Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/32—Alcohol-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present disclosure relates to compositions and methods for potentiating therapeutic effects and/or reducing side-effects of 5-methoxy-2-aminoindan (“MEAI”).
• MEAI 5-methoxy-2-aminoindan
• the present disclosure provides pharmaceutical compositions comprising MEAI and N- acylethanolamines, for example, palmitoylethanolamide (“PEA”) and methods for their use in a variety of indications amenable to treatment with MEAI.
• Binging or binge behavior is a non-controlled excessive behavior of indulgence in a variety of activities such as eating, drinking, drugs, sweets, shopping, sexual conduct, and the like. It is now recognized that all types of binging are ways of dealing with negative emotions that are not rational or healthy.
• Binge disorders are characterized by feelings of powerlessness, secrecy, shame, and social isolation. The occasional overindulgence becomes a real problem once a subject feels a need to binge in private, or schedule binges around (or instead of) work and social obligations. Binge eating is currently the most common eating disorder in adults, compulsive buying disorder (“shopaholism”) is increasing, and binge drinking is widespread.
• Alcohol is one of the favorite, commonly used, yet most dangerous psychoactive substances that may lead to binge behavior upon excessive, uncontrolled consumption. Alcohol is consumed for several reasons, which include quenching thirst, heating or cooling the drinker, for the taste and because of the association alcoholic drinks have with other aspects of life such as food and friendship. The psychological effects of alcohol contribute to some of these reasons.
• Alcohol consumption presents a growing problem worldwide, which some believe may have already overtaken tobacco in terms of overall health and social care costs. Excessive and/or prolonged alcohol consumption may have some undesired physiological and psychological, including short-term, effects such as gastric irritation, anxiety disorders and other excitable states, and longer-term effects such as cirrhosis, fatty liver disease, cardiomyopathy and dementia. Alcohol consumption may lead to intoxication, which, in turn, can have serious consequences such as accidents and uncontrolled violent behavior with subsequent medical complications.
• N-acylethanolamines are lipid-derived signaling molecules. They are formed when one of several types of acyl groups is linked to the nitrogen atom of ethanolamine.
• Examples of N-acylethanolamines include anandamide (the amide of arachidonic acid (20:4 omega-6) and ethanolamine), N-Palmitoylethanolamine (the amide of palmitic acid (16:0) and ethanolamine), N-Oleoylethanolamine (the amide of oleic acid (18:1) and ethanolamine), N-Stearoylethanolamine (the amide of stearic acid (18:0) and ethanolamine) and N-Docosahexaenoylethanolamine (the amide of docosahexaenoic acid (22:6) and ethanolamine).
• anandamide the amide of arachidonic acid (20:4 omega-6) and ethanolamine
• N-Palmitoylethanolamine the amide of palmitic acid (16:0) and ethanolamine
• Palmitoylethanolamide (PEA, also known as N-(2-hydroxyethyl) hexadecanamide; Hydroxyethylpalmitamide; palmidrol; N-palmitoylethanolamine; and palmitylethanolamide) is an endogenous fatty acid amide, belonging to the class of o nuclear factor agonists.
• the chemical structure of PEA is:
• PEA has been demonstrated to bind to a receptor in the cell nucleus (a nuclear receptor) and exerts a variety of biological functions related to chronic pain and inflammation. Studies have shown that PEA interacts with distinct non-CB1/CB2 receptors, suggesting that PEA utilizes a unique "parallel" endocannabinoid signaling system. This concept was further supported by growing evidence that PEA production and inactivation can occur independently of AEA and 2-AG production and inactivation. Much of the biological effects of PEA on cells can be attributed to its affinity to PPAR (particularly PPAR-. alpha, and PPAR-. gamma.).
• PEA was shown to have an affinity to cannabinoid-like G-coupled receptors GPR55 and GPR1 19 as well as the transient receptor potential vanilloid type 1 receptor (TRPV1 ). PEA has been shown to have antiinflammatory, anti-nociceptive, neuro-protective, and anti-convulsant properties.
• the present disclosure provides pharmaceutical compositions comprising combinations of MEAI, or salts thereof, and N-acylethanolamines, or salts thereof. In some embodiments these combinations comprise specific molar ratios between the respective active agents and/or dosages and may be employed in a variety of methods. Particularly, the present disclosure provides methods for preventing and/or treating a variety of conditions responsive to MEAI treatment, such as alcohol consumption, including alcoholism, eating, tobacco consumption, shopping, or sexual conduct.
• the present disclosure provides, in one aspect, a pharmaceutical composition
• 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 the MEAI and the N-acylethanolamine is between about 1 :0.2 to about 1 :2000.
• the molar ratio between the MEAI and the N- acylethanolamine is between about 1 :0.2 to about 1 :5. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is between about 1 :0.5 to about 1 :2. In certain embodiments, the molar ratio between the MEAI and the N- acylethanolamine is between about 1 :15 to about 1 :1800. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is between about 1 :25 to about 1 :450. In certain embodiments, the molar ratio between the MEAI and the N- acylethanolamine is between about 1 :50 to about 1 :100.
• the molar ratio between the MEAI and the N-acylethanolamine is about 1 :50. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :100.
• the pharmaceutical composition comprises about 0.5-10 mg MEAI or a salt thereof. In certain embodiments, the pharmaceutical composition comprises about 1 mg, about 2.5 mg, about 5 mg, or about 10 mg MEAI or a salt thereof. Each possibility represents a separate embodiment of the present disclosure.
• the pharmaceutical composition comprises about 200-1800 mg N-acylethanolamine or a salt thereof. In certain embodiments, the pharmaceutical composition comprises about 250 mg, about 500 mg, about 750 mg, about 1000 mg or about 1500 mg N-acylethanolamine or a salt thereof. Each possibility represents a separate embodiment of the present disclosure.
• the N-acylethanolamine is selected from the group consisting of N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA) , salts thereof and any combination thereof.
• PDA N-palmitoylethanolamine
• Me-PEA Me-palmitoylethanolamide
• palmitoylcyclohexamide palmitoylbutylamide
• palmitoylisopropylamide oleoylethanolamine
• PIA palmitoylisopropylamide
• the N-acylethanolamine is PEA or a salt thereof.
• the N-acylethanolamine consists of PEA or a salt thereof.
• the N-acyl ethanol amine consists of PEA
• the pharmaceutical composition is formulated for systemic administration.
• the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration.
• the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration.
• the pharmaceutical composition is formulated for oral administration.
• the pharmaceutical composition is formulated for oral mucosal administration.
• the pharmaceutical composition is formulated for nasal administration.
• the pharmaceutical composition is formulated for sublingual administration.
• the present disclosure further provides, in another aspect, a dosage unit comprising or consisting of the pharmaceutical composition described above.
• the dosage unit comprises the pharmaceutical composition described above. In certain embodiments, the dosage unit consisting of the pharmaceutical composition described above. In certain embodiments, the dosage unit is formulated as a gel, a powder or a spray. In certain embodiments, the dosage unit is formulated as a gel. In certain embodiments, the dosage unit is formulated as a powder. In certain embodiments, the dosage unit is formulated as a spray.
• the N-acylethanolamine increases the therapeutic potency of the MEAI compared to the same pharmaceutical composition without the N- acylethanolamine. In certain embodiments, the N-acylethanolamine decreases the required therapeutic dosage of the MEAI compared to the same pharmaceutical composition without the N-acylethanolamine. In certain embodiments, the N- acylethanolamine reduces at least one of the side-effects of the MEAI compared to the same pharmaceutical composition without the N-acylethanolamine. In certain embodiments, the N-acylethanolamine expends the therapeutic window of the MEAI compared to the same pharmaceutical composition without the N-acylethanolamine.
• the PEA or salt thereof increases the therapeutic potency of the THC or salt thereof compared to the same pharmaceutical composition without the PEA or salt thereof. In certain embodiments, the PEA or salt thereof decreases the required therapeutic dosage of the THC or salt thereof compared to the same pharmaceutical composition without the PEA or salt thereof. In certain embodiments, the PEA or salt thereof reduces at least one of the side-effects of the THC or salt thereof compared to the same pharmaceutical composition without the PEA or salt thereof. In certain embodiments, the PEA or salt thereof expends the therapeutic window of the THC or salt thereof compared to the same pharmaceutical composition without the PEA or salt thereof.
• the MEAI and the N-acylethanolamine are comprised in the same pharmaceutical composition. In certain embodiments of the methods described above, the MEAI and the N-acylethanolamine are comprised in different pharmaceutical compositions.
• the administration of the MEAI and the N-acylethanolamine is repeated three times a day. In certain embodiments of the methods described above, the administration of the MEAI and the N-acylethanolamine is repeated twice a day. In certain embodiments of the methods described above, the administration of the MEAI and the N-acylethanolamine is repeated once a day. In certain embodiments of the methods described above, the administration of the MEAI and the N-acylethanolamine is repeated once every two days. In certain embodiments of the methods described above, the administration of the MEAI and the N-acylethanolamine is repeated once every three days.
• the present disclosure is directed to a a pharmaceutical composition
• a pharmaceutical composition comprising 5-methoxy-2-aminoindan, or a salt thereof, and an N- acylethanolamine, or a salt thereof, and at least one pharmaceutically acceptable carrier and/or excipient.
• the pharmaceutical composition is a unit dosage form composition. In other embodiments, the pharmaceutical composition is a solid unit dosage form composition. In still other embodiments, the pharmaceutical composition is a liquid unit dosage form composition. In additional embodiments, the pharmaceutical composition is packaged as a single unit dose or as a plurality of single unit doses.
• the unit dosage form comprises from 30 mg to 130 mg of 5- methoxy-2-aminoindan.
• the pharmaceutical composition is formulated for oral administration.
• the disclosure is directed to a method of regulating binge behavior, comprising administrating to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising 5-methoxy-2-aminoindan, or a salt thereof, and an N-acylethanolamine, or a salt thereof, thereby regulating the binge behavior.
• the binge behavior is associated with alcohol consumption, eating, tobacco consumption, shopping, or sexual conduct. In other embodiments, the binge behavior is binge drinking.
• the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and/or excipient.
• the pharmaceutical composition is a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, or a syrup.
• the pharmaceutical composition in the methods of the disclosure is a unit dosage form composition.
• the amount of 5- methoxy-2-aminoindan in the unit dosage form ranges from about 30 mg to about 130 mg. In certain embodiments, the amount of 5-methoxy-2-aminoindan is about 70 mg.
• the pharmaceutical composition is administered orally.
• Fig. 1 shows food consumption presented as mean fold change of each group out of baseline (i.e. food consumption measured before MEAI treatment) +/- SEM, statistical analysis was performed using Student’s T-test of each group vs. control; *p ⁇ 0.05, ***p ⁇ 0.001 for mice in Cycle 1 (Fig. 1A) and Cycle 2 (Fig. 1 B).
• Figs. 2A and 2B show alcohol consumption of mice in Intermittent Access to 20% Alcohol in two-bottle choice (IA2BC) model.
• Results of cycle 1 (Fig. 2A) and cycle 2 (Fig. 2B) are presented as mean of alcohol consumption (g/kg/24h) ⁇ SEM, from Day 1 of consumption until Day 47/50.
• Statistical analysis was performed only on the 6/7 days of treatment, using two-way ANOVA, followed by Bonferroni post-hoc tests for multiple comparisons (*p ⁇ 0.05; **p ⁇ 0.01 ; ***p ⁇ 0.001 ).
• Fig. 3 shows alcohol consumption before and after treatment.
• the results for Cycle 1 are shown in Fig. 3A and for Cycle 2 are shown in Fig. 3B.
• Results are presented as mean of alcohol consumption (g/kg/24h) ⁇ SEM.
• Statistical analysis was preformed using two-way ANOVA (repeated measures) followed by Bonferroni posttests to compare replicate means by row. (**p ⁇ 0.01 ; ***p ⁇ 0.001 ).
• Fig. 4 shows the fold change of each group of consumption during 6-7 alcohol days with MEAI/PEA treatment out of its own baseline consumption prior to treatment.
• Results are presented as mean of fold change + SEM. Mean fold change of all alcohol days together. Statistical analysis was preformed using Student’s T-test (*p ⁇ 0.05).
• Fig. 5 shows water consumption of mice in Intermittent Access to 20% Alcohol in two-bottle choice (IA2BC) model. Results of cycle 1 (Fig. 5A) and cycle 2 (Fig. 5B) are presented as mean of water consumption (g/kg/24h) ⁇ SEM, from Day 1 of consumption until Day 47/50. [38] Fig. 6 shows mean alcohol preference [alcohol consumption g/kg/24h I (total consumption of fluids g/kg/24h) for Cycle 1 (Fig. 6A) and Cycle 2 (Fig. 6B). Results are presented as mean ⁇ SEM. Statistical analysis was performed using two-way ANOVA, followed by Bonferroni post-hoc tests for multiple comparisons (*p ⁇ 0.05; **p ⁇ 0.01 ).
• Fig. 7 shows alcohol consumption of mice in Intermittent Access to 20% Alcohol in two-bottle choice (IA2BC) model.
• Results of cycle 1 (Fig. 7A) and cycle 2 (Fig. 7B) are presented as mean of alcohol consumption (g/kg/24h) ⁇ SEM, from Day 22 (6 consumption days before treatment) until Day 47/50 (6/7 consumption days of treatment).
• Figs. 8A and 8B show mean alcohol consumption of cycle 1 and cycle 2 during 6 alcohol days of consumption during MEAI treatment.
• Figs. 9A and 9B show results presented as mean of alcohol consumption (g/kg/24h) +/- SEM for cycle 1 and cycle groups. Statistical analysis was performed using two-way ANOVA, followed by Bonferroni post-hoc tests for multiple comparisons (*p ⁇ 0.05; **p ⁇ 0.01 ; ***p ⁇ 0.001 ).
• Fig. 10 shows fold change in the cycle 1 group of consumption during 6 alcohol days with MEAI treatment to its own consumption prior to MEAI treatment. Results are presented as mean of fold change ⁇ SEM.
• Fig. 10A shows the mean fold change in each of the six alcohol days.
• Fig. 10B shows mean fold change of all alcohol days together. Statistical analysis of cycle 1 was preformed using paired Student’s T-test.
• Fig. 1 1 shows fold change in the cycle 1 group of consumption during 6 alcohol days with MEAI treatment to its own consumption prior to MEAI treatment. Results are presented as mean of fold change ⁇ SEM.
• Fig. 11 A shows the mean fold change in each of the six alcohol days.
• Fig. 11 B shows mean fold change of all alcohol days together.
• Statistical analysis of cycle 2 was preformed using One-way- repeated- measures ANOVA (repeated measures), followed by Bonferroni posttests to compare all means by row (*p ⁇ 0.05; **p ⁇ 0.01 ; ***p ⁇ 0.005).
• the present disclosure in some embodiments thereof, relates to binge behavior, and more particularly, but not exclusively, to compositions and methods for regulation of binge behavior, such binge drinking.
• Binge behavior includes intensive, short episodes of overuse and over consumption of food, alcohol, smoking products, drugs, sweets, sex and the like. Bingeing behaviors are compulsive in style, intensity, habituation, history, motivation, and difficulty to control and remediate.
• Compulsive behavior refers to driven behaviors which are often influenced by subconscious desires and motives, as well as strong, uncontrollable, hard-to-tame actions and behaviors which have a predictable pattern.
• a subject in need of regulating a binge behavior is typically a subject that experiences episodes of over consumption of the binge's subject (e.g., food, alcohol, smoking, drug use, sweets, sex, shopping, etc.), either on a regular basis, for example, more than once a week, or occasionally, or even rarely, for example once or twice a year, depending on the severity of the binges.
• Blackout drinkers for example, that experience a blackout when consuming alcohol even as rarely as twice per year are defined herein as subjects is need of regulating binge drinking.
• Determining a subject in need of regulating binge behavior can be made, in some cases, according to national or international standards, or by acceptable evaluations by health professionals (e.g., physicians, psychologists, cognitive therapists, social workers, nutritionists, etc., depending on the binge disorder).
• health professionals e.g., physicians, psychologists, cognitive therapists, social workers, nutritionists, etc., depending on the binge disorder.
• binge behavior is associated with alcohol consumption, tobacco consumption, eating, shopping and/or sexual conduct.
• binge drinking used by NHS and the National Office of Statistics describes it as drinking more than double the lower risk guidelines for alcohol in one drinking session, wherein the guidelines advise that people should not regularly drink more than the lower risk guidelines of 3-4 units of alcohol for men (equivalent to a pint and a half of 4% beer (about 852 ml)) and 2-3 units of alcohol for women (equivalent to a 175 ml glass of wine).
• Regularly means drinking every day or most days of the week.
• the method provided herein is for reducing alcohol consumption in a non-binger subject who wishes to control his alcohol consumption, for example, under certain circumstances (for example, during a specific event or time point).
• the term "binge drinking regulation” in a broad interpretation refers to controlling the excessive, uncontrolled consumption of alcoholic beverages. Regulating binge drinking relates to reducing the amount of alcohol consumed in a drinking session and/or reducing the number of drinking sessions.
• binge drinking regulation relates to imparting a feeling of satisfaction, satiety or contentedness which discourages binge drinking.
• Binge drinking regulation as practiced in embodiments of the present disclosure affects a true harm reduction utility by discouraging binge drinking in a way that is easy to implement (by drinking) and non-harmful (pending toxicological validation) to the drinker.
• Ci-Ce alkyl is intended to encompass Ci , C2, C3, C4, C5, Ce, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
• “Isomers” means compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms in space.
• Steps or “optical isomer” mean a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light. Because asymmetric centers and other chemical structure exist in the compounds of the disclosure which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof.
• the compounds of the disclosure and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture.
• stereoisomers can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures.
• individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns.
• Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well-known in the art.
• racemic form of drug may be used, it is often less effective than administering an equal amount of enantiomerically pure drug; indeed, in some cases, one enantiomer may be pharmacologically inactive and would merely serve as a simple diluent.
• ibuprofen had been previously administered as a racemate, it has been shown that only the S-isomer of ibuprofen is effective as an antiinflammatory agent (in the case of ibuprofen, however, although the R-isomer is inactive, it is converted in vivo to the S-isomer, thus, the rapidity of action of the racemic form of the drug is less than that of the pure S-isomer).
• enantiomers may have distinct biological activity.
• S-penicillamine is a therapeutic agent for chronic arthritis
• R- penicillamine is toxic.
• some purified enantiomers have advantages over the racemates, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to the racemic mixture. See U.S. Pat. Nos. 5,114,946 and 4,818,541.
• the compound is a racemic mixture of (S)- and (R)-isomers.
• provided herein is a mixture of compounds wherein individual compounds of the mixture exist predominately in an (S)- or (R)-isomeric configuration.
• the compound mixture has an (S)-enantiomeric excess 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.
• 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
• 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.
• 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.
• Individual stereoisomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by: (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary; (2) salt formation employing an optically active resolving agent; or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
• Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
• Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
• the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers.
• stereoisomers when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbol “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom.
• Stereoisomers include enantiomers and diastereomers.
• enantiomers or diastereomers may be designated “( ⁇ )” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
• an enantiomer or stereoisomer may be provided substantially free of the corresponding enantiomer.
• the present disclosure provides, in one aspect, a pharmaceutical composition
• 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.
• the present disclosure provides, in another aspect, a pharmaceutical composition
• 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 the MEAI and the N-acylethanolamine is between about 1 :0.2 to about 1 :2000.
• a "pharmaceutical composition” refers to a preparation of the active agents 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.
• pharmaceutically acceptable carrier refers to a carrier, an excipient or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. An adjuvant is included under these phrases.
• excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, oils such as vegetable oils or fish oils, and polyethylene glycols.
• carrier refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered.
• Such pharmaceutical carriers can be sterile liquids, such as water and oils.
• Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions.
• Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E. W. Martin, 18th Edition.
• phrases "pharmaceutically acceptable” as used herein refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar toxicity when administered to an individual.
• pharmaceutically acceptable may mean approved by a regulatory agency (for example, the U.S. Food and Drug Agency) or listed in a generally recognized pharmacopeia for use in animals (e.g., the U.S. Pharmacopeia).
• the phrase “pharmaceutically acceptable salt” refers to a charged species of the parent compound and its counter-ion, which is typically used to modify the solubility characteristics of the parent compound and/or to reduce any significant irritation to an organism by the parent compound, while not abrogating the biological activity and properties of the administered compound.
• a pharmaceutically acceptable salt of the compounds described herein may optionally be an acid addition salt comprising at least one basic (e.g., amine) group of the compound which is in a positively charged form (e.g., an ammonium ion), in combination with at least one counter-ion, derived from the selected acid, that forms a pharmaceutically acceptable salt.
• the acid addition salts of the compounds described herein may therefore be complexes formed between one or more basic groups of the drug and one or more equivalents of an acid.
• the acid addition salts may include a variety of organic and inorganic acids, such as, but not limited to, hydrochloric acid which affords a hydrochloric acid addition salt, hydrobromic acid which affords a hydrobromic acid addition salt, acetic acid which affords an acetic acid addition salt, ascorbic acid which affords an ascorbic acid addition salt, benzenesulfonic acid which affords a besylate addition salt, camphorsulfonic acid which affords a camphorsulfonic acid addition salt, citric acid which affords a citric acid addition salt, maleic acid which affords a maleic acid addition salt, malic acid which affords a malic acid addition salt, methanesulfonic acid which affords a methanesulfonic acid (mesylate) addition salt, naphthalenesulfonic acid which affords a naphthalenesulfonic acid addition salt, oxalic acid which affords an oxalic acid addition salt,
• a pharmaceutically acceptable salt of the compounds described herein may optionally be a base addition salt comprising at least one group of the compound which is in a form of an anion, in combination with at least one counter ion (i.e. , cation) that forms a pharmaceutically acceptable salt.
• suitable cations include metal cations of metals such as, but not limited to, sodium, potassium, magnesium, and calcium or ammonium.
• Each of these base addition salts can be either a mono-addition salt or a poly-addition salt, as these terms are defined herein.
• the acid or base additions salts can be either mono-addition salts or poly-addition salts.
• poly-addition salt refers to a salt in which the stoichiometric ratio between the counter-ion and the charged form of the compound is greater than 1 :1 and is, for example, 2:1 , 3:1 , 4:1 and so on, such that the addition salt includes two or more molar equivalents of the counter-ion per one molar equivalent of the compound.
• each of the compounds described herein, including the salts thereof can be in a form of a solvate or a hydrate thereof.
• solvate refers to a complex of variable stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, and so on), which is formed by a solute (the 2-aminoindan
• hydrate refers to a solvate, as defined hereinabove, where the solvent is water.
• N-acylethanolamine as used herein generally refers to a type of fatty
• 25 acid amide lipid-derived signaling molecules, formed when one of several types of acyl group is linked to the nitrogen atom of ethanolamine.
• These amides conceptually can be formed from a fatty acid and ethanolamine with the release of a molecule of water, but the known biological synthesis uses a specific phospholipase D to cleave the phospholipid unit from N-acylphosphatidylethanolamines.
• amine in ethanolamine because it is considered as a free terminal nitrogen in that subunit, while it is termed "amide” when it is considered in association with the adjacent carbonyl group of the acyl subunit. Names for these compounds may be encountered with either "amide” or "amine” in the present application.
• ethanolamine is used in the generic sense and is meant to include mono-ethanolamine, di-ethanolamine, tri-ethanolamine, and mixtures thereof.
• derivative means a compound whose core structure is the same as, or closely resembles that of an N-acylethanolamine compound, but which has a chemical or physical modification, such as different or additional side groups.
• salt refers to any form of an active ingredient in which the active ingredient assumes an ionic form and is coupled to a counter ion (a cation or anion) or is in solution. This also includes complexes of the active ingredient with other molecules and ions, in particular complexes which are complexed by ion interaction.
• the molar ratio between the MEAI and the N- acylethanolamine is between about 1 :0.2 to about 1 :5. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is between about 1 :0.22 to about 1 :4.5, about 1 :0.25 to about 1 :4, between about 1 :0.28 to about 1 :3.5, between about 1 :0.33 to about 1 :3, between about 1 :0.4 to about 1 :2.5, between about 1 :0.5 to about 1 :2 or about 1 :1 .
• Each possibility represents a separate embodiment of the present disclosure.
• the molar ratio between the MEAI and the N- acylethanolamine is between about 1 :15 to about 1 :1800. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is between about 1 :16 to about 1 :1700, about 1 :17 to about 1 :1600, about 1 :18 to about 1 :1500, about 1 :19 to about 1 :1400, about 1 :20 to about 1 :1300, about 1 :21 to about 1 :1200, about 1 :22 to about 1 :1 100, about 1 :23 to about 1 :1000, about 1 :24 to about 1 :900, about 1 :15 to about 1 :800, about 1 :16 to about 1 :700, about 1 :17 to about 1 :600, about 1 :18 to about 1 :500, about 1 :19 to about 1 :490, about 1 :20 to about 1 :480, about 1 :20 to about 1 :
• the molar ratio between the MEAI and the N-acylethanolamine is between about 1 :25 to about 1 :450. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is between about 1 :10 to about 1 :500, about 1 :15 to about 1 :450, about 1 :20 to about 1 :400, about 1 :25 to about 1 :350, about 1 :30 to about 1 :300, about 1 :35 to about 1 :250, about 1 :40 to about 1 :200, or about 1 :45 to about 1 : 150.
• Each possibility represents a separate embodiment of the present disclosure.
• the molar ratio between the MEAI and the N-acylethanolamine is between about 1 :50 to about 1 :100. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :10. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :20. In certain embodiments, the molar ratio between the MEAI and the N- acylethanolamine is about 1 :30. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :40. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :50.
• the molar ratio between the MEAI and the N-acylethanolamine is about 1 :60. In certain embodiments, the molar ratio between the MEAI and the N- acylethanolamine is about 1 :70. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :80. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :90. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :100. In certain embodiments, the molar ratio between the MEAI and the N- acylethanolamine is about 1 :1 10.
• the molar ratio between the MEAI and the N-acylethanolamine is about 1 :120. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :130. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :140. In certain embodiments, the molar ratio between the MEAI and the N- acylethanolamine is about 1 :150. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :160. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :170.
• the molar ratio between the MEAI and the N-acylethanolamine is about 1 :180. In certain embodiments, the molar ratio between the MEAI and the N- acylethanolamine is about 1 :190. In certain embodiments, the molar ratio between the MEAI and the N-acylethanolamine is about 1 :200. In certain embodiments, the molar ratio between the MEAI and the 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.
• the pharmaceutical composition comprises about 0.5-10 mg MEAI or a salt thereof. In certain embodiments, the pharmaceutical composition comprises about 1 -9.5 mg, about 1 .5-9 mg, about 2-8.5 mg, about 2.5-8 mg, about 3- 7.5 mg, about 3.5-7 mg, about 4-6.5 mg, about 4.5-6 mg or about 5-5.5 mg MEAI or a salt thereof.
• 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 MEAI or a salt thereof.
• Each possibility represents a separate embodiment of the present disclosure.
• 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 a salt thereof.
• Each possibility represents a separate embodiment of the present disclosure.
• the pharmaceutical composition comprises about 0.5 mg to about 1 mg, about 0.5 mg to about 1 .5 mg, about 0.5 mg to about 2 mg, about 0.5 mg to about 2.5 mg, about 0.5 mg to about 3 mg, about 0.5 mg to about 3.5 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 4.5 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 5.5 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 6.5 mg, about 0.5 mg to about 7 mg, about 0.5 mg to about 7.5 mg, about 0.5 mg to about 8 mg, about 0.5 mg to about 8.5 mg, about 0.5 mg to about 9 mg or about 0.5 mg to about 9.5 mg MEAI or a salt thereof.
• Each possibility represents a separate embodiment of the present disclosure.
• the pharmaceutical composition comprises about 200-1800 mg N-acylethanolamine or a salt thereof. In certain embodiments, the pharmaceutical composition comprises about 250-1550 mg, about 300-1200 mg, about 350-950 mg, about 400-700 mg, about 450-600 mg or about 500-550 mg N-acylethanolamine or a salt thereof. Each possibility represents a separate embodiment of the present disclosure.
• 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 1 150 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 N-acylethanolamine or a salt thereof.
• 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 N-acylethanolamine or a salt thereof.
• Each possibility represents a separate embodiment of the present disclosure.
• the N-acylcthanolamine is selected from the group consisting of N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexamide, palmitoylbutylamide, palmitoylisopropylamide, oleoylethanolamine (OEA), palmitoylisopropylamide (PIA) , salts thereof and any combination thereof.
• PDA N-palmitoylethanolamine
• Me-PEA Me-palmitoylethanolamide
• palmitoylcyclohexamide palmitoylbutylamide
• palmitoylisopropylamide oleoylethanolamine
• PIA palmitoylisopropylamide
• the N-acylethanolamine is PEA or a salt thereof.
• the N-acylethanolamine consists of PEA or a salt thereof.
• the N-acylethanolamine consists of PE
• the pharmaceutical composition is formulated for systemic administration.
• the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration.
• the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration.
• the pharmaceutical composition is formulated for oral administration.
• the pharmaceutical composition is formulated for oral mucosal administration.
• the pharmaceutical composition is formulated for nasal administration.
• the pharmaceutical composition is formulated for sublingual administration.
• compositions of the present disclosure may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
• the pharmaceutical composition can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
• Such carriers enable the pharmaceutical composition to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient.
• Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries as desired, to obtain tablets or dragee cores.
• Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, and sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
• disintegrating agents such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, may be added.
• oral administration refers to any method of administration in which an active agent can be administered by swallowing, chewing, sucking, or drinking an oral dosage form.
• solid dosage forms include conventional tablets, multi-layer tablets, capsules, caplets, etc., which do not substantially release the drug in the mouth or in the oral cavity.
• Dragee cores are provided with suitable coatings.
• suitable coatings may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
• Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
• compositions that can be used orally include stiff or soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
• the capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
• the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
• stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.
• compositions may take the form of tablets or lozenges formulated in conventional manner or in adhesive carriers.
• the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., a sterile, pyrogen-free, water-based solution, before use.
• compositions suitable for use in the context of the present disclosure include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a “therapeutically effective amount” means an amount of active ingredients effective to prevent, alleviate, or ameliorate symptoms or side effects of a disease or disorder, or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
• a "therapeutically effective amount of a mixture” means an amount of at least two active ingredients, wherein each one of the active ingredients independently may not be in a therapeutically effective amount or wherein both of the active ingredients may not be in a therapeutically effective amount, the mixture is nevertheless effective to prevent, alleviate, or ameliorate symptoms or side effects of a disease or disorder, or prolong the survival of the subject being treated.
• the term "mixture” as used herein refers to a non-covalent combination of two molecules.
• the dosage or the therapeutically effective amount can be estimated initially from in vitro, in vivo and cell culture assays.
• a dose can be formulated in animal models to achieve a desired concentration or titer. Such information can be used to more accurately determine useful doses in humans.
• the dosage of each compound of the claimed combinations depends on several factors, including: the administration method, 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. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular patient may affect dosage used.
• Continuous daily dosing may not be required; a therapeutic regimen may require cycles, during which time a drug is not administered, or therapy may be provided on an as-needed basis during periods of acute disease worsening. Dosage escalation may or may not be required; a therapeutic regimen may require reduction in medication dosage.
• Toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, in cell cultures or experimental animals. The data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage may vary depending upon the dosage form employed and the route of administration utilized.
• Dosing can be of a single or a plurality of administrations, with course of treatment lasting from several days to several weeks, or until cure is affected or diminution of the disease state is achieved.
• the present disclosure further provides, in another aspect, a dosage unit comprising or consisting of the pharmaceutical composition described above.
• the dosage unit comprises the pharmaceutical composition described above. In certain embodiments, the dosage unit consisting of the pharmaceutical composition described above. In certain embodiments, the dosage unit is formulated as a gel, a powder or a spray. In certain embodiments, the dosage unit is formulated as a gel. In certain embodiments, the dosage unit is formulated as a powder. In certain embodiments, the dosage unit is formulated as a spray.
• the present disclosure further provides, in another aspect, a pharmaceutical composition or a 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 MEAL
• treating includes, but is not limited to, any one or more of the following: abrogating, ameliorating, inhibiting, attenuating, blocking, suppressing, reducing, delaying, halting, alleviating or preventing one or more symptoms or side effects of the diseases or conditions of the disclosure.
• chronic means that the length of time of the diseases or conditions of the disclosure can be weeks, months, or possibly years.
• the intensity of the diseases or conditions can differentiate according to various conditions such as patient age, temperature, season, type of disease, etc.
• the term "about” as used herein in relation to a value, a plurality of values or a range of values defined by a lowest and highest values means a value which is 10% lower and/or higher than the corresponding value, plurality of values or range of values.
• 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”
• the phrase “about 1 to about 2” means "0.9 to 2.2”.
• compositions, method or microcapsules may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
• Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 5 o (the dose lethal to 50% of the population) and the ED50 (the dose 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 LD50/ED50.
• Compositions that exhibit large therapeutic indices are preferable.
• the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
• the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
• a therapeutically effective amount may vary with the subject's age, condition, and gender, as well as the severity of the medical condition in the subject.
• the dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.
• Example 1 Evaluation of the Efficacy of MEAI and PEA in Binge Alcohol Consumption in Mice
• Alcohol consumption and alcoholism present a growing problem worldwide, which also believed to overtaken tobacco in terms of overall health and social care costs. Excessive and/or prolonged alcohol consumption may have some undesired physiological and psychological, including short-term effects such as gastric irritation, anxiety disorders and other excitable states, and longer-term effects such as cirrhosis, fatty liver disease, cardiomyopathy and dementia.
• MEAI (5-methoxy-2-aminoindane or 5-MeO-AI) is a derivative of 2-Aminoindan, useful as binge regulators or binge mitigation agents that impart a feeling of satisfaction, satiety or contentedness and regulate (e.g., discourage) binge behavior such as binge drinking.
• Administration of an effective amount of the binge regulating agent, whether alone or in combination with an alcoholic beverage, to a subject is expected to reduce the amount of alcohol consumed in a binge drinking, and to prevent many of the adverse effects associated with excessive alcohol consumption. This relates particularly to short-term effects such as heavy intoxication that leads to serious consequences such as accidents and uncontrolled violent behavior with subsequent medical complications, as well as gastric irritation, anxiety disorders and other excitable states.
• mice were provided during the whole Study with two bottles: one bottle of water, and another bottle of 20% ethanol solution, which were removed and replaced after 24 hours with another buttle of water, for additional 24 hours. In total, the mice were subjected to 20% ethanol 24 hours, three times a week, for seven-eight weeks (21-22 alcohol consumption days).
• Vehicle 1 was prepared from water for injection.
• Vehicle 2 solution was prepared from Ethanol:Kolliphor:Water for injection (1 :1 :18, respectively).
• Test Item 1 (MEAI): was supplied as a powder and was dissolved using Vehicle 1 at several dilutions according to Table 2.
• Test Item 2 was supplied as a powder and was dissolved using Vehicle 2 at 5 mg/mL according to Table 2.
• mice were housed in filtered cages (up to 5 per cage) measuring 36.5 x 20.7 x 13 cm with stainless steel top grill facilitating pelleted food and drinking water in plastic bottle; bedding: steam sterilized clean paddy husk (Envigo, Teklad, Laboratory grade, Sani-chips). Bedding material was changed along with the cage at least once a week.
• NASH National Institute of Health
• AALAC Association for Assessment and Accreditation of Laboratory Animal Care
• mice were fed ad libitum a commercial rodent diet (Teklad Certified Global
• mice were housed under standard laboratory conditions, air conditioned and filtered (HEPA F6/6) with adequate fresh air supply (Minimum 15 air changes/hour). The mice were kept in a climate-controlled environment. Temperatures range was 18-24°C and relative humidity range 30-70% with a reversed 12 hours light and 12 hours dark cycle (6PM/6AM).
• mice were examined by the Attending Veterinarian (AV) to determine they were fit for the study before the experimental phase initiation. Animals were inspected daily for any signs of morbidity of mortality.
• AV Attending Veterinarian
• First dosing day was assigned "Day 1 " and termination day was “Day 50” for Cycle 1 and Day 52 for Cycle 2.
• the study was conducted in two cycles. The first cycle included five groups: four were treated with elevated concentrations of MEAI and control groups of ‘Water for Injection’-Vehicle 1 . In the second cycle, three additional groups of mice with a combination of MEAI+PEA (in elevated dilutions of MEAI), another group of PEA+Vehicle 1 treated mice and another group of Vehicle 2, which includes the solvent of PEA (Ethanol:Kolliphor:Water at 1 :1 :18) were treated.
• mice received only alcohol (three times a week), to establish the IA2BC model and the binge drinking.
• the mice were administered everyday with the Test Items/Vehicles (MEAI, PEA) to examine its effect on the alcohol consumption. The dosing was performed right before the alcohol addition (15-30 min). Five additional mice, 12 weeks of age, were not treated with alcohol and served as naive mice for histology controls.
• BW Body weight
• mice were evaluated for macroscopic findings during gross pathology.
• the pathology findings that were detected in the liver, kidneys, heart and spleen (bright color and/or enlarged) were observed in all groups including the vehicle treated (groups 1 F, 6F and 7F). All groups were treated with alcohol, suggesting that these were most likely related to the alcohol consumption and not to the MEAI treatment.
• white dots were found in mice from groups 9F and 10F in cycle 2, but not cycle 1 , in organs such as the pancreas (see appendix section Figure 8), liver and peritoneum, sub-dermal and fat tissues. It is possible that these white dots are accumulation of the PEA.
• Results showed a significant dose dependent effect for the MEAI treatment in reducing alcohol consumption of the treated animals, with additive effect for the PEA treatment at the lower MEAI doses. There was no significant difference between the animals’ body weight, and the food consumption was also not affected by the MEAI treatment.
• mice from groups 9F and 10F in cycle 2, but not cycle 1 were found in mice from groups 9F and 10F in cycle 2, but not cycle 1 , in organs such as the pancreas, liver and peritoneum, sub-dermal and fat tissues. It is possible that these white dots are accumulation of the PEA.
• the fold change of group 3F was significantly lower compared to the control group 1 F (MEAI 0) (*p ⁇ 0.05).
• the fold change of group 4F was lower than the control, however, not significant.
• Groups 2F MEAI 20 mg/kg
• 5F MEAI 100 mg/kg were similar to the control Group 1 F.
• mice Intermittent access to 20% Alcohol in two-bottle choice (IA2BC) model in mice.
• the mice were subjected to 20% ethanol 24 hours, three times a week, for five weeks (15 alcohol consumption days), and the alcohol consumption was measured by weight.
• the mice were allocated to groups according to their alcohol consumption, and the effect of MEAI/PEA treatment in reducing alcohol consumption was examined.
• Mice were treated, with Vehicle/MEAI/PEA, daily, during days 36-48 in cycle 1 , and during days 36-51 in cycle 2.
• Figures 3A and 3B demonstrate a significant reduction in alcohol consumption, during the 6/7 days of treatment, in the treated mice vs. control, in a dose dependent manner, in both cycles.
• FIG. 4 represents the mean value of alcohol consumption of six alcohol days prior to MEAI treatment in each group (white bars), vs. mean value of six alcohol days of consumption during MEAI treatment in each group (blue bars).
• cycle 1 the alcohol consumption was significantly reduced following treatment with MEAI at a dose of 40 mg/kg and at higher doses (**p ⁇ 0.01 ; ***p ⁇ 0.001) compared to consumption before treatment.
• cycle 2 the alcohol consumption was significantly reduced following dual treatment with 25 mg/kg PEA in addition to MEAI at a dose of 20 mg/kg and at higher doses (**p ⁇ 0.01 , ***p ⁇ 0.001 ) compared to consumption before treatment.
• FIG. 3 represents the mean value of alcohol consumption of six alcohol days prior to MEAI treatment in each group (white bars), vs. mean value of six alcohol days of consumption during MEAI treatment in each group (blue bars).
• cycle 1 Fig. 3A
• the alcohol consumption was significantly reduced following treatment with MEAI at a dose of 40 mg/kg and at higher doses (**p ⁇ 0.01 ; ***p ⁇ 0.001) compared to consumption before treatment.
• cycle 2 Fig. 3B
• the alcohol consumption was significantly reduced following dual treatment with 25 mg/kg PEA in addition to MEAI at a dose of 20 mg/kg and at higher doses (**p ⁇ 0.01 , ***p ⁇ 0.001 ) compared to consumption before treatment.
• Results showed a significant dose dependent effect for the MEAI treatment in reducing alcohol consumption of the treated animals, with additive effect for the PEA treatment at the lower MEAI doses. Furthermore, in reverse correlation, the consumption of water was elevated during the MEAI treatment, in both cycles, hence, the alcohol preference (out of total fluids) was also reduced, at a dose dependent manner.

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