Compositions comprising ibogasine optionally in combination with N-acylethanolamine and uses thereof

Abstract

The present disclosure relates to pharmaceutical compositions comprising ibogine or a salt thereof and a combination of ibogine or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a salt thereof with at least one pharmaceutically acceptable carrier and / or excipient and their use in treatments by administering the composition in a therapeutically effective amount to a subject in need thereof The invention also relates to the use in methods of opioid addiction and opioid dependence.

Description

[0001] Cross Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 485,107, filed February 15, 2023, the contents of which are incorporated herein in their entirety. TECHNICAL FIELD

[0002] The present disclosure relates to compositions and methods for enhancing the therapeutic effects and / or reducing the side effects of ibogaine or a pharmaceutically acceptable salt thereof. The present disclosure provides pharmaceutical compositions comprising ibogaine or a pharmaceutically acceptable salt thereof or pharmaceutical compositions comprising a combination of ibogaine or a pharmaceutically acceptable salt thereof and an N-acyl ethanolamine or a pharmaceutically acceptable salt thereof (e.g., palmitoylethanolamide (“PEA”)) and methods thereof for a variety of indications suitable for treatment, including but not limited to substance addiction or opioid dependence. BACKGROUND

[0003] Ibogaine is a plant indole alkaloid that has been shown to have promising anti-addiction properties (Koenig et al., The anti-addiction drug ibogaine and the heart: a delicate relation. Molecules. 20(2):2208-28 (2015)). The chemical structure of ibogaine is: . There is evidence that ibogaine can relieve drug craving and prevent relapse to drug use. It is currently used in alternative medicine clinics around the world. Administration of ibogaine has been used to treat drug dependence, with the result that withdrawal symptoms continue to subside within 12-18 hours, and drug craving is reduced for long periods of time, up to several weeks. (Brown, T.K., Ibogaine in the treatment of substance dependence. Current drug abuse reviews Volume 6, 1: 3-16 (2013)). Studies have also shown that ibogaine can be useful in treating dependence on substances such as opioids, methamphetamine, alcohol, and nicotine, and can have an impact on compulsive behavior patterns not involving substance abuse or chemical dependence. (Alper et al., Treatment of acute opioid withdrawal with ibogaine. The American Journal on Addictions. 8 (3): 234-42 (1999)).

[0004] N-acyl ethanolamines (NAEs) are lipid-derived signaling molecules. They are formed when one of several types of acyl groups is attached to the nitrogen atom of an ethanolamine. Examples of N-acyl ethanolamines include anandamide (amide of arachidonic acid (20:4 omega-6) with ethanolamine), palmitoyl ethanolamide (amide of palmitic acid (16:0) with ethanolamine), oleoyl ethanolamide (amide of oleic acid (18:1) with ethanolamine), stearoyl ethanolamide (amide of stearic acid (18:0) with ethanolamine), and docosahexaenoyl ethanolamide (amide of docosahexaenoic acid (22:6) with ethanolamine).

[0005] Palmitoyl ethanolamide (PEA, also known as N-(2-hydroxyethyl)hexadecanamide; hydroxyethyl palmitamide; palmitamide ethanol; N-palmitoyl ethanolamine; and palmitoyl ethanolamide) is an endogenous fatty acid amide that belongs to the class of nuclear receptor agonists. The chemical structure of PEA is: . PEA has been shown to bind to receptors in the cell nucleus (nuclear receptors) and to exert a variety of biological functions associated with chronic pain and inflammation. Studies have shown that PEA interacts with different non-CB1 / CB2 receptors, suggesting that PEA utilizes a unique “parallel” endocannabinoid signaling system. Increasing evidence suggests that the production and inactivation of PEA can occur independently of the production and inactivation of AEA and 2-AG, further supporting this view. Most of the biological effects of PEA on cells can be attributed to its affinity for PPARs (particularly PPAR-alpha and PPAR-gamma). PEA has been shown to have affinity for the cannabinoid-like G-coupled receptors GPR55 and GPR119, and the transient receptor potential vanilloid type 1 receptor (TRPV1). PEA has been shown to have anti-inflammatory, anti-nociceptive, neuroprotective, and anticonvulsant properties. SUMMARY

[0006] In some embodiments, the present disclosure provides pharmaceutical compositions comprising ibogaine or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods for preventing and / or treating a variety of conditions responsive to ibogaine treatment, such as substance addiction and opioid dependence.

[0007] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a combination of ibogaine or a pharmaceutically acceptable salt thereof and an N-acyl ethanolamine or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the combinations comprise a specific molar ratio between the active agents and / or their dosages and can be used in a variety of methods. In some embodiments, the present disclosure provides methods for preventing and / or treating a variety of conditions responsive to ibogaine treatment, such as substance addiction and opioid dependence.

[0009] In certain embodiments, the molar ratio between ibogaine and N-acyl ethanolamine is between about 1 :0.2 to about 1 :5. In certain embodiments, the molar ratio between ibogaine and N-acyl ethanolamine is between about 1 :0.5 to about 1 :2. In certain embodiments, the molar ratio between ibogaine and N-acyl ethanolamine is between about 1 :15 to about 1 :1800. In certain embodiments, the molar ratio between ibogaine and N-acyl ethanolamine is between about 1 :25 to about 1 :450. In certain embodiments, the molar ratio between ibogaine and N-acyl ethanolamine is between about 1 :50 to about 1 :100. In certain embodiments, the molar ratio between ibogaine and N-acyl ethanolamine is about 1 :50. In certain embodiments, the molar ratio between ibogaine and N-acyl ethanolamine is about 1 :100. Each possibility represents a separate embodiment of the present disclosure.

[0010] In certain embodiments, the pharmaceutical composition comprises about 0.5-10 mg ibogaine or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises about 1 mg, about 2.5 mg, about 5 mg, or about 10 mg ibogaine or a pharmaceutically acceptable salt thereof. Each possibility represents a separate embodiment of the present disclosure.

[0011] In certain embodiments, the pharmaceutical composition comprises about 200-1800 mg N-acyl ethanolamine or a pharmaceutically acceptable 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-acyl ethanolamine or a pharmaceutically acceptable salt thereof. Each possibility represents a separate embodiment of the present disclosure.

[0012] In certain embodiments, the N-acyl ethanolamine is selected from the group consisting of palmitoyl ethanolamide (PEA), Me-palmitoyl ethanolamide (Me-PEA), palmitoyl cyclohexamide, palmitoyl butyramide, palmitoyl isopropylamide, oleoyl ethanolamide (OEA), palmitoyl isopropylamide (PIA), salts thereof, and any combination thereof. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the N-acyl ethanolamine is PEA or a pharmaceutically acceptable salt thereof. In certain embodiments, the N-acyl ethanolamine consists of PEA or a pharmaceutically acceptable salt thereof. In certain embodiments, the N-acyl ethanolamine consists of PEA.

[0013] 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, inhalational, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration. In certain embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the pharmaceutical composition is formulated for oral administration. In certain embodiments, the pharmaceutical composition is formulated for oral mucosal administration. In certain embodiments, the pharmaceutical composition is formulated for nasal administration. In certain embodiments, the pharmaceutical composition is formulated for sublingual administration.

[0014] In another aspect, the present disclosure also provides a dosage unit comprising or consisting of the above pharmaceutical composition.

[0015] In certain embodiments, the dosage unit comprises the above pharmaceutical composition. In certain embodiments, the dosage unit consists of the above pharmaceutical composition. 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.

[0016] In other embodiments, the present disclosure relates to a method of treating substance addiction comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising ibogaine or a pharmaceutically acceptable salt thereof, thereby treating the condition.

[0017] In other embodiments, the present disclosure relates to a method of treating opioid dependence comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising ketamine or a pharmaceutically acceptable salt thereof, thereby treating the condition.

[0018] In certain embodiments, a therapeutically effective amount of a pharmaceutical composition comprising a combination of ibogaine or a pharmaceutically acceptable salt thereof and an N-acyl ethanolamine or a pharmaceutically acceptable salt thereof is administered to a subject to treat substance addiction.

[0019] In certain embodiments, a therapeutically effective amount of a pharmaceutical composition comprising a combination of ibogaine or a pharmaceutically acceptable salt thereof and an N-acyl ethanolamine or a pharmaceutically acceptable salt thereof is administered to a subject to treat opioid dependence.

[0020] In certain embodiments, the N-acyl ethanolamine enhances the therapeutic efficacy of ibogaine or a pharmaceutically acceptable salt thereof compared to the same pharmaceutical composition without the N-acyl ethanolamine. In certain embodiments, the N-acyl ethanolamine reduces the required therapeutic dose of ibogaine or a pharmaceutically acceptable salt thereof compared to the same pharmaceutical composition without the N-acyl ethanolamine. In certain embodiments, the N-acyl ethanolamine reduces at least one of the side effects of ibogaine or a pharmaceutically acceptable salt thereof compared to the same pharmaceutical composition without the N-acyl ethanolamine. In certain embodiments, the N-acyl ethanolamine expands the therapeutic window of ibogaine or a pharmaceutically acceptable salt thereof compared to the same pharmaceutical composition without the N-acyl ethanolamine. In certain embodiments, the PEA or salt thereof enhances the therapeutic efficacy of ibogaine or a salt thereof compared to the same pharmaceutical composition without the PEA or salt thereof. In certain embodiments, the PEA (or pharmaceutically acceptable salt thereof) reduces the required therapeutic dose of ibogaine (or pharmaceutically acceptable salt thereof) compared to the same pharmaceutical composition without the PEA (or pharmaceutically acceptable salt thereof). In certain embodiments, the PEA (or pharmaceutically acceptable salt thereof) reduces at least one of the side effects of ibogaine (or pharmaceutically acceptable salt thereof) compared to the same pharmaceutical composition without the PEA (or pharmaceutically acceptable salt thereof). In certain embodiments, the PEA (or pharmaceutically acceptable salt thereof) expands the therapeutic window of ibogaine (or pharmaceutically acceptable salt thereof) compared to the same pharmaceutical composition without the PEA (or pharmaceutically acceptable salt thereof).

[0021] In certain embodiments of the above methods, the ibogaine or a pharmaceutically acceptable salt thereof and the N-acyl ethanolamine or a pharmaceutically acceptable salt thereof are comprised in the same pharmaceutical composition. In certain embodiments of the above methods, the ibogaine and the N-acyl ethanolamine or a pharmaceutically acceptable salt thereof are comprised in different pharmaceutical compositions.

[0022] In certain embodiments of the above methods, the administration of the ibogaine and the N-acyl ethanolamine or a pharmaceutically acceptable salt thereof is repeated three times a day. In certain embodiments of the above methods, the administration of the ibogaine and the N-acyl ethanolamine or a pharmaceutically acceptable salt thereof is repeated twice a day. In certain embodiments of the above methods, the administration of the ibogaine and the N-acyl ethanolamine or a pharmaceutically acceptable salt thereof is repeated once a day. In certain embodiments of the above methods, the administration of the ibogaine and the N-acyl ethanolamine or a pharmaceutically acceptable salt thereof is repeated once every two days. In certain embodiments of the above methods, the administration of the ibogaine and the N-acyl ethanolamine or a pharmaceutically acceptable salt thereof is repeated once every three days.

[0023] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising ibogaine (or a pharmaceutically acceptable salt thereof) and an N-acyl ethanolamine (or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable carrier and / or excipient.

[0024] In some embodiments, the pharmaceutical composition is a unit dosage form composition. In other embodiments, the pharmaceutical composition is a solid unit dosage form composition. In still other embodiments, the pharmaceutical composition is a liquid unit dosage form composition. In further embodiments, the pharmaceutical composition is packaged as a single unit dosage or as multiple single unit dosages.

[0025] In further embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient. In other embodiments, the pharmaceutical composition is a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, or a syrup.

[0026] In some embodiments, in the methods of the present disclosure, the pharmaceutical composition is a unit dosage form composition. In other embodiments, the amount of ibogaine or a pharmaceutically acceptable salt thereof in the unit dosage form ranges from about 30 mg to about 130 mg. In certain embodiments, the pharmaceutical composition comprises 200-500 mg or 500-1000 mg of ibogaine or a pharmaceutically acceptable salt thereof in the unit dosage form. In some embodiments, the unit dosage form comprises about 0.5-2 mg / kg body weight, 2-5 mg / kg body weight, 5-10 mg / kg body weight, 10-15 mg / kg body weight, and 15-30 mg / kg body weight of ibogaine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is administered orally. In some embodiments, the pharmaceutical composition is administered intravenously.

[0027] Further embodiments of the present disclosure, and the full scope of their applicability, will become apparent from the detailed description given herein. However, although the detailed description and specific examples provided a preferred embodiment of the present disclosure, it is merely exemplary in nature and, thus, variations that do not depart from the spirit and scope of the present disclosure will become apparent to those skilled in the art from the detailed description. DETAILED DESCRIPTION

[0028] Definitions: When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, "C1-C6 alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl.

[0029] “Isomers” refer to compounds that have the same number and kind of atoms and thus the same molecular weight but differ in the arrangement or configuration of the atoms in space.

[0030] “Stereoisomers” or “optical isomers” refer to stable isomers having at least one chiral atom or restricted rotation resulting in a plane of optical activity (e.g., certain biphenyls, dienes, and spiro compounds) and that can rotate plane-polarized light. Because of the presence of asymmetric centers and other chemical structures in the compounds of the present disclosure, stereoisomerism can occur, and the present disclosure encompasses stereoisomers and mixtures thereof. The compounds of the present disclosure and salts thereof contain asymmetric carbon atoms and can therefore occur in individual stereoisomers, racemates, and as mixtures of enantiomeric and diastereomeric forms. Typically, such compounds are prepared as racemic mixtures. If desired, however, such compounds can be prepared or separated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures of stereoisomers that are enriched in one stereoisomer. As discussed in more detail below, individual stereoisomers of compounds are made by synthesis from optically active starting materials containing the desired chiral center, or by preparation of mixtures of enantiomeric products and subsequent separation or resolution (such as conversion to a mixture of diastereomers followed by separation or re-crystallization, 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 methods described below and resolved by techniques well known in the art.

[0031] It is well understood in the art that the biological and pharmacological activities of compounds are sensitive to their stereochemistry. Thus, for example, enantiomers often exhibit markedly different biological activities, including differences in pharmacokinetic properties (including metabolism, protein binding, etc.) and pharmacological properties (including the type, degree, and toxicity of activity exhibited). Accordingly, one skilled in the art will appreciate that when one enantiomer is enriched relative to the other enantiomer or when one enantiomer is separated from the other enantiomer, its activity can be higher or can exhibit a beneficial effect. Additionally, from the knowledge in the present disclosure and the art, one skilled in the art will know how to separate, enrich, or selectively prepare enantiomers of the compounds of the present disclosure.

[0032] Thus, while racemic forms of drugs can be used, they are generally not as effective as administering an equal amount of an enantiomerically pure drug; in fact, in some cases, one enantiomer can be pharmacologically inactive and will only act as a simple diluent. For example, while ibuprofen was previously administered as a racemate, it was discovered that only the S-isomer of ibuprofen is effective as an anti-inflammatory (however, in the case of ibuprofen, while the R-isomer is inactive, it is converted to the S-isomer in the body, thus, the racemic form of the drug has a slower onset of action than the pure S-isomer). Furthermore, 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 have advantages over racemates because it has been reported that purified individual isomers have a faster rate of transdermal penetration than racemic mixtures. See U.S. Patent Nos. 5,114,946 and 4,818,541.

[0033] In some embodiments, the compound is a racemic mixture of (S)- and (R)- isomers. In other embodiments, provided herein is a mixture of compounds, wherein the individual compounds of the mixture are predominantly in the (S)- or (R)- isomeric configuration. For example, the mixture of compounds has an excess of the (S)-enantiomer 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 other embodiments, the mixture of compounds has an excess of the (S)-enantiomer 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 mixture of compounds has a purity of the (R)-enantiomer 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 mixture of compounds has an excess of the (R)-enantiomer 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.

[0034] Single enantiomers of the compounds of the present disclosure can be prepared from commercially available starting materials containing asymmetric centers or stereogenic centers either synthetically or by preparing racemic mixtures and then resolving them by methods well known to those of ordinary skill in the art. These resolution methods are exemplified by: (1) attachment of the enantiomeric mixture to a chiral auxiliary, separation of the resulting diastereomeric mixture by recrystallization or chromatography, and liberation of the optically pure product from the auxiliary; (2) salt formation with an optically active resolving agent; or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. The 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, crystallization of the compound as a chiral salt complex or crystallization of the compound in chiral solvents. The stereoisomers can also be obtained from stereoisomerically pure intermediates, reagents and catalysts by well known asymmetric synthesis methods.

[0035] Thus, if one enantiomer is more pharmacologically active, less toxic, or has a more preferred distribution in the body than the other, it would be therapeutically more beneficial to administer that enantiomer preferentially. In this way, the patient receiving treatment would be exposed to lower total doses of drug and lower doses of the enantiomer that can be toxic or an inhibitor of the other enantiomer.

[0036] As used herein, the nomenclature for compounds including organic compounds can be given using common names, IUPAC, IUBMB, or CAS recommended nomenclature. If a name is given, one of ordinary skill in the art can readily determine the structure of the compound by systematic derivation of the structure from the nomenclature conventions or by using commercially available software such as CHEMDRAW® TM (Cambridgesoft Corporation, U.S.A.) to easily determine the structure of the compound. Chemical names are generated using PerkinElmer ChemDraw® ® Professional 17.

[0037] The compounds of the present disclosure can contain one or more chiral centers and / or double bonds, and can therefore exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. As used herein, the term “stereoisomers” includes all geometric isomers, enantiomers or diastereomers. These compounds can be designated by the symbols “R” or “S,” depending on the configuration of substituents around a stereogenic carbon atom. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers can be denoted in nomenclature by “(±),” but the skilled artisan will recognize that the structure can implicitly indicate chiral centers. In some embodiments, one enantiomer or stereoisomer can be provided substantially free of the corresponding enantiomer or stereoisomer.

[0038] In one aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a mixture of ibogaine (or a pharmaceutically acceptable salt thereof) and at least one N-acyl ethanolamine (or a pharmaceutically acceptable salt thereof).

[0039] In another aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a mixture of ibogaine (or a pharmaceutically acceptable salt thereof) and at least one N-acyl ethanolamine (or a pharmaceutically acceptable salt thereof), wherein the molar ratio between ibogaine and N-acyl ethanolamine (or a pharmaceutically acceptable salt thereof) is between about 1:0.2 to about 1:2000.

[0040] As used herein, “pharmaceutical composition” refers to a preparation of an active agent described herein with other chemical components such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism. As used herein, the expression “pharmaceutically acceptable carrier” refers to a carrier, excipient or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. Adjuvants are also included under these expressions.

[0041] As used herein, the term “excipient” refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, oils such as vegetable or fish oils, and polyethylene glycols.

[0042] As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a compound is administered. Such a pharmaceutical carrier can be a sterile liquid, such as water and oils. Water or aqueous solutions saline solutions and aqueous dextrose and glycerol solutions are preferred for use as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" 18thEdition by E. W. Martin.

[0043] As used herein, the expression "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction when administered to a subject. Preferably, and particularly where the formulation is for use in humans, the term "pharmaceutically acceptable" can refer to being approved by a regulatory agency (e.g., the U.S. Food and Drug Administration) or listed in a generally recognized pharmacopeia (e.g., the U.S. Pharmacopeia) for use in animals.

[0044] As used herein, the term "N-acyl ethanolamine" generally refers to a type of fatty acid amide, a lipid-derived signaling molecule, formed when one of several types of acyl groups is attached to the nitrogen atom of an ethanolamine. These amides can be conceptually formed from a fatty acid and an ethanolamine, with the release of one water molecule, but the known biosynthesis uses a specific phospholipase D to cleave the phospholipid unit from an N-acyl phosphatidyl ethanolamine. The suffixes -amine and -amide in these names each refer to the single nitrogen atom of the ethanolamine that links the compounds together: it is called an "amine" in the ethanolamine because it is considered to be the free terminal nitrogen in that subunit; and it is called an "amide" when it is considered to be associated with the adjacent carbonyl group of the acyl subunit. In this application, the names of these compounds can appear with "amide" or "amine." The term "ethanolamine" is used in the generic sense and is intended to include monoethanolamine, diethanolamine, triethanolamine, and mixtures thereof.

[0045] As used herein, the term "derivative" means a compound whose core structure is the same or very similar to an N-acyl ethanolamine compound but has a chemical or physical modification such as a different or additional pendant group.

[0046] As used herein, "salt" refers to any form of the active ingredient in which the active ingredient is in ionic form and coupled with a counter-ion (cationic or anionic) or in solution. This also includes complexes of the active ingredient with other molecules and ions, in particular complexes that are complexed through ionic interactions.

[0047] In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine (or pharmaceutically acceptable salt thereof) is between about 1 :0.2 to about 1 :5. In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine (or pharmaceutically acceptable salt thereof) is between about 1 :0.22 to about 1 :4.5, between 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.

[0048] In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine (or pharmaceutically acceptable salt thereof) is between about 1 : 15 and about 1 : 1800. In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine is between about 1 : 16 and about 1 : 1700, about 1 : 17 and about 1 : 1600, about 1 : 18 and about 1 : 1500, about 1 : 19 and about 1 : 1400, about 1 : 20 and about 1 : 1300, about 1 : 21 and about 1 : 1200, about 1 : 22 and about 1 : 1100, about 1 : 23 and about 1 : 1000, about 1 : 24 and about 1 : 900, about 1 : 15 and about 1 : 800, about 1 : 16 and about 1 : 700, about 1 : 17 and about 1 : 600, about 1 : 18 and about 1 : 500, about 1 : 19 and about 1 : 490, about 1 : 20 and about 1 : 480, about 1 : 21 and about 1 : 470, or about 1 : 22 and about 1 : 460. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine is between about 1 : 25 and about 1 : 450. In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine is between about 1 : 10 and about 1 : 500, about 1 : 15 and about 1 : 450, about 1 : 20 and about 1 : 400, about 1 : 25 and about 1 : 350, about 1 : 30 and about 1 : 300, about 1 : 35 and about 1 : 250, about 1 : 40 and about 1 : 200, or about 1 : 45 and about 1 : 150. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine is between about 1 : 50 and about 1 : 100. In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine is about 1 : 10. In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine is about 1 : 20. In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine is about 1 : 30. In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine is about 1 : 40. In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine is about 1 : 50. In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine is about 1 : 60. In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine is about 1 : 70. In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine is about 1 : 80. In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine is about 1 : 90. In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine is about 1 : 100. In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine is about 1 : 110. In certain embodiments, the molar ratio between ibogaine and the N-acyl ethanolamine is about 1 : 120.In certain embodiments, the molar ratio between ibogaine and N-acyl ethanolamine is about 1 : 130. In certain embodiments, the molar ratio between ibogaine and N-acyl ethanolamine is about 1 : 140. In certain embodiments, the molar ratio between ibogaine and N-acyl ethanolamine is about 1 : 150. In certain embodiments, the molar ratio between ibogaine and N-acyl ethanolamine is about 1 : 160. In certain embodiments, the molar ratio between ibogaine and N-acyl ethanolamine is about 1 : 170. In certain embodiments, the molar ratio between ibogaine and N-acyl ethanolamine is about 1 : 180. In certain embodiments, the molar ratio between ibogaine and N-acyl ethanolamine is about 1 : 190. In certain embodiments, the molar ratio between ibogaine and N-acyl ethanolamine is about 1 : 200. In certain embodiments, the molar ratio between ibogaine and N-acyl ethanolamine is at least about 1 : 10, at least about 1 : 20, at least about 1 : 30, at least about 1 : 40, at least about 1 : 50, at least about 1 : 60, at least about 1 : 70, at least about 1 : 80, at least about 1 : 90, or at least about 1 : 100. Each possibility represents a separate embodiment of the present disclosure.

[0049] In certain embodiments, the pharmaceutical composition comprises about 0.5-10 mg ibogaine 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 ibogaine or a salt thereof. In certain embodiments, the pharmaceutical composition comprises about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg ibogaine or a salt thereof. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the pharmaceutical composition comprises less than about 0.5 mg, less than about 1 mg, less than about 1.5 mg, less than about 2 mg, less than about 2.5 mg, less than about 3 mg, less than about 3.5 mg, less than about 4 mg, less than about 4.5 mg, less than about 5 mg, less than about 5.5 mg, less than about 6 mg, less than about 6.5 mg, less than about 7 mg, less than about 7.5 mg, less than about 8 mg, less than about 8.5 mg, less than about 9 mg, less than about 9.5 mg, or about 10 mg ibogaine or a pharmaceutically acceptable salt thereof. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the pharmaceutical composition comprises about 0.5 mg to about 1 mg, about 0.5 mg to about 1.5 mg, about 0.5 mg to about 2 mg, about 0.5 mg to about 2.5 mg, about 0.5 mg to about 3 mg, about 0.5 mg to about 3.5 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 4.5 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 5.5 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 6.5 mg, about 0.5 mg to about 7 mg, about 0.5 mg to about 7.5 mg, about 0.5 mg to about 8 mg, about 0.5 mg to about 8.5 mg, about 0.5 mg to about 9 mg, or about 0.5 mg to about 9.5 mg ibogaine or a pharmaceutically acceptable salt thereof. Each possibility represents a separate embodiment of the present disclosure.

[0050] In certain embodiments, the pharmaceutical composition comprises about 200-1800 mg of an N-acyl ethanolamine or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises about 250-1550 mg, about 300-1200 mg, about 350-950 mg, about 400-700 mg, about 450-600 mg, or about 500-550 mg of an N-acyl ethanolamine or a pharmaceutically acceptable salt thereof. Each possibility represents a separate embodiment of the disclosure. In certain embodiments, the pharmaceutical composition comprises at least about 50 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, at least about 400, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about 850 mg, at least about 900 mg, at least about 950 mg, at least about 1000 mg, at least about 1050 mg, at least about 1100 mg, at least about 1150 mg, at least about 1200 mg, at least about 1250 mg, at least about 1300 mg, at least about 1350 mg, at least about 1400 mg, at least about 1450 mg, at least about 1500 mg, at least about 1550 mg, at least about 1600 mg, at least about 1650 mg, at least about 1700 mg, at least about 1750 mg, or at least about 1800 mg of an N-acyl ethanolamine or a pharmaceutically acceptable 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 an N-acyl ethanolamine or a pharmaceutically acceptable salt thereof. Each possibility represents a separate embodiment of the disclosure.

[0051] In certain embodiments, the N-acyl ethanolamine is selected from the group consisting of N-palmitoyl ethanolamine (PEA), Me-palmitoyl ethanolamide (Me-PEA), palmitoyl cyclohexylamide, palmitoyl butylamide, palmitoyl isopropylamide, oleoyl ethanolamide (OEA), palmitoyl isopropylamide (PIA), pharmaceutically acceptable salts thereof, and any combination thereof. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the N-acyl ethanolamine is PEA or a pharmaceutically acceptable salt thereof. In certain embodiments, the N-acyl ethanolamine consists of PEA or a pharmaceutically acceptable salt thereof. In certain embodiments, the N-acyl ethanolamine consists of PEA.

[0052] In certain embodiments, the pharmaceutical composition is formulated for systemic administration. In certain embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalation, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration. In certain embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, the pharmaceutical composition is formulated for oral administration. In certain embodiments, the pharmaceutical composition is formulated for oral mucosal administration. In certain embodiments, the pharmaceutical composition is formulated for nasal administration. In certain embodiments, the pharmaceutical composition is formulated for sublingual administration.

[0053] Pharmaceutical formulation and administration techniques are well known in the art and can be found, for example, in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA. The pharmaceutical compositions of the present disclosure can be manufactured by methods well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

[0054] For oral administration, 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 in solid, liquid, or gelled forms, for oral ingestion by a patient. Agents for pharmacological formulations for oral use are prepared according to the methods well known in the art of pharmacy. In general, such agents are prepared "to order" for a patient's needs by combining the active ingredient with commonly employed excipients, which are then formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like. Suitable excipients are, for example, sugars, such as lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl cellulose, and sodium carbomethylcellulose; and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, such as a cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0055] The term "oral administration" refers to any method of administration in which the active agent can be administered by swallowing, mastication, sucking, or drinking an oral dosage form. Examples of solid dosage forms include conventional tablets, multilayer tablets, capsules, caplets, and the like, which do not substantially release the drug in the mouth or in the oral cavity.

[0056] Dragee cores are provided with suitable coatings. For this purpose, there can be used concentrated sugar solutions, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablets or dragee coatings to be able to identify or characterize different combinations of active compound doses.

[0057] Pharmaceutical compositions that can be used orally include hard or soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules can contain a mixture of active ingredient with fillers, such as lactose, binders, such as starches, lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers can be added. All formulations for oral administration are suitable in terms of dosage for the chosen route of administration. For buccal and sublingual administration, the compositions can be in the form of tablets or lozenges formulated in a conventional manner or in an adhesive carrier. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle, for example, a sterile, pyrogen-free water-based solution, before use.

[0058] Pharmaceutical compositions suitable for use in 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 the active ingredients effective to prevent, alleviate or ameliorate symptoms or effects of the disease or disorder being treated or to 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. More specifically, a "therapeutically effective amount of a mixture" means an amount of at least two active ingredients, wherein each of the active ingredients can independently not be in a therapeutically effective amount, or wherein two of the active ingredients can not be in a therapeutically effective amount, yet the mixture is effective to prevent, alleviate or ameliorate symptoms or effects of the disease or disorder or to prolong the survival of the subject being treated. As used herein, the term "mixture" refers to a non-covalent combination of two molecules.

[0059] For any preparation used in the methods of the disclosure, the therapeutically effective amount or dosage can be estimated initially from in vitro, in vivo, and cell culture assays. For example, 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 combination depends on several factors, including: the method of administration, the disease to be treated, the severity of the disease, whether the disease is to be treated or prevented, and the age, body weight, and health of the person to be treated. Additionally, information on the pharmacogenomics (the influence of the genotype on the pharmacokinetic, pharmacodynamic, or efficacy profile of a therapy) of a particular patient can influence the dosage employed. Continuous every day administration can not be required; treatment regimens can require periodic, during which the drug is not administered, or treatment can be provided on an as needed basis during periods of acute disease exacerbation. Dose escalation can or can not be required; treatment regimens can require a reduction in the dosage of the drug. Toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, cell cultures, or experimental animals. The data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage can vary according to the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage is chosen by the individual physician in view of the patient's condition. (See e.g., Fingl, E. et al. (1975), "The Pharmacological Basis of Therapeutics," Ch. 1, p. 1). Depending on the severity of the condition to be treated and the response of the patient, administration to a subject can be of a single dose or of multiple doses. The course of treatment lasts from several days to several weeks or until cure is effected or until the progression of the disease state is effectively halted.

[0060] In another aspect, the present disclosure also provides a dosage unit comprising or consisting of the above pharmaceutical composition.

[0061] In certain embodiments, the dosage unit comprises the pharmaceutical composition described above. In certain embodiments, the dosage unit consists of the pharmaceutical composition described above. In certain embodiments, the dosage unit is formulated as a gel, a powder, or a spray. In certain embodiments, the dosage unit is formulated as a gel. In certain embodiments, the dosage unit is formulated as a powder. In certain embodiments, the dosage unit is formulated as a spray.

[0062] In another aspect, the present disclosure also provides the pharmaceutical composition or dosage unit as described above for use in a method of preventing or treating a condition suitable for prevention or treatment by ibogaine or a pharmaceutically acceptable salt thereof.

[0063] As used herein, the term "treatment" includes, but is not limited to, any one or more of eliminating, alleviating, inhibiting, attenuating, blocking, suppressing, reducing, delaying, halting, lessening, or preventing one or more symptoms or side effects of a disease or condition of the present disclosure.

[0064] The term "acute" refers to a condition having a relatively short, severe course.

[0065] As used herein, the term "chronic" refers to a disease or condition of the present disclosure that can be weeks, months, or possibly years in length. The intensity of the disease or condition can vary depending on a variety of circumstances such as patient age, body temperature, season, disease type, etc.

[0066] The term "about," as used herein with respect to a value, a plurality of values, or a range of values defined by a lowest value and a highest value, means a value that is 10% lower and / or higher than the corresponding value, plurality of values, or range of values. For example, the expression "about 1" means "0.9 to 1.1," the expression "about 1 or 2" means "0.9 to 1.1 or 1.8 to 2.2," and the expression "about 1 to about 2" means "0.9 to 2.2."

[0067] The terms "comprises," "comprising," "includes," "including," "has," "having," and their variants mean "including but not limited to."

[0068] The term "consisting of means "including and limited to."

[0069] The term "consisting essentially of means that the composition, method or microcapsule can include additional ingredients, steps and / or components, but only if the additional ingredients, steps and / or components do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

[0070] 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" can include a plurality of compounds, including mixtures thereof.

[0071] Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 ( the dose lethal to 50% of the population) and ED 50 ( 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 LD 50 / ED 50 Compositions that exhibit large therapeutic indices are preferred.

[0072] The data obtained from the cell culture assays or animal studies can be used in formulating a range of dosage for use in humans. The dosage Cancer Chemother. Reports 50 (4):219-244 (1966) and the equivalent surface area dose factors in the table below) can be used to convert the dosage obtained in an animal model to an appropriate dosage in humans.

[0073] Table 1. Equivalent Surface Area Dose Factors The dosage of such compounds is preferably within a range that includes the ED 50 and minimal or no toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. In general, a therapeutically effective dose can vary with age, condition, and sex of the subject, and the severity of the medical condition of the subject. The dose can be determined by a physician and adjusted according to the observed treatment effect.

[0074] The skilled artisan will recognize that both in vivo and in vitro assays can be used to test the ability of a test compound to treat or prevent a given condition, using appropriate, known, and generally accepted cell and / or animal models.

[0075] The skilled artisan will also recognize that human clinical trials, including first-in-human, dose ranging, and efficacy trials, in healthy patients and / or patients suffering from a given condition, can be carried out in accordance with methods well known in the clinical and medical arts.

[0076] In some embodiments, the present disclosure provides pharmaceutical compositions comprising ibogaine or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods for preventing and / or treating a variety of conditions responsive to ibogaine treatment, such as substance addiction and opioid dependence.

[0077] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a combination of ibogaine or a pharmaceutically acceptable salt thereof and an N-acyl ethanolamine or a pharmaceutically acceptable salt thereof. These combinations are defined in part by the specific molar ratio between the individual active agents and / or their dosages and can be used in a variety of methods. In some embodiments, the present disclosure provides methods for preventing and / or treating a variety of conditions responsive to ibogaine treatment, such as substance addiction and opioid dependence.

[0078] One or more embodiments of the present disclosure include the following embodiments 1 to 36: 1. A pharmaceutical composition comprising ibogaine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier and / or excipient.

[0079] 2. The pharmaceutical composition of embodiment 1, wherein the composition is a unit dosage form composition.

[0080] 3. The pharmaceutical composition of embodiment 2, wherein the pharmaceutical composition is a solid unit dosage form composition.

[0081] 4. The pharmaceutical composition of embodiment 2, wherein the pharmaceutical composition is a liquid unit dosage form composition.

[0082] 5. The pharmaceutical composition of embodiment 2, wherein the pharmaceutical composition is packaged as a single unit dose or as multiple single unit doses.

[0083] 6. The pharmaceutical composition of embodiment 2, wherein the unit dosage form comprises 200 mg to 1000 mg ibogaine or a pharmaceutically acceptable salt thereof.

[0084] 7. The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition is formulated for oral administration or intravenous administration.

[0085] 8. A method of treating substance addiction, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising ibogaine or a pharmaceutically acceptable salt thereof.

[0086] 9. A method of treating opioid dependence, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising ibogaine or a pharmaceutically acceptable salt thereof.

[0087] 10. The method of embodiment 8 or 9, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

[0088] 11. The method of embodiment 8 or 9, wherein the pharmaceutical composition is a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, or a syrup.

[0089] 12. The method of embodiment 8 or 9, wherein the pharmaceutical composition is a unit dosage form composition.

[0090] 13. The method of embodiment 8 or 9, wherein the amount of ibogaine or a pharmaceutically acceptable salt thereof in the unit dosage form ranges from about 200 mg to about 1000 mg.

[0091] 14. The method of embodiment 8 or 9, wherein the amount of ibogaine or a pharmaceutically acceptable salt thereof is about 0.5-2 mg / kg body weight, 2-5 mg / kg body weight, 5-10 mg / kg body weight, 10-15 mg / kg body weight, and 15-30 mg / kg body weight.

[0092] 15. The method of embodiment 8 or 9, wherein the pharmaceutical composition is administered orally or intravenously.

[0093] 16. A pharmaceutical composition comprising ibogaine or a pharmaceutically acceptable salt thereof and an N-acyl ethanolamine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier and / or excipient.

[0094] 17. The pharmaceutical composition of embodiment 16, wherein the composition is a unit dosage form composition.

[0095] 18. The pharmaceutical composition of embodiment 17, wherein the pharmaceutical composition is a solid unit dosage form composition.

[0096] 19. The pharmaceutical composition of embodiment 17, wherein the pharmaceutical composition is a liquid unit dosage form composition.

[0097] 20. The pharmaceutical composition of embodiment 17, wherein the pharmaceutical composition is packaged as a single unit dose or packaged as multiple single unit doses.

[0098] 21. The pharmaceutical composition of embodiment 17, wherein the unit dosage form comprises 200 mg to 1000 mg of ibogaine or a pharmaceutically acceptable salt thereof.

[0099] 22. The pharmaceutical composition of embodiment 17, wherein the unit dosage form comprises 50 mg to 1800 mg of an N-acyl ethanolamine or a pharmaceutically acceptable salt thereof.

[0100] 23. The pharmaceutical composition of embodiment 16, wherein the pharmaceutical composition is formulated for oral administration or intravenous administration.

[0101] 24. A method of treating substance addiction, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising ibogaine or a pharmaceutically acceptable salt thereof and an N-acyl ethanolamine or a pharmaceutically acceptable salt thereof.

[0102] 25. A method of treating opioid dependence, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising ibogaine or a pharmaceutically acceptable salt thereof and an N-acyl ethanolamine or a pharmaceutically acceptable salt thereof.

[0103] 26. The method of embodiment 24 or 25, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

[0104] 27. The method of embodiment 24 or 25, wherein the pharmaceutical composition is a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, or a syrup.

[0105] 28. The method of embodiment 24 or 25, wherein the pharmaceutical composition is a unit dosage form composition.

[0106] 29. The method of embodiment 24 or 25, wherein the amount of ibogaine or a pharmaceutically acceptable salt thereof in the unit dosage form ranges from about 200 mg to about 1000 mg.

[0107] 30. The method of embodiment 24 or 25, wherein the amount of N-acyl ethanolamine or a pharmaceutically acceptable salt thereof in the unit dosage form ranges from 50 mg to 1800 mg.

[0108] 31. The method of embodiment 24 or 25, wherein the amount of ibogaine or a pharmaceutically acceptable salt thereof ranges from about 0.5-2 mg / kg body weight, 2-5 mg / kg body weight, 5-10 mg / kg body weight, 10-15 mg / kg body weight, and 15-30 mg / kg body weight.

[0109] 32. The method of embodiment 24 or 25, wherein the pharmaceutical composition is administered orally or intravenously.

[0110] 33. The pharmaceutical composition of any preceding embodiment, wherein the N- acylethanolamine is selected from the group consisting of N-palmitoyl ethanolamine (PEA), Me-palmitoyl ethanolamide (Me-PEA), palmitoyl cyclohexanamide, palmitoyl butyramide, palmitoyl isopropylamide, oleoyl ethanolamide (OEA), palmitoyl isopropylamide (PIA), salts thereof, and any combination thereof.

[0111] 34. The method of any preceding embodiment, wherein the N-acyl ethanolamine is selected from the group consisting of N-palmitoyl ethanolamine (PEA), Me-palmitoyl ethanolamide (Me-PEA), palmitoyl cyclohexanamide, palmitoyl butyramide, palmitoyl isopropylamide, oleoyl ethanolamide (OEA), palmitoyl isopropylamide (PIA), salts thereof, and any combination thereof.

[0112] 35. The pharmaceutical composition of any preceding embodiment, wherein the N- acylethanolamine is PEA or a pharmaceutically acceptable salt thereof.

[0113] 36. The method of any preceding embodiment, wherein the N-acyl ethanolamine is PEA or a pharmaceutically acceptable salt thereof.

Claims

1. A pharmaceutical composition comprising ibogaine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier and / or excipient.

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

3. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is a solid unit dosage form composition.

4. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is a liquid unit dosage form composition.

5. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is packaged as a single unit dose or as multiple single unit doses.

6. The pharmaceutical composition of claim 2, wherein the unit dosage form comprises 200 mg to 1000 mg ibogaine or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated for oral administration or intravenous administration.

8. A method of treating substance addiction, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising ibogaine or a pharmaceutically acceptable salt thereof.

9. A method of treating opioid dependence, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising ibogaine or a pharmaceutically acceptable salt thereof.

10. The method of claim 8 or 9, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

11. The method of claim 8 or 9, wherein the pharmaceutical composition is a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, or a syrup.

12. The method of claim 8 or 9, wherein the pharmaceutical composition is a unit dosage form composition.

13. The method of claim 8 or 9, wherein the amount of ibogaine or a pharmaceutically acceptable salt thereof in the unit dosage form ranges from about 200 mg to about 1000 mg.

14. The method of claim 8 or 9, wherein the amount of ibogaine or a pharmaceutically acceptable salt thereof is about 0.5-2 mg / kg body weight, 2-5 mg / kg body weight, 5-10 mg / kg body weight, 10-15 mg / kg body weight, and 15-30 mg / kg body weight.

15. The method of claim 8 or 9, wherein the pharmaceutical composition is administered orally or intravenously.

16. A pharmaceutical composition comprising ibogaine or a pharmaceutically acceptable salt thereof and an N-acyl ethanolamine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier and / or excipient.

17. The pharmaceutical composition of claim 16, wherein the composition is a unit dosage form composition.

18. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is a solid unit dosage form composition.

19. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is a liquid unit dosage form composition.

20. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is packaged as a single unit dose or as multiple single unit doses.

21. The pharmaceutical composition of claim 17, wherein the unit dose form comprises 200 mg to 1000 mg ibogaine or a pharmaceutically acceptable salt thereof.

22. The pharmaceutical composition of claim 17, wherein the unit dose form comprises 50 mg to 1800 mg N-acyl ethanolamine or a pharmaceutically acceptable salt thereof.

23. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition is formulated for oral administration or intravenous administration.

24. A method of treating substance addiction, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising ibogaine or a pharmaceutically acceptable salt thereof and N-acyl ethanolamine or a pharmaceutically acceptable salt thereof.

25. A method of treating opioid dependence, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising ibogaine or a pharmaceutically acceptable salt thereof and N-acyl ethanolamine or a pharmaceutically acceptable salt thereof.

26. The method of claim 24 or 25, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

27. The method of claim 24 or 25, wherein the pharmaceutical composition is a free-flowing powder, a tablet, a capsule, a lozenge, a liquid, a liquid concentrate, or a syrup.

28. The method of claim 24 or 25, wherein the pharmaceutical composition is a unit dose form composition.

29. The method of claim 24 or 25, wherein the amount of ibogaine or a pharmaceutically acceptable salt thereof in the unit dose form ranges from about 200 mg to about 1000 mg.

30. The method of claim 24 or 25, wherein the amount of N-acyl ethanolamine or a pharmaceutically acceptable salt thereof in the unit dose form ranges from 50 mg to 1800 mg.

31. The method of claim 24 or 25, wherein the amount of ibogaine or a pharmaceutically acceptable salt thereof is about 0.5-2 mg / kg body weight, 2-5 mg / kg body weight, 5-10 mg / kg body weight, 10-15 mg / kg body weight, and 15-30 mg / kg body weight.

32. The method of claim 24 or 25, wherein the pharmaceutical composition is administered orally or intravenously.

33. The pharmaceutical composition of any preceding claim, wherein the N-acyl ethanolamine is selected from the group consisting of N-palmitoyl ethanolamine (PEA), Me-palmitoyl ethanolamide (Me-PEA), palmitoyl cyclohexylamide, palmitoyl butyryl amide, palmitoyl isopropylamide, oleoyl ethanolamide (OEA), palmitoyl isopropylamide (PIA), salts thereof, and any combination thereof.

34. The method of any preceding claim, wherein the N-acyl ethanolamine is selected from the group consisting of N-palmitoyl ethanolamine (PEA), Me-palmitoyl ethanolamide (Me-PEA), palmitoyl cyclohexanamide, palmitoyl butyramide, palmitoyl isopropylamide, oleoyl ethanolamide (OEA), palmitoyl isopropylamide (PIA), salts thereof, and any combination thereof.

35. The pharmaceutical composition of any preceding claim, wherein the N-acyl ethanolamine is PEA or a pharmaceutically acceptable salt thereof.

36. The method of any preceding claim, wherein the N-acyl ethanolamine is PEA or a pharmaceutically acceptable salt thereof.

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