N-Dimethyltryptamine (DMT) and DMT Analogue Compositions, Methods of Making and Using The Same

Abstract

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

Description

[Technical Field]

[0001] The present disclosure relates to novel N,N-dimethyltryptamine (hereinafter "DMT") compositions and methods for treating neurological diseases and conditions. Specifically, the present disclosure provides improved pharmaceutical compositions comprising DMT in a form that allows for controlled transmucosal release of DMT suitable for the treatment of neurological diseases and conditions. [Background technology]

[0002] Lysergic acid diethylamide ("LSD"), psilocybin, and DMT are serotonergic drugs often referred to as "classic hallucinogens" or "psychedelics" that have the ability to induce qualitatively altered states of consciousness such as euphoria, ecstasy, transcendence of time and space, spiritual experiences, or the collapse of personal boundaries, while only minimally producing other effects such as sedation, narcosis, or hyperstimulation. Chemically, serotonergic hallucinogens are either phenylalkylamines or indoleamines, and the indoleamine class is divided into two subsets, ergolines and tryptamines.

[0003] Naturally occurring hallucinogens, such as DMT (found in the South American shrub Psychotria viridis), psilocybin (found in over 200 mushroom species), or mescaline (found in the peyote cactus of southwestern South America and northern Mexico), have been used by indigenous cultures for hundreds of years in ritual or sociocultural and religious ceremonial contexts. While the potential for nonspecific "healing" has been ascribed to the use of naturally occurring hallucinogens in these settings, more scientific investigation of their potential therapeutic applications for defined disorders was not pursued until the discovery of the synthetic ergoline lysergic acid diethylamide ("LSD") in 1943.

[0004] With the emergence of knowledge about the serotonin system and its role in brain function, researchers began to identify the molecular activity of hallucinogens. However, how this activity translated into observed therapeutic effects in psychiatric disorders remained unclear. Two main concepts were proposed. The first, called "psycholytic therapy," emphasized the ability of hallucinogens administered in low doses to promote the loosening of psychological defense mechanisms, which, in combination with psychotherapy, allowed for deep inward insight and the recovery from trauma and its subsequent cathartic process. Thus, the fundamental mechanism considered in psycholytic therapy was the activation and deepening of the accompanying psychotherapeutic process, which required multiple medications and therapy sessions. The second, called "psychedelic therapy," emphasized the ability of hallucinogens administered in a relatively high single dose to induce a so-called "peak hallucinogenic experience." Peak experiences are primarily characterized by a loss of judgment of time and space and the collapse of ego boundaries, which often culminate in the experience of a supremely blissful state and sensation of being a whole and harmonious being in the unity of the universe. Thus, the underlying mechanism believed in psychedelic therapy was to produce a unique, overwhelming experience of psychological integration and harmony, with subsequent intuitive perceptions of self-improvement, as well as enhanced joy in life and a sense of inner peace.

[0005] Scientific research surrounding the use of hallucinogens for the treatment of psychiatric disorders intensified in the 1960s, but recreational use of these substances rapidly increased, and hallucinogens were soon portrayed in the media as highly dangerous drugs of abuse. The perceived danger to public order led to the passage of the U.S. Controlled Substances Act of 1970, under which LSD and other hallucinogens were classified as Schedule 1, the most restrictive category, deemed to contain drugs with no medical use and a high potential for abuse. Over the next 30 years, little progress was made regarding the potential therapeutic uses of hallucinogens.

[0006] Recently, there has been a resurgence of interest in the field of psychedelic therapy, and classical hallucinogens 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 demonstrated significant improvements in a wide range of depression and anxiety rating scales in a randomized, double-blind study (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)).

[0007] DMTs are also understood to hold therapeutic value as hallucinogens, and efficacy trials are underway to evaluate the effects of intravenously administered DMT or DMT fumarate in subjects with major depressive disorder ("MDD"). However, while the unique properties of DMTs make them attractive potential drug treatments, particularly for neurological diseases and conditions, current therapeutic compositions and administration methods may complicate treatment and not provide optimal therapeutic results. For example, when smoked or delivered intravenously, DMT has a very rapid onset of action and a short duration of effect, which presents a challenge in determining a suitable administration regimen with an appropriate dose and frequency of administration of DMT to provide effective therapy for neurological diseases and conditions. This is particularly true for neurological diseases and conditions that would benefit from the presence of therapeutic blood levels of DMT for a longer period following administration than can be achieved with a single dose of DMT via injection or inhalation.

[0008] Thus, there is a significant need for easily administerable drug therapies of DMTs to treat neurological diseases and conditions. Such drug therapies that maximize efficacy while effectively controlling drug side effects are of particular interest, especially if they can be administered via convenient routes, including self-administration.

[0009] Several attempts to develop hallucinogenic formulations using conventional polymer formulations have been described. For example, U.S. Publication No. 2021 / 0015738 by La Rosa et al., entitled "Oral Dissolvable Film Containing Psychedelic Compound," discloses an orally dissolvable film containing DMT for treating neurological conditions. The orally dissolvable film contains (a) a plasticizer, (b) a solvent, (c) a sweetener, (d) a flavoring agent, (e) a binder, (f) a colorant, (g) a preservative, and (h) a psychedelic compound selected from the group consisting of psilocybin, psilocin, baeocystin, mescaline, LSD, ketamine, salvinorin A, ibotenic acid, muscimol, DMT, MDMA, MDEA, MDA, and combinations thereof.

[0010] U.S. Publication No. 2021 / 0322306 to Espinoza (entitled "Oral Dissolvable Film with High Load of Polymeric Binder") discloses a composition comprising: (a) a film matrix including one or more binders, wherein at least one binder 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) pharmaceutically acceptable excipients including at least one of mucoadhesive polymers, plasticizers, fillers, bulking agents, saliva stimulants, stabilizers and thickeners, gelling agents, flavors, taste masking agents, colorants, pigments, lubricants, release-modifying agents, adjuvants, sweeteners, solubilizers and emulsifiers, fragrances, emulsifiers, surfactants, pH adjusters, buffers, lipids, glidants, stabilizers, antioxidants, anti-adherents, humectants, and preservatives.

[0011] 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, particularly for transmucosal delivery. Summary of the Invention

[0012] In one aspect, the present disclosure provides a pharmaceutical composition comprising amorphous DMT or a pharmaceutically acceptable salt or prodrug thereof and a polymeric carrier. Amorphous DMT can be characterized by a powder X-ray diffraction pattern lacking discernible peaks and a differential scanning calorimetry (DSC) spectrum showing the absence of the sharp melting endotherm of crystalline DMT and / or the absence of signs of a phase change (e.g., a glass transition temperature). Stability can be characterized by observing these characteristics over time, particularly after accelerated aging. The inventors have unexpectedly discovered that DMT can be stabilized in an amorphous form within a polymeric carrier suitable for controlled transmucosal release of DMT. Stable amorphous DMT compositions can be provided in a form suitable for therapeutic transmucosal administration, such as a buccal or sublingual film.

[0013] The carrier may be a mucoadhesive polymer matrix. In some embodiments, the carrier matrix may comprise a cellulose derivative, polyacrylic acid, polyacrylate, polyethylene oxide, polyvinylpyrrolidone, polyvinyl alcohol, poly(vinylpyrrolidone-co-vinyl acetate), hydroxypropyl cellulose, hydroxypropyl methylcellulose, propylene glycol alginate ester, tragacanth, alginate, gum, soluble starch, gelatin, lectin, pectin, or chitosan, or a mixture thereof.

[0014] In some embodiments, the composition may include a permeation enhancer, a buffer, and a saliva stimulating agent. The permeation enhancer may include bile salts, cetylpyridinium chloride (CPC), sodium lauryl sulfate (SLS), Tween 80, L-menthol, dimethyl sulfoxide (DMSO), oleic alcohol, oleic acid, oleyl oleate, levulinic acid, propylene glycol, dipropylene glycol, or 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 stimulating agent may be citric acid, malic acid, lactic acid, ascorbic acid, or tartaric acid, or a mixture thereof.

[0015] In some embodiments, the pharmaceutical composition may also include a stability enhancer, which may be an antioxidant or a chelating agent, such as α-tocopherol, tocopherol acetate, L-glutahione, L-cysteine, ascorbic acid, ascorbyl palmitate, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocobiol, or ethylenediaminetetraacetic acid (EDTA), or a mixture thereof.

[0016] The composition may further comprise from about 0% to about 10% by weight, or from about 0.1% to about 10% by weight of a buffering agent, from about 2% to about 9% by weight of a buffering agent, or from about 3% to about 8.5% by weight of a buffering agent.

[0017] The composition may further comprise from about 0.1% to about 5% by weight of an antioxidant.

[0018] The composition may further comprise from about 0% to about 8% by weight, or from about 0.1% to about 8% by weight of a saliva stimulating agent.

[0019] In some embodiments, the pharmaceutical composition may further comprise a hydrophilic adjuvant / additive or matrix solubilizer to facilitate water penetration and affect film disintegration, which may include cellulose derivatives, starch derivatives, cross-linked povidone, cross-linked cellulose, cross-linked starch or alginate, sucrose, maltose, maltodextrin, isomaltose, ascorbic acid, acids, acid salts, sugar alcohols, or mixtures thereof.

[0020] The composition may further comprise from about 0% to about 15% by weight of a hydrophilic adjuvant / additive or matrix solubilizer.

[0021] In some embodiments, the pharmaceutical composition may further comprise a plasticizer, wherein the plasticizer is polyethylene glycol (PEG), propylene glycol, glycerol, triacetin, or castor oil, or a mixture thereof.

[0022] In some embodiments, the pharmaceutical composition may further comprise natural and / or artificial sweeteners and / or flavoring agents. Sweeteners may include sucrose, dextrose, fructose, glucose, maltose, maltitol, saccharin, sucralose, neotame, cyclamate, aspartame, or acesulfame-K, or mixtures thereof. Flavoring agents include natural and / or synthetic flavor oils, oleoresins, and extracts obtained from multiple parts of plants, such as leaves, fruits, and flowers. Flavoring agents may include peppermint oil, cinnamon oil, vanilla extract, menthol, L-menthol, or mixtures thereof.

[0023] The composition may further comprise from about 0% to about 10% by weight of a sweetener.

[0024] The composition may further comprise from about 0% to about 5% by weight of a flavoring agent.

[0025] In some embodiments, the pharmaceutical composition may further comprise natural colors such as cochineal, carotene, annatto, caramel, or synthetic coloring agents such as D&C and FD&C red, yellow, green, blue, inorganic / mineral colors (iron oxide red, iron oxide yellow, titanium dioxide, etc.), used alone or in combination.

[0026] The composition may further comprise from about 0% to about 5% by weight of a colorant / color.

[0027] In certain embodiments, the carrier may include hydroxypropyl cellulose, copolymer of N-vinyl-2-pyrrolidone and vinyl acetate, and hydroxypropyl methylcellulose. The carrier may further include polyethylene glycol, L-glutathione, citric acid, sucralose, maltitol, and L-menthol.

[0028] In some embodiments, the pharmaceutical composition may comprise (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 permeation enhancer. The composition may comprise about 20% to about 35% by weight of N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof. The composition may comprise about 50% to about 60% by weight of a mucoadhesive polymer matrix. The composition may comprise about 0.5% to about 20% by weight of a plasticizer. The composition may comprise about 0.5% to about 5% by weight of a plasticizer. The composition may comprise a mucoadhesive polymer matrix comprising, for example, hydroxypropyl cellulose, a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate, and hydroxypropylmethylcellulose.

[0029] In some embodiments, the pharmaceutical composition may comprise N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof, which can be substantially completely solubilized and released in less than 1 minute after administration of the composition to a patient in need thereof.

[0030] In some embodiments, the pharmaceutical composition may comprise N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof, which can be substantially completely solubilized and released in more than 1 minute and less than 20 minutes after administration of the composition to a patient in need thereof.

[0031] In some embodiments, the pharmaceutical composition may comprise N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof, which can be substantially completely solubilized and released in more than 20 minutes and less than 3 hours after administration of the composition to a patient in need thereof.

[0032] 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.

[0033] In some embodiments, the present invention relates to a method of treating a psychiatric condition or disorder, the method comprising administering a therapeutically effective amount of the composition described above, wherein the psychiatric condition or disorder is major depressive disorder.

[0034] In some embodiments, the present invention relates to a method for making a pharmaceutical composition, comprising: (1) combining N-N-dimethyltryptamine, or a pharmaceutically acceptable salt or prodrug thereof, and an excipient in a solvent; and (2) removing the solvent to provide a polymeric 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, for example, a 0:100 or 100:0 ratio of methanol-water. The method may comprise casting the polymeric matrix by removing the solvent. The solvent may comprise any organic solvent with a boiling point lower than that of water. [Brief explanation of the drawings]

[0035] [Figure 1]FIG. 1 shows the permeability of DMT formulations (1) citric acid / citrate salt, and (2) methanol / water through prepared films of porcine buccal mucosa.

[0036] [Figure 2] FIG. 2 shows the PXRD spectrum of DMT polymeric film formulation 23, showing the presence of crystalline peaks indicative of DMT.

[0037] [Figure 3A] FIG. 3A shows the PXRD spectrum of DMT polymeric film formulation 22, showing the absence of crystalline peaks, including any peaks indicative of DMT.

[0038] [Figure 3B] FIG. 3B shows the PXRD spectrum of DMT polymeric film formulation 24, showing the absence of crystalline peaks, including any peaks indicative of DMT.

[0039] [Figure 4] FIG. 4A shows the disintegration test of formulations 22 and 23.

[0040] FIG. 4B shows the disintegration test of formulation 24.

[0041] [Figure 5] FIG. 5 is a graph showing the dissolution profiles of 40 mg of DMT film in 500 mL of pH 6 buffer for formulations 22, 23, and 24.

[0042] [Figure 6] FIG. 6 is a graph showing DMT permeation through porcine mucosa in phosphate buffer solution at pH=7 for formulations 22, 23, and 24, and the API (DMT in PBS).

[0043] [Figure 7A] FIG. 7A shows the permeation of the DMT film through porcine buccal mucosa in phosphate buffer solution 0.1 M, pH=7.

[0044] [Figure 7B] FIG. 7B shows the effect of pH on DMT film permeation through an artificial PermeaPad membrane in 0.01 M phosphate buffer solution, pH=7.

[0045] [Figure 8] FIG. 8 shows the DSC spectrum of the DMT polymer film (Lot No. RD-2021Dec-01P4).

[0046] [Figure 9] FIG. 9 shows the PXRD spectrum of the DMT polymer film (Lot No. RD-2021Dec-01P4).

[0047] [Figure 10A] FIG. 10A shows the DSC spectrum of a DMT polymer film (Lot No. RD-2021Dec-01P4) aged for 6 months (25°C / 60% relative humidity).

[0048] [Figure 10B] FIG. 10B shows the DSC spectrum of a DMT polymer film (Lot No. RD-2021Dec-01P4) aged for 6 months (40°C / 75% relative humidity).

[0049] [Figure 11A] FIG. 11A shows the PXRD spectrum of a DMT polymer film (Lot No. RD-2021Dec-01P4) at 6 months (25° C. / 60% relative humidity), showing the absence of crystalline peaks, including any peaks indicative of DMT.

[0050] [Figure 11B] FIG. 11B shows the PXRD spectrum of a DMT polymer film (Lot No. RD-2021Dec-01P4) at 6 months (40° C. / 75% relative humidity), showing the absence of crystalline peaks, including any peaks indicative of DMT.

[0051] [Figure 12]FIG. 12 shows the dissolution profiles of 5 mg and 40 mg DMT films in 500 mL of buffer pH=6.8.

[0052] [Figure 13A] FIG. 13A shows the study design for evaluating the in vitro tolerability of the prepared buccal films using the EpiOral in vitro tissue model and for assessing cell viability using the MTT assay.

[0053] [Figure 13B] FIG. 13B shows the results of a post-administration cell viability study according to the study design shown in FIG. 13A. DETAILED DESCRIPTION OF THE INVENTION

[0054] The present invention relates to compositions of amorphous DMT that can stabilize DMT in amorphous form and provide controlled release of DMT in suitable dosage forms, such as transmucosal dosage forms. The present invention also relates to methods of making these amorphous DMT compositions and methods of treating diseases and disorders, such as neurological disorders, by administering these compositions to patients in need thereof.

[0055] Throughout this disclosure, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications in their entireties are incorporated by reference into this disclosure for all purposes in order to more fully describe the state of the art as known to those skilled in the art as of the date of this disclosure. In the event of a conflict between the cited patents, patent applications, and publications and this disclosure, the present disclosure shall control.

[0056] definition For convenience, certain terms employed in the specification, examples, and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0057] The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a pharmaceutically acceptable carrier" may include a plurality of pharmaceutically acceptable carriers, including mixtures thereof.

[0058] The term "and / or" is intended to mean either or both of two components of the present invention.

[0059] The terms "subject," "individual," and "patient" are used interchangeably herein and refer to a human.

[0060] The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered, and includes, but is not limited to, liquids and powders that are hydrophilic substances, hydrophobic substances, and substances with both hydrophilic and hydrophobic properties, such as emulsifying agents.

[0061] As used herein, the term "device" refers to a facility or system capable of delivering a drug to a patient in need thereof.

[0062] The terms "administer," "administering," or "administration," as used herein, refer to administering a compound or a pharmaceutically acceptable salt of the compound, or a composition or formulation comprising a compound or a pharmaceutically acceptable salt of the compound, to a patient.

[0063] The terms "in need of treatment" and "in need of" when referring to treatment are used interchangeably and refer to the judgment that the patient would benefit from treatment administered by a caring person (e.g., a doctor, nurse, nurse practitioner, etc.).

[0064] The terms "treat" and "treatment," as used herein, refer to therapeutic treatment, including prophylactic or preventative measures, where the goal is to prevent or slow (reduce) undesirable physiological changes associated with a disease or condition. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, reduction in the severity of a disease or condition, stabilization of a disease or condition (i.e., where the disease or condition does not worsen), delay or slowing of the progression of a disease or condition, improvement or palliation of a disease or condition, and remission (partial or total) of a disease or condition. "Treatment" can also mean prolonging survival compared to expected survival if not receiving treatment. Those in need of treatment include those already with a disease or condition, as well as those prone to have the disease or condition, or those in whom the disease or condition is to be prevented. "Treatment," when referring to depression, can also include reducing at least one sign or symptom of depression. Examples of signs or symptoms of depression include depressed mood, decreased interest in activities, weight loss or gain, decreased or increased appetite, insomnia or hypersomnia, psychomotor agitation or slowing, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, decreased ability to concentrate or indecisiveness, or suicidal thoughts or behaviors.

[0065] As used herein, the term "pharmaceutically acceptable" refers to a component of a pharmaceutical composition that is compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof.

[0066] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of an active agent that elicits the biological or medicinal response desired by a researcher, medical professional, or individual in a tissue, system, or individual.

[0067] As used herein, the term "neurological disease or condition" includes neuropsychiatric disorders (such as depression (including severe depression such as treatment-resistant depression, major depressive disorder, and persistent depressive disorder), catatonic depression, depressive disorders due to a medical condition, postpartum depression, premenstrual dysphoric disorder, or seasonal affective disorder), anxiety, anxiety disorders, social anxiety disorder, generalized anxiety disorder (GAD), anorexia, bipolar disorder (including bipolar I disorder and bipolar II disorder), post-traumatic stress disorder, body dysmorphic disorder, mood or affect disorders including the above conditions, dysthymia, schizoaffective disorder, schizophrenia, and other psychotic disorders, panic disorder, post-traumatic stress disorder, phobic disorders, and personality disorders with abnormal moods (such as borderline personality disorder, schizotypal disorder, dysthymic disorder, dysthymia, and the like). "Ataxic disorder" means a disease or condition selected from obsessive-compulsive disorder, addiction (including substance use disorders such as addiction to nicotine, alcohol, cocaine, opioids, amphetamines, methamphetamine, heroin, morphine, phencyclidine, 3,4-methylenedioxy-methamphetamine, as well as other addictive substances), eating disorders (including anorexia nervosa, bulimia nervosa, and binge eating disorder), and pain (including pain associated with migraines or headaches, or chronic pain) in which suicidal ideation or rumination / repetitive, unproductive thoughts adversely affect one's behavior / mood / ability to concentrate.

[0068] As used herein, the term "treatment-resistant depression" or "TRD" refers to a depressive disorder that does not respond satisfactorily to appropriate treatment. TRD is a complex phenomenon influenced by variations in depression subtype, psychiatric comorbidity, and coexisting disorders. While TRD symptom manifestations are most commonly associated with major depressive disorder (MDD), they are also seen in the depressive phase of bipolar disorder.

[0069] As used herein, the term "onset" refers to the time to achieve maximum plasma concentration (i.e., Tmax) after administration, and may also be described as "onset of action." "Rapid onset," in the context of this disclosure, refers to the time to achieve maximum plasma concentration (Cmax) after administration within about 20 minutes (e.g., within about 2-10 minutes). max However, the onset of action following administration of a composition according to the present disclosure is less rapid than when the DMT is administered by intravenous injection, and as a result is less "harsh" to the patient. In some cases, Tmax may be between 10 and 90 minutes.

[0070] As used herein, the term "elimination" refers to the decrease in the concentration of DMT from C max "Rapid elimination" refers to the time between the last time that the DMT concentration is ±10% and the first time that the DMT plasma concentration decreases to a threshold level (e.g., about 250 nmol / L or 47.07 ng / mL) below which the drug no longer has any meaningful therapeutic effect. "Rapid elimination," in the context of this disclosure, means less than about 10 minutes. However, although rapid, the elimination is still long enough for the drug to exert a reasonable duration of its hallucinogenic effect.

[0071] The term "buccal delivery" or "buccal administration" refers to a route of administration in which a pharmaceutical dosage form is applied between the patient's cheek and gum (ie, the buccal cavity).

[0072] The term "sublingual delivery" refers to a route of administration in which a pharmaceutical dosage form is applied under the patient's tongue.

[0073] The term "N,N-dimethyltryptamine" or "DMT" includes compounds of formula (I): [ka] This 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 pharmaceutically acceptable salts.

[0074] As used herein with respect to "DMT or a pharmaceutically acceptable salt thereof," the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable acid addition salt. Typically, an acidic reagent may be used to prepare a salt, particularly a pharmaceutically acceptable salt, of DMT. 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. Often, the DMT salt form and embodiments thereof used in the pharmaceutical compositions of the present disclosure or in other methods according to various aspects of the present disclosure are pharmaceutically acceptable salts of the fumarate, hydrochloride, tartrate, succinate, or citrate, e.g., the fumarate salt.

[0075] As used herein, the term "amorphous" refers to a solid that lacks the three-dimensional long-range order of crystalline material, has a more random molecular arrangement, and whose physical properties, such as solubility, are quite different from those of the corresponding crystalline state.

[0076] The term "microenvironmental pH," also known as "local pH" or "surface pH," refers to the pH of the region of the carrier / polymer matrix immediately surrounding the active agent as the matrix hydrates and / or dissolves, for example, in the user's mouth. Buffering agents also affect the disintegration time of the buccal film.

[0077] As used herein, "transmucosal film" refers to a polymeric film in which an active ingredient can be embedded, allowing for transmucosal delivery of the active ingredient for adhesion to the mucosa, complete solubilization or dissolution, diffusion, and systemic absorption.

[0078] As used herein, the term "transmucosal" refers to any route of administration via a mucous membrane. Examples include, but are not limited to, buccal, sublingual, gingival, supralingual, nasal, vaginal, and rectal. In this embodiment, the route of administration is buccal or sublingual.

[0079] The term "mucoadhesion" refers to the phenomenon in which a polymer hydrates in the presence of mucus and adheres to the mucosal surface. Polymers that can easily form gels in an aqueous environment can cause dehydration at the mucosal site of application. The water drawn into the film helps dissolve the active ingredient. As the active ingredient is absorbed, more water is absorbed into the remaining film due to the concentration gradient. This process leads to mixing of the formulation with mucus, thus increasing the contact time with the mucosa. See, for example, "Mucooadhesive Drug Delivery Systems," Flavia Chiva Carvalho, Marcos Luciano Bruschi, Raul Cesar Evangelista, Maria Palmira Daflon Gremiao, BJPS, vol. 46, no. 1, jan. / mar., 2010.

[0080] The term "polymeric carrier matrix or mucoadhesive polymeric matrix" refers to a carrier comprising a combination of polymers with different functional properties, such as, but not limited to, mucoadhesion, stabilization (chemical and physical stabilizers), gelling, film-forming, controlled release, swelling, etc.

[0081] Pharmaceutical Compositions and Delivery The present invention, in one aspect, includes oral transmucosal formulations in which the active ingredient, including DMT, is released in a therapeutically effective manner.

[0082] DMT is a naturally occurring molecule and a known hallucinogen with a rapid onset and relatively short duration of action. DMT is not active upon oral administration and is converted to inactive metabolites in the gastrointestinal (GI) tract and liver before sufficient brain penetration occurs, resulting in poor oral bioavailability. Therefore, the present invention explores alternative routes of administration, such as oral transmucosal (e.g., buccal / sublingual / gingival / mucosal (on the oral mucosa)) or sublingual, to improve DMT bioavailability by avoiding first-pass metabolism in the GI and liver. See "Metabolism GAP Analysis of DMT Literature," Gina Patel, PhD, President and CEO, Patel Kwan Consultancy, August 25, 2020.

[0083] DMT is thought to have good permeability through biological membranes. However, because the free form of DMT is poorly water-soluble, its permeability from oral formulations may depend on its solubility in the buccal mucosa. Therefore, improving the solubility of DMT at the buccal mucosa absorption site is necessary to achieve its bioavailability. To improve the solubility of DMT at the buccal site, several approaches can be used, including, but not limited to, changing the physical form, salt, or prodrug form of DMT, changing the microenvironment pH, solubilizing agents, micronization, nanoparticles, and emulsions. In one embodiment of the present invention, the buccal formulation is designed to change the polymorph / solid form, preferably to an amorphous form, to improve its solubility and improve permeability across the buccal mucosa to achieve desired pharmacokinetics.

[0084] DMT free base is a lipophilic molecule (logP -2.573) with a small backbone (molar weight 188.27 g / mol). We have found that DMT can exist in several polymorphic forms, including at least Forms I-IV. Among the various forms studied, we have found that DMT Form IV is the most stable. We have also found that amorphous N,N-DMT exhibits a low glass transition temperature (-18°C) and readily crystallizes, especially above its Tg. For this reason, DMT is expected to be insufficiently stable to be reliably delivered to patients in its amorphous form without stabilizers.

[0085] 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 containing DMT in a stable, amorphous form suitable for transmucosal administration. For example, conditions for achieving a stable DMT-containing film may include using a specific solvent in a specific amount, either alone or in combination with modifying the pH of the composition. These conditions may be provided to solubilize DMT in a casting solution, whereby the casting solution is cast into an appropriate form, and evaporation of the solvent leads to the production of a polymeric film. Alternatively, or additionally, the process may include spray-drying a polymer or stabilizer and DMT in a suitable solvent to incorporate DMT in a stable, amorphous form. In some embodiments, the resulting spray-dried material may be directly incorporated into a polymeric film, a tablet, or other suitable dosage form.

[0086] As explained in more detail with respect to 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 found that lowering the pH of the DMT / polymer composition can result in ionization of the DMT molecule in a manner that can adversely affect transmucosal delivery. In this aspect, some combination of pH adjustment and the use of an appropriate solvent during DMT / polymer formation may be desirable in preparing a stable amorphous DMT / polymer composition.

[0087] In one aspect, the present invention contemplates the incorporation of DMT into compositions and dosage forms, including, but not limited to, fast-dissolving tablets, microporous hollow fibers, chewing gums, tablets, fast- or rapidly disintegrating tablets, wafers, discs, powders, mucoadhesive gels, ointments, pastes, sponges, emulsions, single-layer films, bilayer films, multilayer films, mouthwashes, aerosols, sprays, drops, gummies, bilayer or multilayer tablets, mucoadhesive tablets, and the like. In one embodiment, a preferred formulation is a buccal / sublingual film. These films may be divided into three main categories based on their dissolution time in the oral cavity: rapid-release (QR) films dissolve within a few seconds, typically less than a minute; intermediate-release films take from a few minutes up to 20 minutes; and sustained-release (SR) films dissolve at a slower rate than intermediate-release films, taking from more than 20 minutes up to several hours.

[0088] QR films release the active ingredient in the oral cavity within seconds, resulting in shorter or no contact time with the buccal or sublingual mucosa. However, moderate-release or SR films provide longer contact time with the mucosal surface, increasing the likelihood that the active ingredient will be directly absorbed through the mucosa. Pharmaceutical compositions containing amorphous DMT or a pharmaceutically acceptable salt thereof suitable for buccal and sublingual administration include fast-dissolving tablets, wafers, films, strips or patches, orally dispersible tablets, oral gels, medicated lollipops, sprays, drops, gummies, and other formulations that are retained on the buccal or sublingual mucosal surface.

[0089] In some embodiments, examples of buccal / sublingual films include rapid / fast release films (simple QR films) and intermediate release compositions that contain a drug present as a solid solution or suspension, or in a partially soluble form, in a mucoadhesive polymeric carrier matrix; upon administration of the film in the oral cavity, the film disintegrates over a specific time period, releasing the drug and allowing absorption through the oral mucosa. QR films and intermediate release films are designed to release the active ingredient immediately after administration.

[0090] The present invention, in one aspect, contemplates an amorphous DMT / polymer composition comprising a matrix polymer or mucoadhesive polymer, a permeation enhancer, a plasticizer, an antioxidant, a buffering agent, and optionally one or more of a sweetener, a saliva stimulant, a colorant, a hydrophilic adjuvant / additive, and / or a flavoring agent.

[0091] Suitable mucoadhesive polymers include one or more polymers selected from cellulose derivatives, polyacrylic acid, polyacrylates, polyethylene oxide, polyvinylpyrrolidone, poly(vinylpyrrolidone-co-vinyl acetate), polyvinyl alcohol, propylene glycol alginate esters, tragacanth, alginates, gums (including karaya gum, guar gum, and xanthan gum), soluble starch, gelatin, lectin, pectin, and chitosan. 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 polyacrylic acid, polyacrylates, celluloses, such as carboxycelluloses (e.g., sodium carboxymethylcellulose), hydroxyalkylcelluloses (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 carbopol (polyacrylic acid), carboxymethylcellulose, carboxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and gums. In some embodiments, mucoadhesion is due to substances containing thiol groups, such as, but not limited to, N-acetylcysteine, glutathione, thiolated polycarbophil (a copolymer of acrylic acid and divinyl glycol), thiolated chitosan, thiolated sodium carboxymethylcellulose, thiolated sodium alginate, thiolated sodium hydroxypropylcellulose, 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-swellable. Typically, the mucoadhesive polymers, alone or in combination, are present in an amount of about 15% to about 80% by weight of the film composition.

[0092] The film composition can further comprise a permeation enhancer. For example, in some embodiments, the film composition comprises one or more permeation enhancers selected from bile salts such as sodium deoxycholate (SDC), sodium deoxycholate (SGDC), sodium taurodeoxycholate (STDC), etc.; cetylpyridinium chloride (CPC), sodium lauryl sulfate (SLS), synthetic surfactants such as Tween 80, L-menthol, dimethyl sulfoxide (DMSO), oleic alcohol, oleic acid, oleyl oleate, levulinic acid, propylene glycol, dipropylene glycol, ethanol, and surfactants. In some embodiments, the permeation enhancer is present in an amount of about 0.1% to about 30% by weight of the film composition.

[0093] In some embodiments, the film composition can further comprise an antioxidant, such as one or more of α-tocopherol, tocopherol acetate, L-glutahione, 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 film composition.

[0094] The film composition may further comprise a plasticizer. The plasticizer improves the flexibility of the film and reduces its brittleness by lowering its glass transition temperature. For example, in some embodiments, the film composition comprises one or more plasticizers selected from, but not limited to, polyethylene glycols (PEGs), such as PEG 300 and PEG 400, propylene glycol, glycerol, triacetin, and 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.

[0095] The film composition may further include a sweetener to improve taste. Stimulating saliva production increases saliva flow, resulting in faster dissolution and absorption of the film and active ingredient. 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, including, but not limited to, one or more selected from sucrose, dextrose, fructose, glucose, liquid glucose, maltose, maltitol, saccharin, sucralose, neotame, cyclamate, aspartame, and acesulfame-K. In some embodiments, the sweetener is present in an amount of about 0% to about 10% by weight of the film composition.

[0096] The film composition may further comprise a saliva stimulant. In some embodiments, citric acid, malic acid, lactic acid, ascorbic acid, succinic acid, fumaric acid, and tartaric acid are used as saliva stimulants. The stimulants, alone or in combination, are used in an amount of about 0% to about 8%, or about 0.1% to about 8% by weight of the dry film composition.

[0097] The film composition may further comprise a flavoring agent. In some examples, natural and / or synthetic flavor oils, oleoresins, and extracts obtained from parts of plants, such as leaves, fruits, and flowers, 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.

[0098] The film composition may further comprise a hydrophilic adjuvant / additive or matrix solubilizer to promote water penetration and affect film disintegration. In some embodiments, cellulose derivatives, starch derivatives, cross-linked povidone, cross-linked cellulose, cross-linked starch or alginate, sucrose, maltose, maltodextrin, isomaltose, ascorbic acid, acids, acid salts, sugar alcohols, or mixtures thereof are used as the 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.

[0099] The film composition may further include natural colors such as cochineal, carotene, annatto, and caramel, or synthetic colorants such as D&C and FD&C red, yellow, green, and blue inorganic / mineral colors (iron oxide red, iron oxide yellow, titanium dioxide, and the like). Colorants may be 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.

[0100] DMT is a weak base with a pKa of 8.86. The pH of the film plays a very important role in balancing the ionized and non-ionized forms at the site. In the present invention, the microenvironment pH is maintained to maintain a balance between the ionized and non-ionized forms and achieve penetration into the mucosa.

[0101] In one embodiment, the pH / diffusion environment of the polymeric film surface, also referred to as the microenvironment pH, can be maintained at a desired pH that approximates the physiological pH of saliva. The microenvironment pH can be adjusted and / or maintained by adjusting the polymeric film pH using methods including, but not limited to, the use of acids, bases, and buffers in the formulation.

[0102] The film composition may include an acid, base, or buffering agent that can affect pH and help maintain a desired microenvironmental pH at the application site in the oral cavity. In some embodiments, the film composition includes an acid, base, or buffering agent, such as, but not limited to, citric acid, tartaric acid, fumaric acid, sodium citrate, sodium tartrate, sodium fumarate, etc. Buffering agents, alone or in combination, are used in an amount of about 0% to about 10%, or about 0.1% to about 10% by weight of the film composition.

[0103] Additionally, an inert backing layer can be added over the active film to reduce or prevent erosion from the backside of the film when applied to a mucosal surface, resulting in a two-layer film. The backing layer can further help improve the taste of the film.

[0104] The amount of active agent, e.g., DMT or a suitable form thereof, incorporated into the polymeric film depends on the desired dose to be administered. For example, DMT or a suitable form thereof may be present in an amount of from about 0.5% to about 60% by weight of the film.

[0105] One added advantage of buccal or sublingual films is that a lower dose is required to achieve the desired bioavailability, as opposed to oral doses that require the concomitant use of a monoamine oxidase inhibitor to achieve oral DMT bioavailability. 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., 06 August 2018 | https: / / doi.org / 10.3389 / fnins.2018.00536.

[0106] In some embodiments, buccal or sublingual films are prepared in thicknesses ranging from about 0.01 mm to about 1.5 mm, more specifically, from about 0.05 to about 0.4 mm. Furthermore, film thickness can vary from 10% to 90% based on the drug-polymer mixture.

[0107] The prepared films were evaluated for physicochemical properties such as appearance, disintegration time, dissolution, assay, water content, degradation products, polymorph evaluation, mechanical properties such as folding durability, elongation, tensile strength, and ex vivo permeability through porcine buccal mucosa or permeation pad membrane.

[0108] DMT solubility evaluation Solubility studies of DMT were carried out in various solvents by preparing supersaturated mixtures and analyzing them using HPLC. The results are shown below.

[0109] The results of DMT solubilization using different solvents are shown in Table 1. [Table 1]

[0110] Dissolution studies were performed on the crystalline form of DMT API as is and the results showed poor water / aqueous solubility, which strongly suggests the need to improve the solubility of DMT API in film formulations for better bioavailability.

[0111] This study also aims to convert the API to its amorphous form to improve solubility and maintain the same form in the formulation during storage. A suitable manufacturing method was selected to convert DMT to its amorphous form, and a combination of various polymers was incorporated into the formulation to stabilize the amorphous form in the film during storage. The polymer selection includes one or more polymers selected from cellulose derivatives, polyacrylic acid, polyacrylate, polyethylene oxide, polyvinylpyrrolidone, poly(vinylpyrrolidone-co-vinyl acetate), polyvinyl alcohol, propylene glycol alginate ester, tragacanth, alginate, gums (including karaya gum, guar gum, and xanthan gum), soluble starch, gelatin, lectin, pectin, and chitosan. In some embodiments, the polymer includes 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 polyacrylic acid, polyacrylate, cellulose, such as carboxycellulose (e.g., sodium carboxymethylcellulose), hydroxyalkylcellulose (e.g., hydroxypropylcellulose, hydroxyethylcellulose, and hydroxyethylethylcellulose), polyvinylpyrrolidone, and polyvinyl alcohol. In some embodiments, the polymer comprises one or more polymers selected from carbopol (polyacrylic acid), carboxymethylcellulose, carboxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and gums.

[0112] Additionally, several excipients for formulating transmucosal films with desired properties were analyzed for compatibility with DMT at 50°C / 75% RH using an HPLC method to detect impurity levels, and the results are shown in Table 2 below. [Table 2]

[0113] Forced degradation tests of DMT were carried out under different stress conditions and the samples were analyzed using HPLC. The results are shown in Table 3 below. [Table 3]

[0114] DMT has been shown to be highly susceptible to oxidation during forced degradation testing, as suggested by the data in the table above. To prevent oxidation of DMT during storage and to form a stable film, it is important to incorporate antioxidants into the formulation.

[0115] From solubility, forced degradation, and compatibility studies, various functional and non-functional excipients have been selected along with several others for further study.

[0116] DMT film manufacturing method Different manufacturing techniques, such as solvent casting, hot-melt extrusion, semi-solid casting, solid dispersion extrusion, and rolling, can be used to prepare DMT polymers, for example, for transmucosal (e.g., buccal, sublingual, etc.) film production. Solvent casting is the most preferred method for buccal film production and has been extensively studied in the past. DMT buccal films are produced using the solvent casting method. DMT as Form I (see "Investigating the Polymorphic Properties of N,N-Dimethyltryptamine by X-ray Diffraction and Differential Scanning Calorimetry," Gaujac et al. (2013)) or Form IV and excipients are mixed with an appropriate solvent system to form a homogeneous mixture with DMT in solution form. The resulting mixture is degassed, used to cast a film, and dried to obtain a film containing DMT in its amorphous form. The film is then cut into strips of the desired size to produce the desired film strength of DMT.

[0117] In this study, the solvent was selected to completely solubilize DMT in the mixture and evaporate it upon casting and drying to form amorphous DMT in the polymer matrix. Well-known techniques, such as PXRD and DSC, were used to confirm the conversion to the amorphous form.

[0118] In some embodiments of the present invention, films containing DMT alone and in amorphous and / or crystalline forms are prepared in combination with other excipients to achieve solubility and permeability. [Example]

[0119] Example 1 In an exemplary embodiment, a DMT polymer film was prepared according to the formula shown in Table 4 below. [Table 4]

[0120] Films using the above compositions were prepared as follows: DMT and excipients were mixed with either aqueous citrate buffer or a methanol-water (70:30) solvent mixture to form a homogeneous mixture. The resulting mixture was degassed. Films were cast using the degassed mixture, dried, and cut into strips.

[0121] Furthermore, the permeability of DMT through the prepared films was evaluated using an ex vivo permeation test, i.e., using porcine buccal mucosa, as presented below. Ex vivo permeation has been extensively studied using Franz diffusion cells, or using chambers utilizing animal mucosa (e.g., porcine or ovine buccal mucosa), or by using commercially available synthetic membranes (e.g., Permeapad®). The Franz diffusion cell consists of two compartments, one donor compartment and the other a 0.785 cm2 membrane with a volume of 18 mL. 2 The effective diffusion area of ​​the receptor compartment is 37°C. The temperature is maintained at 37°C by a water jacket. This technique also provides a good identification tool for optimizing formulation composition to achieve the desired permeability and determining the time the film must be held on the buccal surface to provide the desired rate and extent of DMT absorption. Films prepared using aqueous and water-alcoholic mixtures demonstrated permeability of DMT through porcine buccal mucosa, as shown in Figure 1.

[0122] Example 2 In an exemplary embodiment, DMT polymeric film formation was evaluated using different matrix-forming polymers or combinations thereof according to the formulations shown in Table 5 below. [Table 5]

[0123] Films using the above compositions were prepared 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. Films were cast using the degassed mixture, dried, and cut into strips. DMT films were successfully prepared using all compositions, as shown in the table above.

[0124] Example 3 In various embodiments, DMT was observed to be extensively degraded under oxidative stress. Therefore, antioxidants / chelating agents were incorporated into the buccal / sublingual films to stabilize DMT. Films were prepared using different antioxidants using the solvent casting method described in Example 2 with the compositions shown in Table 6 below. [Table 6]

[0125] The stability of the prepared films was evaluated at 40°C / 75% RH for 8 weeks using an HPLC method to detect impurity levels as shown in Table 7 below. [Table 7]

[0126] From the above stability results, it was found that antioxidants improve the stability of DMT in polymer films.

[0127] Example 4 Additionally, the stability of DMT at various levels of L-glutathione was studied. Therefore, DMT films were prepared using a solvent casting method and the stability was assessed using an HPLC method as described in Table 8 below. [Table 8]

[0128] The stability of the prepared films was evaluated using the HPLC method shown in Table 9 below. o C for one week. [Table 9]

[0129] L-glutathione at both the 0.83% and 1.3% levels showed good stability at temperatures of 50°C for up to one week.

[0130] Example 5 To evaluate the effect of the physical form of DMT on disintegration, dissolution, and permeability through porcine buccal mucosa, DMT polymer films were prepared using different solvent compositions with and without citric acid according to the formulations shown in Table 10 below. [Table 10]

[0131] DMT films using the above composition were prepared as follows: DMT and excipients were mixed with either water (100%) or a methanol-water (50:50) solvent mixture to form a homogeneous mixture, also referred to as a blend. The resulting mixture was degassed. Films were cast using the degassed mixture, dried, and cut into strips. The films were characterized for DMT morphology using PXRD, as shown in Figure 2 and Figures 3A-3B. Figure 2 shows the PXRD spectrum of DMT polymer film formulation 23 (DMT-present crystalline peak). Figure 3A shows the PXRD spectrum of polymer film formulation 22 (DMT-absent crystalline peak). Figure 3B shows the PXRD spectrum of polymer film formulation 24 (DMT-absent crystalline peak).

[0132] Based on the PXRD results, it was confirmed that DMT was present in amorphous form in Formulations 22 and 24. In Formulations 22 and 24, DMT was present completely in solution in the blend, resulting in a film with amorphous DMT. In Formulation 24, DMT was completely dissolved in the blend despite the omission of methanol. This was primarily due to the presence of citric acid, which helped DMT to completely dissolve in the 100% aqueous phase by lowering the blend pH, ultimately resulting in a film with amorphous DMT.

[0133] In contrast, in formulation 23, DMT was present in a crystalline form due to the elimination of methanol and citric acid, which were necessary to help DMT completely dissolve in the mixture.

[0134] Based on the above results, it is speculated that DMT should be completely dissolved in the blend to achieve a film formulation with amorphous DMT.

[0135] Furthermore, as shown in Figures 4A and 4B, the film disintegration and dissolution of the prepared films were evaluated to understand the effect of the physical form of DMT in the film formulation.

[0136] Disintegration time of formulation 24

[0137] Based on the disintegration results above, it was confirmed that the films with amorphous API (Formulations 22 and 24) rapidly disintegrated within 5 minutes, forming a clear solution in PBS pH 7.0, while the film with crystalline API (Formulation 23) showed delayed disintegration at approximately 15 minutes, with film residue not completely dissolved even after 35 minutes in PBS pH 7.0. For DMT film formulations, a longer disintegration time increases the likelihood of swallowing undissolved residue, which ultimately leads to inactivation in the gastrointestinal tract and liver, which is undesirable. The disintegration results for Formulations 22-24 are shown in Figure 5.

[0138] Dissolution Profiles of 40 mg of DMT Film (Formulations 22, 23, and 24) in 500 mL of pH 6.8 Buffer

[0139] Based on the dissolution results presented above, it was confirmed that the films with amorphous API (Formulations 22 and 24) exhibited rapid drug release, with over 80% of the drug dissolved within 5 minutes. Meanwhile, the film with crystalline API (Formulation 23) dissolves more slowly at 5 and 10 minutes compared to the amorphous API film. After 15 minutes, all three formulations showed complete drug release. This is attributed to the complete settling of the films in the 500 mL dissolution medium.

[0140] Additionally, all prepared films were evaluated for permeability through porcine buccal mucosa and compared to the permeability of API dispersions in PBS pH 7.0, as shown in Figure 6. In one aspect, the present invention includes DMT polymeric films that release less than about 5% of DMT at 60 minutes and less than about 15% of DMT at 180 minutes, as measured through porcine mucosa in 0.01M phosphate buffer solution pH=7, as shown in Figure 6. These conditions are met by Formulations 22 and 24, but not by Formulation 23 or the DMT active pharmaceutical ingredient (API) not present in the polymer matrix. Formulation 23 exhibited permeability comparable to the DMT API. For example, as shown in Figure 6, at approximately 180 minutes, Formulation 23 exhibited approximately 29% release, while the DMT API exhibited approximately 33% release.

[0141] Based on the above results, DMT demonstrated permeability through porcine buccal mucosa for films with amorphous DMT (formulations 22 and 24), crystalline DMT (formulation 23), and DMT dispersion in PBS pH 7.0.

[0142] Furthermore, the permeability of the DMT film (Formulation 23) and the DMT dispersion in PBS pH 7.0 was found to be higher compared to the films of Formulations 22 and 24, which may be due to the pH of the donor chamber medium. Formulation 23 and the DMT dispersion in PBS exhibited pHs of 8.9 and 9.5, respectively, which are close to the pKa of DMT, 8.68. Therefore, for Formulation 23 and the DMT dispersion, more non-ionized DMT may be present in the donor chamber than for the films of Formulations 22 and 24, which exhibited pHs of 7.6 and 7.8, where more ionized DMT may be present, resulting in higher permeability.

[0143] To further understand the effect of film pH on in vitro permeability, films with different surface pH were prepared as presented in Example 6.

[0144] Example 6 In an exemplary embodiment, DMT polymer films were prepared according to the formulation shown in the table below. Films were prepared with different levels of citric acid to yield pH values ​​ranging from 5 to 10 to evaluate the effect of pH on permeability, as shown in Table 11. [Table 11]

[0145] DMT films using the above composition were prepared 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. Films were cast using the degassed mixture, dried, and cut into strips. The surface pH of the films was measured, and the data was shown in the composition table above.

[0146] Furthermore, the permeability of DMT through the prepared films was evaluated using ex vivo permeation tests, i.e., porcine buccal mucosa or Permeapad®, as shown below.

[0147] Permeapad® (certification number 014557268) is a barrier consisting of a support layer and a lipid layer. The barrier is composed of soybean phosphatidylcholine S-100 as the lipid layer. Briefly, a thin layer of lipid is applied to a hydrophilic support sheet (Putz GmbH, Taunusstein, Germany) in an organic solution. The solvent is evaporated to form the barrier. The permeability of the model drug metoprolol was measured across Permeapad® and compared with literature data on permeability in TR146 cell layers, ex vivo pig buccal mucosa, and Göttingen minipigs. Results showed good correlation between Permeapad® and the respective in vitro studies, indicating that Permeapad® may be useful as a predictive assay for the pH-dependent permeability of this basic drug substance. Permeapad® is proposed as a preliminary permeability tool for the buccal absorption of metoprolol. When comparing the absolute bioavailability of metoprolol administered bucally in gel form to minipigs with Papp, a superior 2 IVIVC (R = 0.98) was obtained, indicating that for metoprolol, Permeapad® can be used as a faster and less laborious method to mimic the buccal mucosa compared to any of the other mentioned methods. For prediction of buccal absorption, see Use of Permeapad®: Comparison with In Vitro, Ex Vivo, and In Vivo Methods, Hanady Ajine Bibi a, Rene Holm b,1, Annette Bauer-Brandl a,

[0148] Figure 7A shows the permeation of a DMT film through porcine buccal mucosa in 0.01 M phosphate buffer solution, pH = 7. Figure 7B shows the effect of pH on the permeation of a DMT film through an artificial PermeaPad membrane in 0.01 M phosphate buffer solution, pH = 7.

[0149] The stability of the prepared films was evaluated using HPLC method at 50° C. RH for several weeks to detect impurity levels as shown in Table 12 below. [Table 12]

[0150] Surface pH showed an effect on permeation rate. Films with two extreme levels of citric acid, 0 w / w% and 9.3 w / w%, had a surface pH of 9.2, demonstrating better permeation than films with a pH of 5.7. Formulations with citric acid levels of 5.0% and 8.2 w / w% exhibited pH values ​​of 8.2 and 7.5, respectively, similar to the pH of saliva in the oral cavity. As shown in the graph, both formulations exhibited satisfactory permeation through the artificial membrane. Stability data for all formulations over a one-week period at 50°C showed promising results. Based on permeation and stability studies, formulations containing citric acid levels of 4.0-9.0 w / w% and more preferably levels of 5.0-8.5 w / w% were preferred.

[0151] Example 7 In an exemplary embodiment, a DMT polymer film was prepared according to the formulation shown in Table 13 below. [Table 13] Buccal / sublingual films using the above composition were prepared as follows: DMT and excipients were mixed with a methanol-water (50:50) solvent mixture to form a homogeneous mixture. The resulting mixture was degassed. Films were cast using the degassed mixture and dried until a loss on drying (LOD) of the dried film was achieved, preferably in the range of 5-11 w / w%, to form flexible film sheets. The thickness of the flexible film sheets is preferably within 0.05-0.40 mm. The prepared film sheets preferably have a thickness of 3-7 mg / cm. 2 Each prepared film contained amorphous DMT. Each prepared film was cut into strips of various sizes and / or weights to achieve any strength, including 2.5 mg to 80 mg, with 5 mg to 40 mg being preferred. The above batch sheets were cut to form four strengths: 5 mg, 10 mg, 20 mg, and 40 mg. The prepared films were characterized for their mechanical properties, as shown in Table 14 below. [Table 14]

[0152] The stability of the prepared films was evaluated for 5 mg and 40 mg strengths at 2-8°C, 25°C / 60% RH, and 40°C / 75% RH using the bracketing method, as presented in Tables 15-20 below. [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20]

[0153] Furthermore, during the manufacture of the buccal film, a crystalline form of DMT (Form I or IV) was used to produce the polymeric film, and the manufacturing process resulted in the generation of an amorphous form of DMT in the film formulation. The conversion of the amorphous form was confirmed using PXRD and DSC spectra, as shown below. Specifically, note the absence of crystalline peaks in the PXRD diffractogram. Meanwhile, the DSC spectrum lacks the sharp melting endotherm and / or signs of a phase change (e.g., glass transition temperature) of crystalline DMT. The conversion of DMT to the amorphous form is crucial for the buccal film formulation to achieve high water solubility, ensuring drug dissolution at the mucosal surface of the buccal cavity and facilitating transmucosal permeation and systemic absorption of DMT, as shown in Figure 8. The PXRD spectrum of the DMT polymer film (Lot No. RD-2021DEC-01P4) is shown in Figure 9 and confirmed the absence of crystalline peaks, including any peaks associated with DMT.

[0154] In the present invention, amorphous forms of DMT have been successfully produced using various polymer combinations. Furthermore, the addition of these polymers helps maintain a stable amorphous form in the film up to 6 M under accelerated storage conditions, i.e., room temperature (25°C / 60% RH) and even the worst-case conditions of 40°C / 75% RH, as shown in Figures 10A-10B. Figure 10A shows the DSC spectrum of a polymer film (Lot No. RD-2021Dec-01P4) aged for 6 months at 40°C / 75% RH. Figure 10B shows the DSC spectrum of a polymer film (Lot No. RD-2021Dec-01P4) aged for 6 months at 40°C / 75% RH.

[0155] Figure 11A shows the PXRD spectrum of a DMT polymer film (Lot No. RD-2021Dec-01P4) at 25°C / 60% relative humidity for 6 months, showing the absence of crystalline peaks, including any peaks indicative of DMT. Figure 11B shows the PXRD spectrum of a DMT polymer film (Lot No. RD-2021Dec-01P4) at 40°C / 75% relative humidity for 6 months, showing the absence of crystalline peaks, including any peaks indicative of DMT.

[0156] The buccal film was tested for disintegration using 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.

[0157] The solubilities of the buccal film and the unmodified API (crystalline DMT) were also measured in phosphate buffered saline, pH 6.8, and found to be 24.6 mg / mL and 2.3 mg / mL, respectively. This improvement in solubility also suggests that the solubility of DMT in the polymeric film was increased several-fold compared to its crystalline form.

[0158] Additionally, dissolution of 5 mg and 40 mg polymer films was performed in 500 mL of phosphate buffer, pH 6.8, using a USP Type 2 dissolution apparatus at 50 rpm. The dissolution data are shown in the graph below. The films exhibited rapid dissolution, with complete drug release 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. All films exhibited rapid dissolution, releasing more than 85% of the drug within 15 minutes, further confirming the retention of amorphous form in the film formulations. Figure 12 shows the dissolution profiles of 5 mg and 40 mg DMT films in 500 mL of buffer, pH 6.8.

[0159] Furthermore, the in vitro tolerability of the prepared buccal films was evaluated using an EpiOral in vitro tissue model, and cell viability was evaluated using an MTT assay. The study design and cell viability results are described in Figures 13A and 13B, respectively.

[0160] The study was conducted using a positive control with 1.0% Triton X100 and a negative control without any formulation. Samples included the native API in acidic and basic solutions, as well as placebo and formulated DMT films at different time points, as shown in the study design above.

[0161] The results based on cell viability are presented as bar graphs in the figure above and showed promising values ​​at 10, 20, and up to 60 minutes when compared to the negative and positive controls. The films showed faster disintegration times of less than 10 minutes, with approximately 90% dissolution at 5 minutes. The DMT polymer film was found to exhibit greater than 80% cell viability at 20 minutes, and based on the disintegration and dissolution data, the film is expected to dissolve in the buccal mucosa within 20 minutes. Therefore, the DMT polymer film is unlikely to cause buccal mucosa irritation during clinical trials.

[0162] Based on physicochemical characterization, in vitro tolerability, and ex vivo permeability data, the amorphous form of DMT from the film formulation is expected to be sufficiently solubilized / rapidly dissolved at the buccal site. Furthermore, based on favorable surface pH, the solubilized form of DMT should exhibit rapid transmucosal permeability (rapid onset) and in vivo bioavailability.

[0163] Example 8 Alternatively, or additionally, amorphous DMT can also be produced using a spray-drying process. Briefly, a polymer and / or stabilizer and DMT are mixed 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]

[0164] Additionally, amorphous DMT can be formulated as tablets using a direct compression process. Briefly, spray-dried N,N-dimethyltryptamine powder is blended with a filler / diluent, binder, disintegrant, glidant, and lubricant to produce a powder blend that is then compressed to form tablets. The composition of such tablets is shown in Table 21 below. [Table 22]

[0165] Additionally, amorphous DMT may also be formulated as tablets such as polymeric films, fast- or rapidly disintegrating tablets, fast-dissolving tablets, orodispersible tablets, bilayer or multilayer tablets, mucoadhesive tablets, or any other suitable dosage form.

[0166] Other embodiments and uses of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. All references cited herein, including 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 considered exemplary only, with the true scope and spirit of the invention being indicated by the following claims.

Claims

1. A composition comprising a pharmaceutically effective amount of amorphous N,N-dimethyltryptamine (DMT) incorporated within a polymeric carrier matrix.

2. 10. The composition of claim 1, wherein the DMT is characterized by a powder X-ray diffraction pattern that does not contain any discernible peaks.

3. 10. The composition of claim 1, wherein the DMT is characterized by a differential scanning calorimetry (DSC) spectrum lacking the sharp melting endotherm of crystalline DMT and / or lacking any indication of a phase change.

4. The composition of claim 1 , wherein the polymeric carrier matrix is ​​a mucoadhesive polymer.

5. The composition of claim 1 , wherein the DMT is DMT free base.

6. The pharmaceutical composition has a T ｍａｘ The composition of claim 1, which is capable of producing

7. The composition of claim 1 , wherein the polymeric carrier matrix is ​​suitable for transmucosal application.

8. 8. The composition of claim 7, wherein the transmucosal application is buccal, sublingual, gingival, supragingual, nasal, vaginal, or rectal application.

9. The composition of claim 7, wherein the transmucosal application is buccal application.

10. 10. The composition of claim 1, wherein the polymeric carrier matrix comprises a cellulose derivative, polyacrylic acid, polyacrylate, polyethylene oxide, polyvinylpyrrolidone, poly(vinylpyrrolidone-co-vinyl acetate), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, propylene glycol alginate ester, tragacanth, alginate, gum, soluble starch, gelatin, lectin, pectin, or chitosan, or a mixture thereof.

11. 10. The composition of claim 1, further comprising a permeation enhancer, a buffer, and a saliva stimulator.

12. 12. The composition of claim 11, wherein the permeation enhancer is bile salts, cetylpyridinium chloride (CPC), sodium lauryl sulfate (SLS), Tween 80, L-menthol, dimethyl sulfoxide (DMSO), oleic alcohol, oleic acid, oleyl oleate, levulinic acid, propylene glycol, dipropylene glycol, ethanol, or a mixture thereof.

13. 12. The composition of claim 11, wherein the buffering agent is citric acid, tartaric acid, fumaric acid, succinic acid, malic acid, sodium citrate, sodium tartrate, sodium succinate, sodium fumarate, or a mixture thereof.

14. 12. 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.

15. 12. The composition of claim 11, further comprising a stability enhancer comprising an antioxidant or a chelating agent.

16. 16. The composition of claim 15, wherein the stability enhancing agent is α-tocopherol, tocopheryl acetate, L-glutahione, L-cysteine, ascorbic acid, ascorbyl palmitate, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocobiol, ethylenediaminetetraacetic acid (EDTA), or a mixture thereof.

17. The composition of claim 11 further comprising a plasticizer.

18. 18. The composition of claim 17, wherein the plasticizer is polyethylene glycol (PEG), propylene glycol, glycerol, triacetin, castor oil, or a mixture thereof.

19. The composition of claim 11 further comprising a sweetener and / or a flavoring agent.

20. 12. The composition of claim 11, further comprising a sweetener comprising sucrose, dextrose, fructose, glucose, maltose, maltitol, saccharin, sucralose, neotame, cyclamate, aspartame, acesulfame-K, or mixtures thereof.

21. 12. The composition of claim 11, further comprising a flavoring agent comprising peppermint oil, cinnamon oil, vanilla extract, menthol, L-menthol, or a mixture thereof.

22. 12. The composition of claim 11, further comprising a colorant comprising D&C or FD&C red, yellow, green, blue, iron oxide red, iron oxide yellow, titanium dioxide, or a mixture thereof.

23. 12. The composition of claim 11, further comprising a hydrophilic adjuvant / additive or matrix solubilizer, wherein the hydrophilic adjuvant and / or additive is a cellulose derivative, a starch derivative, cross-linked povidone, cross-linked cellulose, cross-linked starch or alginate, sucrose, maltose, a sugar alcohol, or a mixture thereof.

24. 10. 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 methylcellulose.

25. 25. The composition of claim 24, further comprising polyethylene glycol, L-glutathione, citric acid, sucralose, maltitol, and L-menthol.

26. 1. A composition comprising: about 0.5% to about 60% by weight of amorphous N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof; about 15% to about 80% by weight of a mucoadhesive polymer matrix; and about 0.1% to about 30% by weight of a permeation enhancer.

27. 27. The composition of claim 26, comprising about 20% to about 35% by weight of said N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof.

28. 27. The composition of claim 26, comprising about 50% to about 60% by weight of said mucoadhesive polymer matrix.

29. 27. The composition of claim 26, further comprising about 0.5% to about 20% by weight of a plasticizer.

30. 27. The composition of claim 26, comprising from about 0.5% to about 5% by weight of said plasticizer.

31. 27. The composition of claim 26, further comprising about 0.1% to about 10% by weight of a buffering agent.

32. 27. The composition of claim 26, comprising from about 2% to about 9% by weight of said buffering agent.

33. 27. The composition of claim 26, comprising from about 3% to about 8.5% by weight of said buffering agent.

34. 27. The composition of claim 26, further comprising about 0.1% to about 5% by weight of an antioxidant.

35. 27. The composition of claim 26, further comprising about 0.1% to about 8% by weight of a saliva stimulating agent.

36. 27. 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 methylcellulose.

37. 2. The composition of claim 1, wherein the DMT or a pharmaceutically acceptable salt or prodrug thereof can be substantially completely solubilized and released in less than 1 minute after administration of the composition to a patient in need thereof.

38. 10. The composition of claim 1, wherein DMT or a pharmaceutically acceptable salt or prodrug thereof can be substantially completely solubilized and released in more than 1 minute and less than 20 minutes after administration of the composition to a patient in need thereof.

39. 2. The composition of claim 1, wherein the DMT or a pharmaceutically acceptable salt or prodrug thereof can be substantially completely solubilized and released in more than 20 minutes and less than 3 hours after administration of the composition to a patient in need thereof.

40. The composition of claim 1 , wherein the polymeric carrier matrix is ​​an oral transmucosal film.

41. 41. The composition of claim 40, wherein the film thickness is from about 0.01 mm to about 1.5 mm.

42. 42. The composition of claim 41, wherein the film thickness is from about 0.05 mm to about 0.4 mm.

43. 41. The composition of claim 40, wherein the film has a loss on drying (LOD) of about 5-11 w / w%.

44. 44. The composition of claim 43, wherein the loss on drying (LOD) of the film is about 7-9 w / w%.

45. 3 to 7 mg / cm ２ 41. The composition of claim 40, comprising amorphous DMT.

46. 10. The composition of claim 1, wherein the DMT remains in an amorphous state after aging for 6 months at 25°C and 60% relative humidity.

47. 47. The composition of claim 46, characterized by a powder X-ray diffraction pattern that does not contain any discernible peaks.

48. 47. The composition of claim 46, characterized by a differential scanning calorimetry (DSC) spectrum showing the absence of a sharp melting endotherm of crystalline DMT and / or the absence of signs of a phase change (e.g., a glass transition temperature).

49. 10. The composition of claim 1, wherein the DMT can remain in an amorphous state after aging at 40°C and 75% relative humidity for 6 months.

50. 50. The composition of claim 49, characterized by a powder X-ray diffraction pattern that does not contain any discernible peaks.

51. 50. The composition of claim 49, characterized by a differential scanning calorimetry (DSC) spectrum showing the absence of a sharp melting endotherm of crystalline DMT and / or the absence of any sign of a phase change.

52. 52. The composition of claim 51, wherein the indicia of a phase change is a glass transition temperature.

53. 10. A method for treating major depressive disorder, comprising administering a therapeutically effective amount of the composition of claim 1.

54. 1. A method of making a pharmaceutical composition, comprising: combining N-N-dimethyltryptamine, or a pharmaceutically acceptable salt or prodrug thereof, and 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.

55. 55. The method of claim 54, wherein the solvent comprises methanol and water, or only water.

56. 55. The method of claim 54, wherein the solvent comprises methanol-water in a 50:50 ratio or water alone.

57. 55. The method of claim 54, wherein the method comprises casting the polymeric matrix to form a film by removing the solvent.

58. 58. The method of claim 57, wherein the composition is an oral transmucosal film.

59. 58. The method of claim 57, wherein the film thickness is from about 0.01 mm to about 1.5 mm.

60. 60. The method of claim 59, wherein the film thickness is from about 0.05 mm to about 0.4 mm.

61. 58. The method of claim 57, wherein the loss on drying (LOD) of the film is about 5-11 w / w%.

62. 62. The method of claim 61, wherein the loss on drying (LOD) of the film is about 7-9 w / w%.

63. The amorphous DMT content is 3 to 7 mg / cm ２ 58. The method of claim 57, wherein the

64. 55. The method of claim 54, wherein the process comprises spray drying.

65. 55. A composition prepared according to the method of claim 54.

66. 66. 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.

67. 67. The composition of claim 66, characterized by a powder X-ray diffraction pattern that does not contain any discernible peaks.

68. 67. The composition of claim 66, characterized by a differential scanning calorimetry (DSC) spectrum showing the absence of a sharp melting endotherm of crystalline DMT and / or the absence of any sign of a phase change.

69. 69. The composition of claim 68, wherein the indicia of the phase change is a glass transition temperature.

70. 66. The composition of claim 65, wherein the DMT can remain in an amorphous state after aging at 40° C. and 75% relative humidity for 6 months.

71. 71. The composition of claim 70, characterized by a powder X-ray diffraction pattern that does not contain any discernible peaks.

72. 71. The pharmaceutical composition of claim 70, characterized by a differential scanning calorimetry (DSC) spectrum showing the absence of a sharp melting endotherm of crystalline DMT and / or the absence of any sign of a phase change.

73. 71. The composition of claim 70, wherein the indicia of a phase change is a glass transition temperature.

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