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WO2025170990A1 - Libération transmuqueuse contrôlée de dmt en combinaison avec un inhibiteur de monoamine oxydase - Google Patents

Libération transmuqueuse contrôlée de dmt en combinaison avec un inhibiteur de monoamine oxydase

Info

Publication number
WO2025170990A1
WO2025170990A1 PCT/US2025/014571 US2025014571W WO2025170990A1 WO 2025170990 A1 WO2025170990 A1 WO 2025170990A1 US 2025014571 W US2025014571 W US 2025014571W WO 2025170990 A1 WO2025170990 A1 WO 2025170990A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
kit
dmt
pharmaceutically acceptable
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/014571
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English (en)
Inventor
Glenn Short
Srinivas G. Rao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Atai Therapeutics Inc
Original Assignee
Atai Therapeutics Inc
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Filing date
Publication date
Application filed by Atai Therapeutics Inc filed Critical Atai Therapeutics Inc
Publication of WO2025170990A1 publication Critical patent/WO2025170990A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches

Definitions

  • Naturally occurring psychedelics such as the DMT, which is contained in the South American shrub Psychotria viridis, psilocybin, which is contained in over 200 mushroom species, or mescaline, which is contained in the Peyote cactus of the American Southwest and Northern Mexico, have been used for centuries by indigenous cultures in ritualistic or sociocultural contexts, and in the context of religious sacraments. While an unspecific “healing” potential had been ascribed to the use of naturally occurring psychedelics in those settings, more scientific investigations into their potential therapeutic application for defined diseases had not been pursued until after the discovery of the synthetic ergoline lysergic acid diethylamide (“LSD”) in 1943.
  • LSD synthetic ergoline lysergic acid diethylamide
  • the basic mechanism considered in the psycholytic approach was therefore the activation and deepening of the concomitant psychotherapeutic process, and it required multiple drug and therapy sessions.
  • the second concept was coined as “psychedelic therapy” and it emphasized the ability of psychedelics given at relatively high single doses to induce so called “peak psychedelic experiences.” Peak experiences are predominantly characterized by the loss of judgment to time and space and the dissolution of ego boundaries, which often culminates in the experience of a blissful state and feelings of being a whole and harmonious existence in the cosmic unity.
  • the basic mechanism considered in the psychedelic approach was therefore to produce a unique, overwhelming experience with an intuitive perception of psychological integration and harmony and subsequent self-improvements and enhanced joy in living and a sense of inner peace.
  • DMT is also understood to hold therapeutic value as a psychedelic, with efficacy trials ongoing to assess the effect of DMT or DMT fumarate administered intravenously to subjects with major depressive disorder (“MDD”).
  • MDD major depressive disorder
  • DMT ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 make it an attractive possible medication, especially for neurological diseases and conditions
  • current therapeutic compositions and modes of administration complicate treatment and may not provide optimal therapeutic results.
  • DMT when smoked or delivered intravenously, DMT has a very fast onset of action and a short duration of effect, which presents a challenge to determine a suitable administration regimen with appropriate dosage and frequency of administration of DMT to provide effective therapy for neurological diseases and conditions.
  • transmucosal e.g., buccal/sublingual/gingival/mucosal (on the oral mucosa), on the tongue, nasal, vaginal, or rectal application
  • transmucosal e.g., buccal/sublingual/gingival/mucosal (on the oral mucosa)
  • oral mucosa on the oral mucosa
  • rectal application has looked to improve DMT bioavailability by circumventing GI and hepatic first pass metabolism.
  • compositions or kits for transmucosal administration to a subject comprising: (a) N,N-dimethyltryptamine (DMT) or a pharmaceutically acceptable salt or prodrug thereof; and (b) a monoamine oxidase inhibitor (MAOI) or a pharmaceutically acceptable salt thereof.
  • DMT N,N-dimethyltryptamine
  • MAOI monoamine oxidase inhibitor
  • 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 50.5. [0017] The term “subject ” “individual” and “patient” are used interchangeably herein and refers to a human.
  • 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. Salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc.
  • compositions or kits further comprise one or more monoamine oxidase inhibitors (MAOIs) or a pharmaceutically acceptable salt thereof.
  • MAOIs monoamine oxidase inhibitors
  • the DMT and the MAOI are formulated in a single pharmaceutical composition, together with at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • the single ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 pharmaceutical composition is formulated for oral administration.
  • the single pharmaceutical composition is formulated for transmucosal administration.
  • the DMT and the MAOI are formulated in separate pharmaceutical compositions, together with at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • the MAOI decreases metabolization of the DMT and prolongs exposure time (e.g., T max ) of DMT.
  • the present disclosure provides compositions or kits for transmucosal administration comprising (a) an active layer comprising DMT or a pharmaceutically acceptable salt or prodrug thereof in a polymeric carrier matrix, and (b) a backing layer.
  • the compositions or kits of the present disclosure for transmucosal administration further comprise one or more MAOIs.
  • the composition or kits of the present disclosure comprises an active layer comprising about 0.5 wt % to about 60 wt % of N,N-dimethyltryptamine (DMT) or a pharmaceutically acceptable salt or prodrug thereof in a polymeric carrier matrix and about 15 wt% to about 90 wt% of the polymeric carrier matrix.
  • DMT N,N-dimethyltryptamine
  • the DMT in the composition is in an amorphous form as characterized by a powder x-ray diffractogram free of any discernable peaks that are attributable to crystalline DMT.
  • the DMT in the composition is amorphous as characterized by a differential scanning calorimetry (DSC) thermogram lacking a sharp melting endotherm of crystalline DMT and/or lacking an indication of phase change.
  • the indication of phase change is glass transition temperature.
  • the active layer comprises about 0.5 wt% to about 60 wt%, including about 0.5 wt% to about 5 wt%, about 5 wt% to about 10 wt%, about 10 wt% to about 20 wt%, about 20 wt% to about 30 wt%, or about 30 wt% to about 60 wt% (including all values and ranges therebetween) of DMT or a pharmaceutically acceptable salt or prodrug thereof.
  • the active layer comprises DMT or a pharmaceutically acceptable salt or prodrug thereof of greater than about 27 wt%, including from about 28 wt%, about 29 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, about 50 wt%, about 51 wt%, about 52 wt%, about 53 wt%, about 54 wt%, about 55 wt%, ATTORNEY DOCKET NO.: ATAI-096/01WO 3380
  • the active layer of the present disclosure comprises about 1 mg to about 400 mg of DMT or a pharmaceutically acceptable salt or prodrug thereof, for example, about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 190 mg, about 195 mg
  • more than one active layers may be layered on another (e.g., to provide multiple DMT and/or MAOI-containing layers, such as a bilayer of active layer), optionally in combination with a backing layer (e.g., to provide a composition having multiple DMT and/or MAOI-containing active layers with a backing layer).
  • the composition comprises 1, 2, 3, or more active layers.
  • each active layer of the multiple DMT-containing active layers comprises about 1 mg to about 400 mg of DMT or a pharmaceutically acceptable salt or prodrug thereof.
  • each active layer of the multiple DMT-containing active layers comprises the same amount of DMT or a pharmaceutically acceptable salt or prodrug thereof or different amount of DMT or a pharmaceutically acceptable salt or prodrug thereof.
  • the composition of the present disclosure comprises a first active layer and a second active layer, wherein the first active layer comprises about 1 mg to about 400 mg of DMT or a pharmaceutically acceptable salt or prodrug thereof and the second active layer comprises about 1 mg to about 400 mg of DMT or a pharmaceutically acceptable salt or prodrug thereof, including all values and ranges therebetween.
  • the active layer has a surface of about 2 cm 2 to about 10 cm 2 , for example, about 2 cm 2 , about 4 cm 2 , about 6 cm 2 , about 8 cm 2 , or about 10 cm 2 .
  • the active layer comprises about 1 mg/cm 2 to about 15 mg/cm 2 amorphous DMT, for example, about 1 mg/cm 2 , about 5 mg/cm 2 , about 10 mg/cm 2 , or about 15 mg/cm 2 , including all values and ranges therebetween.
  • the active layer comprises about 2 mg/cm 2 to about 10 mg/cm 2 amorphous DMT.
  • the active layer comprises about 1 wt% to about 99 wt%, including from about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 90 wt%, about 95%, or about 99% of the polymeric carrier matrix.
  • the active layer comprises about 15 wt% to about 90 wt% of the polymeric carrier matrix.
  • the active layer comprises 15 wt% to about 50 wt% of the polymeric carrier matrix. In embodiments, the active layer comprises 30 wt% to about 50 wt% of the polymeric carrier matrix. In embodiments, the active layer comprises about 33 wt% to about 40 wt% of the polymeric carrier matrix. In embodiments, the active layer comprises about 35 wt% to about 36.5 wt% of the polymeric carrier matrix. [0039] In embodiments, the active layer comprises a buffering agent. In embodiments, the active layer comprises about 0.1 wt% to about 10 wt% of the buffering agent.
  • the buffering agent comprises one or more of citric acid, tartaric acid, fumaric acid, succinic acid, malic acid, sodium citrate, sodium tartrate, sodium succinate, sodium fumarate, or any combination thereof.
  • the active layer comprises a buffering agent, and/or a saliva stimulating agent.
  • the buffering agent is used with a pH adjusting agent, such as sodium hydroxide.
  • the saliva stimulating agent comprises one or more of citric acid, malic acid, lactic acid, ascorbic acid, tartaric acid, or any combination thereof.
  • ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 [0040]
  • the active layer comprises a permeation enhancer.
  • the active layer comprises about 1 wt% to about 10 wt%, about 1 wt% to about 5 wt%, about 4 wt% to about 8 wt%, or about 5 wt% to about 6 wt% of the permeation enhancer.
  • the permeation enhancer comprises d- -tocopheryl polyethylene glycol succinate (“Vitamin E TPGS”), a bile salt, cetylpyridinium chloride (CPC), sodium lauryl sulfate (SLS), Tween 80, L-menthol, dimethyl sulfoxide (DMSO), oleic alcohol, oleic acid, oleyl oleate, levulinic acid, propylene glycol, dipropylene glycol, ethanol, or any combination thereof.
  • the permeation enhancer comprise Vitamin E TPGS.
  • the composition comprises other stability enhancers including antioxidants or chelators.
  • the active layer comprises an antioxidant.
  • the active layer comprises about 0.5 wt% to about 3 wt% of the antioxidant.
  • the permeation enhancer comprises both permeation enhancing and antioxidant properties.
  • vitamin E may include both permeation enhancing and antioxidant characteristics.
  • the active layer comprises about 1 wt% to about 10 wt%, about 4 wt% to about 8 wt%, or about 5 wt% to about 6 wt% of the permeation enhancer and the antioxidant.
  • the active layer comprises a plasticizer.
  • the active layer comprises about 1 wt% to about 10 wt% of the plasticizer.
  • the plasticizer is a polyethylene glycol (PEG) (e.g., PEG300), propylene glycol, glycerol, triacetin, castor oil, or mixtures thereof.
  • the active layer comprises a sweetening agent and/or a flavoring agent.
  • the sweetening agent comprises one or more of Advantame, sucrose, dextrose, fructose, glucose, maltose, maltitol, saccharin, sucralose, neotame, cyclamate, aspartame, acesulfame-K, or any combination thereof.
  • the flavoring agent comprises one or more of lime flavor, lemon flavor, peppermint oil, cinnamon oil, vanilla extract, menthol, L-menthol, or any combination thereof.
  • the active layer comprises a coloring agent.
  • the coloring agent comprises one or more of D&C or FD&C red, yellow, green, blue, iron oxide red, iron oxide yellow, titanium dioxide, or any combination thereof.
  • the active layer comprises an anti-foaming agent (e.g., simethicone).
  • the active layer comprises a hydrophilic adjuvant/additive or matrix solubilizing agent.
  • the hydrophilic adjuvant and/or additive comprises cellulose derivative, starch derivative, cross linked povidone, cross linked cellulose, cross linked starch or alginate, sucrose, maltose, sugar alcohol or mixtures thereof.
  • the active layer composition is as shown in Table 2.
  • the active layer composition is as shown in Table 3.
  • the active layer composition is as shown in Table 4.
  • the active layer composition is as shown in Table 5.
  • the active layer composition is as shown in Table 6.
  • the active layer composition is as shown in Table 7.
  • the active layer of the present disclosure has a pH of about 7.5 to about 9, including about 8 to about 9, about 8.5 to about 9, or about 8.6.
  • the pH can be measured by a method known to one skilled in the art, such as a standardized method according to United States Pharmacopeial Convention (USP) (e.g., a pH meter or pH electrode).
  • USP United States Pharmacopeial Convention
  • the composition comprises a backing layer and an active layer (e.g., a DMT mucoadhesive film) as described herein.
  • the backing layer forms the back side (i.e., the non-adhesive side) of the transmucosal composition of the present disclosure.
  • the backing layer is adjacent to the DMT mucoadhesive film.
  • the backing layer is adapted to reduce or prevent DMT from being transported across the backing layer while the mucoadhesive therapeutic product is being administered.
  • the backing layer is substantially impermeable to diffusion of DMT to the back side of the transmucosal bilayer film.
  • the backing layer serves as a protective barrier to prevent, substantially prevent or reduce the amount of saliva contacting the DMT active agent and/or erosion of the back side of transmucosal bilayer film.
  • the backing layer comprises a polymeric matrix and a pigment.
  • the backing layer comprises carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC), sodium carboxymethylcellulose, polyethylene glycol (PEG), copovidone (a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate), or any combination thereof.
  • CMC includes, but is not limited to, Aqualon TM 7LF PH sodium CMC of 90.5 KDa having a solution viscosity (mPa ⁇ s) of 25-50 cps in a 2 wt% aqueous solution (Ashland Global Holdings Inc.).
  • Exemplary copovidone includes, but is not limited to, PlasdoneTM S-630 copovidone of 43 KDa having a solution viscosity (mPa ⁇ s) of 25-31 cps in a 2 wt% aqueous solution (Ashland Global Holdings Inc.). PlasdoneTM S-630 copovidone is a 60:40 linear random copolymer of N-vinyl-2- pyrrolidone and vinyl acetate.
  • the composition of the present disclosure comprises an active layer of about 70 wt% to about 90 wt%, including from about 70 wt%, about 75 wt%, about 80 wt%, or about 85 wt%, to about 90 wt% of the composition.
  • the transmucosal bilayer film composition of the present disclosure comprises a backing layer of about 10 wt% to about 30 wt%, including from about 10 wt%, about 15 wt%, about 20 wt%, or about 25 wt%, to about 30 wt% of the composition.
  • the MAOI comprises reversible, irreversible, competitive, non-competitive, selective, or non-selective inhibitors, as well as any substance that indirectly modulates or regulates monoamine oxidase activity through allosteric, regulatory, or indirect mechanisms.
  • the MAOI is an MAO-A-selective inhibitor.
  • the MAOI is an MAO-B-selective inhibitor.
  • the MAOI is a non- selective inhibitor.
  • the MAOI is a naturally occurring or commercially available reversible inhibitor of monoamine oxidase (RIMA).
  • the MAOI is isocarboxazid, phenelzine, selegiline, tranylcypromine, moclobemide, rasagiline, pargyline, minaprine, iproniazid, iproniazid, or nialamide.
  • the MAOI is a reversible inhibitor of ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 monoamine oxidase A (RIMA).
  • the RIMA is a natural source RIMA.
  • the natural source RIMA is curcumin, harmaline, or harmine.
  • the RIMA is a commercially available RIMA.
  • the commercially available RIMA is brofaromine, cimoxatone, moclobemide, amiflamine caroxazone, eprobemide, minaprine, metralindole, methylene blue, moclobemide, pirlindole, or toloxatone.
  • the MAOI is selected from the group consisting of isocarboxazid, pargyline, selegiline, furazolidone, phenelzine, amiflamine, iproniazid, nialamide, tranylcypromine, octamoxin, phenoxypropazine, pivalyl benzhydrazine, iproclozide, iproniazide, bifemelane, prodipine, benmoxin, etryptamine, fenoxypropazine, mebanazine, pheniprazine, safrazine, hypericine, iproniazid phosphate, phenelzine sulphate, tranylcypromine sulphate, methylene blue, moclobemide, brofaromine, befloxatone, toloxatone, clorgyline, CX157, cimoxatone, chili
  • the MAOI is selected from the group consisting of moclobemide, brofaromine, caroxazone, eprobemide, metralindole, minaprine, pirlindole, harmaline, harmine, rosiridin, amiflamine, befloxatone, cimoxatone, esuprone, sercloremine, tetrindole, 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin-10,10-dioxide (CX157), and 3-(2,2,2-trifluoroethoxy)phenoxathiin-10, 10-dioxide (CX009).
  • the MAOI is selected from the group consisting of moclobemide, metralindole, pirlindole, harmaline, harmine, tetrindole, CX157, and CX009. [0063] In embodiments, the MAOI is a reversible inhibitor of MAO-A. In embodiments, the MAOI is a MAO-A selective inhibitor. In embodiments, the MAOI has a selectivity for MAO- A inhibition over monoamine oxidase B (MAO-B) inhibition of at least about 5-fold, about 10- fold, about 50-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 500- fold, or about 1000-fold.
  • MAO-B monoamine oxidase B
  • the reversible inhibitor of MAO-A is CX157.
  • the composition and kit comprises a molar ratio of MAOI to DMT that is about 1:1 or less than 1.
  • the composition and kit comprises a weight ratio of the inhibitor of MAOI to DMT ranging from about 1:1 to about 1:500 (e.g., about 1:2, about 1:5, about 1:10, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:110, about 1:120, about 1:30, about 1:140, about 1:150, about 1:160, about 1:170, about 1:180, about 1:190, about 1:200, about 1:210, about 1:220, about 1:230, ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 about 1:240, about 1:250, about 1:260, about 1:270, about 1:280, about 1:290, about 1:300, about 1
  • compositions and kits are suitable for transmucosal application.
  • the compositions and kits are suitable for buccal, sublingual, gingival, on the tongue, nasal, vaginal, or a rectal application.
  • the film is placed in the oral cavity with the backing layer facing away from the subject’s skin (i.e., on the side of the film opposite that which is put into contact with the subject’s skin).
  • the composition or kit is administered by a sublingual, buccal, or otherwise oral transmucosal route of administration.
  • the administration of the composition to the oral mucosa of a subject in need thereof provides a C max of DMT of about 1 ng/mL to about 200 ng/mL, for example, about 1 ng/mL, about 5 ng/mL, about 10 ng/mL, about 15 ng/mL, about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL, about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL, about 80 ng/mL, about 85 ng/mL, about 90 ng/mL, about 95 ng/mL, about 100 ng/mL, about 105 ng/mL, about 110 ng/mL, about 115 ng/mL, about 120 ng/m
  • the administration of the composition to the oral mucosa of a subject in need thereof provides a AUClast of DMT of about 1 ng ⁇ h/mL to about 100 ng ⁇ h/mL, for example, about 1 ng ⁇ h/mL, about 2 ng ⁇ h/mL, about 3 ng ⁇ h/mL, about 4 ng ⁇ h/mL, about 5 ng ⁇ h/mL, about 10 ng ⁇ h/mL, about 15 ng ⁇ h/mL, about 20 ng ⁇ h/mL, about 25 ng ⁇ h/mL, about 30 ng ⁇ h/mL, about 35 ng ⁇ h/mL, about 40 ng ⁇ h/mL, about 45 ng ⁇ h/mL, about 50 ng ⁇ h/mL, about 55 ng ⁇ h/mL, 60 ng ⁇ h/mL, about 65 ng ⁇ h/mL, about 70 ng ⁇ h/mL, about 75 ng ⁇ h/mL, about 80 ng ⁇ h
  • DMT is not orally active as it is rapidly inactivated by monoamine oxidase (MAO) enzymes during first-pass metabolism (Nichols, Pharmacological Reviews, 2016;68(2):264-355).
  • MAO-A monoamine oxidase A
  • MAO-A is the main metabolizing enzyme of DMT and the two main circulating metabolites of DMT are DMT-NO and IAA.
  • DMT is metabolized by both MAO and CYP enzymes.
  • CYP oxidation results in primarily the DMT-NO formation, while MAO-A metabolism primarily results in IAA, but not DMT-NO.
  • a scheme illustrating the common oxidation is presented in Scheme 1.
  • the present disclosure provides methods of increasing the oral bioavailability, decreasing the (in vitro or in vivo) rate of degradation, or increasing the (in vitro or in vivo) half-life of the DMT or a pharmaceutically acceptable salt or prodrug thereof.
  • the methods of the present disclosure comprise administering to a subject in need thereof a therapeutically effective amount of an MAOI or a pharmaceutically acceptable salt thereof in an amount effective to inhibit MAO metabolism of DMT, and a therapeutically effective amount of DMT or a pharmaceutically acceptable salt or prodrug thereof.
  • the present disclosure provides methods of increasing or prolonging exposure of DMT in plasma or brain of a subject in need thereof comprising administering to the subject a therapeutically effective amount of a MAOI in an amount effective to inhibit MAO metabolism of DMT, and a therapeutically effective amount of DMT or a pharmaceutically acceptable salt or prodrug thereof.
  • the MAOI is administered before the DMT.
  • the MAOI is administered at the same time as the DMT.
  • the methods of the present disclosure comprise increasing exposure of DMT in plasma or brain, as compared to a subject administered the same dose of DMT or a pharmaceutically acceptable salt or prodrug thereof without administration of a MAOI in an amount effective to inhibit MAO metabolism of DMT.
  • the exposure of DMT in plasma or brain is increased by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 135%, about 140%, about 145%, about 150%, about 155%, about 160%, about 165%, about 170%, about 175%, about 180%, about 185%, about 190%, about 195%, about 200%, including all values and ranges therein.
  • the methods of the present disclosure comprise prolonging exposure of DMT in plasma or brain, as compared to a subject administered the same dose of DMT or a pharmaceutically acceptable salt or prodrug thereof without administration of a MAOI in an amount effective to inhibit MAO metabolism of DMT.
  • the exposure of DMT in plasma or brain is prolonged by about 0.5 hour, about 0.75 hour, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2.0 hours, about 2.25 hours, about 2.5 hours, about 2.75 ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 hours, about 3.0 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4.0 hours, about 4.25 hours, about 4.5 hours, about 4.75 hours, about 5.0 hours, about 5.25 hours, about 5.5 hours, about 5.75 hours, about 6.0 hours, about 6.25 hours, about 6.5 hours, about 6.75 hours, about 7.0 hours, about 7.25 hours, about 7.5 hours, about 7.75 hours, about 8.0 hours 8.25 hours, about 8.5 hours, about 8.75 hours, about 9.0 hours, about 9.25 hours, about 9.5 hours, about 9.75 hours, about 10.0 hours, about 10.25 hours, about 10.5 hours, about 10.75 hours, about 11.0 hours, about 11.25 hours,
  • the present disclosure provide methods of treatment of a disease or disorder, wherein the methods comprise administering a therapeutically effective amount of the composition or kit of the present disclosure to a subject in need thereof.
  • the disease or disorder is neurological disease, disorder, or condition, for example, a neuropsychiatric disorder.
  • a “neurological disease, disorder, or condition” refers to a disease, disorder, or condition comprising: a neuropsychiatric disorder, such as depressive disorder or depression (including severe depression such as treatment-resistant depression (TRD), major depressive disorder (MDD) and persistent depressive disorder), alexithymia, catatonic depression, a depressive disorder due to a medical condition, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, anxiety, anxiety disorder, social anxiety disorder (SAD), general anxiety disorder (GAD), avolition disorder, bipolar disorder (including bipolar I disorder and bipolar II disorder), post-traumatic stress disorder (PTSD), body dysmorphic disorder, abnormalities of mood or emotion, including the above conditions, dysthymia, schizoaffective ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 disorder, schizophrenia and other psychotic disorders, panic disorder, traumatic stress disorders, phobic disorders, and personality disorders with
  • treatment-resistant depression means a depressive disorder which does not respond satisfactorily to adequate treatment.
  • TRD is a complex phenomenon influenced by variety in depressive subtypes, psychiatric comorbidity, and coexisting medical illnesses. Although TRD episodes are most commonly associated with major depressive disorder (MOD), they are also seen in the depressed phase of bipolar disorder.
  • MOD major depressive disorder
  • the neurological disease or condition is addiction.
  • Examples of addiction which can be treated with DMT or a pharmaceutically acceptable salt or prodrug thereof include substance use disorder such as addiction to nicotine, alcohol, cocaine, opioids, amphetamine, methamphetamine, heroin, morphine, phencyclidine, 3,4-methylenedioxy- methamphetamine, as well as other addictive substances.
  • the neurological disease or condition is addictive behavior.
  • addictive behavior which can be treated with DMT or a pharmaceutically acceptable salt or prodrug thereof include addiction to eating, gambling, sex, pornography, videogames, work, exercise, spiritual obsession, self-harm, travel, shopping and substance use disorder (SUD).
  • the present disclosure provides methods of treating depression (including severe depression such as treatment-resistant depression, major depressive disorder and persistent depressive disorder, catatonic depression, a depressive disorder due to a medical ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 condition, or postpartum depression), comprising administering a therapeutically effective amount of the composition or kit of the present disclosure to a subject in need thereof.
  • Dosing Regimens [0081] In embodiments, about 1 mg to about 400 mg of DMT free base or an equivalent dose of the pharmaceutically acceptable salt or prodrug thereof is administered to a subject in need thereof.
  • the therapeutically effective amount comprises a dose of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about
  • the therapeutically effective amount of an MAOI or a pharmaceutically acceptable salt thereof comprises a dose in an amount effective to inhibit MAO metabolism of DMT.
  • the composition or kit comprises a molar ratio of MAOI to DMT being about 1:1 or less than 1.
  • the composition comprises a molar ratio of MAOI to DMT ranging from about 1:1 to about 1:500 (e.g., about 1:2, about 1:5, about 1:10, about ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:110, about 1:120, about 1:30, about 1:140, about 1:150, about 1:160, about 1:170, about 1:180, about 1:190, about 1:200, about 1:210, about 1:220, about 1:230, about 1:240, about 1:250, about 1:260, about 1:270, about 1:280, about 1:290, about 1:300, about 1:310, about 1:320, about 1:330, about 1:340, about 1:350, about 1:360, about 1:370, about 1:380, about 1:390, about 1:400, about 1:410, about 1:410,
  • the therapeutically effective amount of an MAOI or a pharmaceutically acceptable salt thereof comprises a dose ranging from about 0.1 mg to about 400 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about
  • the MAOI or a pharmaceutically acceptable salt thereof is administered concomitantly or concurrently with the DMT or a pharmaceutically acceptable salt or prodrug thereof.
  • the MAOI or a pharmaceutically acceptable salt thereof and the DMT or a pharmaceutically acceptable salt or prodrug thereof are formulated in a single composition and the DMT and MAOI-containing composition is administered to a subject in need thereof.
  • the MAOI or a pharmaceutically acceptable salt thereof and the DMT or a pharmaceutically acceptable salt or prodrug thereof are formulated in separate compositions and the DMT composition and the MAOI composition are administered concomitantly to a subject in need thereof.
  • the MAOI is administered before the first dose of DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the MAOI is administered as a single dose before the first dose of DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the MAOI is administered within about 0.5 hour, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours , about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours or about 15 hours of administration of the DMT or a pharmaceutically acceptable salt or prodrug thereof.
  • the MAOI is administered as a single daily dose for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days or 10 days before the first dose of DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the MAOI is administered before each dose of DMT or a pharmaceutically acceptable salt or prodrug thereof. In embodiments, the MAOI is administered before a dose of DMT or a pharmaceutically acceptable salt or prodrug thereof as needed.
  • a subject in need thereof is administered a composition or kit comprising DMT or a pharmaceutically acceptable salt or prodrug thereof and an MAOI or a pharmaceutically acceptable salt thereof via transmucosal administration multiple times over a set a period of time.
  • the subject is administered the composition or kit once every time period of between about 2 weeks and about 6 months for a set treatment period.
  • the subject is administered the composition or kit once every time period of between about 2 weeks and about 3 months for a set treatment period.
  • the subject is administered the composition or kit once every about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks.
  • the methods described herein for treating a neurological disease or condition comprise administering DMT or a pharmaceutically acceptable salt or prodrug thereof in combination with one or more additional active agents.
  • one or more additional agents comprise therapeutic agents appropriate for the disease or disorder that is being treated, as is known in the art.
  • DMT or a pharmaceutically acceptable salt or prodrug thereof may be administered to the subject in combination with one or more anti-depressant or antianxiety drugs, such as SSRls, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), or serotonin norepinephrine reuptake inhibitors (SNRls).
  • the disclosure provides methods of reducing anxiety in a subject undergoing treatment with DMT or a pharmaceutically acceptable salt or prodrug thereof, the method comprising administering to the subject: i) DMT or a pharmaceutically acceptable salt or prodrug thereof and ii) one or more benzodiazepines.
  • the one or more benzodiazepines are administered to the subject at or around the same time as DMT or a pharmaceutically acceptable salt or prodrug thereof.
  • the benzodiazepine is selected from adinazolam, alprazolam, bentazepam, bretazenil, bromazepam, bromazolam, brotizolam, camazepam, chlordiazepoxide, cinazepam, cinolazepam, clobazam, clonazepam, clonazolam, clorazepate, clotiazepam, cloxazolam, delorazepam, deschloroetizolam, diazepam, diclazepam, estazolam, ethyl carfluzepate, ethyl loflazepate, etizolam, flualprazolam, flubromazepam, flubromazolam, fluclotizolam, flunitrazepam, flunitrazolam, flurazepam, flutazolam, flutopraz
  • a subject is administered DMT or a pharmaceutically acceptable salt thereof as described herein along with one or more 5-HT2A specific antagonists and/or inverse agonists.
  • the subject is administered DMT or a pharmaceutically acceptable salt thereof and the one or more 5-HT2A specific antagonists and/or inverse agonists at the same time.
  • Suitable 5-HT2A reverse agonists include but are not limited to, AC-90179, nelotanserin (APD-125), eplivanserin, pimavanserin (ACP-103), and volinaserin.
  • the disclosure provides a method of reducing the negative side effects associated with a traumatic psychedelic experience in a subject undergoing treatment with DMT or a pharmaceutically acceptable salt or prodrug thereof.
  • the method comprises administering to the subject: i) DMT or a pharmaceutically acceptable salt or prodrug thereof, and ii) one or more 5-HT 2A specific antagonists and/or inverse agonists.
  • the method comprises administering to the subject: i) DMT or a pharmaceutically acceptable salt or prodrug thereof, and ii) one or more cannabinoids or cannabinoid derivatives.
  • the cannabinoid is selected from THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid); CBD (cannabidiol); CBDA (cannabidiolic acid); CBN (cannabinol); CBG (cannabigerol); CBC (cannabichromene); CBL (cannabicyclol); CBV (cannabivarin); THCV (tetrahydrocannabivarin); CBDV (cannabidivarin); CBCV (cannabichromevarin); CBGV (cannabigerovarin); CBGM (cannabigerol monomethyl ether); CBE (cannabielsoin); or CBT (cannabicitran).
  • the cannabinoid is CBD (cannabidiol).
  • Dosage regimens may be adjusted to provide the optimum desired response. Treatment dosages may be titrated using routine methods known to those of skill in the art to optimize safety and efficacy.
  • compositions or kits of the present disclosure are administered in conjunction with psychotherapy, talk therapy, cognitive behavioral therapy, exposure therapy, biofeedback therapy (e.g.
  • compositions or kits of the present disclosure are administered to treat depression in conjunction with digital cognitive behavioral therapy, for example, using the digital program DEPREXIS®.
  • compositions or kits of the present disclosure are administered (for example, to treat depression or anxiety) in conjunction with therapy using a transdiagnostic approach (cf. J Consult Clin Psychol.
  • composition or kit of embodiment 2 wherein the MAOI or a pharmaceutically acceptable salt thereof is formulated in the film composition in combination with the DMT or a pharmaceutically acceptable salt or prodrug thereof.
  • ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 The composition or kit of embodiment 2, wherein the DMT or a pharmaceutically acceptable salt or prodrug thereof and the MAOI or a pharmaceutically acceptable salt thereof are formulated in separate compositions.
  • the composition or kit of embodiment 2, wherein the film composition is a single layer film.
  • the film composition is a bilayer film or a multilayer film.
  • the film composition comprises a backing layer.
  • composition or kit of any one of the preceding embodiments wherein the DMT or a pharmaceutically acceptable salt or prodrug thereof is amorphous as determined by a differential scanning calorimetry (DSC) thermogram lacking a sharp melting endotherm of crystalline DMT and/or lacking an indication of phase change.
  • DSC differential scanning calorimetry
  • the active layer comprises about 1 wt% to about 60 wt% of the DMT or a pharmaceutically acceptable salt or prodrug thereof.
  • composition or kit of any one of the preceding embodiments, wherein the composition comprises about 1 mg to about 200 mg of the DMT or an equivalent amount of the pharmaceutically acceptable salt or prodrug thereof.
  • composition or kit of embodiment 14 wherein the composition comprises about 1 mg, about 5 mg, about 15 mg, about 20 mg, about 40 mg, about 60 mg, or about 80 mg of the DMT or an equivalent amount of the pharmaceutically acceptable salt or prodrug thereof.
  • the polymeric carrier matrix comprises a mucoadhesive polymer.
  • composition or kit of embodiment 8, wherein the polymeric carrier matrix comprises a cellulose derivative, a polyacrylic acid, a polyacrylate, a polyethylene oxide, polyvinyl pyrrolidone, poly(vinyl pyrrolidone-co-vinyl acetate), hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), hydroxypropylmethyl cellulose, polyvinyl alcohol, propylene glycol alginate ester, tragacanth, alginate, a gum, a soluble starch, gelatin, lectin, pectin, chitosan, or any combination thereof.
  • the polymeric carrier matrix comprises a cellulose derivative, a polyacrylic acid, a polyacrylate, a polyethylene oxide, polyvinyl pyrrolidone, poly(vinyl pyrrolidone-co-vinyl acetate), hydroxyethyl cellulose, hydroxypropyl cellulose (HPC
  • the active layer comprises a permeation enhancer.
  • composition or kit of embodiment 22, wherein the permeation enhancer comprises d- -tocopheryl polyethylene glycol succinate (Vitamin E TPGS), a bile salt, cetylpyridinium chloride (CPC), sodium lauryl sulfate (SLS), Tween 80, L-menthol, oleic alcohol, oleic acid, oleyl oleate, levulinic acid, propylene glycol, dipropylene glycol, ethanol, or any combination thereof.
  • ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 The composition or kit of embodiment 8, wherein the active layer comprises a stability enhancer or an antioxidant.
  • composition or kit of embodiment 24, wherein the stability enhancer or the antioxidant comprises -tocopherol, tocopherol acetate, L-Glutathione, L-cysteine, ascorbic acid, ascorbyl palmitate, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), Tocobiol, Ethylenediaminetetraacetic acid (EDTA), or any combination thereof.
  • the active layer comprises a sweetening agent and/or a flavoring agent.
  • ATTORNEY DOCKET NO.: ATAI-096/01WO 338067-2634 The composition or kit of embodiment 8, wherein the backing layer comprises sodium hydroxide.
  • composition or kit of any one of the preceding embodiments wherein the composition or kit is suitable for buccal, sublingual, gingival, on the tongue, nasal, vaginal, or a rectal application.
  • the composition or kit of any one of the preceding embodiments, wherein the molar ratio of MAOI to DMT is about 1:1 to about 1:500.
  • the composition or kit of any one of the preceding embodiments, wherein the MAOI decreases metabolization of DMT and prolongs a DMT T max .
  • composition or kit of any one of the preceding embodiments, wherein the MAOI is isocarboxazid, phenelzine, selegiline, tranylcypromine, moclobemide, rasagiline, pargyline, minaprine, iproniazid, iproniazid, or nialamide.
  • RIMA monoamine oxidase A
  • the composition or kit of embodiment 40, wherein the RIMA is a natural source RIMA.
  • the composition or kit of embodiment 41, wherein the natural source RIMA is curcumin, harmaline, or harmine.
  • composition or kit of embodiment 41 wherein the RIMA is a commercially available RIMA.
  • a method of treating a neurological disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition or kit of embodiments 1-44.
  • 49. The method of embodiment 47, wherein the MAOI or a pharmaceutically acceptable salt thereof is administered between about 15 minutes to about 75 minutes before the administration of the DMT or a pharmaceutically acceptable salt or prodrug thereof. 50.

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Abstract

L'invention concerne des compositions pharmaceutiques pour l'administration transmuqueuse d'un sel acceptable de N-N-diméthyltryptamine (DMT) ou d'un promédicament de celui-ci en combinaison avec un inhibiteur de monoamine oxydase afin d'obtenir la biodisponibilité souhaitée appropriée pour le traitement de troubles neurologiques.
PCT/US2025/014571 2024-02-06 2025-02-05 Libération transmuqueuse contrôlée de dmt en combinaison avec un inhibiteur de monoamine oxydase Pending WO2025170990A1 (fr)

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WO2023036473A1 (fr) * 2021-09-08 2023-03-16 Cybin Irl Limited Associations médicamenteuses
US20230233537A1 (en) * 2020-06-22 2023-07-27 University Of Zürich Compositions and Kits of Parts Comprising N,N-Dimethyltryptamine and Harmine and Their Use in Therapy
US20230321039A1 (en) * 2021-04-26 2023-10-12 ATAI Life Sciences AG N-n-dimethyltryptamine (dmt) and dmt analog compositions, methods of making, and methods of use thereof
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US20230372295A1 (en) * 2020-05-08 2023-11-23 Psilera Inc. Novel compositions of matter and pharmaceutical compositions
US20230233537A1 (en) * 2020-06-22 2023-07-27 University Of Zürich Compositions and Kits of Parts Comprising N,N-Dimethyltryptamine and Harmine and Their Use in Therapy
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