Ibogaine formulations

Abstract

Provided herein are aqueous compositions comprising ibogaine or a pharmaceutically acceptable salt thereof and a complexing agent, as well as methods of making and using the same.

Description

Attorney Docket No.: ATAI-llO / OIWO 338067-2790IBOGAINE FORMULATIONSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. Provisional Application No. 63 / 742,944, filed January 8, 2025, which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] Opioid use disorder (OUD) is a problematic pattern of opioid use leading to clinically significant impairment or distress. OUD affects over 16 million people worldwide and 6-7 million in the US. Overdoses involving opioids killed more than 80,000 people in the US in 2021, and nearly 88% of those deaths involved synthetic opioids, particularly fentanyl. The number of overdose deaths involving opioids — including both prescription and illicit opioids — in 2021 was 10x the number in 1999.

[0003] As such, there is a need in the art to develop formulations and methods for administration of compounds for OUD treatment.SUMMARY

[0004] In embodiments, the present disclosure provides for an aqueous composition comprising:about 0.5 wt% to about 10 wt% of ibogaine or a pharmaceutically acceptable salt thereof; about 3.0 wt% to about 50 wt% of a complexing agent, wherein the complexing agent comprises a cyclodextrin; andabout 1 mM to about 100 mM of a buffering agent.

[0005] In embodiments, the present disclosure provides for an aqueous solution consisting essentially of:about 0.5 wt% to about 10 wt% of ibogaine or a pharmaceutically acceptable salt thereof; about 3.0 wt% to about 50 wt% of a complexing agent, wherein the complexing agent comprises cyclodextrin; andabout 1 mM to about 100 mM of a buffering agent.

[0006] In embodiments, the present disclosure provides for a method of administering ibogaine or a pharmaceutically acceptable salt thereof to a patient in need thereof, the method comprising:diluting the aqueous composition as otherwise described herein with a pharmaceutically acceptable diluent to provide a parenteral composition, wherein the parenteralAttorney Docket No.: ATAI-110 / 01WO 338067-2790composition comprises about 0.1% to about 1.5% by weight ibogaine or a pharmaceutically acceptable salt thereof; andintravenously administering the parenteral composition to a patient in need thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Fig. 1 displays the results of assay testing of compositions according to the present disclosure.

[0008] Fig. 2 displays the results of impurity testing of compositions according to the present disclosure.

[0009] Fig. 3 displays the results of pH testing of compositions according to the present disclosure.DETAILED DESCRIPTION

[0010] Clinical studies indicate the potential efficacy of ibogaine in treating OUD. Oral ibogaine is associated with significantly reduced opioid cravings, both at discharge and at one-month post¬ treatment. However, oral administration of ibogaine results in highly variable ibogaine exposure, marked noribogaine exposure, and pronounced, dose-dependent QT prolongation. As such, oral ibogaine administration presents pharmaceutical development risks for efficacy in trials with some patients having very high exposure that could be linked to adverse events, while others will have negligible serum concentration of ibogaine, potentially reducing efficacy. In contrast, intravenous delivery of ibogaine may allow for improved treatment outcomes compared to oral administration.

[0011] In order to achieve effective intravenous administration of ibogaine, compositions and formulations must be developed that solubilize and stabilize ibogaine, which is a poorly soluble compound.Definitions

[0012] Throughout this disclosure, various patents, patent applications and publications (including non- patent publications) are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.Attorney Docket No.: ATAI-llO / OIWO 338067-2790

[0013] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0014] The term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55,... ”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5.

[0015] The term “ibogaine” refers to a compound having the following structural formula:

[0016] In embodiments, the aqueous composition comprises ibogaine by weight with reference to the ibogaine hydrochloride salt. In embodiments, the ibogaine hydrochloride has with a salt factor of 1.117.

[0017] The terms "administer," "administering" or "administration" as used herein refer to administering a compound or pharmaceutically acceptable salt of the compound or a composition or formulation comprising a compound or pharmaceutically acceptable salt of the compound to a patient.

[0018] The terms “effective amount” and “therapeutically effective amount” are used interchangeably in this disclosure and refer to an amount of a compound, or a pharmaceutically acceptable salt thereof, that, when administered to a patient, is capable of performing the intended result. For example, an effective amount of an ibogaine is that amount that is required to reduce at least one symptom of OUD in a patient, e.g. opioid cravings in a patient.

[0019] The phrase “pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals withoutAttorney Docket No.: ATAI-llO / OIWO 338067-2790excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0020] The term “salts” as used herein embraces pharmaceutically acceptable salts commonly used to form alkali metal salts of free acids and to form addition salts of free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Appropriate organic acids can be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2- hy dr oxy ethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, 3 -hydroxy butyric, galactaric and galacturonic acid.

[0021] The term “therapeutic effect” as used herein refers to a desired or beneficial effect provided by the method and / or the composition. For example, the method for treating opioid use disorder provides a therapeutic effect when the method improves at least one symptom of OUD, e.g., a reduction in opioid cravings, in a patient.

[0022] The term “treating” as used herein with regard to a patient, refers to improving at least one symptom of the patient’s disorder. Treating can be improving or at least partially ameliorating a disorder. For example, a patient’s opioid use disorder is treated when the method reduces at least one symptom of OUD, e.g., reduced opioid cravings, in the patient.Compositions and Methods

[0023] In embodiments, the present disclosure provides for an aqueous composition comprising:about 0.5 wt% to about 10 wt% of ibogaine or a pharmaceutically acceptable salt thereof; about 3.0 wt% to about 50 wt% of a complexing agent, wherein the complexing agent comprises a cyclodextrin; andabout 1 mM to about 100 mM of a buffering agent.

[0024] In embodiments, the weight ratio of ibogaine or a pharmaceutically acceptable salt thereof to cyclodextrin is about 1:20 to 1:2. In embodiments, the weight ratio of ibogaine or aAttorney Docket No.: ATAI-llO / OIWO 338067-2790pharmaceutically acceptable salt thereof to cyclodextrin is about 2:20 to 1:2, or 3:20 to 1:2, or 4:20 to 1:2, or 1:20 to 8:20, or 2:20 to 8:20, or 3:20 to 6:20.

[0025] In embodiments, the composition comprises about 0.5 wt% to about 2.0 wt% of ibogaine or a pharmaceutically acceptable salt thereof. In embodiments, the composition comprises about 0.8 wt% to about 1.5 wt% of ibogaine or a pharmaceutically acceptable salt thereof, or about 1 wt% to about 1.2 wt% of ibogaine or a pharmaceutically acceptable salt thereof. In embodiments, the composition comprises about 2 wt% to about 5 wt% of ibogaine or a pharmaceutically acceptable salt thereof. In embodiments, the composition comprises about 2.2 wt% to about 4 wt% of ibogaine or a pharmaceutically acceptable salt thereof, or about 3 wt% to about wt% of ibogaine or a pharmaceutically acceptable salt thereof.

[0026] In embodiments, the ibogaine or a pharmaceutically acceptable salt thereof comprises ibogaine hydrochloride.

[0027] In embodiments, the aqueous composition comprises about 3.0 wt% to about 50 wt% of a complexing agent. In embodiments, the aqueous composition comprises about 5.0 wt% to about 50 wt%, or about 10 wt% to about 50 wt%, or about 15 wt% to about 50 wt%, or about 20 wt% to about 50 wt%, or about 25 wt% to about 50 wt%, or about 30to about 50 wt%, or about 3.0 wt% to about 40 wt%, or about 3.0 wt% to about 35 wt%, or about 3.0 wt% to about 30 wt%, or about 3.0 wt% to about 25 wt%, or about 5.0 wt% to about 45 wt%, or about 5.0 wt% to about 40 wt%, or about 10 wt% or about 40 wt%, or about 10 wt% to about 35 wt%, or about 15 wt% to about 35 wt%, or about 15 wt% to about 30 wt%, or about 15 wt% to about 25 wt% of a complexing agent.

[0028] In embodiments, the cyclodextrin comprises a β-cyclodextrin. In embodiments, the p- cyclodextrin comprises 2-hydroxypropyl-P-cyclodextrm, sulfobutylether-p-cyclodextrin or m ethy 1 - P~ cy cl odextr in.

[0029] In embodiments, the cyclodextrin comprises an a-cyclodextrin. In embodiments, the a-cyclodextrin comprises 2-hydroxypropyl-a-cyclodextrin.

[0030] In embodiments, the cyclodextrin comprises a y-cyclodextrin. In embodiments, the y- cyclodextrin comprises 2-hydroxypropyl-y-cyclodextrin.

[0031] In embodiments, the aqueous composition further comprises 5% to 40% by weight of a co¬ solvent. In embodiments, the aqueous composition further comprises 5% to 35%, or about 5% to about 30%, or about 5% to about 25%, or about 5% to about 20%, or about 5% to about 15%, orAttorney Docket No.: ATAI-llO / OIWO 338067-2790about 10% to about 40%, or about 15% to about 40%, or about 20% to about 40%, or about 10% to about 30% by weight of a co-solvent. In embodiments, the co-solvent comprises polyethylene glycol, glycerol, propylene glycol, ethyl alcohol or benzyl alcohol. In embodiments, the polyethylene glycol is PEG400 or PEG4000.

[0032] In embodiments, the aqueous composition further comprises about 0.5% to about 10%, or about 1% to about 5% by weight of solubilizer or surfactant. In embodiment, the solubilizer or surfactant comprises a polysorbate, a kolliphor, a poloxamer, or a Vitamin E derivative.

[0033] In embodiments, the polysorbate is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

[0034] In embodiments, the kolliphor is a polyethoxylated castor oil such as Kolliphor EL.

[0035] In embodiments, the poloxamer is poloxamer 108, poloxamer 124, poloxamer 182, poloxamer 183, poloxamer 188, poloxamer 212, poloxamer 217, poloxamer 237, poloxamer 238, poloxamer 288, poloxamer 331, poloxamer 335, poloxamer 338, or poloxamer 407. In embodiments, the poloxamer is poloxamer 188.

[0036] In embodiments, the Vitamin E derivative is D-alpha-tocopherol polyethylene glycol succinate (Vitamin E TPGS).

[0037] In embodiments, the aqueous composition comprises about 1 mM to about 100 mM of a buffering agent. In embodiments, the aqueous composition comprises about 1 mM to about 80 mM, or about 2 mM to about 60 mM, or about 2.5 mM to about 50 mM, or about 2.5 mM to about 30 mM, or about 5 mM to about 50 mM, or about 5 mM to about 25 mM, or about 5 mM to about 15 mM, or about 10 mM of a buffering agent.

[0038] In embodiments, the buffering agent comprises acetic acid, citric acid, maleic acid, succinic acid tartaric acid, phosphate, tris (hydroxymethyl)-aminomethane (tris), or L-histidine.

[0039] In embodiments, the pH of the aqueous composition is about 4.5 to about 7.5, or about 5 to about 7, or about 6.

[0040] In embodiments, the present disclosure provides for an aqueous solution consisting essentially of:about 0.5 wt% to about 10 wt% of ibogaine or a pharmaceutically acceptable salt thereof; about 3.0 wt% to about 50 wt% of a complexing agent, wherein the complexing agent comprises cyclodextrin; andabout 1 mM to about 100 mM of a buffering agent.Attorney Docket No.: ATAI-110 / 01WO 338067-2790

[0041] In embodiments, the present disclosure provides for a method of administering ibogaine or a pharmaceutically acceptable salt thereof to a patient in need thereof, the method comprising: diluting the aqueous composition as otherwise described herein with a pharmaceutically acceptable diluent to provide a parenteral composition, wherein the parenteral composition comprises about 0.1% to about 1.5% by weight ibogaine or a pharmaceutically acceptable salt thereof; andintravenously administering the parenteral composition to a patient.

[0042] In embodiments, the parenteral composition comprises about 0.1% to about 1.2%, or about 0.5% to about 1.5%, or about 0.1% to about 1.0%, or about 0.1% to about 0.8%, or about 0.5% to about 1.2%, or about 1%, or about 1.2% by weight ibogaine or a pharmaceutically acceptable salt thereof.

[0043] In embodiments, the pharmaceutically acceptable diluent comprises a buffered intravenous aqueous solution.

[0044] In embodiments, the buffered intravenous aqueous solution is 0.9% sodium chloride or 5% dextrose in water (D5W).

[0045] In embodiments, the ibogaine or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof, wherein the patient has opioid use disorder.

[0046] In embodiments, the ibogaine or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof, wherein the patient has a chemical addiction or a neurological disorder and / or condition.

[0047] In embodiments, the opioid use disorder is associated with opioid or opioid-like drug, wherein the opioid or opioid-like drug comprises fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, buprenorphine, codeine, oripavine, thebaine, buprenorphine, methadone, meperidine, tramadol, tapentadol, levorphanol, oxymorphone, cocaine, ketamine, methamphetamine, opium, opium poppy, poppy straw, or an extract or concentrate thereof.

[0048] EXAMPLES

[0049] The present disclosure is further illustrated by reference to the following Examples. However, it should be noted that these Examples, like the embodiments described above, are illustrative and are not to be construed as restricting the scope of the disclosure in any way.

[0050] Example 1: Compositions Comprising Ibogaine

[0051] Aqueous compositions 1-6 were formulated according to the present disclosure:Attorney Docket No.: ATAI-110 / 01WO 338067-2790Composition: 1 2 3 4 5 6 Ibogaine (%, w / v) 4.5 1.5 2.5 4.5 2.8 2.8 Citrate buffer pH 6 10.0 10.0 I 10.0 10.0 10.0 I 10.0 (mM)SBE-β-CD (%, w / v) 20.0 | - 20.0HP-β-CD (%, w / v) - | 20.0 - 20.0 20.0 PEG 400 (%, w / v) - 30.0 - TBD TBD - Polysorbate 80 (%, I ~ 4.0 w / v)Propylene glycol (%, - 20.0 w / v)1.0 M HCI / NaOH q.s. pH q.s. pH q.s. pH q.s. pH q.s. pH q.s. pH 6.0 6.0 6.0 6.0 6.0 6.0 Water for injection q.s. to q.s. to q.s. to q.s. to q.s. to q.s. to 100.0 mL 100.0 mL 100.0 mL 100.0 mL 100.0 mL 100.0 mL

[0052] Ibogaine HC1 (salt factor 1.117) was used for manufacturing these compositions. Compositions 1, 4, 5, and 6 were initially formulated to contain 45 mg / mL of ibogaine. However, due to incomplete dissolution overnight, compositions 5 and 6 were diluted to 28 mg / mL of ibogaine. Composition 2 contained 15 mg / mL of ibogaine based upon ibogaine solubility in PEG400. Composition 3 contained 25 mg / mL based upon ibogaine solubility in HPBCD. Compositions 1 and 4 exhibited complete solubility at 45 mg / mL of ibogaine.

[0053] Example 2: Stability Data

[0054] Compositions 1-6 were subjected to stability testing at three different conditions: (i) 5 °C, (ii) 25 °C and 60% RH, and (iii) 40 °C and 75% RH. The compositions were tested at one week, two weeks, and four weeks for ibogaine assay, impurity content, and pH. The results are show in Fig. 1–3.

[0055] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.Attorney Docket No.: ATAI-llO / OIWO 338067-2790

[0056] While the invention has been described in connection with proposed specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.

Claims

Attorney Docket No.: ATAI-llO / OIWO 338067-2790CLAIMS1. An aqueous composition comprising:about 0.5 wt% to about 10 wt% of ibogaine or a pharmaceutically acceptable salt thereof; about 3.0 wt% to about 50 wt% of a complexing agent, wherein the complexing agent comprises a cyclodextrin; andabout 1 mM to about 100 mM of a buffering agent.

2. The aqueous composition of claim 1, wherein the weight ratio of ibogaine or a pharmaceutically acceptable salt thereof to cyclodextrin is about 1:20 to 1:2.

3. The aqueous composition of claim 1 or claim 2, wherein the composition comprises about 0.5 wt% to about 2.0 wt% of ibogaine or a pharmaceutically acceptable salt thereof.

4. The aqueous composition of claim 1 or claim 2, wherein the composition comprises about 2 wt% to about 5 wt% of ibogaine or a pharmaceutically acceptable salt thereof.

5. The aqueous composition of any of claims 1-4, wherein the ibogaine or a pharmaceutically acceptable salt thereof comprises ibogaine hydrochloride.

6. The aqueous composition of any of claims 1-5, wherein the cyclodextrin comprises a β-cyclodextrin,7. The aqueous composition of claim 6, wherein the β-cyclodextrin comprises 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin or methyl-β-cyclodextrin,8. The aqueous composition of any of claims 1-5, wherein the cyclodextrin comprises an a- cyclodextrin,9. The aqueous composition of claim 8, wherein the a-cyclodextrin comprises 2- hydroxypropyl-a-cyclodextrin.

10. The aqueous composition of any of claims 1-5, wherein the cyclodextrin comprises a y- cyclodextrin.Attorney Docket No.: ATAI-110 / 01WO 338067-279011. The aqueous composition of claim 10, wherein the y-cyclodextrin comprises 2- hydroxypropyl-γ-cyclodextrin.

12. The aqueous composition of any of claims 1-11, wherein the aqueous composition further comprises 5% to 40% by weight of a co-solvent.

13. The aqueous composition of claim 12, wherein the co-solvent comprises polyethylene glycol, glycerol, propylene glycol, ethyl alcohol or benzyl alcohol.

14. The aqueous composition of any of claims 1-11, wherein the aqueous composition further comprises about 0.5% to about 10% by weight of solubilizer or surfactant, such as polysorbates, kolliphors, poloxamers or vitamin E TPGS15. The aqueous composition of any of claims 1-14, wherein the buffering agent comprises acetic acid, citric acid, maleic acid, succinic acid tartaric acid, phosphate, tris (hydroxymethyl)-aminomethane (tris), or L-histidine.

16. The aqueous composition of any of claims 1-15, wherein the aqueous composition comprises about 2.5 mM to about 50 mM of the buffering agent.

17. The aqueous composition of any of claims 1-16, wherein the pH of the aqueous composition is about 4.5 to about 7.5.

18. An aqueous composition consisting essentially of:about 0.5 wt% to about 10 wt% of ibogaine or a pharmaceutically acceptable salt thereof; about 3.0 wt% to about 50 wt% of a complexing agent, wherein the complexing agent comprises cyclodextrin; andabout 1 mM to about 100 mM of a buffering agent.

19. A method of administering ibogaine or a pharmaceutically acceptable salt thereof to a patient in need thereof, the method comprising:diluting the aqueous composition of any of claims 1-18 with a pharmaceutically acceptable diluent to provide a parenteral composition, wherein the parenteral composition comprises about 0.1% to about 1.5% by weight ibogaine or a pharmaceutically acceptable salt thereof; andAttorney Docket No.: ATAI-110 / 01WO 338067-2790intravenously administering the parenteral composition to a patient.

20. The method of claim 19, wherein the pharmaceutically acceptable diluent comprises a buffered intravenous aqueous solution.

21. The method of claim 20 wherein the buffered intravenous aqueous solution is 0.9% sodium chloride or 5% dextrose in water (D5W).

22. The method of any of claims 19-21, wherein the ibogaine or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof, wherein the patient has opioid use disorder.

23. The method of claim 22, wherein the opioid use disorder is associated with opioid or opioidlike drug, wherein the opioid or opioid-like drug comprises fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, buprenorphine, codeine, oripavine, thebaine, buprenorphine, methadone, meperidine, tramadol, tapentadol, levorphanol, oxymorphone, cocaine, ketamine, methamphetamine, opium, opium poppy, poppy straw, or an extract or concentrate thereof.

24. The method of any of claims 19-21, wherein the ibogaine or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof, wherein the patient has a chemical addiction or a neurological disorder and / or condition.

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