TW202423415A - N-n-dimethyltryptamine (dmt) and dmt analog compositions, methods of making, and methods of use thereof - Google Patents

Abstract

Pharmaceutical compositions including an amorphous N-N-dimethyltryptamine (DMT) or a pharmaceutically acceptable salt or prodrug thereof, and a polymeric carrier are described. These compositions are suitable for buccal or sublingual administration to a patient. Methods of treating disorders, including neurological disorders, by administration of these compositions are described.

Description

N-N-dimethyltryptamine (DMT) and DMT analog composition, preparation method and use method thereof

The present invention relates to novel N,N-dimethyltryptamine (hereinafter referred to as "DMT") compositions and methods for treating neurological diseases and conditions. In particular, the present invention provides improved pharmaceutical compositions comprising DMT in a form that allows for transmucosal controlled release of DMT and is suitable for treating neurological diseases and conditions.

Lysergic acid diethylamide ("LSD"), psilocybin and DMT are serotonergic drugs, often referred to as "classic psychedelics" or "hallucinogens", and are capable of inducing qualitatively altered states of consciousness, such as euphoria, trance, time-space transcendence, spiritual experiences or the dissolution of ego boundaries, while other effects such as sedation, anesthesia or overstimulation are minimal. Chemically, serotonergic hallucinogens are either phenylalanamines or indoleamines, of which the indoleamine class is also divided into two subgroups, namely ergolines and tryptamines.

Naturally occurring hallucinogens, such as DMT found in the South American bush worm (Psychotria viridis), psilocybin found in more than 200 species of mushrooms, or mescaline found in the peyote cactus of the southwestern United States and northern Mexico, have been used for centuries by indigenous cultures in ritual or socio-cultural and religious sacraments. Although the use of naturally occurring hallucinogens in these contexts was thought to have non-specific "healing" potential, it was not until the discovery of the synthetic ergoline lysergic acid diethylamide ("LSD") in 1943 that more scientific research began on the potential for therapeutic use of hallucinogens for specific medical conditions.

As knowledge of the serotonin system and its role in brain function increased, researchers began to define the molecular activity of psychedelic drugs. However, how this activity translates into the therapeutic effects observed in psychiatric disorders remains less clear. Two main concepts have been proposed: The first concept has been called "psycholytic therapy" and emphasizes that low doses of psychedelics can promote the relaxation of psychological defense mechanisms, which, combined with psychotherapy, can produce deep introspective insights and enable trauma reversal and subsequent catharsis. Therefore, the basic mechanism considered by the psychotherapeutic approach is the activation and deepening of the psychotherapeutic process simultaneously, and it requires multiple medications and treatment stages. The second concept is called "psychedelic therapy" and emphasizes the ability of hallucinogens, given in relatively high single doses, to induce so-called "peak psychedelic experiences." Peak experiences are characterized by a loss of perception of time and space and a dissolution of ego boundaries, often culminating in a state of ecstasy and a sense of being a complete and harmonious being in a cosmic unity. The basic mechanism contemplated by the psychedelic approach is thus the production of a unique and overwhelming experience of intuitive psychological integration and harmony, with attendant self-perfection, increased enjoyment of life, and a sense of inner peace.

Although scientific research surrounding the use of psychedelics to treat mental illness flourished in the 1960s, recreational use of these substances also grew rapidly, and soon psychedelics were being portrayed in the media as highly dangerous drugs of abuse. The perceived danger to social order led to the passage of the Controlled Substances Act in the United States in 1970, under which LSD and other psychedelics were placed on Schedule 1, the most restrictive category, which contains drugs that are considered to have no medical use and have a high potential for abuse. For the next 30 years, little progress was made in research into the possible therapeutic uses of psychedelic drugs.

Recently, there has been a resurgence of interest in the field of psychedelic therapy, and classic psychedelics have shown preclinical and clinical promise in the treatment of psychiatric disorders (Carhart-Harris and Goodwin, The Therapeutic Potential of Psychedelic Drugs: Past, Present and Future, Neuropsychopharmacology; 42, 2105-2113 (2017)). Specifically, psilocybin has been shown to produce significant improvements on a range of depression and anxiety rating scales in a randomized double-blind trial (Griffiths et al., Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial, Journal of Psychopharmacology 30(12), 1181-1197 (2016)).

It is also understood that DMT has therapeutic value as a hallucinogen, and efficacy trials are currently underway to evaluate the effects of intravenous administration of DMT or DMT fumarate to individuals suffering from major depressive disorder ("MDD"). However, while the intrinsic properties of DMT make it an extremely attractive possible drug, particularly in the treatment of neurological diseases and disorders, current therapeutic compositions and modes of administration complicate treatment and may not provide optimal therapeutic effects. For example, when smoked or delivered intravenously, DMT has an extremely rapid onset of action and a short duration of action, thus creating a challenge in determining an appropriate dosing regimen with adequate dosing and frequency of administration for DMT to provide effective treatment for neurological diseases and conditions. This is particularly true for neurological diseases and conditions, as these neurological diseases and conditions would benefit from DMT being present in therapeutic blood levels for a longer period of time after administration than a single dose of DMT administered by injection or inhalation.

Therefore, there is an urgent need for DMT drugs that are easy to administer for the treatment of neurological diseases and conditions. Drugs that can maximize the efficacy of the drug while effectively controlling the side effects of the drug are particularly interesting, especially those that can be administered (including self-administration) via convenient routes.

Several attempts to develop psychedelic formulations using traditional polymeric formulations have been described. For example, U.S. Publication No. 2021/0015738, entitled "Oral Dissolvable Film Containing Psychedelic Compound" by La Rosa et al. discloses an orally dissolvable film with DMT for the treatment of neurological disorders. The orally dissolvable film comprises: (a) a plasticizer, (b) a solvent, (c) a sweetener, (d) a flavoring agent, (e) a binder, (f) a coloring agent, (g) a preservative, and (h) a hallucinogenic compound selected from the group consisting of psilocin, psilocin, baeocystin, mescaline, LSD, ketamine, salvinorin A, ibotenic acid, muscimol, DMT, MDMA, MDEA, MDA, and combinations thereof.

Espinoza's U.S. Publication No. 2021/0322306, entitled "Oral Dissolvable Film With High Load of Polymeric Binder," discloses a composition comprising (a) a film matrix comprising one or more binders, at least one of which is a polymeric binder having a glass transition temperature (Tg) of at least 45°C; (b) a solvent; (c) an active pharmaceutical ingredient (API); and (d) a pharmaceutically acceptable excipient comprising a mucosal At least one of adhesion polymers, plasticizers, fillers, bulking agents, saliva stimulants, stabilizers and thickeners, gelling agents, flavoring agents, taste masking agents, coloring agents, pigments, lubricants, release regulators, adjuvants, sweeteners, solubilizers and emulsifiers, fragrances, emulsifiers, surfactants, pH regulators, buffers, lipids, slip agents, stabilizers, antioxidants, anti-adhesive agents, moisturizers and preservatives.

The above publications did not study the stability of the compositions disclosed therein. There remains a need for stable DMT compositions that can provide controlled release of DMT, especially for transmucosal delivery.

The present invention provides, in one aspect, a pharmaceutical composition comprising amorphous DMT or a pharmaceutically acceptable salt or prodrug thereof, and a polymeric carrier. Amorphous DMT may be characterized by a powder X-ray diffraction pattern that does not contain any discernible peaks and a differential scanning calorimetry (DSC) spectrum that lacks the sharp melting endotherms and/or phase transitions of crystalline DMT. Stability may be characterized by observing these characteristics over time, especially after accelerated aging. The inventors have unexpectedly discovered that DMT can be stabilized in an amorphous form in a polymeric carrier that is suitable for controlled transmucosal release of DMT. Stable amorphous DMT compositions may be provided in a form suitable for transmucosal administration (e.g., buccal or sublingual membranes).

The carrier may be a mucoadhesive polymer matrix. In some embodiments, the carrier matrix may include cellulose derivatives, polyacrylic acid, polyacrylate, polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, poly (vinyl pyrrolidone-co-vinyl acetate), hydroxypropyl cellulose, hydroxypropyl methyl cellulose, propylene glycol alginate, tragacanth, alginate, gum, soluble starch, gelatin, lectin, pectin or polyglucosamine or a mixture thereof.

In some embodiments, the composition may include a permeation enhancer, a buffer and a saliva stimulant. The permeation enhancer may include bile salt, cetylpyridinium chloride (CPC), sodium lauryl sulfate (SLS), Tween 80, L-menthol, dimethyl sulfoxide (DMSO), oleyl alcohol, oleic acid, oleyl oleate, acetyl propionic acid, propylene glycol, dipropylene glycol, ethanol or a mixture thereof. The buffer may be citric acid, tartaric acid, fumaric acid, sodium citrate, sodium tartrate or sodium fumarate or a mixture thereof. The saliva stimulant may be citric acid, malic acid, lactic acid, ascorbic acid or tartaric acid or a mixture thereof.

In some embodiments, the pharmaceutical composition may also include a stability enhancer, wherein the stability enhancer is an antioxidant or a chelating agent. The stability enhancer may be α-tocopherol, tocopheryl acetate, L-glutathione, L-cysteine, ascorbic acid, ascorbic acid palmitate, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), Tocobiol or ethylenediaminetetraacetic acid (EDTA) or a mixture thereof.

The composition may further comprise about 0 wt % to about 10 wt %, or about 0.1 wt % to about 10 wt % of a buffer, about 2 wt % to about 9 wt % of a buffer, or about 3 wt % to about 8.5 wt % of a buffer.

The composition may further comprise about 0.1 wt % to about 5 wt % of an antioxidant.

The composition may further comprise about 0 wt % to about 8 wt % or about 0.1 wt % to about 8 wt % of a saliva stimulating agent.

In some embodiments, the pharmaceutical composition may further include a hydrophilic adjuvant/additive or matrix solubilizer to promote water entry and affect film disintegration. It may include cellulose derivatives, starch derivatives, cross-linked polyvidone, cross-linked cellulose, cross-linked starch or alginate, sucrose, maltose, maltodextrin, isomaltose, ascorbic acid, acid, acid salt, sugar alcohol or a mixture thereof.

The composition may further comprise about 0 wt % to about 15 wt % of a hydrophilic adjuvant/additive or matrix solubilizer.

In some embodiments, the pharmaceutical composition may further include a plasticizer, wherein the plasticizer is polyethylene glycol (PEG), propylene glycol, glycerol, triacetin or castor oil or a mixture thereof.

In some embodiments, the pharmaceutical composition may further include natural and/or artificial sweeteners and/or flavorings. Sweeteners may include sucrose, dextrose, fructose, glucose, maltose, maltitol, saccharin, sucralose, neotame, cyclamate, aspartame or acesulfame K or a mixture thereof. Flavorings include natural and/or synthetic flavoring oils, oleoresins and extracts obtained from various parts of plants (such as leaves, fruits, flowers, etc.). Flavorings may include peppermint oil, cinnamon oil, vanilla extract, menthol, L-menthol or a mixture thereof.

The composition may further comprise about 0 wt % to about 10 wt % of a sweetener.

The composition may further comprise about 0 wt % to about 5 wt % of a flavoring agent.

In some embodiments, the pharmaceutical composition may further include natural colorants such as cochineal dye, carotene, carmine dye, caramel dye, etc. or synthetic colorants such as D&C or FD&C red, yellow, green, blue, inorganic/mineral pigments (red iron oxide, yellow iron oxide, titanium dioxide, etc.). The colorants are used alone or in combination.

The composition may further comprise about 0 wt % to about 5 wt % of a colorant/pigment.

In certain embodiments, the carrier may include hydroxypropyl cellulose, copolymer of N-vinyl-2-pyrrolidone and vinyl acetate, and hydroxypropyl methyl cellulose. The carrier may further include polyethylene glycol, L-glutathione, citric acid, sucralose, maltitol, and L-menthol.

In some embodiments, the pharmaceutical composition may include (1) about 0.5% to about 60% by weight of amorphous N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof; (2) about 15% to about 80% by weight of a mucoadhesive polymer matrix; and (3) about 0.1% to about 30% by weight of a penetration enhancer. The composition may include about 20% to about 35% by weight of N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof. The composition may include about 50% to about 60% by weight of a mucoadhesive polymer matrix. The composition may include about 0.5% to about 20% by weight of a plasticizer. The composition may include about 0.5% to about 5% by weight of a plasticizer. The composition may comprise, for example, a mucoadhesive polymer matrix comprising hydroxypropyl cellulose, a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate, and hydroxypropyl methyl cellulose.

In some embodiments, the pharmaceutical composition may include N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof, which is capable of substantially complete dissolution and release in less than 1 minute after administration of the composition to a patient in need thereof.

In some embodiments, the pharmaceutical composition may include N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof, which is capable of substantially complete dissolution and release in greater than 1 minute and less than 20 minutes after administration of the composition to a patient in need thereof.

In some embodiments, the pharmaceutical composition may include N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof, which is capable of substantially complete dissolution and release within greater than 20 minutes and less than 3 hours after administration of the composition to a patient in need thereof.

In some embodiments, the composition is an oral film. The oral film may have a film thickness of about 0.05 mm to about 0.4 mm.

In some embodiments, the invention relates to a method of treating a mental health condition or disorder comprising administering a therapeutically effective amount of the above composition, wherein the mental health condition or disorder is major depressive disorder.

In some embodiments, the present invention relates to a method for preparing a pharmaceutical composition, comprising the steps of: (1) combining N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof with an excipient in a solvent; (2) removing the solvent to obtain a polymer matrix comprising amorphous N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof. The solvent may comprise methanol or an organic solvent in water, which may, for example, comprise methanol-water in a ratio of 0:100 or 100:0. The method may comprise casting the polymer matrix by removing the solvent. The solvent may comprise any organic solvent having a boiling point lower than water.

The present invention relates to compositions of amorphous DMT that stabilize DMT in an amorphous form and provide controlled release of DMT in a suitable dosage form (e.g., transmucosal dosage form). The present invention also relates to methods of preparing such amorphous DMT compositions and methods of treating diseases and disorders (e.g., neurological disorders) by administering such compositions to patients in need thereof.

Throughout this invention, references are made to various patents, patent applications, and publications. The entire disclosures of such patents, patent applications, and publications are incorporated herein by reference for all purposes to more fully describe the state of the art as generally known to those skilled in the art as of the date of this invention. In the event of any inconsistency between such cited patents, patent applications, and publications and this invention, the present invention will control. Definitions

For convenience, some terms used in the specification, examples and patent application are collected here. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those generally understood by those skilled in the art to which the present invention belongs.

Unless the context clearly dictates otherwise, the singular forms "a", "an" and "the" include plural references. For example, the term "a pharmaceutically acceptable carrier" may include a plurality of pharmaceutically acceptable carriers, including mixtures thereof.

The term "and/or" is intended to mean either or both of the two components of the present invention.

The terms "subject," "individual," and "patient" are used interchangeably herein and refer to a human being.

The term "carrier" refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and includes, but is not limited to, liquids and powders of hydrophilic substances, hydrophobic substances, and substances having both hydrophilic and hydrophobic properties (such as emulsifiers).

As used herein, the term "device" refers to an apparatus or system capable of delivering a drug to a patient in need thereof.

As used herein, the terms "administer," "administering," or "administration" refer to administering a compound or a pharmaceutically acceptable salt of the compound, or a composition or formulation comprising the compound or a pharmaceutically acceptable salt of the compound, to a patient.

When referring to treatment, the term "requiring treatment" and the term "in need" are used interchangeably and refer to the judgment made by a caregiver (e.g., physician, nurse, nurse practitioner) that a patient will benefit from treatment.

The terms "treat" and "treatment" refer to therapeutic treatment, including prophylactic or preventative measures, in which the goal is to prevent or slow down (lessen) undesirable physiological changes associated with a disease or condition. Beneficial or desired clinical results include, but are not limited to, relief of symptoms, reduction in the severity of the disease or condition, stabilization of the disease or condition (i.e., wherein the disease or condition does not get worse), delay or reduction in the progression of the disease or condition, improvement or palliation of the disease or condition, and remission (whether partial or total) of the disease or condition. "Treatment" may also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already suffering from the disease or condition as well as those who are susceptible to it or those in whom it should be prevented. When referring to depression, "treatment" also includes the reduction of at least one sign or symptom of depression. Examples of signs or symptoms of depression include depressed mood, loss of interest in activities, weight loss or gain, decreased or increased appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, decreased concentration or indecisiveness, or suicidal thoughts or behaviors.

As used herein, the term "pharmaceutically acceptable" refers to components of a pharmaceutical composition that are compatible with the other ingredients of the formulation and do not produce undue deleterious effects to the recipient.

As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of an active agent that elicits the biological or medicinal response in a tissue, system or individual that is being sought by a researcher, healthcare provider or individual.

As used herein, the term "neurological disease or condition" means a disease or condition including a neurological disorder such as depression (including major depression, such as treatment-resistant depression, major depressive disorder and persistent depressive disorder), tension depression, depressive disorder caused by a medical condition, postpartum depression, premenstrual affective disorder or seasonal affective disorder, anxiety, anxiety disorder, social Anxiety disorder, generalized anxiety disorder (GAD), avolitional disorder, bipolar disorder (including bipolar I and bipolar II), post-traumatic stress disorder, body dysmorphic disorder, mood or affective disorder (including the above), depression, schizoaffective disorder, schizophrenia and other psychotic disorders, panic disorder, traumatic stress disorder, phobia and personality disorder with abnormal emotions, all Such as borderline personality disorder, schizophrenia and schizotypal personality disorder and suicidal ideation, or rumination/unhelpful repetitive thoughts that negatively affect personal behavior/mood/ability to concentrate, obsessive-compulsive disorder, addiction (including substance use disorders such as addiction to nicotine, alcohol, cocaine, opioids, amphetamines, methamphetamines, heroin, morphine, phencyclidine, 3,4-MDMA and other addictive substances), addictive behaviors (including addictions to eating, gambling, sex, pornography, video games, work, exercise, obsessions, self-harm, travel, and shopping), eating disorders (including anorexia nervosa, bulimia nervosa, and binge eating disorder), and pain (including pain associated with migraines or headaches or chronic pain).

As used herein, the term "treatment-resistant depression" or "TRD" means depression that has not responded satisfactorily to adequate treatment. TRD is a complex phenomenon that is influenced by multiple depressive subtypes, psychiatric comorbidities, and coexisting medical illnesses. Although TRD episodes are most commonly seen in major depressive disorder (MDD), they can also occur during the depressive phase of bipolar disorder.

As used herein, the term "onset of action" means the time to reach maximum plasma concentration after administration (i.e., Tmax) and can also be described as "onset of action". In the context of the present invention, "rapid onset" means that the drug reaches _Cmax within about 20 minutes (e.g., within about 2 minutes to 10 minutes). However, compared to administration of DMT by IV injection, the onset of action of the composition according to the present invention after administration is not as rapid, and therefore the "irritation" to the patient is also less. In some cases, Tmax may be between 10 minutes and 90 minutes.

As used herein, the term "excursion" means the time between the last time the concentration of DMT was within ±10% of _Cmax and the first time the plasma concentration of DMT drops to a critical level below which the drug no longer has any significant therapeutic effect (e.g., about 250 nmol/L or 47.07 ng/mL). "Rapid excursion" in the context of the present invention means less than about 10 minutes. However, despite the rapid excursion, the excursion is still long enough for the drug to exert a reasonable duration of hallucinogenic effect.

The term "transbuccal delivery" or "transbuccal administration" formulation refers to a route of administration in which the pharmaceutical dosage form is administered between the cheek and gum (i.e., the buccal cavity) of a patient.

The term "sublingual delivery" refers to a route of administration in which a pharmaceutical dosage form is administered under the patient's tongue.

The term "N,N-dimethyltryptamine" or "DMT" includes compounds of formula (I): (I) includes pharmaceutically acceptable forms of DMT, including but not limited to salts, esters, polymorphs/solid forms, and prodrugs. The term "DMT free form" or "DMT free base" refers to a compound of formula (I) without a pharmaceutically acceptable salt.

The term "pharmaceutically acceptable salt" used herein when referring to "DMT or a pharmaceutically acceptable salt thereof" means a pharmaceutically acceptable acid addition salt. Typically, an acidic reagent can be used to prepare a salt of DMT, specifically, a pharmaceutically acceptable salt. Examples of suitable acidic reagents include fumaric acid, hydrochloric acid, tartaric acid, citric acid, hydrobromic acid, sulfuric acid, succinic acid, phosphoric acid, acetic acid, maleic acid, lactic acid, tartaric acid, and gluconic acid. Typically, the DMT salt form and embodiments thereof used in the pharmaceutical compositions of the present invention or in other ways according to various aspects of the present invention is a fumarate, hydrochlorate, tartrate, succinate or citrate, such as a pharmaceutically acceptable salt of a fumarate.

As used herein, the term "amorphous" refers to a solid that lacks the three-dimensional long-range order of a crystalline material, has a more random arrangement of molecules, and has physical properties (such as solubility) that are distinct from those of its corresponding crystalline state.

The term "microenvironmental pH" also referred to as "local pH" or "surface pH" refers to the pH of the area of the carrier/polymer matrix immediately adjacent to the active agent as the matrix hydrates and/or dissolves, for example, in the user's mouth. Buffers also affect the disintegration time of buccal films.

As used herein, "transmucosal film" refers to a polymeric film capable of embedding an active ingredient that allows mucosal adhesion, complete dissolution or dissolution, diffusion, and transmucosal delivery of the active ingredient for systemic absorption.

As used herein, the term "transmucosal" refers to any route of administration across the mucosa. Examples include, but are not limited to, buccal, sublingual, gingival, supragingual, nasal, vaginal, and rectal. In this embodiment, the route of administration is buccal or sublingual.

The term "mucoadhesion" refers to the phenomenon that polymers become hydrated and adhere to mucosal surfaces in the presence of mucus fluids. Polymers that readily form gels in aqueous environments can cause dehydration at the mucosal site of application. Water absorbed into the membrane will help dissolve the active ingredient. Once the active ingredient is absorbed, the remaining membrane absorbs more water due to the concentration gradient. This process produces a mixture of formulation and mucus, and thus can increase the contact time with the mucosa. See, e.g., Mucoadhesive drug delivery systems, Flávia Chiva Carvalho, Marcos Luciano Bruschi, Raul Cesar Evangelista, Maria Palmira Daflon Gremião, BJPS, Vol. 46, No. 1, January/March 2010.

The term "polymeric carrier matrix or mucoadhesive polymeric matrix" refers to a carrier comprising a combination of polymers having different functional properties such as (but not limited to) mucoadhesion, stabilization (chemical and physical stabilizers), gelation, film formation, release control, swelling, etc. Pharmaceutical Compositions and Delivery

In one aspect, the present invention relates to an oral mucosal formulation in which an active ingredient comprising DMT is released in a therapeutically effective manner.

DMT is a naturally occurring molecule and a known hallucinogenic drug with rapid onset and relatively short duration of action. DMT is inactive when administered orally and is converted to inactive metabolites in the gastrointestinal tract (GI) and liver, which then penetrate well into the brain, resulting in low oral bioavailability. Therefore, alternative routes of administration such as transmucosal (e.g., buccal/sublingual/gingival/mucosal (on the oral mucosa) or transtongue) are investigated in the present invention to increase DMT bioavailability by avoiding first-pass metabolism in the GI and liver. See Metabolic GAP Analysis of DMT Literature, Gina Patel, Mpharm, PhD, President and CEO, Patel Kwan Consultancy, August 25, 2020.

It is believed that DMT has good permeability throughout the biomembrane. However, the free form of DMT exhibits poor water solubility, and therefore the permeability of DMT in buccal formulations depends on the solubility of DMT in the buccal mucosa. Therefore, it is necessary to enhance the solubility of DMT at the absorption site at the buccal mucosa to achieve its bioavailability. Several approaches can be used to enhance the solubility of DMT at the buccal site, such as (but not limited to) changing the physical form of DMT, salts, prodrug forms, changing the microenvironment pH, solubilizers, micronization, nanoparticles, emulsions, etc. In one aspect of the invention, the buccal formulation is designed to target a polymorphic form/solid state, preferably an amorphous form, to improve its solubility and thus improve overall permeability within the buccal mucosa to obtain desired pharmacokinetic.

DMT free base is a lipophilic molecule (logP -2.573) with a small main chain (Mol wt. 188.27 g/mol). The inventors have discovered that DMT can exist in several polycrystalline forms, including at least Forms I-IV, with Form IV of DMT being the most stable of the different forms studied. The inventors have also discovered that amorphous N,N-DMT exhibits a low glass transition temperature (-18°C) and readily crystallizes, especially at temperatures above Tg. For this reason, the stability of DMT is not expected to be sufficient for reliable delivery to patients in an amorphous form without a stabilizer.

The inventors have discovered that by controlling the conditions under which DMT is incorporated into a polymeric film, it is possible to obtain a film comprising DMT in a stable amorphous form suitable for transmucosal administration. For example, the conditions under which a stable DMT-containing film is achieved may include the use of a specific amount of a specific solvent alone or in combination with the pH of the modified composition. These conditions may be provided to the dissolved DMT in a casting solution, whereby the casting solution is molded into a suitable form, and the solvent is evaporated so that a polymeric film is produced. Alternatively or in addition, the method may include spraying a dry polymer or stabilizer and DMT in a suitable solvent to incorporate a stable amorphous form of DMT. In some embodiments, the resulting spray-dried material can be directly incorporated into a polymeric film or tablet or other suitable dosage form.

As explained in further detail in the examples of the present application, proper control of pH and/or solvent conditions during the formation of the DMT/polymer composition is an important factor in achieving a stable amorphous DMT/polymer composition. The inventors have discovered that lowering the pH of the DMT/polymer composition can cause ionization of the DMT molecules in a manner that can adversely affect transmucosal delivery. In this regard, some combination of adjusting the pH during the DMT/polymer formation process and using an appropriate solvent may be desirable in preparing a stable amorphous DMT/polymer composition.

In one aspect, the present invention encompasses incorporating DMT into compositions and dosage forms, including but not limited to fast dissolving tablets, microporous hollow fibers, chewable tablets, tablets, fast or rapidly disintegrating tablets, powder tablets, discs, powders, mucoadhesive gels, ointments, pastes, sponges, emulsions, monolayer films, bilayer films, multilayer films, mouthwashes, aerosols, sprays, drops, gums, bilayer or multilayer tablets, mucoadhesive tablets, etc. In one embodiment, the preferred formulation is a buccal/sublingual film. These films can be divided into three main categories, depending on how long they take to dissolve in the mouth. Quick-release (QR) films dissolve in a few seconds, usually less than a minute; intermediate-release films, which take a few minutes to up to 20 minutes; and sustained-release (SR) films, which dissolve more slowly than intermediate-release films, taking more than 20 minutes to several hours.

QR films can release active substances in the oral cavity within a few seconds, with short or no contact time with the buccal membrane or sublingual mucosa. However, intermediate release films or SR films have a longer contact time on the mucosal surface, thereby increasing the chance of direct absorption of the active ingredient through the mucosa. Pharmaceutical compositions containing amorphous DMT or its pharmaceutically acceptable salt suitable for buccal and sublingual administration include rapidly dissolving tablets, powders, films, strips or patches, orally disintegrating tablets, oral gels, medical lollipops, sprays, drops, gums and other formulations that remain on the buccal or sublingual mucosal surface.

In some embodiments, examples of buccal/sublingual films include fast/rapid release films (QR films only) and intermediate release compositions, which include a drug in a mucoadhesive polymeric carrier matrix in the form of a solid solution or suspension or in a partially soluble form, wherein after administration of the film in the oral cavity, the film disintegrates within a specified time to release the drug and make it available for absorption through the oral mucosa. QR films and intermediate release films are designed to provide instantaneous release of the active ingredient after administration.

In one aspect, the present invention encompasses an amorphous DMT/polymer composition comprising a matrix polymer or a mucoadhesive polymer, a penetration enhancer, a plasticizer, an antioxidant, a buffer, and optionally one or more of a sweetener, a saliva stimulant, a colorant, a hydrophilic adjuvant/additive, and/or a flavoring agent.

Suitable mucoadhesive polymers include one or more polymers selected from the following: cellulose derivatives, polyacrylic acid, polyacrylates, polyethylene oxide, polyvinyl pyrrolidone, poly (vinyl pyrrolidone-co-vinyl acetate), polyvinyl alcohol, propylene glycol alginate, tragacanth, alginates, gums (including caraway gum, guar gum, xanthan gum), soluble starch, gelatin, lectin, pectin and polyglucosamine. In some embodiments, the mucoadhesive polymer comprises one or more polymers selected from hydrophilic polymers, polysaccharides and their derivatives and hydrogels. In some embodiments, the mucoadhesive polymer comprises one or more polymers selected from the group consisting of polyacrylic acid, polyacrylate, cellulose (e.g., carboxycellulose (e.g., sodium carboxymethylcellulose)), hydroxyalkylcellulose (e.g., hydroxypropylcellulose, hydroxyethylcellulose, and hydroxyethylethylcellulose), polyvinylpyrrolidone, poly(vinylpyrrolidone-co-vinyl acetate), and polyvinyl alcohol. In some embodiments, the mucoadhesive polymer comprises one or more polymers selected from the group consisting of Carbopol (polyacrylic acid), carboxymethylcellulose, carboxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and resin. In some embodiments, mucoadhesion is due to substances containing thiol groups, such as (but not limited to) N-acetylcysteine, glutathione, thiolated polycarbophil (copolymer of acrylic acid and divinyl glycol), thiolated polyglucosamine, thiolated sodium carboxymethyl cellulose, thiolated sodium alginate, thiolated sodium hydroxypropyl cellulose, thiolated hyaluronic acid, and thiolated pectin. See, e.g., Thiolation of Biopolymers for Developing Drug Delivery Systems with Enhanced Mechanical and Mucoadhesive Properties: A Review, Vivek Puri, Ameya Sharma, Pradeep Kumar, Inderbir Singh. Polymers 2020, 12, 1803; doi:10.3390/polym12081803. In some embodiments, the mucoadhesive polymer is water soluble. Typically, the mucoadhesive polymer is present alone or in combination in a total amount of about 15% to about 80% by weight of the film composition.

The membrane composition may further include a permeation enhancer. For example, in some embodiments, the membrane composition comprises a permeation enhancer, such as one or more permeation enhancers selected from the following: bile salts, such as sodium deoxycholate (SDC), including sodium glycoside deoxycholate (SGDC), sodium taurodeoxycholate (STDC) and others; synthetic surfactants, such as cetylpyridinium chloride (CPC), sodium lauryl sulfate (SLS), Tween 80 and others, but not limited to L-menthol, dimethyl sulfoxide (DMSO), oleyl alcohol, oleic acid, oleyl oleate, acetyl propionic acid, propylene glycol, dipropylene glycol, ethanol and surfactants. In some embodiments, the permeation enhancer is present in an amount from about 0.1% to about 30% by weight of the membrane composition.

In some embodiments, the membrane composition may further include an antioxidant, such as one or more antioxidants, such as α-tocopherol, tocopheryl acetate, L-glutathione, L-cysteine, ascorbic acid, ascorbyl palmitate, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), Tocobiol and ethylenediaminetetraacetic acid (EDTA). In some embodiments, the antioxidant is present in an amount of about 0.1% to about 5% by weight of the membrane composition.

The film composition may further include a plasticizer. The plasticizer improves the flexibility of the film and reduces the brittleness of the film by lowering the glass transition temperature of the film. For example, in some embodiments, the film composition comprises a plasticizer, such as one or more plasticizers selected from, but not limited to, polyethylene glycol (PEG), such as PEG 300, PEG 400, etc.; propylene glycol, glycerol, triacetin, castor oil. In some embodiments, the plasticizer is present in an amount of about 0.5% to about 20% by weight of the film composition.

The film composition may further include a sweetener to improve taste. Stimulating saliva production increases saliva production, which will help the film dissolve faster and help the faster absorption of the activity. In some examples, natural or artificial sweeteners are used to improve the palatability of the formulation. For example, in some embodiments, the film composition includes a sweetener, such as one or more selected from (but not limited to) the following: sucrose, dextrose, fructose, glucose, liquid glucose, maltose, maltitol, saccharin, sucralose, neotame, cyclamate, aspartame and acesulfame K, etc. In some embodiments, the sweetener is present in an amount of about 0% by weight to about 10% by weight of the film composition.

The film composition may further include a saliva stimulant. In some examples, citric acid, malic acid, lactic acid, ascorbic acid, succinic acid, fumaric acid, and tartaric acid are used as saliva stimulants. The stimulants are used alone or in combination in an amount of about 0% to about 8% or about 0.1 to about 8% w/w of the dry film composition weight.

The film composition may further include a flavoring agent. In some examples, natural and/or synthetic flavoring oils, oleoresins, and extracts obtained from various parts of plants (such as leaves, fruits, flowers, etc.) (such as peppermint oil, cinnamon oil, vanilla extract, menthol, L-menthol, or mixtures thereof) are used as flavoring agents. In some embodiments, the flavoring agent is present in an amount of about 0% to about 5% by weight of the film composition.

The film composition may further include a hydrophilic adjuvant/additive or matrix solubilizer to promote water entry and affect film disintegration. In some examples, a cellulose derivative, a starch derivative, a crosslinked polyvidone, a crosslinked cellulose, a crosslinked starch or alginate, sucrose, maltose, maltodextrin, isomaltose, ascorbic acid, an acid, an acid salt, a sugar alcohol or a mixture thereof is used as a hydrophilic adjuvant/additive or matrix solubilizer. In some embodiments, the hydrophilic adjuvant/additive or matrix solubilizer is present in an amount of about 0% to about 15% by weight of the film composition.

The film composition may further include natural colorants such as cochineal dye, carotene, carmine dye, caramel dye, etc. or synthetic colorants such as D&C or FD&C red, yellow, green, blue, inorganic/mineral pigments (red iron oxide, yellow iron oxide, titanium dioxide, etc.). The colorants are used alone or in combination. In some embodiments, the colorant is present in an amount of about 0% to about 5% by weight of the film composition.

DMT is a weak base with a pKa of 8.86. The pH of the membrane plays an extremely important role in balancing the ionized and unionized forms of DMT in the membrane. In the present invention, the pH of the microenvironment is maintained to achieve a balance between the ionized and unionized forms, thereby achieving permeation of the entire mucosa.

In one aspect, the polymer membrane surface pH/diffusion environment (also referred to as microenvironment pH) can be maintained at a desired pH close to the physiological pH of saliva. The microenvironment pH can be adjusted and/or maintained by adjusting the polymer membrane pH, including but not limited to using acids, bases, buffers in the formulation.

The film composition may include an acid, base, or buffer, which can affect the pH and help maintain the desired microenvironmental pH at the site of application in the oral cavity. In some embodiments, the film composition comprises an acid, base, or buffer, but is not limited to citric acid, tartaric acid, fumaric acid, sodium citrate, sodium tartrate, sodium fumarate, etc. Buffers are used alone or in combination in an amount between about 0% to about 10% or about 0.1 to about 10% w/w of the film composition.

In addition, an inactive backing layer can be added on top of the active film to make it a double layer film to reduce or prevent erosion from the back side of the film when applied to the mucosal surface. The backing layer can further help improve the taste of the film.

The amount of active substance (e.g., DMT or a suitable form thereof) to be incorporated into the polymeric film depends on the desired dosage to be administered. For example, DMT or a suitable form thereof may be present in about 0.5% to about 60% by weight of the film.

Another benefit of the buccal or sublingual film is that a smaller dose is required to achieve the desired bioavailability of DMT compared to the oral dose required to co-administer a monoamine oxidase inhibitor to achieve oral bioavailability of DMT. See, e.g., N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function. Steven A. Barker, Front. Neurosci., August 6, 2018 | https://doi.org/10.3389/fnins.2018.00536.

In some embodiments, the buccal or sublingual film is prepared with a thickness ranging from about 0.01 mm to about 1.5 mm, and more particularly from about 0.05 to about 0.4 mm. In addition, the film thickness can vary between 10% to 90% of these ranges based on the drug-polymer mixture.

The prepared films were evaluated for physicochemical properties such as appearance, disintegration time, dissolution, analysis, water content, degradation products, polymorphic form evaluation, mechanical properties such as flexural strength, elongation, tensile strength, etc. and in vivo permeability through the buccal mucosa or permeable membranes. DMT solubility evaluation

The solubility study of DMT has been conducted in various solvents by preparing supersaturated mixtures and analyzed using HPLC. The results are shown below.

The results of dissolving DMT with different solvents are shown in Table 1. Table 1 Solvent Solubility (mg/mL) acetone > 126 Tetrahydrofuran ＞ 106 p-Dioctane > 104 Ethanol ＞ 98 Methanol ＞ 98 Acetonitrile ＞ 94 Methyl isobutyl ketone > 90 Isopropyl alcohol water >98 water ＜1 Saliva buffer (pH 6.8) 2.3 Methanol:water (70:30) > 50 Methanol:water (50:50) 26

Solubility studies were conducted on the crystalline form of DMT API as is and the results showed poor water/aqueous solubility. Therefore, there is a great need to improve the solubility of DMT API in membrane formulations for better bioavailability.

The present work also aims to convert the API into its amorphous form to improve the solubility in the formulation and maintain the same form throughout the shelf life. Suitable manufacturing methods have been selected to convert DMT into an amorphous form and various combinations of polymers have been incorporated into the formulation to stabilize the amorphous form in the film during the shelf life. The selection of polymers includes one or more polymers selected from the following: cellulose derivatives, polyacrylic acid, polyacrylates, polyethylene oxide, polyvinyl pyrrolidone, poly (vinyl pyrrolidone-co-vinyl acetate), polyvinyl alcohol, propylene glycol alginate, tragacanth, alginates, gums (including caraway gum, guar gum, xanthan gum), soluble starch, gelatin, lectin, pectin and polyglucosamine. In some embodiments, the polymer comprises one or more polymers selected from hydrophilic polymers, polysaccharides and their derivatives, and hydrogels. In some embodiments, the polymer comprises one or more polymers selected from the following: polyacrylic acid, polyacrylate, cellulose (e.g., carboxycellulose (e.g., sodium carboxymethylcellulose)), hydroxyalkyl cellulose (e.g., hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxyethylethyl cellulose)), polyvinyl pyrrolidone, and polyvinyl alcohol. In some embodiments, the polymer comprises one or more polymers selected from the following: carbomer (polyacrylic acid), carboxymethyl cellulose, carboxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and resin.

In addition, the compatibility of several excipients used to formulate transmucosal films with desired properties with DMT has been analyzed using an HPLC method at 50°C/75%RH to detect impurity levels. The results are shown in Table 2 below. Table 2 Binary mixtures Impurity count Total impurities% DMT 6 2.17 DMT+BHT 3 1.33 DMT+Citric Acid 5 0.94 DMT+Sodium Citrate Anhydrous 6 0.92 DMT+sucrose 10 5.88 DMT+Magnasweet 9 2.60 DMT+Advantame 7 4.45 DMT+L-Menthol 6 1.62 DMT+Propylparaben 9 4.94 DMT+Maltitol 6 2.86 DMT+Sodium Bisulfite twenty two 8.37 DMT+Titanium Dioxide 6 2.55 DMT+ Evospray Nat Lime 9 4.52 DMT+ NA2EDTA-dihydrate 15 7.63 DMT+ Plasdone S630 5 2.30 DMT+ HPMC E50 6 1.90 DMT+Pullulan 8 3.54 DMT+ HPC SSL NISSO 6 1.70 DMT+ PVP K90 10 3.86 DMT+ PEO WSR N80 6 2.12 DMT+Xanthan Gum 9 5.56 DMT+ CMC CEKOL 150 12 6.06 DMT+Gum Arabic 9 4.24 DMT+Maltodextrin M180 9 4.94 DMT+ corn starch purity 21C 7 3.14 DMT+ HPC LF Klucel 6 1.65 DMT+ PEG300 6 2.74 DMT+Glycerin 8 4.44 DMT+ tween 20 CRODA 6 2.05 DMT+ OH Soy Lecithin 7 3.81 DMT + Sorbitol 6 2.60 DMT+propylene glycol 6 2.41

Forced degradation studies of DMT were conducted under different stress conditions and samples were analyzed using HPLC. The results are shown in Table 3 below. table 3 Condition ( exposure overnight ) analyze % 0.1N HCl 99.7% 0.1N NaOH 99.4% 3% Peroxide 26.6% 70℃ 98.5%

It has been shown, as indicated by the data in the table above, that DMT is highly susceptible to oxidation in force degradation studies. It is important to incorporate an antioxidant in the formulation to prevent oxidation of DMT during shelf life and to form a stable film.

Based on solubility, forced degradation and compatibility studies, various functional and non-functional excipients have been selected for further study along with several other excipients. DMT membrane fabrication process

Different manufacturing techniques, such as solvent casting, hot melt extrusion, semi-solid casting, solid dispersion extrusion, rolling methods, etc. can be used for the formation of DMT polymers, for example, for the preparation of mucosal (e.g., buccal, sublingual, etc.) film manufacturing. The solvent casting method is the best method for making buccal films and has been well studied in the past. Buccal films of DMT were made using the solvent casting method. DMT in form I (Investigations into the polymorphic properties of N,N-dimethyltryptamine by X-ray diffraction and differential scanning calorimetry, Gaujac et al. (2013)) or in form IV and a plasticizer are mixed with a suitable solvent system to form a homogeneous mixture with DMT in solution form. The resulting mixture is degassed, used to cast a film, dried, and a film containing DMT in amorphous form is obtained. The film is then cut into strips of the desired size to produce a DMT film with the desired strength.

In the present work, the solvent has been chosen so that DMT is completely dissolved in the mixture and the solvent evaporates upon casting and drying to form amorphous DMT in the polymer matrix. The conversion to the amorphous form has been confirmed using well-known techniques such as PXRD and DSC.

In some examples of the present invention, DMT alone and films containing DMT in amorphous and/or crystalline form have been prepared in combination with other excipients to achieve solubility and permeability. Example 1

In an exemplary embodiment, a DMT polymer film was prepared according to the recipe given in Table 4 below. Table 4 Preparation 1 2 Element Membrane composition (% w/w) DMT 12.99 21.11 Citric Acid 3.98 --- Anhydrous Sodium Citrate 4.55 --- Propylene glycol 1.74 8.861 sucrose 0.87 0.800 Povidone (PVP K-90) 25.18 22.32 HPC (Nisso HPC-L) 50.26 44.644 L-Menthol --- 1.849 Methanol (% w/w solvent composition) --- 70 Water (% w/w solvent composition) 100 (Water-based formula in citrate buffer) 30

The membranes were prepared using the above composition as follows: DMT and excipients were mixed with water-based citrate buffer or methanol-water (70:30) solvent mixture to form a homogeneous mixture. The resulting mixture was degassed. The degassed mixture was used to cast membranes, dried and cut into strips.

In addition, the permeation rate of DMT through the prepared membranes was evaluated using in vitro permeation studies (i.e., using porcine buccal mucosa as presented below). In vitro permeation is well studied using Franz diffusion cells or using chambers that utilize animal mucosa (e.g., porcine or sheep buccal mucosa) or by using commercially available synthetic membranes (e.g., Permeapad®). Franz diffusion cells consist of two compartments; one compartment is the donor compartment and the other compartment is the recipient compartment with a capacity of 18 mL and an effective diffusion area of 0.785 cm ^2. The temperature is maintained at 37° C. by a water jacket. This technique also establishes a good identification tool to optimize the formulation composition to achieve the desired permeability and to determine the time required for the membrane to remain at the buccal surface to provide the desired rate and extent of DMT absorption. The membranes prepared using aqueous and hydroalcoholic mixtures exhibited permeation of DMT through the porcine buccal mucosa, as shown in Figure 1. Example 2

In an exemplary embodiment, DMT polymeric film formation was evaluated using different matrix-forming polymers or combinations thereof according to the formulations given in Table 5 below: table 5 Preparation 3 4 5 6 7 8 Element Membrane composition (% w/w) DMT 22.101 22.108 26.601 19.031 27.574 27.574 Citric Acid 4.033 4.034 3.800 3.473 8.272 8.272 L-Cysteine 0.968 0.968 0.912 0.833 --- --- L-Glutathione --- --- --- --- 0.248 0.248 sucrose 0.838 0.838 0.789 0.721 0.573 0.573 L-Menthol 1.936 1.936 1.824 1.667 1.324 1.324 Copolyvinylpyrrolidone (Plasdone S-360) 23.392 --- 22.040 20.142 15.993 15.993 Povidone (PVP K-90) --- 35.058 --- --- --- --- HPC (Nisso HPC-L) 46.733 35.058 44.034 40.241 31.952 31.952 HPMC E50 --- --- 0 6.946 5.515 5.515 Propylene glycol --- --- --- --- 3.033 --- PEG 300 --- --- --- --- --- 3.033 Methanol (% w/w solvent composition) 70 70 70 70 70 70 Water (% w/w solvent composition) 30 30 30 30 30 30

The membranes were prepared using the above compositions as follows: DMT and excipients were mixed with a methanol-water (70:30) solvent mixture to form a homogeneous mixture. The resulting mixture was degassed. The degassed mixture was used to cast a membrane, dried and cut into strips. DMT membranes were successfully prepared using all the compositions presented in the above table. Example 3

In various examples, it was observed that DMT was extensively degraded under oxidative stress. Therefore, antioxidants/chelators were incorporated into the buccal/sublingual films to stabilize DMT. Films were prepared using the solvent casting method described in Example 2 using different antioxidants and had the composition shown in Table 6 below. Table 6 Preparation 9-19 Element Formulation composition (% w/w) DMT 18.67 PVPK-90 27.26 Nisso HPC-L 54.07 Antioxidants/chelating agents 0-2.0* Methanol (% w/w solvent composition) 80 Water (% w/w solvent composition) 20 Note: The amount of antioxidants was compensated by Nisso HPC-L. The formulation without antioxidants was evaluated as a control. *The amount of antioxidants used is shown in the table below.

The stability of the prepared membranes was evaluated using HPLC method at 40 ^° C/75% RH for 8 weeks to detect the impurity content as shown in Table 7 below. Table 7 Preparation Antioxidants / chelating agents Antioxidant content in film * (% w/w) T=0 40 ^o C /75% RH 3W 6W 8W ( Total impurities % mg/mg) 9 EDTA 0.063 1.22 0.96 2.16 2.03 10 BHT 0.059 0.77 0.92 1.65 1.45 11 Cupric chloride dihydrate 0.0014 0.39 1.34 2.20 1.86 12 L-Cysteine 0.83 0.38 0.65 1.05 0.76 13 Ascorbic acid 6-palmitate 0.142 0.85 0.89 1.62 1.40 14 Reduced L-glutathione 0.26 0.38 0.753 1.53 1.30 15 Propyl Gallate 0.10 1.15 1.215 1.74 1.69 16 Nutrabiol (pure alpha-tocopherol) 0.11 0.95 1.036 1.6 1.42 17 Tocobiol (a mixture of alpha-, beta-, gamma- and delta-tocopherols other than ascorbyl palmitate) 0.11 0.67 0.718 1.27 1.23 18 Ascorbic acid 1.72 2.10 2.254 3.43 3.16 19 Control (no antioxidant) N/A 0.91 1.10 NA 1.56

Based on the above stability results, it was found that antioxidants improved the stability of DMT in the polymer film. Example 4

In addition, the stability of DMT was studied under various levels of L-glutathione. Therefore, DMT films were prepared using a solvent casting method and the stability was evaluated using the HPLC method as described in Table 8 below. Table 8 Preparation 20 twenty one Element Membrane composition (% w/w) N,N DMT 27.816 27.65 Citric Acid 8.206 8.24 Antioxidants --- --- L-Glutathione 0.834 1.31 L-Menthol 1.335 1.33 sucrose 0.578 0.57 Copolyvinylpyrrolidone (plasdone s-630) 16.133 16.04 Nisso HPC-L 32.232 32.04 HPMC E50 5.563 5.53 Maltitol 5.563 5.53 PEG 300 1.739 1.75 Methanol (% w/w solvent composition) 70 70 Water (% w/w solvent composition) 30 30

The stability of the prepared membranes was evaluated at a higher temperature of 50°C for 1 week using the HPLC method shown in Table 9 below. Table 9 Preparation L- Glutathione (% w/w) Stability conditions DMT N- oxide Tryptamine Nm -tryptamine Impurities % ( reported) Impurities% ( Total) RRT 1.12 API ( impurities removed) Impurities % ( reported ) Impurities % ( Total ) 20 0.83% T0 0.04 0.02 0.07 0.59 0.85 Not reported 0.26 1W/50℃ 0.13 0.04 0.15 0.86 1.02 0.28 0.44 twenty one 1.3% T0 0.05 0.05 0.09 0.52 0.82 Not reported 0.30 1W/50℃ 0.07 0.03 0.14 0.69 1.00 0.14 0.45

At 50°C, L-glutathione with a content of 0.83% and 1.3% showed good stability within 1 week. Example 5

To evaluate the effect of the physical form of DMT on disintegration, dissolution, and permeability through the porcine buccal mucosa, DMT polymer films were prepared using different solvent compositions with or without citric acid according to the formulations given in Table 10 below. Table 10 Preparation twenty two twenty three twenty four Element Membrane composition (% w/w) N,N-dimethyltryptamine 27.151 29.541 27.626 Copolyvinylpyrrolidone (PlasdoneS-630) 15.748 17.134 16.029 Hydroxypropyl Cellulose (NissoHPC-L) 31.462 34.232 32.010 Hydroxypropyl Methylcellulose (HPMC E50) 7.240 7.877 7.371 Polyethylene glycol 300 1.720 1.871 1.749 L-Glutathione 1.290 1.404 1.311 Citric Acid 8.091 --- 8.233 sucrose 0.564 0.614 0.571 Maltitol 5.430 5.909 5.525 L-Menthol 1.303 1.418 1.324 Methanol (% w/w solvent composition) 50 --- --- Water (% w/w solvent composition) 50 100 100

DMT membranes using the above composition were prepared as follows: DMT and the excipient were mixed with water (100%) or a methanol-water (50:50) solvent mixture to form a uniform mixture (also referred to as an admixture). The resulting mixture was degassed. The degassed mixture was used to cast a film, dried and cut into strips. PXRD was used to characterize the DMT form of the membrane, as shown in FIG. 2 and FIG. 3A to FIG. 3B. FIG. 2 shows the PXRD spectrum of DMT polymer membrane formulation 23 (the crystallization peak of DMT is present). FIG. 3A shows the PXRD spectrum of polymer membrane formulation 22 (the crystallization peak of DMT is not present). FIG. 3B shows the PXRD spectrum of polymer membrane formulation 24 (the crystallization peak of DMT is not present).

Based on the PXRD results, it was confirmed that DMT existed in a non-crystalline form in formulations 22 and 24. In formulations 22 and 24, DMT existed completely in the blend in solution, resulting in a film having amorphous DMT. In formulation 24, although methanol was not included, DMT was completely dissolved in the blend, mainly due to the presence of citric acid, which helped DMT to completely dissolve in the 100% aqueous phase by lowering the pH of the blend and ultimately produced a film having amorphous DMT.

In Formulation 23, DMT existed in a crystalline form due to the lack of methanol and citric acid which are necessary to facilitate complete dissolution of DMT in the admixture.

Based on the above results, it was inferred that DMT should be completely dissolved in the blend to obtain a film formulation with amorphous DMT.

In addition, the prepared films were evaluated for film disintegration and dissolution as shown in FIG. 4A-4B to understand the effect of the physical form of DMT on the film formulation.

Disintegration time of formulation 24

Based on the disintegration results presented above, it was confirmed that the films with amorphous API (Formulations 22 and 24) disintegrated rapidly and formed clear solutions in PBS (pH 7.0) within 5 minutes, while the film with crystalline API (Formulation 23) showed delayed disintegration in PBS (pH 7.0) at about 15 minutes and the film residues were not completely dissolved even after 35 minutes. Longer disintegration times are undesirable for DMT film formulations because they increase the probability of swallowing undissolved residues, which eventually lose activity in the gastrointestinal tract and liver. The disintegration results of formulations 22 to 24 are shown in Figure 5.

Dissolution curves of 40 mg DMT films (Formulations 22, 23, and 24) in 500 mL buffer (pH 6.8)

Based on the dissolution results presented above, it was confirmed that the films with amorphous API (Formulations 22 and 24) showed rapid drug release, with more than 80% of the drug dissolved within 5 minutes. On the other hand, the film with crystalline API (Formulation 23) showed slower dissolution during the 5 min and 10 min time points compared to the amorphous API film. At 15 minutes, all three formulations showed complete drug release, which was attributed to the complete sink condition of the film in a 500 mL dissolution medium volume.

In addition, all prepared membranes were evaluated for permeability through porcine buccal mucosa and compared to the permeability of a dispersion of the API in PBS (pH 7.0), as shown in FIG6 . In one aspect, the present invention relates to a DMT polymeric membrane that releases about 5% or less of DMT in 60 minutes and about 15% or less of DMT in 180 minutes when measured through porcine mucosa in a phosphate buffer solution 0.01 M pH=7, as shown in FIG6 . It will be found that formulations 22 and 24 meet these conditions, while formulation 23 or the DMT active pharmaceutical ingredient (API) not present in a polymer matrix does not meet these conditions. Formulation 23 exhibits permeability comparable to that of the DMT API. For example, at about 180 minutes, Formulation 23 exhibited about 29% release, while the DMT API exhibited about 33% release, as shown in FIG. 6 .

Based on the results presented above, DMT exhibited permeability through the buccal mucosa for the membranes with amorphous DMT (Formulations 22 and 24), the membrane with crystalline DMT (Formulation 23), and the dispersion of DMT in PBS (pH 7.0).

In addition, the permeability of the DMT membrane (Formulation 23) and the dispersion of DMT in PBS (pH 7.0) was found to be higher than that of the membranes of Formulations 22 and 24, which can be attributed to the pH of the donor chamber medium. Formulations 23 and the dispersion of DMT in PBS exhibited pH of 8.9 and 9.5, respectively, which is close to the pKa of DMT of 8.68, and therefore it is believed that for Formulations 23 and DMT dispersions, there may be more unionized DMT in the donor chamber, resulting in higher permeability than the membranes of Formulations 22 and 24, which have pH values of 7.6 and 7.8, respectively, and thus there may be more ionized DMT.

In addition, in order to understand the effect of membrane pH on in vivo permeability, membranes with different surface pH were prepared as shown in Example 6. Example 6

In an exemplary embodiment, DMT polymer membranes were prepared according to the formulations given in the table below. Membranes with different levels of citric acid were prepared to produce pHs in the range of pH 5 to 10 and the effect of pH on permeability was evaluated, as shown in Table 11. Table 11 Preparation 25 (159-32) 26 (159-29-B) 27 28 (159-66) 29 (159-73) Element Membrane composition (% w/w) DMT 23.887 21.661 29.10 27.652 28.752 Plasdone S-630 19.792 17.948 16.88 16.038 16.676 Nisso HPC-L 39.541 35.858 33.72 32.042 33.317 HPMC E50 6.825 6.189 5.82 5.530 5.751 PEG 300 --- --- 1.76 1.751 1.754 L-Glutathione --- 1.32 1.313 0.805 L-Cysteine 0.785 0.743 --- --- --- Citric Acid --- 9.283 3.59 8.240 5.012 sucrose 0.709 0.643 0.60 0.574 0.597 Maltitol 6.825 6.189 5.82 5.530 5.751 L-Menthol 1.638 1.485 1.40 1.327 1.380 Methanol (% w/w solvent composition) 70 70 70 70 70 Water (% w/w solvent composition) 30 30 30 30 30 Membrane surface pH 9.3 5.7 9.3 7.2 8.2

DMT membranes were prepared using the above composition as follows: DMT and excipients were mixed with a methanol-water (70:30) solvent mixture to form a homogeneous mixture. The resulting mixture was degassed. The degassed mixture was used to cast membranes, dried and cut into strips. The membranes were measured for surface pH and the data presented in the above composition table.

In addition, the permeation rate of DMT through the prepared membranes was evaluated using in vitro permeation studies (i.e., porcine buccal mucosa or Permeapad® as presented below).

Permeapad® (Certification No. 014557268) is a barrier consisting of a support layer and a lipid layer. The barrier is made of soybean phospholipid acetylcholine S-100 as the lipid layer. Briefly, a thin lipid layer is applied to a hydrophilic support pad (Pütz GmbH, Taunusstein, Germany) in an organic solution. The solvent is allowed to evaporate to form the barrier. The permeability of the model drug metoprolol was determined in the pad and compared with literature data on permeability in TR146 cell layers, isolated porcine buccal mucosa and Göttingen minipigs. The results showed a good correlation between Permeapad® and the respective in vitro studies, which indicates that Permeapad® seems suitable for use as a predictive assay for the pH-dependent permeability of this alkaline drug substance. Permeapad® is recommended as a preliminary permeability tool for buccal absorption of metoprolol. When comparing Papp with the absolute bioavailability of metoprolol administered buccally in gel form to minipigs, an excellent 2 IVIVC (R=0.98) was obtained, indicating that in the case of metoprolol Permeapad® can be used to simulate the buccal mucosa in a faster and less laborious manner than any other mentioned method. See Use of Permeapad® for prediction of buccal absorption: A comparison to in vitro, ex vivo and in vivo method, Hanady Ajine Bibi a, René Holm b,1, Annette Bauer-Brandl a,

Figure 7A shows the permeability of DMT membrane through porcine buccal mucosa in phosphate buffer solution (0.01 M, pH = 7). Figure 7B shows the effect of pH on the permeability of DMT membrane through artificial PermeaPad membrane in phosphate buffer solution (0.01 M pH = 7).

The stability of the prepared membranes was evaluated using HPLC method at 50°C RH for several weeks to detect the impurity content as shown in Table 12 below. Table 12 Preparation Stability conditions DMT N- oxide Tryptamine Nm -tryptamine Impurities% ( Total) 27 (3.59 % w/w citric acid) T0 0.07 0.04 0.07 0.87 1W/50C 0.23 0.03 0.14 1.23 28 (8.24 % w/w citric acid) T0 0.05 0.05 0.09 0.82 1W/50C 0.07 0.03 0.14 1.00 29 (5 % w/w citric acid) T0 0.08 0.04 0.09 0.95 1W/50C 0.15 0.09 0.34 1.63

Surface pH has been shown to have an effect on permeability. Membranes containing two extreme levels of citric acid, 0% w/w and 9.3% w/w, had a surface pH of 9.2 and showed better permeability compared to the pH 5.7 membrane. Formulations with citric acid levels of 5.0% and 8.2% w/w produced a pH close to saliva pH in the oral cavity, pH 8.2 and 7.5, respectively, and both formulations showed satisfactory artificial membrane permeability, as shown in the figure. The stability of all formulations at 50°C for 1 week showed promising data. Based on the permeability and stability studies, the formulation containing citric acid in an amount of 4.0 to 9.0% w/w, and more preferably 5.0 to 8.5% w/w, is preferred. Example 7

In an exemplary embodiment, a DMT polymer film was prepared according to the recipe given in Table 13 below. Table 13 Preparation 30 ( RD2021-DEC-01M ) Element Membrane composition (% w/w) N,N-dimethyltryptamine 27.151 Copolyvinylpyrrolidone (Plasdone S-630) 15.748 Hydroxypropyl Cellulose (Nisso HPC-L) 31.462 Hydroxypropyl Methylcellulose (Hydroxypropyl Methylcellulose 2910 / Methylcellulose E50) 7.240 Polyethylene glycol 300 1.720 L-Glutathione 1.290 Anhydrous Citric Acid 8.091 sucrose 0.564 Maltitol 5.430 L-Menthol 1.303 Methanol (% w/w solvent composition) 50 Water (% w/w solvent composition) 50 The above composition is used to prepare buccal/sublingual films as follows: DMT and excipients are mixed with a methanol-water (50:50) solvent mixture to form a uniform mixture. The resulting mixture is degassed. The degassed mixture is used to cast the film and dried until the loss on drying (LOD) of the dry film is achieved, preferably within 5 to 11% w/w, to form a flexible film sheet. The thickness of the flexible film sheet is preferably within 0.05 to 0.40 mm. The prepared film sheet contains amorphous DMT preferably within 3-7 mg/ ^cm2 . Individually prepared films are cut into strips of different sizes and/or weights to achieve any strength, including 2.5 mg to 80 mg. Preferably 5 mg to 40 mg. Sheets were cut from the above batch to form four strengths: 5 mg, 10 mg, 20 mg and 40 mg. The prepared films were characterized by having the mechanical properties presented in Table 14 below. Table 14 batch# Folding strength Elongation(%) Tensile strength(kPa) Formulation #30 (10 mg) >10 62 ± 19 245±89 Formulation #30 (40 mg) >10 61 ± 7 158±5

The stability of the prepared films was evaluated at 2 to 8C, 25°C/60%RH, 40°C/75%RH for 5 mg and 40 mg strength using the classification method presented in Tables 15 to 20 below. Table 15- Stability of DMT polymer film (5 mg) Batch No. RD2021-DEC-01P1 Storage conditions 2-8℃ Container closure Each film was packaged in a heat-sealable laminated aluminum bag. 10 pouches were placed in a box. Test points and results Test Acceptance criteria T0 3M 6M Appearance Report results White to off-white film White to off-white film White film Analysis (LC%) 90.0 - 110.0% 99.0 103.6 98.4 Degradation products (HPLC), area % Tryptamine NMT 1.0% 0.10 0.10 0.10 N-methyltryptamine NMT 1.0% 0.05 0.06 0.08 DMT N-oxide NMT 1.0% < 0.05 - 0.05 Unspecified (RRT XX) NMT 0.50% - - 0.01 (RRT 0.43) 0.02 (RRT 0.60) 0.01 (RRT 0.97) 0.03 (RRT 1.29) 0.02 (RRT 1.75) Total NMT 3.0% 0.15 0.16 0.23 Water content (%w/w) Report results 3.5 3.9 - Dissolve NLT Q at 15 minutes (80%) > 85% within 15 minutes > 85% within 15 minutes > 85% within 15 minutes Table 16 - Stability of DMT polymer film (5 mg) Batch No. RD2021-DEC-01P1 Storage conditions 25℃/60%RH Container closure Each film was packaged in a heat-sealable laminated aluminum bag. 10 pouches were placed in a box. Test points and results Test Acceptance criteria T0 2M 3M 6M Appearance Report results White to off-white film Yellow film Yellow film Yellow film Analysis (LC%) 90.0 - 110.0% 99.0 103.0 102.2 99.4 Degradation products (HPLC), area % Tryptamine NMT 1.0% 0.10 0.10 0.09 0.08 N-methyltryptamine NMT 1.0% 0.05 0.10 0.10 0.15 DMT N-oxide NMT 1.0% < 0.05 0.05 0.06 0.15 Unspecified (RRT XX) NMT 0.50% - - - 0.02 (RRT 0.43) 0.03 (RRT 0.60) 0.03 (RRT 0.97) 0.03 (RRT 1.19) 0.03 (RRT 1.29) 0.01 (RRT 1.75) Total NMT 3.0% 0.15 0.25 0.25 0.38 Water content (%w/w) Report results 3.5 - 4.6 - Dissolve NLT Q at 15 minutes (80%) > 85% within 15 minutes > 85% within 15 minutes > 85% within 15 minutes > 85% within 15 minutes Table 17 - Stability of polymer films (5 mg) Batch No. RD2021-DEC-01P1 Storage conditions 40℃/75%RH Container closure Each film was packaged in a heat-sealable laminated aluminum bag. 10 pouches were placed in a box. Test points and results Test Acceptance criteria T0 1M 2M 3M 6M Appearance Report results White to off-white film - Yellow film Yellow film Yellow film Analysis (LC%) 90.0 -- 110.0% 99.0 103.0 104.5 99.8 103.6 Degradation products (HPLC), area % Tryptamine NMT 1.0% 0.10 0.10 0.08 0.07 0.04 N-methyltryptamine NMT 1.0% 0.05 0.10 0.14 0.16 0.22 DMT N-oxide NMT 1.0% < 0.05 0.06 0.19 0.26 0.53 Unspecified (RRT XX) NMT 0.50% - - - 0.07 (RRT 1.18) 0.02 (RRT 0.43) 0.02 (RRT 0.60) 0.07 (RRT 0.97) 0.18 (RRT 1.19) 0.03 (RRT 1.29) 0.07 (RRT 1.75) Total NMT 3.0% 0.15 0.26 0.41 0.56 1.07 Water content (%w/w) Report results 3.5 - - 4.3 - Dissolve NLT Q at 15 minutes (80%) > 85% within 15 minutes - > 85% within 15 minutes > 85% within 15 minutes > 85% within 15 minutes Table 18 - Stability of DMT polymer film (40 mg) Batch No. RD2021-DEC-01P4 Storage conditions 2-8℃ Container closure Each film was packaged in a heat-sealable laminated aluminum bag. 10 pouches were placed in a box. Test points and results Test Acceptance criteria T0 3M 6M Appearance Report results White to off-white film White to off-white film White Analysis (LC%) 90.0 -- 110.0% 99.7 100.7 96.2 Degradation products (HPLC), area % Tryptamine NMT 1.0% 0.10 0.10 0.09 N-methyltryptamine NMT 1.0% 0.05 0.06 0.08 DMT N-oxide NMT 1.0% - - 0.06 Unspecified (RRT XX) NMT 0.50% - - 0.01 (RRT 0.43) 0.02 (RRT 0.60) 0.01 (RRT 0.97) 0.01 (RRT 1.29) 0.07 (RRT 1.75) Total NMT 3.0% 0.15 0.15 0.23 Water content (%w/w) Report results 3.5 3.6 - Dissolve NLT Q at 15 minutes (80%) > 85% within 15 minutes > 85% within 15 minutes > 85% within 15 minutes Table 19 - Stability of DMT polymer film (40 mg) Batch No. RD2021-DEC-01P4 Storage conditions 25℃/60%RH Container closure Each film was packaged in a heat-sealable laminated aluminum bag. 10 pouches were placed in a box. Test points and results Test Acceptance criteria T0 2M 3M 6M Appearance Report results White to off-white film Yellow film Yellow film Yellow film Analysis (LC%) 90.0 -- 110.0% 99.7 99.3 99.4 96.6 Degradation products (HPLC), area % Tryptamine NMT 1.0% 0.10 0.10 0.10 0.09 N-methyltryptamine NMT 1.0% 0.05 0.09 0.11 0.14 DMT N-oxide NMT 1.0% - - 0.07 0.08 Unspecified (RRT XX) NMT 0.50% - 0.05 - 0.01 (RRT 0.43) 0.02 (RRT 0.60) 0.02 (RRT 0.97) 0.03 (RRT 1.19) 0.03 (RRT 1.29) 0.01 (RRT 1.75) Total NMT 3.0% 0.15 0.24 0.28 0.31 Water content (%w/w) Report results 3.5 - 4.0 - Dissolve NLT Q at 15 minutes (80%) > 85% within 15 minutes > 85% within 15 minutes > 85% within 15 minutes > 85% within 15 minutes Table 20 - Stability of DMT polymer film (40 mg) Batch No. RD2021-DEC-01P4 Storage conditions 40℃/75%RH Container closure Each film was packaged in a heat-sealable laminated aluminum bag. 10 pouches were placed in a box. Test points and results Test Acceptance criteria T0 1M 2M 3M 6M Appearance Report results White to off-white film - Yellow film Yellow film Yellow film Analysis (LC%) 90.0 -- 110.0% 99.7 98.0 101.1 98.9 98.9 Degradation products (HPLC), area % Tryptamine NMT 1.0% 0.10 0.10 0.08 0.07 0.04 N-methyltryptamine NMT 1.0% 0.05 0.09 0.13 0.15 0.22 DMT N-oxide NMT 1.0% - - 0.08 0.11 0.25 Unspecified (RRT XX) NMT 0.50% - - - 0.05 (RRT 1.18) 0.02 (RRT 0.43) 0.04 (RRT 0.97) 0.14 (RRT 1.19) 0.03 (RRT 1.29) 0.07 (RRT 1.75) Total NMT 3.0% 0.15 0.19 0.29 0.38 0.68 Water content (%w/w) Report results 3.5 - - 4.3 - Dissolve NLT Q at 15 minutes (80%) > 85% within 15 minutes - > 85% within 15 minutes > 85% within 15 minutes > 85% within 15 minutes

Additionally, during the manufacture of the buccal film, a crystalline form of DMT (Form I or IV) is used to make the polymeric film, and the manufacturing process produces an amorphous form of DMT in the film formulation. The conversion to the amorphous form is confirmed using PXRD and DSC spectra as presented below. Specifically, it should be noted that the PXRD diffraction pattern does not contain crystalline peaks. And the DSC spectrum lacks the sharp melting endotherm and/or phase transition signs (e.g., glass transition temperature) of crystalline DMT. As shown in FIG8 , the conversion of DMT to an amorphous form is critical for achieving high water solubility in the buccal film formulation to ensure that the drug dissolves at the mucosal surface in the buccal cavity, thereby promoting transmucosal penetration and systemic absorption of DMT. The PXRD spectrum of the DMT polymer film (Batch # RD-2021DEC-01P4) is shown in Figure 9, confirming the absence of crystalline peaks, including any peaks associated with DMT.

In the present invention, a combination of various polymers has been used to successfully produce an amorphous form of DMT. In addition, as shown in Figures 10A to 10B, the addition of these polymers (up to 6 M) helps to maintain a stable amorphous form in the film even under accelerated storage conditions, i.e., room temperature (25°C/60% RH) and even under the worst conditions of 40°C/75% RH. Figure 10A shows the DSC spectrum of the polymer film (batch # RD-2021Dec-01P4) at 40°C/75% relative humidity for 6 months. Figure 10B shows the DSC spectrum of the DMT polymer film (batch # RD-2021Dec-01P4) at 40°C/75% relative humidity for 6 months.

Figure 11A shows a PXRD spectrum of a DMT polymer film (batch # RD-2021Dec-01P4) at 25°C/60% relative humidity for 6 months, which shows the absence of crystallization peaks, including any peaks indicative of DMT. Figure 11B shows a PXRD spectrum of a DMT polymer film (batch # RD-2021Dec-01P4) at 40°C/75% relative humidity for 6 months, which shows the absence of crystallization peaks, including any peaks indicative of DMT.

The buccal films were tested for disintegration in 20 mL of phosphate buffered saline, pH 7.0, in a Petri dish. The film disintegration time was found to be between 3 and 10 minutes.

In addition, the solubility of buccal membrane and pure API (crystalline DMT) was measured in phosphate buffered saline at pH 6.8 and found to be 24.6 mg/mL and 2.3 mg/mL, respectively. This improved solubility also indicates that the solubility of DMT in the polymeric membrane is increased several times compared to the crystalline form of the polymeric membrane.

In addition, 5 mg and 40 mg polymer films were dissolved in 500 mL of phosphate buffer at pH 6.8 using a USP Type 2 dissolution apparatus at 50 rpm. The dissolution data are presented in the figure below. The films showed rapid dissolution and the drug was completely released within 15 minutes. The stability of these films was evaluated for 6 months at 2-8°C, 25°C/60% RH and 40°C/75% RH, and all films showed rapid dissolution and more than 85% drug release within 15 minutes, which further confirmed the retention of amorphous form in the film formulation. Figure 12 shows the dissolution curves of 5 mg and 40 mg DMT films in 500 mL buffer (pH=6.8).

In addition, the in vitro tolerance of the prepared buccal membranes was evaluated using the EpiOral in vitro tissue model and the cell viability was evaluated using the MTT assay. The study design and cell viability results are shown in Figures 13A and 13B, respectively.

The study used a positive control containing 1.0% Triton X100 and a negative control without formulation. Samples included pure API in acidic and alkaline solutions as well as placebo and formulated DMT membrane at different time points as indicated in the study design above.

The results based on cell viability are presented as a bar graph in the table above, which showed promising values at 10, 20 and up to 60 minutes when compared to negative and positive controls. The films showed a relatively fast disintegration time of less than 10 minutes, and were approximately 90% dissolved within 5 minutes. The DMT polymer film was found to exhibit over 80% cell viability at the 20 minute time point, and based on the disintegration and dissolution data, it is expected that the film will dissolve in the buccal mucosa within 20 minutes. Therefore, the DMT polymer film is unlikely to cause buccal mucosal irritation during the clinical study.

Based on the physicochemical characterization, in vitro tolerability, and in vitro permeability data, it is expected that the amorphous form of DMT from the film formulation will dissolve well/rapidly at the buccal site. In addition, based on the favorable surface pH, the dissolved form of DMT should exhibit rapid transmucosal permeability (rapid onset of action) and in vivo bioavailability. Example 8

Alternatively or additionally, amorphous DMT can also be made using a spray drying process. Briefly, a polymer and/or stabilizer is mixed with DMT in a suitable solvent/mixture to form a solution, which is then spray dried under controlled conditions to form a stable amorphous DMT powder. The composition of this polymer is shown in Table 21 below. Table 21 Preparation 31 Element Composition (% w/w) N,N-dimethyltryptamine 20.0 - 90.0 Polymers (e.g., hydroxypropyl cellulose, copolyvidone, hydroxypropyl methylcellulose) 5.0 - 80.0 Buffers (e.g., citric acid, tartaric acid, succinic acid) 0.0-10.0 Stabilizers (such as casein) 0.0-50.0 Organic solvent (e.g. methanol, ethanol, methyl ethyl ketone) (% w/w solvent composition) 0-100 Water (% w/w solvent composition) 0-100

In addition, amorphous DMT can be formulated into tablets using a direct compression process. Briefly, spray dried N,N-dimethyltryptamine powder is blended with fillers/diluents, binders, disintegrants, glidants, and lubricants to produce a powder blend that is subsequently compressed to form tablets. The composition of such tablets is shown in Table 21 below. Table 21 Preparation 31-A Element Composition (% w/w) Spray-dried N,N-dimethyltryptamine powder 10.0 - 80.0 Fillers/diluents (e.g. microcrystalline cellulose, lactose, starch) 20.0 - 90.0 Binders (e.g., hydroxypropyl methylcellulose, polyvinyl pyrrolidone, starch) 0.0-25.0 Disintegrants (e.g., cellulose, polyvinylpyrrolidone, starch) 0.5-10.0% Slip Agent 0.0-5.0% Lubricant 0.0-5.0%

In addition, amorphous DMT can also be formulated into polymer films, tablets (such as fast or rapidly disintegrating tablets), fast dissolving tablets, orally disintegrating tablets, double-layer or multi-layer tablets, mucoadhesive tablets, etc., or any other suitable dosage form.

Other embodiments and uses of the invention will become apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. All references cited herein (including all U.S. and foreign patents and patent applications) are specifically and entirely incorporated herein by reference. It is intended that the specification and examples be regarded as illustrative only, with the true scope and spirit of the invention being indicated by the following claims.

Figure 1 shows the permeation rates of DMT formulations (1) citric acid/citrate salt and (2) methanol/water through prepared porcine buccal mucosal membranes.

FIG. 2 shows the PXRD spectrum of DMT polymer film formulation 23, which shows the presence of crystalline peaks indicative of DMT.

FIG. 3A shows the PXRD spectrum of DMT polymer film formulation 22, which shows the absence of crystalline peaks, including any peaks indicative of DMT.

FIG. 3B shows the PXRD spectrum of DMT polymer film formulation 24, which shows the absence of crystalline peaks, including any peaks indicative of DMT.

FIG. 4A shows the disintegration test of formulations 22 and 23.

FIG. 4B shows the disintegration test of formulation 24.

FIG. 5 is a graph showing the dissolution curves of 40 mg DMT film of Formulations 22, 23 and 24 in 500 mL buffer at pH 6.

FIG. 6 is a graph showing the DMT permeation rate through porcine mucosa of Formulations 22, 23 and 24 and API (DMT in PBS) in a phosphate buffer solution at pH = 7.

Figure 7A shows the permeability of DMT membrane through porcine buccal mucosa in phosphate buffer solution (0.1 M, pH = 7).

Figure 7B shows the effect of pH on the permeability of DMT membrane through artificial PermeaPad membrane in 0.01 M pH = 7 phosphate buffer solution.

Figure 8 shows the DSC spectrum of DMT polymer film (Batch # RD-2021Dec-01P4).

Figure 9 shows the PXRD spectrum of DMT polymer film (Batch # RD-2021Dec-01P4).

FIG. 10A shows the DSC spectrum of DMT polymer film (Batch # RD-2021Dec-01P4) at 25°C/60% relative humidity for 6 months.

FIG. 10B shows the DSC spectrum of DMT polymer film (Batch # RD-2021Dec-01P4) at 40°C/75% relative humidity for 6 months.

FIG. 11A shows the PXRD spectrum of a DMT polymer film (Batch # RD-2021Dec-01P4) at 25° C./60% relative humidity after 6 months, which shows the absence of crystalline peaks, including any peaks indicative of DMT.

FIG. 11B shows the PXRD spectrum of a DMT polymer film (Batch # RD-2021Dec-01P4) at 40° C./75% relative humidity after 6 months, which shows the absence of crystalline peaks, including any peaks indicative of DMT.

Figure 12 shows the dissolution curves of 5 mg and 40 mg DMT membranes in 500 mL buffer (pH = 6.8).

Figure 13A shows the study design for evaluating the in vitro tolerance of prepared buccal membranes using the EpiOral in vitro tissue model and evaluating cell viability using the MTT assay.

FIG. 13B shows the results of a cell viability test after drug administration according to the study design shown in FIG. 13A .

Claims (73)

A composition comprising a pharmaceutically effective amount of amorphous N,N-dimethyltryptamine (DMT) incorporated into a polymeric carrier matrix. The composition of claim 1, wherein the DMT is characterized by a powder X-ray diffraction pattern without any discernible peaks. The composition of claim 1, wherein the DMT is characterized by the absence of a sharp melting endotherm of crystalline DMT and/or the absence of signs of phase change in a differential scanning calorimetry (DSC) spectrum. The composition of claim 1, wherein the polymeric carrier matrix is a mucoadhesive polymer. The composition of claim 1, wherein the DMT is DMT free base. The composition of claim 1, wherein the pharmaceutical composition is capable of producing a T _max between 10 minutes and 90 minutes after administration. The composition of claim 1, wherein the polymeric carrier matrix is suitable for transmucosal administration. The composition of claim 7, wherein the transmucosal administration is buccal, sublingual, intragingival, supragingual, nasal, vaginal or rectal administration. The composition of claim 7, wherein the transmucosal administration is transbuccal administration. The composition of claim 1, wherein the polymer carrier matrix comprises a cellulose derivative, polyacrylic acid, polyacrylate, polyethylene oxide, polyvinyl pyrrolidone, poly(vinyl pyrrolidone-co-vinyl acetate), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, propylene glycol alginate, tragacanth, alginate, gum, soluble starch, gelatin, lectin, pectin or polyglucosamine or a mixture thereof. The composition of claim 1, further comprising a penetration enhancer, a buffer and a saliva stimulant. The composition of claim 11, wherein the penetration enhancer is bile salt, cetylpyridinium chloride (CPC), sodium lauryl sulfate (SLS), Tween 80, L-menthol, dimethyl sulfoxide (DMSO), oleyl alcohol, oleic acid, oleyl oleate, acetylacetic acid, propylene glycol, dipropylene glycol, ethanol or a mixture thereof. The composition of claim 11, wherein the buffer is citric acid, tartaric acid, fumaric acid, succinic acid, apple acid, sodium citrate, sodium tartrate, sodium succinate, sodium fumarate or a mixture thereof. The composition of claim 11, wherein the saliva stimulating agent is citric acid, malic acid, lactic acid, ascorbic acid, tartaric acid or a mixture thereof. The composition of claim 11, further comprising a stability enhancer, wherein the stability enhancer comprises an antioxidant or a chelating agent. The composition of claim 15, wherein the stability enhancer is α-tocopherol, tocopheryl acetate, L-glutathione, L-cysteine, ascorbic acid, ascorbic acid palmitate, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), Tocobiol, ethylenediaminetetraacetic acid (EDTA) or a mixture thereof. The composition of claim 11, further comprising a plasticizer. The composition of claim 17, wherein the plasticizer is polyethylene glycol (PEG), propylene glycol, glycerin, triacetin, castor oil or a mixture thereof. The composition of claim 11, further comprising a sweetener and/or a flavoring agent. The composition of claim 11, further comprising a sweetener, wherein the sweetener includes sucrose, dextrose, fructose, glucose, maltose, maltitol, saccharin, sucralose, neotame, cyclamate, aspartame, acesulfame K or a mixture thereof. The composition of claim 11, further comprising a flavoring agent, wherein the flavoring agent comprises peppermint oil, cinnamon oil, vanilla extract, menthol, L-menthol or a mixture thereof. The composition of claim 11, further comprising a colorant, the colorant comprising D&C or FD&C red, yellow, green, blue, red iron oxide, yellow iron oxide, titanium dioxide or a mixture thereof. The composition of claim 11, further comprising a hydrophilic adjuvant/additive or a matrix solubilizer, wherein the hydrophilic adjuvant and/or additive is a cellulose derivative, a starch derivative, cross-linked polyvidone, cross-linked cellulose, cross-linked starch or alginate, sucrose, maltose, sugar alcohol or a mixture thereof. The composition of claim 1, wherein the polymeric carrier matrix comprises hydroxypropyl cellulose, a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate, and hydroxypropyl methyl cellulose. The composition of claim 24, further comprising polyethylene glycol, L-glutathione, citric acid, sucralose, maltitol and L-menthol. A composition comprising: About 0.5 wt % to about 60 wt % of amorphous N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof; About 15 wt % to about 80 wt % of a mucoadhesive polymer matrix; and About 0.1 wt % to about 30 wt % of a penetration enhancer. The composition of claim 26, comprising about 20% to about 35% by weight of the N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof. The composition of claim 26, comprising about 50 wt % to about 60 wt % of the mucoadhesive polymer matrix. The composition of claim 26, further comprising about 0.5 wt % to about 20 wt % of a plasticizer. The composition of claim 26, comprising about 0.5 wt % to about 5 wt % of the plasticizer. The composition of claim 26, further comprising about 0.1 wt % to about 10 wt % of a buffer. The composition of claim 26, comprising about 2 wt % to about 9 wt % of the buffer. The composition of claim 26, comprising about 3 wt % to about 8.5 wt % of the buffer. The composition of claim 26, further comprising about 0.1 wt % to about 5 wt % of an antioxidant. The composition of claim 26, further comprising about 0.1 wt % to about 8 wt % of a saliva stimulating agent. The composition of claim 26, wherein the mucoadhesive polymer matrix comprises hydroxypropyl cellulose, a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate, and hydroxypropyl methyl cellulose. The composition of claim 1, wherein the DMT or a pharmaceutically acceptable salt or prodrug thereof is capable of being substantially completely dissolved and released in less than 1 minute after administration of the composition to a patient in need thereof. The composition of claim 1, wherein DMT or a pharmaceutically acceptable salt or prodrug thereof is capable of being substantially completely dissolved and released within greater than 1 minute and less than 20 minutes after administering the composition to a patient in need thereof. The composition of claim 1, wherein the DMT or a pharmaceutically acceptable salt or prodrug thereof is capable of being substantially completely dissolved and released within greater than 20 minutes and less than 3 hours after administering the composition to a patient in need thereof. The composition of claim 1, wherein the polymeric carrier matrix is an oral transmucosal film. The composition of claim 40, wherein the film thickness is from about 0.01 mm to about 1.5 mm. The composition of claim 41, wherein the film thickness is from about 0.05 mm to about 0.4 mm. The composition of claim 40, wherein the film has a loss on drying (LOD) of about 5 to 11% w/w. The composition of claim 43, wherein the film has a loss on drying (LOD) of about 7 to 9% w/w. The composition of claim 40, comprising 3 to 7 mg/ ^cm2 of amorphous DMT. The composition of claim 1, wherein the DMT remains amorphous after aging for 6 months at 25°C and 60% relative humidity. The composition of claim 46, characterized by a powder X-ray diffraction pattern lacking any identifiable peaks. The composition of claim 46, characterized by the absence of a sharp melting endotherm and/or phase transition sign (e.g., glass transition temperature) of crystalline DMT in a differential scanning calorimetry (DSC) spectrum. The composition of claim 1, wherein the DMT is capable of maintaining an amorphous state after aging for 6 months at 40° C. and 75% relative humidity. The composition of claim 49, characterized by a powder X-ray diffraction pattern lacking any identifiable peaks. The composition of claim 49, characterized by the absence of a sharp melting endotherm and/or phase transition of crystalline DMT in a differential scanning calorimetry (DSC) spectrum. The composition of claim 51, wherein the phase change is indicative of a glass transition temperature. A method for treating major depression, comprising administering a therapeutically effective amount of the composition of claim 1. A method for making a pharmaceutical composition comprising the steps of: combining N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof with an excipient in a solvent; and removing the solvent to provide a polymeric matrix comprising amorphous N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof. The method of claim 54, wherein the solvent comprises methanol and water or only water. The method of claim 54, wherein the solvent comprises methanol-water or water alone in a ratio of 50:50. The method of claim 54, wherein the method comprises casting the polymeric matrix by removing the solvent to form a film. The method of claim 57, wherein the composition is an oral transmucosal film. The method of claim 57, wherein the film thickness is from about 0.01 mm to about 1.5 mm. The method of claim 59, wherein the film thickness is from about 0.05 mm to about 0.4 mm. The method of claim 57, wherein the membrane has a loss on drying (LOD) of about 5 to 11% w/w. The method of claim 61, wherein the loss on drying (LOD) of the membrane is about 7 to 9% w/w. The method of claim 57, wherein the amorphous DMT content is within a range of 3 to 7 mg/ ^cm2 . The method of claim 54, wherein the method comprises spray drying. A composition prepared according to the method of claim 54. The composition of claim 65, wherein the DMT is capable of remaining in an amorphous state after aging for 6 months at 25°C and 60% relative humidity. The composition of claim 66, characterized by a powder X-ray diffraction pattern lacking any identifiable peaks. The composition of claim 66, characterized by the absence of a sharp melting endotherm and/or phase transition evidence of crystalline DMT in a differential scanning calorimetry (DSC) spectrum. The composition of claim 68, wherein the phase change is indicative of a glass transition temperature. The composition of claim 65, wherein the DMT is capable of remaining in an amorphous state after aging for 6 months at 40°C and 75% relative humidity. The composition of claim 70, characterized by a powder X-ray diffraction pattern lacking any discernible peaks. The pharmaceutical composition of claim 70, characterized in that there is no evidence of a sharp melting endotherm and/or phase transition of crystalline DMT in the differential scanning calorimetry (DSC) spectrum. The composition of claim 70, wherein the phase change is indicative of a glass transition temperature.