rats are placed in a less preferred compartment for 20 minutes. On the 6th day, CPP test (same as baseline period) is performed to determine whether MEAI gives a reward-like effect similar to cocaine. As previously described, the duration spent in each compartment is calculated as the difference (seconds) between baseline time and test time.

[0120] Elucidation of MEAI as an anti-reward / addiction-like agent

[0121] In the first part of this study, we examined whether administration of four different doses of MEAI had no effect on reward.

[0122] We started testing with 20mg / kg MEAI. At this dose, 65.7% of rats showed side effects such as anxiety, aggression, piloerection, tremor, low posture, diarrhea and secretion of "vaginal plugs". Rats receiving this dose showed a short duration (seconds) spent in non-preferred places, which indicates low reward. Due to these side effects, we decided to test lower doses of MEAI instead of higher doses. Therefore, the following test dose is 10mg / kg of MEAI. Compared with the 20mg / kg dose, 51% of the rats receiving this dose had side effects, including anxiety, aggression, piloerection, tremor, low posture, diarrhea and secretion of "vaginal plugs", with a trend of improved symptoms, although not statistically significant. We see that at this dose, rats spend longer durations in non-preferred places, indicating the presence of a rewarding effect. Based on these results, we selected 5mg / kg and 2.5mg / kg as the next two doses to administer. 20.2% of the rats that received the 5 mg / kg dose exhibited side effects, and 21.4% of the rats that received the 2.5 mg / kg dose exhibited side effects, which consisted of anxiety, diarrhea, and secretion of a "vaginal plug." For both doses, the duration in the non-preferred place was negative, demonstrating an anti-rewarding effect. Overall, the mean values ​​for the dose of 5 mg / kg were the most negative, so we decided to test the efficacy of this dose as a treatment for cocaine preference in rats.

[0123] Figure 1 Results of the CPP assay are shown. The Y axis represents the time spent in the less preferred compartment during the baseline test. Behavioral data were analyzed using ordinary one-way ANOVA. Data are expressed as mean ± SEM and are considered **** A probability value of p < 0.0001 was significant. n = 5-14 rats / group.

[0124] Testing the MEAI as a treatment for cocaine preference in rats.

[0125] Based on the previous results, we selected 5mg / kg MEAI as the treatment dose because it has a satisfactory anti-reward effect. 12 rats were regulated with cocaine (15mg / kg), injected with MEAI (5mg / kg, intraperitoneal) on the test day, and then they were made to wait for 10 minutes in a cage. The treated rats were then put into the middle compartment of the activity place for testing. The result was mixed, that is, there was a rat (negative value) showing a preference for the non-preferred compartment and a rat (positive value) still preferring the baseline preference compartment. We use K-cluster test to determine whether we can separate two different groups with statistical significance in the group.

[0126] The two groups were divided into values ​​below 100 seconds in the non-preferred compartment (MEAI A) and values ​​above 100 seconds in the non-preferred compartment (MEAI B). We then decided to examine a higher dose (10 mg / kg, ip) to see if a higher dose would be a more effective treatment option. As we can see in Figure 2 As seen in Figure 2, 5 mg / kg MEAI gave better results in reducing reward. Figure 2 The Y axis in represents the time spent in the less preferred compartment during the baseline test. Behavioral data were analyzed using ordinary one-way ANOVA. Data are expressed as mean ± SEM and are considered * Values ​​with a probability of p < 0.001 were significant. n = 5-12 rats / group.

[0127] MEAI (5 mg / kg) values ​​were assigned to two different groups using the K-Cluster method: MEAI A represents values ​​below 100 (seconds), and MEAI B represents values ​​above 100 (seconds).

[0128] The many features and advantages of the present disclosure are apparent from the detailed description, and thus the appended claims are intended to cover all such features and advantages of the present disclosure that fall within the true spirit and scope of the present disclosure. Furthermore, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the present disclosure to the exact construction and operation illustrated and described, and therefore, all suitable modifications and equivalents falling within the scope of the present disclosure may be resorted to.

[0129] Therefore, those skilled in the art will appreciate that the concepts upon which the present disclosure is based can be readily used as a basis for designing other structures, methods and / or systems for carrying out the several purposes of the present disclosure. Therefore, the claims should not be considered limited by the foregoing description or examples.

Claims

1. A method for treating cocaine addiction, the method comprising administering to a subject in need thereof a therapeutically acceptable amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof, thereby treating the cocaine addiction.

2. The method of claim 1, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 25 to about 100 mg.

3. The method of claim 1, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 21 to about 84 mg.

4. The method of claim 1, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 21 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

5. The method of claim 2, wherein the daily dose is administered in a single dose or in more than one divided dose.

6. The method of claim 1, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered twice a day.

7. The method of claim 1, wherein the therapeutically effective amount comprises about 0.36 to about 1.4 mg / kg body weight / day, about 0.5 to about 1.3 mg / kg body weight / day, about 0.6 to about 1.2 mg / kg body weight / day, about 0.7 to about 1.1 mg / kg body weight / day, or about 0.8 to about 1.0 mg / kg body weight / day.

8. The method of claim 1, wherein the cocaine addiction is withdrawal symptoms following cocaine abstinence.

9. The method of claim 1, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

10. The method of claim 9, wherein the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, liquid concentrate, suspension or syrup.

11. The method of claim 10, wherein the pharmaceutical composition is a unit dosage composition.

12. The method of claim 11, wherein the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof in the unit dosage form is about 21 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

13. The method of claim 12, wherein the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is about 50 mg.

14. The method of claim 1, wherein the pharmaceutical composition is administered orally, sublingually, buccally, vaginally, rectally, parenterally, transdermally, or by inhalation.

15. The method of claim 14, wherein the parenteral administration is intravenous, intramuscular or subcutaneous.

16. The method of claims 1-15, wherein treating the cocaine addiction reduces craving for cocaine.

17. Use of the pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof according to claims 1 to 16 for treating cocaine addiction.

18. A method for reducing the likelihood of relapse to cocaine addiction, the method comprising administering to a subject in need thereof a therapeutically acceptable amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof, thereby reducing the likelihood of relapse to cocaine addiction.

19. The method of claim 18, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 25 to about 100 mg.

20. The method of claim 18, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 21 to about 84 mg.

21. The method of claim 18, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 21 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

22. The method of claim 19, wherein the daily dose is administered in a single dose or in more than one divided dose.

23. The method of claim 19, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered twice a day.

24. The method of claim 18, wherein the therapeutically effective amount comprises about 0.36 to about 1.4 mg / kg body weight / day, about 0.5 to about 1.3 mg / kg body weight / day, about 0.6 to about 1.2 mg / kg body weight / day, about 0.7 to about 1.1 mg / kg body weight / day, or about 0.8 to about 1.0 mg / kg body weight / day.

25. The method of claim 18, wherein the cocaine addiction is withdrawal symptoms following cocaine abstinence.

26. The method of claim 18, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

27. The method of claim 26, wherein the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, liquid concentrate, suspension or syrup.

28. The method of claim 27, wherein the pharmaceutical composition is a unit dosage composition.

29. The method of claim 28, wherein the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof in the unit dosage form is about 21 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

30. The method of claim 29, wherein the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is about 50 mg.

31. The method of claim 18, wherein the pharmaceutical composition is administered orally, sublingually, buccally, vaginally, rectally, parenterally, transdermally, or by inhalation.

32. The method of claim 31 , wherein the parenteral administration is intravenous, intramuscular or subcutaneous.

33. Use of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof according to claims 18 to 32 for reducing the likelihood of relapse in cocaine addiction.

34. A method for treating cocaine addiction, the method comprising administering to a subject in need thereof a therapeutically acceptable amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof, thereby treating cocaine addiction.

35. The method of claim 34, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 25 to about 100 mg.

36. The method of claim 34, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 21 to about 84 mg.

37. The method of claim 34, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 21 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

38. The method of claim 37, wherein the daily dose is administered in a single dose or in more than one divided dose.

39. The method of claim 37, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered twice a day.

40. The method of claim 34, wherein the therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof comprises about 0.36 to about 1.4 mg / kg body weight / day, about 0.5 to about 1.3 mg / kg body weight / day, about 0.6 to about 1.2 mg / kg body weight / day, about 0.7 to about 1.1 mg / kg body weight / day, or about 0.8 to about 1.0 mg / kg body weight / day.

41. The method of claim 34, wherein the cocaine addiction is withdrawal symptoms following cocaine abstinence.

42. The method of claim 34, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

43. The method of claim 42, wherein the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, liquid concentrate, suspension or syrup.

44. The method of claim 43, wherein the pharmaceutical composition is a unit dosage composition.

45. The method of claim 44, wherein the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof in the unit dosage form is about 21 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

46. ​​The method of claim 45, wherein the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is about 50 mg.

47. The method of claim 34, wherein the pharmaceutical composition is administered orally, sublingually, buccally, vaginally, rectally, parenterally, transdermally, or by inhalation.

48. The method of claim 47, wherein the parenteral administration is intravenous, intramuscular or subcutaneous.

49. The method of claims 34-48, wherein the N-acylethanolamine is palmitoylethanolamine or a pharmaceutically acceptable salt thereof.

50. The method of claims 34-49, wherein the N-acylethanolamine or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 200 to about 1800 mg, about 250 to about 1550 mg, about 300 to about 1200 mg, about 350 to about 950 mg, about 400 to about 700 mg, about 450 to about 600 mg, or about 500 to about 550 mg.

51. The method of claims 34-50, wherein treating cocaine addiction reduces craving for cocaine.

52. Use of a pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof and palmitoylethanolamine or a pharmaceutically acceptable salt thereof according to claims 34-51 for treating cocaine addiction.

53. A method for reducing the likelihood of relapse 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-aminoindan or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof, thereby reducing the likelihood of relapse of cocaine addiction.

54. The method of claim 53, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 25 to about 100 mg.

55. The method of claim 53, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 21 to about 84 mg.

56. The method of claim 53, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 21 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

57. The method of claim 54, wherein the daily dose is administered in a single dose or in more than one divided dose.

58. The method of claim 54, wherein the 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is administered twice a day.

59. The method of claim 53, wherein the therapeutically effective amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof comprises about 0.36 to about 1.4 mg / kg body weight / day, about 0.5 to about 1.3 mg / kg body weight / day, about 0.6 to about 1.2 mg / kg body weight / day, about 0.7 to about 1.1 mg / kg body weight / day, or about 0.8 to about 1.0 mg / kg body weight / day.

60. The method of claim 53, wherein the cocaine addiction is withdrawal symptoms following cocaine abstinence.

61. The method of claim 53, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

62. The method of claim 61, wherein the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, liquid concentrate, suspension or syrup.

63. The method of claim 62, wherein the pharmaceutical composition is a unit dosage composition.

64. The method of claim 63, wherein the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof in the unit dosage form is about 21 to about 100 mg, about 25 to about 90 mg, about 30 to about 80 mg, about 40 to about 70 mg, or about 50 to about 60 mg.

65. The method of claim 64, wherein the amount of 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof is about 50 mg.

66. The method of claim 53, wherein the pharmaceutical composition is administered orally, sublingually, buccally, vaginally, rectally, parenterally, transdermally, or by inhalation.

67. The method of claim 66, wherein the parenteral administration is intravenous, intramuscular or subcutaneous.

68. The method of claims 53-67, wherein the N-acylethanolamine is palmitoylethanolamine or a pharmaceutically acceptable salt thereof.

69. The method of claims 53-68, wherein the N-acylethanolamine or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 200 to about 1800 mg, about 250 to about 1550 mg, about 300 to about 1200 mg, about 350 to about 950 mg, about 400 to about 700 mg, about 450 to about 600 mg, or about 500 to about 550 mg.

70. Use of the pharmaceutical composition comprising 5-methoxy-2-aminoindan or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof according to claims 53-69 for reducing the likelihood of relapse in cocaine addiction.

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