CN118450893A - Injectable and inhalable preparations - Google Patents

Abstract

The present invention relates to aqueous pharmaceutical formulations, to a process for their preparation and to their use. The aqueous pharmaceutical formulation comprises a salt of an optionally substituted dimethyltryptamine compound and water, has a pH of from 5 to 6.5, preferably from about 5 to about 6, and a concentration of the optionally substituted dimethyltryptamine compound of about 10mg/ml or more on a free base equivalent basis. These formulations may contain an effective dose of an optionally substituted dimethyltryptamine compound for use in the vagal adjuvant therapy in a volume of less than 5 ml. Such formulations are surprisingly suitable for both intramuscular injection as well as aerosol inhalation, are both stable and clinically acceptable, and have potential use in the treatment of mental or neurological disorders.

Description

Injectable and inhalable preparations

Technical Field

The present invention relates to aqueous pharmaceutical preparations, methods for their preparation and uses thereof. The aqueous pharmaceutical preparations contain salts of optionally substituted dimethyltryptamine compounds and water, have a pH of 5 to 6.5, and a concentration of the optionally substituted dimethyltryptamine compound of about 10 mg/ml or more in terms of free base equivalents. The preparations may have a pH of about 5 to about 6, or a pH of 5 to 6. These preparations contain an effective dose of optionally substituted dimethyltryptamine compounds for psychedelic-assisted therapy in a volume of 5 ml or less. Such preparations are surprisingly suitable for both intramuscular (IM) injection and nebulized inhalation, are stable and clinically acceptable, and have potential uses in the treatment of mental or neurological disorders.

Background technique

Classical hallucinogens have shown preclinical and clinical promise in the treatment of psychiatric disorders (Carhart-Harris and Goodwin, Neuropsychopharmacology 42, 2105-2113 (2017)). In particular, psilocybin was shown to significantly improve a range of depression and anxiety rating scales in a randomized double-blind study (Griffiths et al., Journal of Psychopharmacology, 30 (12), 1181-1197 (2016)).

N,N-dimethyltryptamine (DMT) is also understood to have therapeutic value as a short-acting hallucinogen. A review of the biosynthesis and metabolism of DMT in the brain and peripheral tissues, methods and results of DMT detection in body fluids and the brain is provided by S.A. Barker in Front. Neurosci., 12, 536, 1-17 (2018). Barker et al. stated that "further characterization of DMT cellular distribution, receptors, and general biochemistry may lead to new targets for more effective drugs and interventions."

The injection of saline solution of DMT fumarate into human volunteers is described in C. Timmermann et al., Sci. Rep., 9, 16324 (2019). The effects of DMT fumarate on the power spectrum and signal diversity of human brain activity were recorded via multivariate EEG and compared with the results obtained by injecting a placebo (saline solution). It has been found that DMT fumarate inhibits alpha power and normalizes/increases delta and theta power relative to the results obtained with placebo. Alpha power is associated with higher mental functions, top-down predictive processing, and related feedback connections, while theta and delta power are typically associated with REM sleep dreaming and related "fantasy" states. It is described that these results link the injection of DMT fumarate to the experience of feeling deeply immersed in a completely different world.

Silviera et al. (Molecules, 2020, 25, 2072) discussed the stability profile of ayahuasca. Piries et al. (Phytochem. Anal. 2009, 20, 149-153) discussed a method for simultaneously determining the main active ingredients found in ayahuasca tea samples.

According to the Human Metabolome Database (HMDB), N,N-dimethyltryptamine degrades relatively quickly in solution (see specifically http://www.hmdb.ca/metabolites/HMDB0005973 ). Therefore, there is a need in the art for an injectable solution of DMT that is stable over a long period of time and clinically acceptable and formulated in a manner that minimizes the discomfort and cost associated with administering dimethyltryptamine-based drugs. The present invention addresses this need.

Summary of the invention

The present invention relates to an aqueous pharmaceutical formulation suitable for both intramuscular injection and nebulization inhalation, comprising about 10 mg/ml or more (in terms of free base equivalent) of a salt of an optionally substituted dimethyltryptamine compound and water, wherein the formulation has a pH value of 5 to 6.5 and a typical osmolality of about 250 to about 350 mOsm/Kg. The formulation may have a pH of about 5 to about 6 or a pH of 5 to 6. These formulations are capable of delivering an effective dose of an optionally substituted dimethyltryptamine compound for psychedelic-assisted therapy (pharmacologically assisted psychotherapy) in a volume of less than 5 ml, making them particularly suitable for both intramuscular injection and nebulization inhalation. Preferably, the formulation is capable of delivering an effective dose of an optionally substituted dimethyltryptamine compound for psychedelic-assisted therapy in a volume of less than 4 ml, less than 3 ml, less than 2.5 ml, less than 2 ml, less than 1 ml or less than 0.5 ml.

The present invention solves the problem of providing a pharmaceutical preparation suitable for intramuscular injection or aerosol inhalation, and the preparation has significantly reduced degradation products compared with known preparations when stored under standard or stress conditions. This shows an improved shelf life relative to such known pharmaceutical preparations. In addition, deuterated optionally substituted dimethyltryptamine compounds, such as deuterated compounds of formula IA or IB, show significantly improved exposure and Cmax (see Figures 1A and 1B) by intramuscular injection compared with their undeuterated analogs. Therefore, the present invention provides for the first time an aqueous pharmaceutical preparation with an effective dose (for humans of at least average body weight) of an optionally substituted dimethyltryptamine compound via intramuscular injection or aerosol inhalation with a volume of less than 5ml, preferably less than 4ml, or less than 3ml, or less than 2.5ml, or less than 2ml, or less than 1ml, or less than 0.5ml.

Therefore, from the first aspect, the present invention provides a pharmaceutical preparation suitable for both intramuscular injection and nebulized inhalation, comprising a salt of an optionally substituted dimethyltryptamine compound, an alkaline agent, water; and an optional buffer separated from the salt; wherein the preparation has a pH of about 5 to about 6.5, a concentration of about 10 mg/ml or more in terms of free base, and an osmolality of about 250 to about 350 mOsm/Kg. The preparation may have a pH of about 5 to about 6, or a pH of 5 to 6.

In some embodiments of the first aspect of the invention, the formulation comprises about 10 mg/ml to about 150 mg/ml, about 10 mg/ml to about 100 mg/ml, about 10 mg/ml to about 80 mg/ml, about 15 mg/ml to about 70 mg/ml, about 15 mg/ml to about 50 mg/ml, or about 20 mg/ml to about 40 mg/ml (based on free base equivalents) of the salt of the optionally substituted dimethyltryptamine compound. Typically, the formulation comprises about 25 mg/ml (based on free base equivalents) of the salt of the optionally substituted dimethyltryptamine compound.

In a preferred embodiment of the first aspect of the invention, the pharmaceutical formulation comprises an effective dose of an optionally substituted dimethyltryptamine compound for psychedelic-assisted therapy in a volume of 5 ml or less, preferably in a volume of 4 ml or less, 3 ml or less, 2.5 ml or less, 2 ml or less, 1 ml or less or 0.5 ml or less.

Viewed from a second aspect, the invention provides a kit suitable for preparing the formulation of the first aspect, the kit comprising a salt of an optionally substituted dimethyltryptamine compound; an alkaline agent, an optional buffering agent separate from the salt, and an optional tonicity agent and/or pH adjusting agent. In a preferred embodiment of the second aspect of the invention, the kit comprises an effective dose of an optionally substituted dimethyltryptamine compound for psychedelic assisted therapy in a volume of 5 ml or less, preferably in a volume of 4 ml or less, 3 ml or less, 2.5 ml or less, 2 ml or less, 1 ml or less or 0.5 ml or less.

From a third aspect, the invention provides a method for preparing the pharmaceutical formulation of the first aspect, comprising contacting a salt, water, an alkaline agent, optionally a buffer separate from the salt, and optionally a tonicity agent and/or a pH adjuster. In a preferred embodiment of the third aspect of the invention, the formulation comprises an effective dose of an optionally substituted dimethyltryptamine compound for psychedelic assisted therapy in a volume of 5 ml or less, preferably in a volume of 4 ml or less, 3 ml or less, 2.5 ml or less, 2 ml or less, 1 ml or less or 0.5 ml or less.

In some embodiments, the formulations or kits of the first and second aspects comprise a tonicity agent. In some embodiments, the formulations or kits of the first and second aspects comprise a pH adjusting agent. In some embodiments, the formulations or kits of the first and second aspects comprise a buffer. In some embodiments, the formulations or kits of the first and second aspects comprise a buffer and a tonicity agent. In some embodiments, the formulations or kits of the first and second aspects comprise a buffer and a pH adjusting agent. In some embodiments, the formulations or kits of the first and second aspects comprise a buffer, a tonicity agent, and a pH adjusting agent.

Due to the known instability of the free base of N,N-dimethyltryptamine in solution, the solution containing the optionally substituted dimethyltryptamine compound is usually prepared immediately before or near the time of use, i.e., to avoid storing the solution of the optionally substituted dimethyltryptamine compound. Alternatively, the solution of the optionally substituted dimethyltryptamine compound is frozen. The inventors have found that when a buffer separated from the salt is used, the resulting preparation is more stable than the preparation prepared in the absence of a buffer separated from the salt. In addition, when a container suitable for preventing ultraviolet light from penetrating is used, the resulting preparation is more stable than the preparation stored in a container allowing ultraviolet light to penetrate.

From a fourth aspect, the present invention provides the preparation of the first aspect and the kit of the second aspect for use as a medicine or in combination with psychological therapy.

Viewed from a fifth aspect, the invention provides the formulation of the first aspect and the kit of the second aspect for use in a method of treating a mental or neurological disorder in a patient.

Viewed from a sixth aspect, the invention provides a method of treating a psychiatric or neurological disorder comprising administering to a patient in need thereof a formulation according to the first aspect.

Viewed from a seventh aspect, the invention provides a method of treating a psychotic disorder comprising administering to a patient in need thereof a formulation of the first aspect in combination with psychotherapy.

From an eighth aspect, the invention provides an aqueous pharmaceutical formulation comprising a salt and water, having a pH of from about 5 to about 6.5, and a concentration of a compound of formula IA of from about 10 mg/ml or more calculated as a free base equivalent salt, said salt comprising a Bronsted ester having a pKa of from about 3 to about 5 at 25°C. Acid and compound of formula IA

in:

R ^1a is independently selected from -R ^4a , -OH, -OR ^4a , -O(CO)R ^4a , monohydrogen phosphate, -F, -Cl, -Br and -I;

n is selected from 0, 1, 2, 3 or 4;

R ^2a is C( ^xa H) ₃ ;

R ^3a is C( ^xaH ) ₃ ;

Each R ^4a is independently selected from C ₁ -C ₄ alkyl; and

Each ^xa H and ^ya H is independently selected from protium or deuterium;

Preferably, the formulation may have a pH of about 5 to about 6, or a pH of 5 to 6. In a preferred embodiment of the eighth aspect of the invention, the pharmaceutical formulation comprises an effective dose of a compound of formula IA for psychedelic-assisted therapy in a volume of 5 ml or less, preferably in a volume of 4 ml or less, 3 ml or less, 2.5 ml or less, 2 ml or less, 1 ml or less or 0.5 ml or less.

From a ninth aspect, the invention provides an aqueous pharmaceutical formulation comprising a salt and water, having a pH of from about 5 to about 6.5, and a concentration of a compound of formula IB of about 10 mg/ml or more calculated as a free base equivalent salt, the salt comprising a Bronsted acid having a pKa of from about 3 to about 5 at 25°C and a compound of formula IB

in:

R ^1b is independently selected from -R ^4b , -OH, -OR ^4b , -O(CO)R ^4b , monohydrogen phosphate, -F, -Cl, -Br and -I;

n is selected from 0, 1, 2, 3 or 4;

R ^2b is C( ^xb H) ₃ ;

R ^3b is C( ^xb H) ₃ ;

Each R ^4b is independently selected from C ₁ -C ₄ alkyl; and

Each of ^xb H, ^yb H and ^z H is independently selected from protium or deuterium;

Preferably, the formulation may have a pH of about 5 to about 6, or a pH of 5 to 6. In a preferred embodiment of the ninth aspect of the invention, the pharmaceutical formulation comprises an effective dose of a compound of formula IB for psychedelic assisted therapy in a volume of 5 ml or less, preferably in a volume of 4 ml or less, 3 ml or less, 2.5 ml or less, 2 ml or less, 1 ml or less or 0.5 ml or less. For the avoidance of doubt, the embodiments of the eighth aspect of the invention apply mutatis mutandis to the ninth aspect of the invention.

Viewed from a tenth aspect, the present invention provides a lyophilized powder formulation comprising a formulation as defined in the first aspect of the present invention which has been lyophilized.

Viewed from an eleventh aspect, the present invention provides a method for preparing a lyophilized powder formulation, comprising drying the formulation as defined in the first aspect of the invention by lyophilization.

From a twelfth aspect, the present invention provides a method for preparing an aqueous formulation, comprising mixing a lyophilized powder formulation as defined in the tenth aspect or prepared in the method of the eleventh aspect into water to provide a formulation comprising a salt of an optionally substituted dimethyltryptamine compound, an alkaline agent, water and an optional buffer separate from the salt, to provide a formulation having a pH of about 5 to about 6.5, a concentration of about 10 mg/ml or more as a free base and an osmotic pressure of about 250 to about 350 mOsm/Kg. Preferably, the formulation may have a pH of about 5 to about 6, or a pH of 5 to 6.

For the avoidance of doubt, embodiments of the first aspect of the present invention apply mutatis mutandis to the tenth, eleventh and twelfth aspects of the present invention.

For the avoidance of doubt, embodiments relating to each aspect of the invention apply mutatis mutandis to other aspects of the invention.

Further aspects and embodiments of the invention will be apparent from the following discussion.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Figures 1A and 1B show graphs of mean plasma N,N-dimethyltryptamine (SPL026), _d2 -N,N-dimethyltryptamine (SPL028i), and _d8 -N,N-dimethyltryptamine (SPL028viii) concentrations over time following a 3.5 mg/kg (as fumarate) IM dose; added in vivo as a kit. Figure 1A - linear graph, Figure 1B - semi-logarithmic graph. All three drug substances achieved a Cmax greater than 50 ng/ml, indicating a therapeutically relevant dose. SPL028i and SPL028viii each demonstrated significantly higher plasma levels at 30 minutes compared to non-deuterated DMT.

Figures 2A and 2B show graphs of mean plasma _d2 -DMT (SPL028i) concentrations over time following IM doses of 3.5 mg/kg and 10 mg/kg (as fumarate) in vivo. Figure 2A - linear graph, Figure 2B - semi-log graph, SEM error bars.

FIG. 3 shows the pH-solubility curve of N,N-dimethyltryptamine from pH 4 to pH 10. FIG.

Detailed ways

Throughout this specification, one or more aspects of the invention may be combined with one or more features described in the specification to define different embodiments of the invention.

Unless otherwise stated, measurements are made at room temperature and pressure, ie, 20° C. (293.15 K, 68° F.) and 1 atm (14.696 psi, 101.325 kPa), respectively. Ambient conditions refer to room temperature and pressure, unless otherwise stated.

In the discussion below, a number of terms are mentioned, and unless the context clearly indicates otherwise, these terms will be understood to have the meanings provided below. The nomenclature used herein for the hallucinogenic agents used in the formulations of the present invention is as commonly used in the art. The compounds described herein may also be referred to according to the compound rules of the International Union of Pure and Applied Chemistry (IUPAC), in particular the nomenclature of the "IUPAC Chemical Terminology Compendium (Gold Book)" (see A.D. Jenkins et al., Pure & Appl. Chem., 1996, 68, 2287-2311). For the avoidance of doubt, if the rules of the IUPAC organization are contrary to the definitions provided herein, the definitions herein shall prevail.

Unless the context implies otherwise, reference herein to a noun in the singular includes the plural of the noun and vice versa.

Throughout this specification, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of stated elements, integers or steps, or groups of elements, integers or steps, but not the exclusion of any other elements, integers or steps, or groups of elements, integers or steps. The term "comprising" includes within its scope the terms "consisting" or "consisting essentially of.

The term "consisting" or variations thereof should be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, and the exclusion of any other element, integer or step, or group of elements, integers or steps.

The term "consisting essentially of" or variations thereof should be understood to imply inclusion of the recited elements, integers or steps, or groups of elements, integers or steps, and that additional components may be present, but only those that do not materially affect the basic characteristics of the preparation, composition or compound.

As used herein, the term "about" is used to refer to values within ±5% of the specified value when defining a number or value. For example, if the osmotic range is specified as about 250 to about 350 mOsm/Kg, values of 238 to 367 are included; the pH range is specified as about 5 to about 6, and values of 4.75 to 6.3 are included. For the avoidance of doubt, where a number or value is specified herein without the term "about", the number or value should be understood according to the number of decimal places according to standard numerical rounding conventions. For example, an integer such as 6 should be understood to include values ≥5.5 and <6.5. Similarly, a number with one decimal place after the decimal point, such as 5.3, should be understood to include values ≥5.25 and <5.35.

As used herein, the term "aqueous" refers to a formulation that includes water and may also include additional solvents.

The preparations of the present invention can be used for therapy and can be administered to patients in need thereof. As used herein, the term "patient" preferably refers to a mammal. Typically, the mammal is a human, but may also refer to a domestic mammal. The term does not include laboratory mammals.

As used herein, the term "effective dose" refers to a dose that, on average, induces a clinical response, ie, improvement of symptoms.

As used herein, the term "in combination with psychotherapy" refers to the treatment of a mental disorder by psychological means, which is enhanced by the administration of the formulation of the invention. The terms "psychedelic-assisted therapy" and "pharmacologically-assisted therapy" are used herein to refer to treatment in combination with psychotherapy.

The term "treatment" defines the therapeutic treatment of a patient in order to slow down or stop the rate of progression of a disorder, or to improve or cure the disorder. It also includes preventing a disorder as a result of treatment. Reference to prevention herein is not intended to require complete prevention of the disorder: rather, its development may be hindered by treatment according to the invention. Typically, treatment is not preventive, and the formulation is administered to a patient with a diagnosed or suspected disorder.

As understood in the art, a mental or neurological disorder is a disorder that may be associated with one or more cognitive impairments. As used herein, the term "mental disorder" is a clinically significant behavioral or psychological syndrome or pattern that occurs in an individual and is associated with current pain (e.g., pain symptoms) or disability (i.e., the impairment of one or more important areas of function) or is associated with a significantly increased risk of death, pain, disability, or a significant loss of freedom.

The diagnostic criteria for the mental or neurological disorders referred to herein are provided in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).

As used herein, the term "psychedelic-assisted therapy" is defined as any psychotherapeutic practice provided in conjunction with a psychedelic therapeutic formulation, including, for example, any formulation defined by the present invention.

As used herein, the term "obsessive-compulsive disorder" (OCD) is defined as the presence of obsessive thoughts or compulsive behaviors, but usually both exist. These symptoms may cause serious functional impairment and/or pain. Obsessive thoughts are defined as undesirable intrusive thoughts, images or impulses that repeatedly enter the mind of a person. Compulsive behaviors are repeated behaviors or mental activities that a person feels driven to perform. Typically, OCD manifests as one or more obsessive thoughts, which drive the adoption of compulsive behaviors. For example, the obsessive thoughts to bacteria may drive the compulsive behaviors of cleaning, or the obsessive thoughts to food may drive the compulsive behaviors of overeating, eating too little or vomiting after eating (i.e., the obsessive thoughts to food may manifest themselves as eating disorders). Compulsive behaviors can be explicit and observed by others, such as checking whether the door is locked, or recessive mental activities that cannot be observed, such as repeating a certain phrase in the mind.

As used herein, the term "eating disorder" is defined as a severe and persistent disturbance in eating behavior and associated distressing thoughts and emotions. The term "eating disorder" includes anorexia nervosa and bulimia nervosa, binge eating disorder, avoidant restrictive food intake disorder, other specific food intake and eating disorders, pica, and rumination disorder.

Eating disorders often co-occur with anxiety disorders and obsessive-compulsive disorders. Neziroglu and Sandler distinguish between OCD and eating disorders: “Whereas patients with eating disorders are primarily driven by concerns about their appearance and therefore alter their eating patterns in order to lose weight accordingly, the reasons for restrictive eating in patients with OCD may be quite different from body image issues” ( https://iocdf.org/expert-opinions/expert-opinion-eating-disorders-and-ocd/ ).

The present invention provides a formulation or kit according to the first and second aspects of the present invention for use in a method for treating an eating disorder. The term "eating disorder" includes anorexia nervosa, bulimia nervosa and binge eating disorder (BED). Symptoms of anorexia nervosa include eating too little and/or exercising too much in order to keep body weight as low as possible. Symptoms of bulimia nervosa include eating a lot of food in a very short period of time (i.e., overeating), and then deliberately vomiting, using laxatives, eating too little and/or exercising too much to prevent weight gain. Symptoms of BED include eating large amounts of food frequently until uncomfortably full, and feeling uneasy or guilty about it.

As used herein, the term "depressive disorder" includes major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, and depression in terminally ill patients.

As used herein, the term "major depressive disorder" (MDD, also called major depressive disorder or clinical depression) is defined as the presence of five or more of the following symptoms on most days, nearly every day, over a period of more than two weeks (also referred to herein as a "major depressive episode"):

Depressed mood, such as feeling sad, empty, or tearful (in children and adolescents, depressed mood may manifest as persistent irritability);

Significantly reduced interest or unpleasantness in all or most activities;

Significant weight loss when not dieting, weight gain, or decreased or increased appetite (in children, failure to gain weight as expected);

Insomnia or increased desire to sleep;

Restlessness or slowed behavior that is observable by others;

Fatigue or loss of energy;

Feelings of worthlessness, or excessive or inappropriate guilt;

Difficulty making decisions, or difficulty thinking or concentrating;

Recurrent thoughts of death or suicide, or suicide attempts.

At least one of these symptoms must be a depressed mood or a loss of interest or pleasure.

Persistent depressive disorder, also known as dysthymia, is defined as patients who exhibit both of the following characteristics:

A. Depressed mood most of the day, nearly every day, for at least 2 years. Children and adolescents may have irritable moods for at least 1 year.

B. During depression, a person experiences at least two of the following symptoms:

Either overeating or lack of appetite.

Sleeping too much or having trouble sleeping.

· Fatigue and lack of energy.

Low self-esteem.

Difficulty concentrating or making decisions.

As used herein, the term "treatment-resistant major depressive disorder" describes MDD that fails to achieve an adequate response to appropriate treatment with standard of care therapies.

As used herein, "bipolar disorder," also known as manic-depressive illness, is a disorder that causes abnormal changes in mood, energy, activity level, and ability to perform daily tasks.

There are two defined subclasses of bipolar disorder; all of which involve marked changes in mood, energy, and activity levels. These moods range from extreme "up," elation, and energetic behavior (called manic episodes, and defined further below) to periods of great sadness, "down," or hopelessness (called depressive episodes). Less severe manic periods are called hypomanic episodes.

Bipolar I disorder - defined as a manic episode lasting at least 7 days, or manic symptoms severe enough to require immediate hospitalization. Often, a depressive episode also occurs, typically lasting at least 2 weeks. Depressive episodes with mixed features (having both depressive and manic symptoms) are also possible.

Bipolar II disorder—defined as a pattern of depressive episodes and hypomanic episodes, but not the full-blown manic episodes described above.

As used herein, "bipolar depression" is defined as an individual experiencing an episode of depressive symptoms with preceding or coexisting manic symptoms, but who does not meet clinical criteria for bipolar disorder.

As used herein, the term "anxiety disorder" includes generalized anxiety disorder, phobias, panic disorder, social anxiety disorder, and post-traumatic stress disorder.

As used herein, "generalized anxiety disorder" (GAD) refers to a chronic disorder characterized by chronic anxiety that is not focused on any one object or situation. Those suffering from GAD experience nonspecific persistent fears and worries, and become overly concerned with everyday affairs. GAD is characterized by chronic excessive worry accompanied by more than three of the following symptoms: restlessness, fatigue, concentration problems, irritability, muscle tension, and sleep disturbances.

A "phobia" is defined as a persistent fear of an object or situation that the affected person will go to great lengths to avoid, typically out of proportion to the actual danger posed. If the phobic object or situation cannot be completely avoided, the affected person experiences marked distress and significant interference with social or occupational activities.

Patients with "panic disorder" are defined as those who experience one or more brief episodes of intense terror and fear (also called panic attacks), often characterized by shaking, tremors, confusion, dizziness, nausea, and/or difficulty breathing. A panic attack is defined as sudden onset and peak fear or discomfort in less than ten minutes.

Social anxiety disorder is defined as an intense fear and avoidance of negative public scrutiny, public embarrassment, humiliation, or social interaction. Social anxiety often manifests itself in specific physical symptoms, including blushing, sweating, and difficulty speaking.

Post-traumatic stress disorder (PTSD) is an anxiety disorder caused by a traumatic experience. Post-traumatic stress can result from extreme situations such as combat, natural disasters, rape, hostage situations, child abuse, bullying, or even serious accidents. Common symptoms include hypervigilance, flashbacks, avoidance behaviors, anxiety, anger, and depression.

As used herein, the term "post-partum depression" (PPD, also known as postnatal depression) is a form of depression experienced by either parent of a newborn. Symptoms typically appear within 4 weeks of the birth of the baby and often include extreme sadness, fatigue, anxiety, loss of interest or pleasure in hobbies and activities, irritability, and changes in sleeping or eating patterns.

As used herein, the term "substance abuse" means a patterned use of a drug in which the user consumes the substance in amounts or in a manner that is harmful to oneself or others.

As used herein, the term "gambling disorder" means persistent and recurring problematic gambling behavior that results in clinically significant impairment or distress. The disorder has similarities to substance abuse.

As used herein, the term "deficit motivation disorder" refers to a disorder that includes symptoms of decreased motivation to initiate and perform self-directed purposeful activities.

The present invention provides an aqueous pharmaceutical preparation suitable for intramuscular injection and/or aerosol inhalation, comprising a salt of an optionally substituted dimethyltryptamine compound; an alkali agent; water; and an optional buffer separated from the salt; wherein the preparation has a pH of about 5 to about 6.5 and an osmotic pressure of about 250 to about 350 mOsm/Kg. The preparation can have a pH of about 5 to about 6, or a pH of 5 to 6.

In a preferred embodiment of the present invention, the pharmaceutical formulation contains an effective dose of an optionally substituted dimethyltryptamine compound for use in psychedelic-assisted therapy in a volume of 5 ml or less, preferably in a volume of 4 ml or less, 3 ml or less, 2.5 ml or less, 2 ml or less, 1 ml or less or 0.5 ml or less.

The inventors have found that the formulation is surprisingly more stable than formulations prepared at higher pH (particularly at a pH matched to human serum, i.e., those prepared at a pH of about 7.4). The greater stability of the formulations of the present invention relative to isotonic formulations is discussed in more detail in the Examples section.

Osmolality is formally defined as the quotient of the negative natural logarithm of the rational activity of water and the molar mass of water, as expressed by the following formula:

Wherein, p is the vapor partial pressure of water in solution, and p* is the vapor partial pressure of pure water. In simpler terms, osmotic density is the number of osmotically active particles (the number of solute particles) in 1 kg of solution. Therefore, osmotic density is only a function of the number of particles and is independent of particle molecular weight, size, shape or charge (see D.K.Faria et al., M.E.Mendes and N.M.Sumita, J.Bras.Patol.Med.Lab., 53, 1, 38-45 (2017) for a review of serum osmotic density measurements). For example, 1 mole of non-dissociated substance (e.g., DMT in the form of free alkali) dissolved in 1 kg of water has an osmotic density of 1 Osm/kg (1000 mOsm/kg), while 1 mole of a substance (e.g., DMT fumarate) dissolved in 1 kg of water that dissociates into two separate species in solution has an osmotic density of 2 Osm/kg (2000 mOsm/kg).

When a first solution is defined herein as being isotonic with a second solution, the solutions have the same osmotic density. For example, when a formulation is defined as being isotonic with human serum, the formulation has the same osmotic density as human serum. Human serum typically has an osmotic density of about 275 to about 300 mOsm/Kg (L. Hooper et al., BMJ Open, 2015; 5(10): e008846).

Preparation of the present invention is suitable for aerosol inhalation. Typically, the particles present in the preparation for aerosol inhalation have a mass average aerodynamic diameter (MMAD) of about 0.1 to about 10 μm, preferably about 0.3 to about 8 μm, preferably about 0.3 to about 7 μm, more preferably about 0.5 to about 5 μm or about 3 to about 7 μm. MMAD will be selected according to the type of nebulizer, such as jet nebulizer, mesh nebulizer or ultrasonic nebulizer. Suitably, multi-stage cascade impactor (CI) equipment can be used to determine the size of the graded aerosol according to the aerodynamic particle size distribution (APSD) of the aerosol. MMAD is calculated by APSD and is defined as the diameter when the particles of 50% by mass of the aerosol are larger and the particles of 50% by weight of the aerosol are smaller.

The formulation (i.e., the formulation of the present invention) is suitable for intramuscular injection, which means that it meets the pharmacopoeial requirements for sterility, contaminants and pyrogens (see, e.g., The United States Pharmacopeial Convention, General Requirements/<1>Injections, p. 33). Sometimes, the formulation contains a microbial growth inhibitor (e.g., an antimicrobial preservative) and/or an antioxidant.

Preparations suitable for parenteral administration typically have a pH of about 3 to 9 and an osmotic pressure of about 250 to about 600 mOsm/Kg. I. Usach et al. reported in Adv. Ther., 36, 2986-2996 (2019) that pH values above 9 are associated with tissue necrosis (death of cells within tissues), while pH values below 3 are reported to cause pain and phlebitis (inflammation of veins). However, Usach et al. reported that " pH values close to physiological pH are recommended to minimize pain, irritation, and tissue damage" (emphasis is indicated by the author). It is reported that osmotic pressure values greater than 600 mOsm/Kg can also cause pain. Usach et al. also recommended that parenteral preparations should be formulated as isotonic solutions (osmotic pressures of about 300 mOsm/Kg), and an upper limit of 600 mOsm/Kg is recommended to minimize pain.

The formulation (ie of the present invention) is also suitable for inhalation, in particular for aerosol inhalation.

The formulation comprises a salt of an optionally substituted dimethyltryptamine compound. The formulation according to the invention may comprise one or more than one salt of an optionally substituted dimethyltryptamine compound. For the avoidance of doubt, when the formulation comprises an ion of an optionally substituted dimethyltryptamine compound and an ion (counter ion) that counteracts the charge of the optionally substituted dimethyltryptamine ion, the formulation comprises an optionally substituted dimethyltryptamine salt. An optionally substituted dimethyltryptamine salt may therefore be formed within the formulation, for example by contacting an optionally substituted dimethyltryptamine in free base form with an aqueous solution comprising an excess of a buffer relative to a molar amount of the optionally substituted dimethyltryptamine.

The dimethyltryptamine compound is optionally substituted with deuterium, wherein a deuterium atom is a hydrogen atom having an additional neutron.

In some embodiments, the dimethyltryptamine compound is substituted at the 4 or 5 position with an acetoxy or methoxy group, or with a monohydrogen phosphate at the 4 position. The term "acetoxy" (commonly abbreviated as OAc) defines a monovalent group derived from acetic acid by removing a hydrogen atom from an OH moiety. The term "methoxy" (commonly abbreviated as OMe) defines a monovalent group derived from methanol by removing a hydrogen atom from an OH moiety. The term monohydrogen phosphate defines a divalent group of formula HPO ₄ derived from phosphoric acid by removing protons from two of the three OH moieties, and thus represents a substituent of the formula -OP(O)(OH) ^O- .

When the dimethyltryptamine compound is substituted with a monohydrogen phosphate at the 4-position, this reflects that psilocybin (also known as [3-(2-dimethylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate) in water generally has a monohydrogen phosphate at the 4-position, which is generally understood to be the major form because the pKa values of the two terminal phosphate oxygen atoms are estimated to be 1.3 and 6.5. It is also understood that the monohydrogen phosphate-containing form of psilocybin exists as a zwitterion (i.e., an inner salt) in which the nitrogen atom of the dimethylamino moiety is protonated. Therefore, this form and psilocybin are considered to be salts of the dimethyltryptamine compound substituted with a monohydrogen phosphate at the 4-position.

For the avoidance of doubt, positions 4 and 5 of the optionally substituted dimethyltryptamine salt refer to the positions marked in the structures below (substitutions not shown).

The preparation optionally comprises a buffer separated from the salt, i.e., the buffer is not merely the counter ion of the optionally substituted dimethyltryptamine. For example, when the salt is N,N-dimethyltryptamine fumarate (i.e., the fumarate of N,N-dimethyltryptamine), a buffer exceeding and more than the amount of the buffering effect provided by the fumarate may be required. The term "buffer" is well known in the art and refers to a chemical substance that resists changes in pH when an acid or base is added to the preparation when included in the preparation. As used herein, the term "buffer" refers to a buffer system or a buffering agent. Suitable buffer systems for the preparations of the present invention include weak acids and their conjugate bases. Suitable buffer systems include acids with pKa values within ±1 of the desired pH of the preparation. For example, if the desired pH of the preparation is about 5.0, a suitable buffer system includes a weak acid with a pKa value of about 4.0 to about 6.0. If the acid of the buffer system has more than one pKa value (i.e., each acid molecule can contribute more than one proton), in order to make the buffer suitable, at least one of the pKa values is within the desired pH range.

The weak acid and conjugate base of the buffer system are in equilibrium with each other. According to Le Chatelier's principle (if a constraint (e.g., a change in reactant concentration) is imposed on an equilibrium system, the equilibrium will shift to offset the effect of the constraint), adding an acid or base to the formulation shifts the equilibrium position in favor of the conjugate base or weak acid, respectively. Therefore, the concentration of free protons in the formulation (and therefore the pH) remains relatively unchanged.

As described above, the formulations of the present invention have a pH of about 5 to about 6.5, preferably about 5 to about 6, preferably about 5.0 to about 6.0. Preferably, the pH is 5 to 6, preferably 5.0 to 6.0. Preferably, the pH is about 5.2 to about 5.8, or about 5.5 to 6.0. Preferably, the pH is about 5.7 to about 6.5, or about 5.7 to about 6. More preferably, the pH is about 5.5 or about 6.

In some embodiments, the formulation comprises a buffer. In some embodiments, the buffer is separate from the salt.

Suitable buffer systems include acetate and acetic acid (pKa = 4.75); citrate and citric acid (pKa = 3.13, 4.76 and 6.40); and phosphoric acid (pKa = 2.14, 7.20 and 12.37); or mixtures thereof. The pKa values cited herein are reported as those in water at 25°C. Typically, the buffer system includes only one of the pairs listed above, i.e., an acid and its conjugate base.

In some embodiments, the buffer system comprises acetate and acetic acid; citrate and citric acid; or phosphate and phosphoric acid.

Sometimes, the buffer system comprises acetate and acetic acid; or citrate and citric acid.

In some embodiments, the buffer system comprises acetate and acetic acid, typically sodium acetate and acetic acid, or potassium acetate and acetic acid.

As used herein, the term "buffering agent" refers to a weak acid or a weak base. Any pharmaceutically acceptable buffering agent can be used in the formulations of the present invention, including phosphoric acid, citric acid, acetic acid, phosphates, citrates, and acetates. In some embodiments, the buffer comprises sodium phosphate, sodium citrate, or sodium acetate.

Preferably, the pharmaceutical preparation contains an effective dose of an optionally substituted dimethyltryptamine compound for use as a drug or for psychedelic assisted therapy, which means that the preparation contains a salt of a dimethyltryptamine compound within a dose range that causes a psychedelic experience in a human patient of average weight. Typically, the dose range is from about 5 to about 250 mg, or from about 10 to about 150 mg, suitably from about 10 to about 100 mg, suitably from about 20 to about 100 mg (in free base equivalents). In some embodiments, the dose range is from about 20 to about 70 mg, or from about 20 to about 50 mg. For example, a suitable dose is about 9 mg, or about 12 mg, or about 17 mg, or about 21.5 mg, or about 24 mg, or about 30.5 mg, or about 34 mg, or about 33 mg, or about 36 mg, or about 38.5 mg, or about 43 mg, or about 51 mg, or about 52 mg, or about 55 mg, or about 60 mg, or about 64.5 mg. The dosage ranges and suitable dosages provided in this paragraph refer to free base equivalent dosages.

The concentration of the buffer in the preparation is typically enough to resist the significant pH change of the preparation when the preparation is stored for two weeks (i.e., the pH typically fluctuates less than about 0.1 pH units), while also ensuring that the osmotic pressure of the preparation is within the desired range of about 250 to about 350 mOsm/Kg. The technician can assess suitable buffer concentrations and achieve this. Typically, the concentration of the buffer is about 15 mM to about 75 mM, such as about 20 mM to about 30 mM. In some embodiments, the concentration of the buffer is about 25 mM.

As described above, the formulation comprises a salt of an optionally substituted dimethyltryptamine compound at a concentration of about 10 mg/ml or more based on free base equivalent.

The salt comprises an acid and an optionally substituted dimethyltryptamine compound, or the salt comprises a dimethyltryptamine compound substituted with a monohydrogen phosphate, preferably substituted at the 4-position of the indole ring system. An example of a salt comprising an acid and a dimethyltryptamine compound is N,N-dimethyltryptamine fumarate, which is a fumarate of N,N-dimethyltryptamine. P.H.Stahl and C.G.Wermuth provide an overview of pharmaceutical salts and the acids contained therein in Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zürich: Wiley-VCH/VHCA, 2002. The acid described in this review is an acid suitable for inclusion in the salt of the preparation.

The salt may comprise an acid selected from the group consisting of fumaric acid, tartaric acid, citric acid, acetic acid, lactic acid, gluconic acid, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, caprylic acid, carbonic acid, cinnamic acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid Acid, formic acid, galactonic acid, gentisic acid, glucoheptanoic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, niacin, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, thiocyanic acid, toluenesulfonic acid and undecylenic acid.

In some embodiments, where the salt comprises an acid and a dimethyltryptamine compound, the acid is a Bronsted acid having a pKa of about 3 to about 5 in water at 25° C. In these embodiments, the Bronsted acid can act as a counterion for the dimethyltryptamine compound and can also act as a buffer. Thus, when the salt comprises such an acid, the formulation can be stabilized to a greater extent, i.e., the degradation of the dimethyltryptamine compound can be further improved.

In some embodiments, the salt comprises a Bronsted acid having a pKa of about 3 to about 5 at 25°C and a compound of Formula IA

in:

R ^1a is independently selected from -R ^4a , -OH, -OR ^4a , -O(CO)R ^4a , monohydrogen phosphate, -F, -Cl, -Br and -I;

n is selected from 0, 1, 2, 3 or 4;

R ^2a is C( ^xa H) ₃ ;

R ^3a is C( ^xaH ) ₃ ;

Each R ^4a is independently selected from C ₁ -C ₄ alkyl; and

Each ^xa H and ^ya H is independently selected from protium or deuterium.

In some embodiments, the salt comprises a Bronsted acid having a pKa of about 3 to about 5 at 25°C and a compound of formula IB

in:

R ^1b is independently selected from -R ^4b , -OH, -OR ^4b , -O(CO)R ^4b , monohydrogen phosphate, -F, -Cl, -Br and -I;

n is selected from 0, 1, 2, 3 or 4;

R ^2b is C( ^xb H) ₃ ;

R ^3b is C( ^xb H) ₃ ;

Each R ^4b is independently selected from C ₁ -C ₄ alkyl; and

Each of ^xb H, ^yb H and ^z H is independently selected from protium or deuterium.

In some embodiments, the compound has (i) Formula IA, wherein each R ^1a is independently selected from -OR ^4a , -O(CO)R ^4a , monohydrogen phosphate, and -OH, or (ii) Formula IB, wherein each R ^1b is independently selected from -OR ^4b , -O(CO)R ^4b , monohydrogen phosphate, and -OH.

It will be appreciated that formula IA is a subformula of IB wherein each ^z H is hydrogen.

In some embodiments, the compound has (i) Formula IA, wherein R ^4a is methyl, or (ii) Formula IB, wherein R ^4b is methyl.

In some embodiments, the compound is of Formula IA or Formula IB according to any of the preceding embodiments, wherein n is 1, 2, 3, or 4.

In some embodiments, the compound is of Formula IA or Formula IB according to any of the preceding embodiments, wherein n is 1.

In some embodiments, the compound has (i) Formula IA according to any of the preceding embodiments, wherein n is 0; or n is 1, and R ^1a is at the 4-position or the 5-position; or (ii) Formula IB according to any of the preceding embodiments, wherein n is 0; or n is 1, and R ^1b is at the 4-position or the 5-position.

In some embodiments, the compound has (i) Formula IA according to any of the preceding embodiments, wherein each R ^1a is independently selected from -OH, -OMe, -OCD ₃ , -OAc, -O(CO)Me, and monohydrogen phosphate; or (ii) Formula IB, wherein each R ^1b is independently selected from -OH, -OMe, -OCD ₃ , -OAc, -O(CO)Me, and monohydrogen phosphate.

In some embodiments, the compound has (i) Formula IA according to any of the preceding embodiments, wherein n is 0; or n is 1 and R ^1a is selected from 5-methoxy, 5-bromo, 4-acetoxy, 4-monohydrogen phosphate, 4-hydroxy and 5-hydroxy; or (ii) Formula IB according to any of the preceding embodiments, wherein n is 0; or n is 1 and R ^1b is selected from 5-methoxy, 5-bromo, 4-acetoxy, 4-monohydrogen phosphate, 4-hydroxy and 5-hydroxy.

In some embodiments, the compound has Formula IA or IB, wherein n is 0.

In some embodiments, the compound has (i) Formula IA according to any of the preceding embodiments, wherein both ^ya H are deuterium, or (ii) Formula IB according to any of the preceding embodiments, wherein both ^yb H are deuterium.

In some embodiments, the compound has (i) Formula IA according to any of the preceding embodiments, wherein both ^ya H are protium, or (ii) Formula IB according to any of the preceding embodiments, wherein both ^yb H are deuterium.

In some embodiments, the compound has (i) Formula IA according to any of the preceding embodiments, wherein one ^ya H is protium and one ^ya H is deuterium, or (ii) Formula IB according to any of the preceding embodiments, wherein one ^yb H is protium and one ^yb H is deuterium.

In some embodiments, the compound has formula IB, wherein both ^z H are deuterium. In some embodiments, the compound has formula IB, wherein both ^z H are protium. In some embodiments, the compound has formula IB, wherein one ^z H is protium and one ^z H is deuterium.

In some embodiments, the compound has (i) Formula IA according to any of the preceding embodiments, wherein each ^xa H is D, or (ii) Formula IB according to any of the preceding embodiments, wherein each ^xb H is D. In some embodiments, the compound has (i) Formula IA according to any of the preceding embodiments, wherein R ^2a and R ^3a are both C( ^xa H) ₃ , or (ii) Formula IB according to any of the preceding embodiments, wherein R ^2b and R ^3b are both C( ^xb H) ₃ .

In some embodiments, the compound has (i) Formula IA according to any of the preceding embodiments, wherein two C( ^xaH ) ₃ are the same, or (ii) Formula IB according to any of the preceding embodiments, wherein two C( ^xbH ) ₃ are the same.

In some embodiments, the compound has (i) Formula IA according to any of the preceding embodiments, wherein both R ^2a and R ^3a are CD ₃ , or (ii) Formula IB according to any of the preceding embodiments, wherein both R ^2b and R ^3b are CD ₃ .

In some embodiments, the compound has (i) Formula IA according to any of the preceding embodiments, wherein both R ^2a and R ^3a are CH ₃ , or (ii) Formula IB according to any of the preceding embodiments, wherein both R ^2b and R ^3b are CH ₃ .

In some embodiments, the compound has (i) Formula IA according to any of the preceding embodiments, wherein R ^2a is CD ₃ and R ^3a is CH ₃ , or (ii) Formula IB according to any of the preceding embodiments, wherein R ^2b is CD ₃ and R ^3b is CH ₃ .

In some embodiments, the C ₁ -C ₄ alkyl group may be a deuterated C ₁ -C ₄ alkyl group, such as CD ₃ .

For the avoidance of doubt, certain optionally substituted dimethyltryptamine compounds encompassed by the present invention include compounds known in the art by two or more names, including:

The compound N,N-dimethyltryptamine (DMT) may also be referred to as N,N-dimethyl-1H-indole-3-ethylamine (CAS number 61-50-7).

The compound 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) may also be referred to as 5-methoxy-N,N-dimethyl-1H-indole-3-ethylamine (CAS No. 1019-45-0).

The compound 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT) may also be referred to as 4-acetoxy-N,N-dimethyltryptamine, O-acetyldimethyl-4-hydroxytryptamine, psilacetin or [3-[2-(dimethylamino)ethyl]-1H-indol-4-yl]acetate (CAS No. 92292-84-7).

The compound 4-hydroxy-N,N-dimethyltryptamine- _d6 may also be referred to as dimethyl-4-hydroxytryptamine- _d6 or 3-(2-(bis(methyl- _d3 )amino)ethyl)-1H-indol-4-ol.

The compound N,N-di(trideuteriomethyl)tryptamine may also be referred to as N,N-hexadeuterio-dimethyltryptamine or _D6 -DMT.

The compound 5-hydroxy-N-mono(trideuterated methyl)tryptamine may also be referred to as N-methyl-serotonin-D ₃ (CAS No. 1794811-18-9).

The compound N-mono(trideuteratedmethyl)tryptamine may also be referred to as N-methyl-tryptamine-D ₃ (CAS No. 1794745-39-0).

The compound α,α-dideutero-N,N-dimethyltryptamine may also be referred to as D ₂ -DMT or 2-(1H-indol-3-yl)-N,N-dimethylethane-1-amine-1,1-d ₂ .

The compound α,α,β,β-tetradeuterated-N,N-dimethyltryptamine may also be referred to as D ₄ -DMT or 2-(1H-indol-3-yl)-N,N-dimethylethane-1-amine-1,1,2,2-d ₄ .

The compound α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine may also be referred to as D ₁₀ -DMT or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethane-1-amine-1,1,2,2-d ₄ .

In some embodiments, the optionally substituted dimethyltryptamine compound is N,N-dimethyltryptamine. In some embodiments, the optionally substituted dimethyltryptamine compound is a deuterated dimethyltryptamine compound, including α,α-dideutero-N,N-dimethyltryptamine, N,N-di(trideuteromethyl)tryptamine, α,α-dideutero-N,N-di(trideuteromethyl)tryptamine, α,α,β,β-tetradeutero-N,N-dimethyltryptamine and α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine.

Salts of deuterated N,N-dimethyltryptamine compounds as defined above can be synthesized according to the synthesis schemes disclosed in WO 2020/245133A1, WO 2021/116503 and WO 2021/089873A1 (all Small Pharma Ltd), which are particularly advantageous bulk drugs for the preparations of the present invention. It has been found that deuterated N,N-dimethyltryptamine compounds as described above exhibit kinetic isotope effects, which can be used to extend their half-lives in biological systems. The inventors have now found in vivo that preparations of the present invention comprising deuterated N,N-dimethyltryptamine compounds and deuterated substituted N,N-dimethyltryptamine compounds have significantly higher Cmax and exposure relative to their undeuterated analogs (see Figures 1A and 1B).

If desired, a composition for use in the preparation of the present invention can be prepared, which comprises a certain amount of N,N-dimethyltryptamine and a deuterated N,N-dimethyltryptamine compound, wherein the relative proportion of N,N-dimethyltryptamine to the deuterated N,N-dimethyltryptamine compound (as defined above) can be controlled by changing the ratio of lithium aluminum hydride and lithium aluminum deuteride in the reducing agent, for example as described in WO 2021/116503 (Small Pharma Ltd).

Compositions containing an amount of N,N-dimethyltryptamine and/or a deuterated N,N-dimethyltryptamine compound can be used to provide a salt of an optionally substituted dimethyltryptamine compound such that the formulation contains one or more optionally substituted dimethyltryptamine compounds, each in the form of a salt described herein.

The composition contained in the formulation may contain α,α-dideutero-N,N-dimethyltryptamine in an amount of 90% or more, 95% or more, preferably 97% or more, more preferably 98% or more, most preferably 99% or more by weight of the composition.

The composition included in the formulation may comprise N,N-dimethyltryptamine in an amount of 5% or less, preferably 2% or less, more preferably 1% or less, most preferably 0.5% or less by weight of the composition.

The composition included in the formulation may comprise α-protonated-α-deuterated-N,N-dimethyltryptamine in an amount of 5% or less, preferably 2% or less, more preferably 1% or less, most preferably 0.5% or less by weight of the composition.

In some embodiments, the composition contained in the formulation can contain, by weight of the composition, a) more than 90% of an α,α-dideutero-N,N-dimethyltryptamine compound, b) less than 10% of an α-protonated-α-deutero-N,N-dimethyltryptamine compound, and c) less than 2% of N,N-dimethyltryptamine, wherein the total weight of the α,α-dideutero-N,N-dimethyltryptamine compound, the α-protonated-α-deutero-N,N-dimethyltryptamine compound, and N,N-dimethyltryptamine is 100%.

In some embodiments, the composition contained in the formulation can contain, by weight of the composition, a) more than 95% of an α,α-dideutero-N,N-dimethyltryptamine compound, b) less than 5% of an α-protonated-α-deutero-N,N-dimethyltryptamine compound, and c) less than 1% of N,N-dimethyltryptamine, wherein the total weight of the α,α-dideutero-N,N-dimethyltryptamine compound, the α-protonated-α-deutero-N,N-dimethyltryptamine compound, and N,N-dimethyltryptamine is 100%.

For the avoidance of doubt, N,N-dimethyltryptamine may be absent, may be present in the composition in trace amounts, may be present in the composition in an amount of 2% or less by weight of the composition, or may be present in the composition in an amount of 1% or less by weight of the composition. In the case of 4, 5, 6 or 7-substituted dimethyltryptamine compounds, the above 2% or less or 1% or less of N,N-dimethyltryptamine should be understood to include, for example, undeuterated 4, 5, 6 or 7-substituted N,N-dimethyltryptamine, such as 5-methoxy-N,N-dimethyltryptamine. For example, in a composition comprising 5-methoxy-α,α-dideutero-N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine may be absent, may be present in the composition in trace amounts, or may be present in the composition in an amount of 2% or less, or 1% or less by weight of the composition.

As used herein, the term "α,α-dideutero-N,N-dimethyltryptamine compound" includes the compound α,α-dideutero-N,N-dimethyltryptamine ( _d2 -DMT) as well as α,α-dideutero-N,N-dimethyltryptamine compounds containing deuteration at other positions, such as α,α,β,β-tetradeutero-N,N-dimethyltryptamine (d4 _- DMT), α,α-dideutero-N,N-di(trideuteromethyl)tryptamine (d8 _- DMT), α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine ( _d10 -DMT), and substituted α,α-dideutero-N,N-dimethyltryptamine compounds, such as 5-methoxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine.

As used herein, the term "α-protonated-α-deuterated-N,N-dimethyltryptamine compound" includes the compound α-protonated-α-deuterated-N,N-dimethyltryptamine ( _d1 -DMT) as well as α-protonated-α-deuterated-N,N-dimethyltryptamine compounds containing deuteration at other positions, such as α-protonated-α,β,β-trideuterated N,N-dimethyltryptamine ( _d3 -DMT), α-protonated-α-deuterated-N,N-di(trideuteriomethyl)tryptamine (d7-DMT), α-protonated-α,β,β-trideuterated N,N-di(trideuteriomethyl)tryptamine (d9 _- DMT), and α-protonated-α,β,β-trideuterated N,N _- di(trideuteriomethyl)tryptamine. -DMT), and substituted α-protonated-α-deuterated-N,N-dimethyltryptamine compounds, such as 5-methoxy-α-protonated-α-deuterated-N,N-di(trideuterated methyl)tryptamine. In some embodiments, the composition contained in the formulation may contain a) 90% or more of the optionally substituted N,N-di(trideuterated methyl)tryptamine compound, preferably 95% or more. The optionally substituted N,N-di(trideuteriomethyl)tryptamine compound can be N,N-di(trideuteriomethyl)tryptamine (d ₆ -DMT), α,α-dideuterio-N,N-di(trideuteriomethyl)tryptamine (d ₈ -DMT), α,α,β,β-tetradeuterio-N,N-di(trideuteriomethyl)tryptamine (d ₁₀ -DMT), 5-methoxy-N,N-di(trideuteriomethyl)tryptamine, 5-methoxy-α,α-dideuterio-N,N-di(trideuteriomethyl)tryptamine and 5-methoxy-α,α,β,β-tetradeuterio-N,N-di(trideuteriomethyl)tryptamine.

In some embodiments, the salt is a salt of an optionally substituted dimethyltryptamine compound and an acid selected from the group consisting of fumaric acid, tartaric acid, citric acid, acetic acid, lactic acid and gluconic acid, typically fumaric acid.

Thus, salts may include:

Any one or a combination of N,N-dimethyltryptamine, α-monodeuterated-N,N-dimethyltryptamine, α,α-dideuterated-N,N-dimethyltryptamine, α,β-dideuterated-N,N-dimethyltryptamine, α,α,β-trideuterated-N,N-dimethyltryptamine, α,β,β-trideuterated-N,N-dimethyltryptamine, α,α,β,β-tetradeuterated-N,N-dimethyltryptamine, N,N-di(trideuterated methyl)tryptamine (d ₆ -DMT) and α,α-dideuterated-N,N-di(trideuterated methyl)tryptamine (d ₈ -DMT); or

Any one or a combination of 4-acetoxy-N,N-dimethyltryptamine, 4-acetoxy-α-monodeuterated-N,N-dimethyltryptamine, 4-acetoxy-α,α-dideuterated-N,N-dimethyltryptamine, 4-acetoxy-N,N-di(trideuterated methyl)tryptamine, 4-acetoxy-α,α-dideuterated-N,N-di(trideuterated methyl)tryptamine, and 4-acetoxy-α,α,β,β-tetradeuterated-N,N-di(trideuterated methyl)tryptamine; or

Any one or a combination of 5-methoxy-N,N-dimethyltryptamine, 5-methoxy-α-monodeuterated-N,N-dimethyltryptamine, 5-methoxy-α,α-dideuterated-N,N-dimethyltryptamine, 5-methoxy-N,N-di(trideuterated methyl)tryptamine, 5-methoxy-α,α-dideuterated-N,N-di(trideuterated methyl)tryptamine and 5-methoxy-α,α,β,β-tetradeuterated-N,N-di(trideuterated methyl)tryptamine; or

Any one or a combination of 4-monohydrogen phosphate-N,N-dimethyltryptamine, 4-monohydrogen phosphate-α-monodeuterated-N,N-dimethyltryptamine, 4-monohydrogen phosphate-α,α-dideuterated-N,N-dimethyltryptamine, 4-monohydrogen phosphate-N,N-di(trideuterated methyl)tryptamine, 4-monohydrogen phosphate-α,α-dideuterated-N,N-di(trideuterated methyl)tryptamine and 4-monohydrogen phosphate-α,α,β,β-tetradeuterated-N,N-di(trideuterated methyl)tryptamine; or

Acid selected from the group consisting of fumaric acid, tartaric acid, citric acid, acetic acid, lactic acid and gluconic acid, typically fumaric acid.

In some embodiments, the salt is dimethyltryptamine fumarate, ie, it comprises dimethyltryptamine as the optionally substituted dimethyltryptamine compound and fumaric acid.

The dimethyltryptamine compound (used interchangeably herein with optionally substituted dimethyltryptamine compounds) can have a purity of about 80 to 100%. Sometimes, the purity is about 90 to 100%, such as about 95 to 100%. Typically, the dimethyltryptamine compound has a purity of about 99 to 100%, i.e., a purity greater than or equal to 99%. The percentage of purity herein is determined by HPLC.

It is particularly advantageous to prepare the formulation of the present invention with a bulk drug comprising an optionally substituted dimethyltryptamine compound or a salt thereof having a purity greater than 99%. As understood in the art, a bulk drug means an active ingredient intended to provide pharmacological activity or other direct action or influence on the structure or any function of the patient concerned in the diagnosis, cure, alleviation, treatment or prevention of a disease, but does not include intermediates used to synthesize such ingredients. It will be understood that a bulk drug may include one or more such active ingredients.

Preferred embodiments of any aspect of the invention include a drug substance comprising an optionally substituted dimethyltryptamine compound or a salt thereof having a purity greater than or equal to 99% when measured by HPLC. Particularly preferred embodiments include a drug substance comprising an optionally substituted dimethyltryptamine compound or a salt thereof having a purity greater than or equal to 99.5%, even more preferably 99.7%, and even more preferably 99.9% when measured by HPLC.

The concentration of the salt of the optionally substituted dimethyltryptamine compound in the formulation can be any desired concentration to reach greater than or equal to 10 mg/ml free base equivalent, provided that the osmotic pressure of the formulation is about 250 to about 350 mOsm/Kg. The concentration of the dimethyltryptamine compound can be greater than 20 mg/mL. A concentration of 28 mg/mL of dimethyltryptamine provides about 148 mOsm/kg (about 296 mOsm/kg when considering counterions). This allows an additional 54 mOsm/kg to be provided by other components of the formulation (e.g., optional buffer). The concentration of the salt of the dimethyltryptamine compound can be greater than 20 mg/mL, greater than 25 mg/mL, greater than 30 mg/mL, greater than 40 mg/mL, greater than 50 mg/mL, greater than 60 mg/mL, or greater than 70 mg/mL (in free base equivalent). Additionally or alternatively, the concentration of the optionally substituted dimethyltryptamine compound can be about 10 mg/ml to about 150 mg/ml, about 10 mg/ml to about 100 mg/ml, about 10 mg/ml to about 80 mg/ml, about 15 mg/ml to about 70 mg/ml, about 15 mg/ml to about 50 mg/ml or about 20 mg/ml to about 40 mg/ml (in free base equivalent). Typically, the concentration of the optionally substituted dimethyltryptamine compound can be about 25 mg/ml (in free base equivalent).

The total dose of the salt of the optionally substituted dimethyltryptamine compound to be used in any one of the fourth to sixth aspects of the invention is suitably from 10 mg to about 150 mg, preferably from about 10 mg to about 120 mg, preferably from about 10 mg to about 100 mg, preferably from about 10 mg to about 80 mg.

As described above, the formulations of the present invention have an osmotic mass of about 250 to about 350 mOsm/Kg. In some embodiments of the present invention, the osmotic mass of the formulation is about 250 to about 400 mOsm/Kg. In some embodiments, the osmotic mass of the formulation of the present invention is about 275 to about 325 mOsm/Kg, such as about 280 to about 310 mOsm/Kg. Typically, the osmotic mass of the formulation is about 295 to about 305 mOsm/Kg.

Sometimes, the concentration of the optionally substituted dimethyltryptamine salt and the optional buffer in the formulation produces the desired osmotic pressure. Alternatively, the desired osmotic pressure can be achieved by including one or more tonicity agents in the formulation. Therefore, in some embodiments, the formulation further comprises a tonicity agent. A tonicity agent is defined herein as a chemical substance that increases the osmotic pressure of a formulation when included in the formulation. As described above, osmotic pressure is the number of osmotically active particles (the number of solute particles) in 1 kg of solution. Therefore, a chemical substance that acts as a solute when incorporated into a formulation is within the definition of a tonicity agent.

If the formulation further comprises a tonicity agent, the concentration of the tonicity agent depends on the concentration of other components in the formulation, such as optionally substituted dimethyltryptamine and buffer. For example, when the formulation without a tonicity agent has an osmotic pressure of about 60 mOsm/kg, at least about 190 mOsm/kg is provided by a tonicity agent (e.g., 95 mM sodium chloride). M.F.Powell, T.Nguyen, and L.Baloian reviewed excipients suitable for parenteral use (except administration by mouth or digestive tract) in PDA J.Pharm.Sci.Technol., 52, 238-311 (1998). All soluble excipients listed in the review article that can be administered by intravenous route will contribute to osmotic pressure when added to the formulation and can therefore be considered tonicity agents.

Suitable excipients for use in the formulations of the present invention may be selected from ethanol, citric acid, trisodium citrate, benzalkonium chloride, microcrystalline cellulose, sodium carboxymethylcellulose, chlorobutanol, disodium edetate, glycerol, hydrochloric acid, methylparaben, polyethylene glycol, propylene glycol, propylparaben, sodium saccharin, sodium bicarbonate, sodium bisulfate, sodium bisulfite, sodium chloride, sodium hydroxide, sodium metabisulfite, sodium phosphate, sodium citrate, sulfuric acid, trisodium citrate, tromethamine, and mixtures thereof.

Some excipients can serve as cosolvents. Suitable solvents or cosolvents for the preparation of the present invention can be selected from ethanol, polyethylene glycol, propylene glycol and mixtures thereof. In some embodiments, the preparation comprises a cosolvent. In some embodiments, the preparation does not comprise a cosolvent. Especially, when the salt of the optionally substituted dimethyltryptamine compound is a fumarate, such as N, N-dimethyltryptamine fumarate or α, α-dideutero-N, N-dimethyltryptamine fumarate, the preparation does not comprise a cosolvent.

Suitable buffers for use in the formulations of the present invention may be selected from phosphoric acid, citric acid, acetic acid, sodium phosphate, sodium citrate, sodium acetate, and mixtures thereof.

It will be appreciated that some excipients may have more than one function. For example, citric acid may be used as a buffer component, a flavoring agent, or an antioxidant. A pH adjuster, such as hydrochloric acid, may also function as a tonicity agent.

In some embodiments, the tonicity agent is any one or a combination selected from the following groups: dextrose, sodium chloride; phosphoric acid; phosphates such as sodium phosphate or potassium phosphate; acetic acid; ethanol; citric acid; citrates such as sodium citrate or potassium citrate; arginine; edetic acid; edetate salts such as sodium edetate or calcium edetate; propylene glycol; sodium bicarbonate; sodium hydroxide; and hydrochloric acid;.

Some of the tonicity agents listed above may be used to buffer the formulation (e.g., acetate, acetic acid, citrate, citric acid, phosphate, phosphoric acid). For the avoidance of doubt, when one of the tonicity agents listed above is used as a buffer, it is also not a tonicity agent as defined, i.e., when the formulation additionally comprises a tonicity agent, the tonicity agent is different from the buffer. Typically, the tonicity agent is sodium chloride or dextrose.

In some embodiments, the formulation comprises a tonicity agent, such as sodium chloride, at a concentration of about 120 mM to about 140 mM, such as about 125 mM to about 135 mM. Sometimes, the concentration of a tonicity agent, such as sodium chloride, within the formulation is about 130 mM.

In some embodiments, it is essentially composed of optionally substituted dimethyltryptamine salts, water, alkaline agents, optional buffers and optional tonicity agents and/or pH regulators. This means, for example, that additional components are allowed to exist in the formulation, provided that the amount of such additional components does not substantially affect the basic characteristics of the formulation in a harmful manner. Considering that the intention behind including optionally substituted dimethyltryptamine salts, water, alkaline agents, optional buffers and optional tonicity agents and/or pH regulators in the formulation is to prepare a pharmaceutical formulation of optionally substituted dimethyltryptamine suitable for intramuscular injection and aerosol inhalation and stable for at least several weeks when stored, it will be understood that components containing components that substantially affect the stability of the formulation or its injection suitability (e.g., osmotic weight or pH) in a harmful manner are excluded from the formulation. On the other hand, it will be understood that the presence of any component that does not substantially affect the stability of the formulation or its injection suitability in a harmful manner is included. Such components include antioxidants and antimicrobial preservatives. For an overview of pharmaceutical excipients and their properties, including those with antioxidant and antimicrobial properties, see P. J. Sheskey, W G Cook and C G Cable, Handbook of Pharmaceutical Excipients, 8th ed., Pharmaceutical Press, London, 2017.

The alkali agent adjusts the pH of the formulation to a desired pH range, such as pH 5 to pH 6. The pH of a formulation comprising an optionally substituted dimethyltryptamine salt, water and a buffer is typically low, such as less than pH 5, and therefore an alkali agent may be required to adjust the pH. The technician will be able to assess a suitable alkali agent to adjust the pH of the solution without the risk of degradation of the optionally substituted dimethyltryptamine salt. The alkali agent may be sodium hydroxide or potassium hydroxide.

In some embodiments, the formulation further comprises an antioxidant. Suitable antioxidants generally used in the formulations of the present invention include citric acid, sodium metabisulfite, and mixtures thereof.

In some embodiments, the formulation further comprises an antimicrobial preservative. Suitable antimicrobial preservatives for use in the formulations of the present invention include propylparaben (n-propyl paraben), benzalkonium chloride, and mixtures thereof.

Preferably, the formulation has an oxygen content of less than 5 ppm, preferably less than 2 ppm, such as between 0.1 ppm and 2 ppm. The skilled person can use any suitable technique known in the art, such as using a dissolved oxygen meter (e.g. Jenway 970 Enterprise dissolved oxygen meter, available from Keison Products: http://www.keison.co.uk/products/jenway/970.pdf ) to determine the oxygen content of the formulation.

The preparation can be stored in any suitable container. In some embodiments, the container can have a volume of less than 10ml, less than 5ml, less than 4ml, less than 2ml, less than 1ml or less than 0.5ml. In some embodiments, in order to further improve the degradation of the preparation, the preparation is stored in a container suitable for preventing ultraviolet light from penetrating, such as an amber glass vial. In other cases, the container in which the preparation is stored is not suitable (and can be made of, for example, transparent glass), and if necessary, protection for ultraviolet light can be provided by secondary packaging (for example, a packaging in which a container containing the preparation can be placed). Generally, the container is airtight, and the preparation is stored under an inert atmosphere, such as under nitrogen or argon, typically under nitrogen. The preparation can be stored at room temperature, for example, at about 20 to about 30°C or at a colder temperature, for example, at about 2 to about 8°C. Alternatively, in order to further improve the degradation of the preparation, it can be stored in a refrigerator.

Preferably, the formulation is purged with an inert gas such as nitrogen or argon to reduce the oxygen content of the formulation.

Viewed from a second aspect, the invention provides a kit suitable for preparing the formulation of the first aspect, the kit comprising a salt of an optionally substituted dimethyltryptamine compound; an alkaline agent, optionally a buffer separate from the salt; and optionally a tonicity agent and/or a pH adjuster. In a preferred embodiment of the second aspect of the invention, the kit comprises an effective dose of an optionally substituted dimethyltryptamine compound for pharmacologically assisted psychotherapy (psychedelic assisted therapy) in a volume of 5 ml or less, preferably in a volume of 4 ml or less, 3 ml or less, 2.5 ml or less, 2 ml or less, 1 ml or less or 0.5 ml or less.

Also provided is a kit for producing the formulation of the first aspect, the kit comprising:

- a first composition comprising a salt of an optionally substituted dimethyltryptamine compound; and

- a second composition comprising an alkaline agent and optionally a buffering agent, and/or a tonicity agent, and/or a pH adjusting agent, separate from said salt,

Wherein the first and second compositions are mixed with water and the resulting mixture produces the formulation of the first aspect.

For the avoidance of doubt, the embodiments relating to the optionally substituted dimethyltryptamine salt and the buffer and other features and embodiments of the first aspect of the invention as defined herein apply mutatis mutandis to the second aspect. For example, the optionally substituted dimethyltryptamine salt of the kit may comprise a Bronsted acid having a pKa of about 3 to about 5 at 25°C and a compound of Formula IA or Formula IB, and/or the buffer may comprise acetate and acetic acid.

The optionally substituted dimethyltryptamine salt in the test kit can be a solid, for example in a powder or crystalline form. In order to improve the degradation of the optionally substituted dimethyltryptamine salt in solid form, the salt can be lyophilized (freeze dried) and then introduced into the test kit. Lyophilizing the salt includes freezing the salt in the presence of a solvent (typically, water) and separating the solvent from the salt by sublimation.

When the kit further comprises a tonicity agent, the embodiments relating to the optional tonicity agent of the first aspect of the invention as defined herein apply mutatis mutandis to the second aspect.For example, the tonicity agent may be any one or combination selected from the group listed above.

From a third aspect, the present invention provides a method for preparing the pharmaceutical formulation of the first aspect. The method comprises contacting an optionally substituted dimethyltryptamine salt, an alkaline agent, an optional buffer, and an optional tonicity agent and/or a pH adjuster with water. In a preferred embodiment of the third aspect of the present invention, the optionally substituted dimethyltryptamine salt is contained in an effective dose of an optionally substituted dimethyltryptamine compound for pharmacologically assisted psychotherapy (psychedelic assisted therapy) in a volume of 5 ml or less, preferably in a volume of 4 ml or less, 3 ml or less, 2.5 ml or less, 2 ml or less, 1 ml or less or 0.5 ml or less. For the avoidance of doubt, the embodiments of the first aspect of the present invention apply mutatis mutandis to the third aspect. For example, the salt may be dimethyltryptamine fumarate; the buffer may comprise acetic acid and acetate or phosphoric acid and phosphate; and the tonicity agent may comprise sodium chloride.

It will be appreciated that the contacting of the method can be achieved in a variety of ways. Typically, the optionally substituted dimethyltryptamine salt is dissolved in water to form a first solution, to which an alkaline agent and an optional buffer are added and dissolved to form a second solution. If a tonicity agent or pH adjusting agent is used, it is typically added to the second solution and dissolved in the second solution. Additional solvents or cosolvents may be added to the first solution or the second solution.

In some embodiments, an aqueous solution of a buffer is contacted with a salt, wherein the aqueous solution of the buffer has a pH of about 5 to about 6.5, such as about 5 to about 6, or about 5.3 to about 6, or about 5.5 to about 6. In some embodiments, the aqueous solution of the buffer may have a pH of 5 to 6. In some embodiments, the aqueous solution of the buffer has a pH of about 5.5 or about 6.

The optionally substituted dimethyltryptamine salt within the formulation can be formed by contacting the optionally substituted dimethyltryptamine in free base form with an aqueous solution comprising an amount of a buffer suitable for stabilizing the pH and acting as a counterion for the optionally substituted dimethyltryptamine when protonated. Thus, the method of the invention can include contacting the optionally substituted dimethyltryptamine in free base form with a buffer, water, and an optional tonicity agent.

The method also includes using an alkaline agent to adjust the pH of the solution obtained by contacting. The pH of the solution obtained by the contacting step is generally low, so a subsequent pH adjustment step is required. pH adjustment generally includes contacting the solution with a suitable alkaline agent (e.g., a strong alkaline agent). The technician can assess which bases are suitable for adjusting the pH of the solution obtained by contacting without the risk of degradation of the optionally substituted dimethyltryptamine salt. The pH of the solution obtained by contacting is adjusted with an alkaline agent, which can be a suitable base, preferably sodium hydroxide or potassium hydroxide.

In some embodiments, pH is additionally adjusted with a pH adjusting agent to reach a desired pH. The pH adjusting agent can be a suitable acid, such as an acid selected from acetic acid, aspartic acid, benzenesulfonic acid, benzoic acid, citric acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, propionic acid, tartaric acid, fumaric acid, lactic acid, phosphoric acid, maleic acid and sulfuric acid or a mixture thereof. Preferably, the pH adjusting agent is selected from acetic acid, aspartic acid, benzenesulfonic acid, benzoic acid, citric acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, tartaric acid, fumaric acid, maleic acid and sulfuric acid or a mixture thereof. Preferably, the preparation of the present invention comprises a pH adjusting agent, which is hydrochloric acid.

As described above, in order to further improve the degradation of the formulation, it may be desirable to minimize the total oxygen content within the container in which the formulation is stored, the oxygen within the container being balanced between the formulation and the headspace (if any) within the container. Thus, it may be desirable to store the formulation under an inert atmosphere, for example by purging the headspace to reduce its oxygen content from about 20% typically found in air to less than, for example, 1% or less than 0.5%. Additionally or alternatively, in some embodiments, the method further comprises purging the solution obtained by contacting with an inert gas such as nitrogen or argon, typically nitrogen.

As described above, dimethyltryptamine has a possible therapeutic effect in the treatment of depression, obsessive-compulsive disorder and substance abuse disorder (S.A.Barker, 2018, supra). Therefore, from the fourth aspect, the present invention provides a preparation of the first aspect or a kit of the second aspect, which is used as a drug or in combination with psychotherapy. In a preferred embodiment of the fourth aspect of the present invention, the preparation is contained in a volume of 5 ml or less, preferably in a volume of 4 ml or less, 3 ml or less, 2.5 ml or less, 2 ml or less, 1 ml or less or 0.5 ml or less for pharmacologically assisted psychotherapy or psychedelic assisted therapy. The effective dose of the optionally substituted dimethyltryptamine compound.

From a fifth aspect, the present invention provides a formulation of the first aspect and a kit of the second aspect for use in a method of treating a mental or neurological disorder in a patient. In a preferred embodiment of the fifth aspect of the invention, the formulation comprises an effective dose of an optionally substituted dimethyltryptamine compound for use in pharmacologically assisted psychotherapy or psychedelic assisted therapy in a volume of 5 ml or less, preferably 4 ml or less, 3 ml or less, 2.5 ml or less, 2 ml or less, 1 ml or less or 0.5 ml or less.

Typically, the mental or neurological disorder is selected from the group consisting of: (i) obsessive-compulsive disorder, (ii) depressive disorder, (iii) anxiety disorder, (iv) substance abuse and gambling disorder, and (v) motivational disorder. Typically, the disorder is selected from the group consisting of: major depressive disorder, refractory major depressive disorder, postpartum depression, obsessive-compulsive disorder and eating disorder such as compulsive eating disorder.

From the sixth aspect, the present invention provides a method for treating a mental or neurological disorder, comprising administering the preparation of the first aspect to a patient in need thereof. In a preferred embodiment of the sixth aspect of the present invention, the preparation is contained in a volume of 5 ml or less, preferably in a volume of 4 ml or less, 3 ml or less, 2.5 ml or less, 2 ml or less, 1 ml or less or 0.5 ml or less for a pharmacologically assisted psychotherapy or psychedelic assisted therapy in an effective dose of an optionally substituted dimethyltryptamine compound. The mental or neurological disorder can be any of those described with respect to the fifth aspect. For example, the disorder can be selected from the group consisting of: major depressive disorder, refractory major depressive disorder, postpartum depression, obsessive-compulsive disorder and eating disorders such as compulsive eating disorder.

In a sixth aspect of the invention, the formulation of the first aspect may be administered in combination with psychotherapy (ie in pharmacologically assisted psychotherapy).

For treating the disorder, the formulation contains an effective amount of a dimethyltryptamine compound, ie, an amount sufficient to reduce or stop the rate of progression of the disorder, or sufficient to ameliorate or cure the disorder and thereby produce the desired therapeutic or inhibitory effect.

The formulation is suitable for intramuscular injection, and thus administration thereof to a patient typically involves injection of the formulation.

The formulation may be suitable for bolus injection, wherein a discrete amount of the optionally substituted dimethyltryptamine salt is administered in one injection, resulting in a rapid increase in the concentration of the optionally substituted dimethyltryptamine in the body.

Typically, IM injections are administered in dose volumes of 5 mL or less, using a 19-27 gauge needle, more typically a 20-25 gauge needle. The concentrated formulations of the present invention allow for the use of a higher gauge needle (suitably 22-27) to administer a lower volume, which can reduce the pain associated with the injection. The injection volume can be about 0.5 to about 4 mL, about 0.5 to about 3 mL, or about 0.5 to about 2.5 ml.

The formulation is also suitable for nebulization and thus administering it to a patient may comprise inhaling the formulation using a nebulizer.

When the formulations of the invention contain deuterated N,N-dimethyltryptamine compounds, such as α,α-dideutero-N,N-dimethyltryptamine (d ₂ -DMT), α,α,β,β-tetradeutero-N,N-dimethyltryptamine (d ₄ -DMT), N,N-di(trideuteromethyl)tryptamine (d ₆ -DMT), α,α-dideutero-N,N-di(trideuteromethyl)tryptamine (d ₈ -DMT), and α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine (d ₁₀ -DMT), lower doses may be effective, making the formulations of the invention particularly suitable for lower dose volumes. This has the advantage of allowing IM formulations to be administered at a wider range of injection sites. The higher concentrations and lower dose volumes of the formulations of the invention may also enable the use of a wide range of nebulizer devices and may allow for shorter inhalation times.

In a tenth aspect, the present invention provides a lyophilized powder formulation comprising a formulation as defined in the first aspect of the invention which has been lyophilized (ie freeze-dried).

Lyophilization (also known as freeze drying or cryodesiccation) is a drying process performed at low temperatures. Lyophilization generally involves reducing the temperature and pressure to below the triple point of the substance and removing the frozen solvent (e.g., water ice) by sublimation. For aqueous compositions, such as those disclosed herein, lyophilization can be performed at a temperature of about -50°C to -80°C, preferably about -70°C, and a pressure of about 1000 Pa (0.01 bar) to about 100 Pa (0.001 bar), preferably about 800 Pa (0.008 bar).

In an eleventh aspect, the present invention provides a method for preparing a lyophilized powder formulation as defined in the tenth aspect, comprising drying the formulation as defined in the first aspect of the invention by lyophilization.

In a twelfth aspect, the present invention provides a method for preparing an aqueous formulation, comprising mixing a lyophilized powder formulation as defined in the tenth aspect or as prepared in the method of the eleventh aspect into water to provide a formulation comprising a salt of an optionally substituted dimethyltryptamine compound, a buffer separate from the salt, an alkaline agent and water, the formulation having a pH of about 5 to about 6.5, a concentration of about 10 mg/ml or more as free base and an osmotic pressure of about 250 to about 350 mOsm/Kg. The formulation may have a pH of about 5 to about 6, or a pH of 5 to 6. For the avoidance of doubt, the embodiments of the first aspect of the present invention apply mutatis mutandis to the tenth, eleventh and twelfth aspects of the present invention.

For the avoidance of doubt, embodiments of each aspect of the invention apply mutatis mutandis to other aspects of the invention.Each and each reference mentioned herein is incorporated herein by reference in its entirety, as if the entire contents of each reference were set forth herein in their entirety.

The entire contents of PCT/EP2021/073189, UK Patent Application No. 2119021.0 and US Patent Application No. 17/574,424 and any validly claimed priority documents are incorporated herein by reference.

The synthesis of compounds used in the formulations of the present invention can be carried out according to the schemes and examples described in WO 2020/245133 A1, WO 2021/116503 and WO 2021/089873 A1 (all belonging to Small Pharma Ltd). For deuterated compounds, the degree of deuteration is determined according to the methods described in WO 2020/245133 A1, WO 2021/116503 and WO 2021/089873 A1.

Example

Example 1: N,N-dimethyltryptamine

N,N-DMT 220.9 g (free base form) was prepared as N,N-DMT fumarate salt using the chemistry disclosed in Scheme 2 and the Examples section of WO 2021/089873. An additional 4-6 g of a mixture of six partial deuterations was also prepared using modified conditions.

Example 2: Deuterated N,N-dimethyltryptamine

Synthesis of Deuterated Mixtures of DMT Compounds

A modified synthesis using a solid LiAlH ₄ /LiAlD ₄ mixture was employed, using 1.8 equivalents of LiAlH ₄ /LiAlD ₄ relative to 0.9 equivalents of LiAlH ₄ , using the method described above for N,N-dimethyltryptamine (as disclosed in WO 2021/089873). Deuterated dimethyltryptamine compounds include α-protonated, α-deuterated-dimethyltryptamine and α,α-dideuterated-dimethyltryptamine.

The data for the six deuterated reactions are listed in the table below:

5- and 4-substituted dimethyltryptamine and deuterated dimethyltryptamine compounds can be prepared by similar methods using appropriate starting materials. To synthesize 5-methoxy-N,N-dimethyltryptamine or 4-methoxy-N,N-dimethyltryptamine, 3-indoleacetic acid can be replaced by 5-methoxyindole-3-acetic acid (see the synthesis of α,α-dideutero-5-methoxydimethyltryptamine described below) or 4-methoxyindole-3-acetic acid, respectively, both of which are commercially available (for 5-methoxyindole-3-acetic acid, for example, from Sigma-Aldrich (code M14935-1G), for 4-methoxyindole-3-acetic acid, see, for example, Aaron chemicals (code AR00VTP1)).

5-Methoxy-N,N-dimethyltryptamine (see Sigma-Aldrich code M-168-1ML), 4-methoxy-N,N-dimethyltryptamine (see Cayman Chemical code 9000895), 4-acetoxy-N,N-dimethyltryptamine (see Cayman Chemical code 14056) and 3-[2-(dimethylamino)ethyl]-1H-indol-4-yl phosphate (psilocybin, see Sigma-Aldrich CAS No. 520-52-5) are also commercially available.

Example 3: α,α-dideutero-5-methoxydimethyltryptamine

Synthesis of α,α-Dideutero-5-Methoxydimethyltryptamine

Phase 1:

Under _N2 , a 100 mL three-necked flask was charged with 5-methoxyindole-3-acetic acid (3.978 g, 19.385 mmol), HOBt (-20% wet) (3.927 g, 23.261 mmol) and DCM (40 mL). EDC.HCl (4.459 g, 23.261 mmol) was then charged in portions at <30°C over 15 minutes. The reaction mixture was stirred at ambient temperature for 1 hour, and then 2M dimethylamine (14.54 mL, 29.078 mmol) was added dropwise at <25°C over 15 minutes. After stirring for 1 hour, HPLC indicated that no SM remained. The reaction mixture was then charged with 10% _K2CO3 (20 mL), stirred for 5 minutes, and then separated. The lower aqueous layer was removed and back-extracted with DCM (10 mL x 2). The organic extracts _were combined, washed with saturated brine (10 mL), then dried over _MgSO4 and filtered. The filtrate was concentrated in vacuo at 45 °C to provide 3.898 g of active (yield = 87%) product with HPLC purity of 95.7%.

Phase 2:

Under N ₂ , a 100mL three-necked flask was charged with stage 1 methoxy derivative (3.85g, 16.586mmol) and THF (19.25ml). Then 2.4M LiAlD ₄ (6.22mL, 14.927mmol) in THF was added dropwise at <40°C over 30 minutes. The reaction mixture was heated to 60°C for 1 hour, where HPLC indicated a remaining 0.1% SM. The reaction mixture was then cooled to ambient temperature and quenched dropwise at <30°C over 30 minutes to 25% Rochelle salt (38.5mL). The resulting suspension was stirred for 1 hour and then separated. The lower aqueous layer was then removed and the upper organic layer was washed with saturated brine (9.6mL). The organic matter was then dried over MgSO ₄ , filtered and concentrated in vacuo, and then azeotroped with EtOH (10mL x 2). This provided 3.196g of active (yield = 88%) product with an HPLC purity of 91.5%.

Phase 3:

Under _N2 , a 50mL three-necked flask was charged with a solution of fumaric acid (1.675g, 14.430mmol) and the stage 2 methoxy derivative (3.15g, 14.299mmol) in EtOH (37.8mL). The mixture was then heated to 75°C for 1 hour, which did not produce a solution as expected, and the mixture was further heated to reflux (78°C), which still did not provide a solution. Therefore, the suspension was cooled to 0-5°C, filtered and washed with EtOH (8mL x 2), then dried at 50°C overnight. This provided 3.165g (yield = 65%) of HPLC purity of 99.9%.

Additional compounds for use in the formulations of the invention can be prepared according to the methods described in WO 2021/116503.

Example 4: d ₆ -dimethyltryptamine

Synthesis of d ₆ -DMT

Phase 1

EDC.HCl (15.7 g, 81.90 mmol) was added to 3-indoleacetic acid (12.0 g, 68.50 mmol) and HOBt.H ₂ O (1.16 g, 75.75 mmol) in DCM (108 mL) at room temperature. The reaction was stirred for 1 hour before N,N-diisopropylethylamine (DIPEA) (35.6 mL, 205.75 mmol) and d ₆ -dimethylamine.HCl (9.0 g, 102.76 mmol) were added (temperature maintained below 30° C.). The reaction was stirred at room temperature for 1 hour after which HPLC analysis indicated 65.6% product with 28.9% of 3-indoleacetic acid remaining. DIPEA (11.9 mL, 68.78 mmol) was added and the reaction was stirred at room temperature for 1 hour. HPLC indicated no change in conversion. Aqueous potassium carbonate (6.0 g in 54 mL water) was added and the phases separated. The aqueous phase was extracted with DCM (2 x 30 mL). The combined organics were washed with brine (2 x 30 mL), then with aqueous citric acid (20 w/w%, 50 mL), dried over MgSO ₄ and filtered. The filtrate was stripped and the resulting solid was slurried in TBME (120 mL) and isolated by filtration. Purification by flash column chromatography yielded 8.34 g of the desired product (58% yield). ¹ H NMR confirmed the identity of the product.

Phase 2

LiAlH ₄ (1M in THF, 17.3 mL, 17.28 mmol) was added to a suspension of stage 1 (4.0 g, 19.20 mmol) in THF (10 mL) at <30°C. The resulting reaction was heated to 60-65°C and stirred for 2 hours. HPLC analysis indicated complete consumption of stage 1, forming 97.3% product. The reaction was cooled to room temperature and quenched into an aqueous solution of Rochelle salt (10 g in 30 mL of water) at <30°C. After stirring for 1 hour, the phases were separated. The aqueous phase was extracted with THF (20 mL). The combined organics were washed with brine (20 mL), dried over MgSO ₄ , filtered and stripped (azeotroped with ethanol, 20 mL) to produce the desired amber oil product (3.97 g). ¹ H NMR confirmed the identity of the product and indicated the presence of 8.5% ethanol (without THF), yielding 3.63 g, 97% active material yield.

Phase 3

_d6 -DMT free base (3.6 g active material, 18.53 mmol) was dissolved in ethanol (43 mL) at room temperature. Fumaric acid (2.15 g, 18.53 mmol) was added and the solution was heated to 75°C (solids crystallized during heating and did not redissolve). The resulting suspension was cooled to 0-5°C and stirred for 1 hour. The solids were isolated by filtration, washed with ethanol (2 x 7 mL) and tapped to dryness. Further drying in a vacuum oven at 50°C gave the desired _d6 -DMT fumarate salt (4.98 g, 87%).

Example 5: d ₈ -dimethyltryptamine

Synthesis of d ₈ -DMT

Stage 1 (coupling of 3-indoleacetic acid with d ₆ -dimethylamine) was carried out according to the method described in Stage 1 of Example 4 above.

Phase 2

LiAlD ₄ (1M in THF, 17.3 mL, 17.28 mmol) was added to a suspension of the product of stage 1 (4.0 g, 19.20 mmol) in THF (10 mL) at <30°C. The resulting reaction was heated to 60-65°C and stirred for 2 hours. HPLC analysis indicated complete consumption of stage 1, forming 97.3% product. The reaction was cooled to room temperature and quenched into an aqueous solution of Rochelle salt (10 g in 30 mL of water) at <30°C. After stirring for 1 hour, the phases were separated. The aqueous phase was extracted with THF (20 mL). The combined organics were washed with brine (20 mL), dried over MgSO ₄ , filtered and stripped (azeotroped with ethanol, 20 mL) to produce the desired amber oil product (4.01 g). ¹ H NMR confirmed the identity of the product and indicated the presence of 8.6% ethanol (without THF), yielding 3.66 g, 97% active material yield.

Phase 3

_d8 -DMT free base (3.6 g active material, 18.53 mmol) was dissolved in ethanol (43 mL) at room temperature. Fumaric acid (2.15 g, 18.53 mmol) was added and the solution was heated to 75°C (solids crystallized during heating and did not redissolve). The resulting suspension was cooled to 0-5°C and stirred for 1 hour. The solids were isolated by filtration, washed with ethanol (2 x 7 mL) and tapped to dryness. Further drying in a vacuum oven at 50°C gave the desired _d8 -DMT fumarate salt (4.62 g, 81%).

Example 6: d ₆ -5-methoxydimethyltryptamine

Synthesis of d ₆ -5-MeO-DMT

Phase 1

Coupling of 5-methoxy-3-indoleacetic acid and _d6 -dimethylamine was performed on a 20 g scale by a method similar to that described above in Example 4, Stage 1. Purification by flash column chromatography gave a light brown solid (87%) with HPLC purity of 97.8%. Molecular weight: 238.32.

Phase 2

The product of Example 6 Stage 1 was reacted with LiAlH ₄ in THF according to the procedure described in Example 4 Stage 2. The reaction was carried out on a 9 g scale to produce d ₆ -5-MeO-DMT as an amber oil in 8.22 g yield (7.40 g active material, 87.3%) with HPLC purity of 98.4%. Molecular weight: 224.34.

Phase 3

The fumarate salt of _d6-5 -MeO-DMT was prepared according to the method described in Example 4, Stage 3. 6.04 g (65%) of off-white solid was obtained with HPLC purity of 99.61%. NMR and XRPD data indicated that the hemi-salt was isolated. Molecular weight: 564.74 (hemi-salt form).

Example 7: d ₈ -5-methoxydimethyltryptamine

Synthesis of d ₈ -5-MeO-DMT

Phase 1

Coupling of 5-methoxy-3-indoleacetic acid with _d6 -dimethylamine was performed on a 20 g scale by a method similar to that described above in Example 4, Stage 1. Purification by flash column chromatography gave a light brown solid (87%) with HPLC purity of 97.8%. Molecular weight: 238.32.

Phase 2

The product of Example 7 Stage 1 was reacted with _LiAlH4 in THF on a 9 g scale according to the procedure described in Example 5 Stage 2. Purification yielded 8.12 g (7.58 g active material, 88.7%) of the product _d8-5 -MeO-DMT as an amber oil with a HPLC purity of 97.9%. Molecular weight: 226.35.

Phase 3

The fumarate salt of d ₈ -5-MeO-DMT was prepared according to the method described in Example 4, Stage 3. 9.6 g of product fumaric acid d ₈ -5-MeO-DMT was obtained with an HPLC purity of 99.71%. Molecular weight: 342.42.

The degree of deuteration

Notes: N/D = not detectable; LT = less than.

_D6-5 -hydroxydimethyltryptamine and _d8-5 -hydroxydimethyltryptamine can be prepared by methods analogous to those described in Examples 6 and 7, respectively, using 5-hydroxy-3-indoleacetic acid as the starting material. Alternatively, _d6-5 -hydroxydimethyltryptamine and _d8-5 -hydroxydimethyltryptamine can be prepared from _d6-5 -methoxydimethyltryptamine and _d8-5 -methoxydimethyltryptamine, respectively, by demethylation of the 5-methoxy group using standard procedures such as _BBr3 demethylation.

Example 8: In vivo study of pharmacokinetic (PK) properties

The pharmacokinetic (PK) properties of N,N-dimethyltryptamine (DMT, SPL026), α,α,-bis-deuterated-N,N-dimethyltryptamine (d ₂ -DMT, SPL028i), and α,α,-bis-deuterated-N,N-hexadeuterated-dimethyltryptamine (d ₈ -DMT, SPL028viii) after intramuscular (IM) administration were studied in rats.

Test compound

Compound Chemical Name Molecular formula Salt molecular weight Free base molecular weight SPL026 N,N-Dimethyltryptamine (DMT) Fumarate C ₁₂ H ₁₆ N ₂ 304.34 188.27 SPL028i α,α,-Bis-deuterium-N,N-dimethyltryptamine fumarate C ₁₂ H ₁₄ D ₂ N ₂ 306.31 190.24 SPL028viii α,α,Bis-deuterated-N,N-hexadeuterated-dimethyltryptamine fumarate C ₁₂ H ₈ D ₈ N ₂ 312.35 196.32

method

Twelve male (7-8 weeks old) Sprague Dawley rats (weight 250-300 g) were dosed as follows:

Housing and feeding

Dosage regimen

Cassette doses of 3.5 mg/kg SPL026 fumarate and 3.5 mg/kg SPL028viii fumarate were administered as single IM doses to 4 different male animals to allow direct inter-animal comparisons of SPL026 and SPL028viii, thereby avoiding the confounding effects of inter-animal variability. Single IM doses of 3.5 mg/kg and 10 mg/kg SPL028i fumarate were administered to 4 different male animals.

Dosage Procedure

Animals were weighed on the morning of dosing and doses were administered based on body weight and prescribed dose volume.

The IM dosing device consists of an appropriately sized insulin syringe. Shave the injection site on the morning of dosing. During dosing, dispense the dose directly into the thigh muscle.

PK sampling

Following dosing, serial whole blood samples (approximately 200 μL) will be collected from the lateral tail vein via an indwelling cannula into separate K ₂ EDTA-treated containers. Samples will be collected at the following times post-dose:

IM before, 5, 10, 25, 30, 45, 60, 90, 120, and 180 minutes

The blood samples were placed on a cooling block and then centrifuged at 10,000 g for 2 minutes at approximately 4°C and the resulting plasma was drawn. All samples will be stored at approximately -80°C.

Biological analysis

Bioanalysis of DMT, d8-DMT, and d2-DMT in rat K ₂ EDTA plasma was performed using LC-MS/MS. The following table details the 2 methods that qualified:

The concentrations of DMT and _d8 -DMT were quantified using 20.0 μL of rat plasma with a target lower limit of quantification (LLOQ) of approximately 0.310 ng/mL for DMT, _d8 -DMT, and _d2 -DMT, and were checked for compliance using the following method:

● Assay Linearity - Calibration curves were prepared in duplicate containing ≥ 8 concentration levels plus control blank and zero (IS only). Acceptance Criteria - A minimum of 75% of calibration standards (non-zero samples) must be ≤ ± 20% relative error (RE) of the nominal concentration at which they were prepared (≤ ± 25% RE at the lower limit of quantitation).

• Sensitivity - minimum signal-to-noise ratio must be 5:1 at LLOQ concentration.

• Precision and Accuracy - Single analytical batch containing QCs at low, medium and high concentrations in replicates (n=6). Acceptance criteria - Intra-batch precision (CV) and accuracy (RE) ≤ 20%.

Selectivity - Qualitative assessment of the presence of potential interfering peaks in the chromatogram of a control blank matrix from at least one source. Acceptance criteria - The response of any co-eluting interference must be ≤ 25% of the peak area of the LLOQ calibration standard. The response of any co-eluting interference must be less than 5% of the zero sample peak area of the internal standard.

• Stability - The stability of the QC Med matrix in replicates (minimum n=3) will be assessed for at least 2 hours at the sample processing temperature of the DMT only. Acceptance criteria - Precision (CV) and Accuracy (RE) ≤ 20%.

Carryover - Assessed in at least one control blank matrix sample (carryover blank) analyzed immediately after the upper limit of quantitation (ULOQ) calibration standard. Acceptance criteria - Analyte carryover should be ≤ 25% of the analyte peak area in the LLOQ standard. Internal standard carryover should be ≤ 5% of the internal standard peak area in the LLOQ standard sample.

PK parameters

Pharmacokinetic parameters of DMT (SPL026), _d8 -DMT (SPL028viii), and _d2 -DMT (SPL028i) in plasma were derived by non-compartmental analysis using the plasma concentration-time profiles of each animal.

result

The results are presented in Figure 1. These data demonstrate that _d8 -DMT(SPL028viii) and _d2 -DMT(SPL028i) had greater overall exposure when compared to DMT(SPL026) following IM dosing at 3.5 mg/kg.

Figures 1A and 1B show linear and semi-logarithmic plots of mean DMT (SPL026), _d8 -DMT (SPL028viii) and _d2 -DMT (SPL028i) concentrations over time following a 3.5 mg/kg in vivo fumarate IM dose (added as a cassette).Figure 1A - linear plot, Figure 1B - semi-logarithmic plot, SEM error bars.

Figures 2A and 2B show linear and semi-logarithmic plots of mean _d2 -DMT (SPL028i) concentrations over time following 3.5 mg/kg and 10 mg/kg in vivo fumarate IM doses. Figure 2A - Linear plot, Figure 2B - Semi-logarithmic plot, SEM error bars.

Pairwise ANOVA was performed to analyze the effect of dose group on PK parameters. After administration of equal IM doses to both groups, there were statistically significant differences in the mean area under the curve (AUC _0-inf ) extrapolated from time 0 to infinity between the SPL026 and SPL028viii groups and between SPL026 and SPL028i, indicating that the total systemic exposure of SPL028viii and SPL028i was significantly higher than that of SPL026 after a single IM dose.

AUC _0-inf (min.ng/mL) P-value SPL026 (3.5 mg/kg) versus SPL028viii (3.5 mg/kg) <0.001*** SPL026 (3.5 mg/kg) versus SPL028i (3.5 mg/kg) <0.001***

Following IM administration, Cmax was found to be significantly higher for _d8 -DMT (SPL028viii) and _d2 -DMT (SPL028i) when compared to DMT (SPL026) (p=0.005**).

When compared to the 3.5 mg/kg dose level, the Cmax of _d2 -DMT (SPL028i) at the 10 mg/kg dose was increased by 144% and the AUC0 _{- inf} was increased by 237%. The dose-response relationship level differences in Cmax and AUC0-inf were significantly different from each other (p<0.05* and p<0.001***, respectively), indicating a significant dose-response relationship.

The present invention is further illustrated by the following embodiments.

Formulation Development

All concentrations stated below are expressed as free base (ie in the absence of fumarate counterion). For this purpose, a correction factor of 1.59 was applied to the specific batch of drug substance provided.

Experimental details

The stability of N,N-dimethyltryptamine (DMT) fumarate preparations was evaluated at 20 mg/mL concentration and pH 4, 5, 6, 7, 8 and 9. The pH was changed using the Britton-Robinson (B-R) buffer system (also referred to as a universal buffer). The B-R buffer system is typically composed of a mixture of 0.04M boric acid, 0.04M phosphoric acid and 0.04M acetic acid, and is titrated to the desired pH with 0.2M sodium hydroxide. The system is capable of changing pH while maintaining constant osmotic pressure.

Seven solutions were prepared in Britton-Robinson (B-R) buffer solution, each containing a nominal concentration of 20 mg/mL DMT fumarate. When DMT fumarate was dissolved in each test formulation (DMT fumarate is very soluble and only requires rotation and shaking in each test formulation), the pH of each test formulation was then adjusted to pH 4, 5, 6, 7, 8, and 9 using sodium hydroxide solution.

The solubility of DMT fumarate at a concentration of 20 mg/mL was confirmed at pH 4, 5, 6, and 7: these solutions were clear and colorless. The pH 8 sample was turbid, and the pH 9 and pH 10 samples contained precipitates. After storage overnight under ambient conditions, the pH of each solution was measured and the results showed no change from the initial pH value. Each sample was then filtered and analyzed for content. Each solution, including the high pH solution where precipitates were present, contained approximately the same amount of DMT fumarate.

pH stability

In 40mM Britton-Robinson buffer solution, the pH stability of DMT fumarate at a nominal concentration of 2.5mg/mL was evaluated in a buffer solution pH range of 4 to 9 (nominal). The pH of each preparation was measured at the time of preparation, then stored at 40°C for 7 days, then further stored at 40°C for another 3 days and further stored at 50°C for 7 days (thus further stored for a total of 10 days). These preparations were analyzed at the time of preparation, and then analyzed for content (assay) and related substances after storage for 7 days and 17 days.

Two additional aliquots of the pH 7 (nominal) solution were taken for additional testing, one of which was purged with nitrogen and the second was stressed for 4 hours under strong UV light, equivalent to 1 ICH unit (200 watt-hours UVA, 600,000 lux hours).

During preparation of each formulation, the pH dropped in the range of 0.14 units (pH 4 formulation) to 1.29 units (pH 9 formulation) due to the acidic nature of the drug substance. Once prepared, the pH of each formulation remained stable at two subsequent stability time points (Table 1).

The concentration of DMT fumarate was determined by HPLC during preparation and in two subsequent stability tests (Table 2). All results confirmed that the preparation was accurate, with no significant concentration changes on the 7th or 17th day. The only significant change during the experiment was a decrease in concentration after light stress was applied to aliquots of the nominal pH 7 formulations. This was accompanied by a significant increase in observed degradation products.

For related substances, only peaks greater than 0.05% of the total peak area are reported. Summarized related substance data are found in Table 3, and individual values are found in Table 4 (7 days storage at 40°C) and Table 5 (10 days storage at 40°C and 7 days storage at 50°C).

When preparing, there is no related substance peak.On the 7th day, only pH 9 preparation contains peak at 1.11 relative retention time 1.11.Only observe minimum extra peak after 7 days' storage of improvement, make preparation further bear stress (storage temperature increases over time), and in the analysis after storage 17 days, there is other peak in some preparations, and visible obvious trend: along with pH increase, peak number and peak area increase, range from no peak (pH 4) to 3 peaks, total peak area is 0.61% (pH 9).Preparation (pH 7) purged with nitrogen is significantly more stable than its unpurged equivalent, confirms that oxidation is degradation pathway.Preparation through light stress is the most serious sample of degradation, and total related substance value is 1.68%.

Table 1 - pH stability measurements of SPL026 in Britton-Robinson buffer

Table 1 shows that pH stability decreases with increasing pH, especially for formulations at pH ≥ 7.

Table 2 - pH stability of SPL026 in Britton-Robinson buffer (assay)

As can be seen in Table 2, in solutions with a nominal pH ≥ 7, the concentration of DMT fumarate decreased over 17 days.

Table 3 - pH stability of SPL026 in Britton-Robinson buffer Total related substances determination

Table 3 clearly shows that the amount of related substances increases with increasing pH, indicating a decrease in stability.

The data given in Tables 1-5 above clearly show that the stability of the tested formulations decreases with increasing pH. In particular, the stability of formulations with a pH of less than 7 was found to be improved.

As described above, when developing a formulation for injection, the pH of the formulation is typically matched to the pH of the patient's serum. The pH of human serum is about 7.4. Therefore, an obvious formulation of a salt of an optionally substituted dimethyltryptamine compound is one in which the pH is about 7.4. The greater stability of a formulation of such a salt prepared at a pH value less than 7.0 is unpredictable.

Preparation

The details of each individual example formulation are presented in the table below. Each formulation can be prepared by methods similar to the following examples.

Aliquots of each formulation can be used for assay/related substances and osmolality checks.The remainder of each formulation is filtered (filter size 0.2 μm) into clear glass multidose vials, purged with nitrogen and capped.

Preparation of Example Formulations (25 mg/mL, pH 5.5)

1) Weigh the required amount of API into a suitable container (glass weigh boat). Ensure the quality of the API is correct for salt and purity.

2) Carefully transfer the weighed API to a beaker. Rinse the weighing container with water for injection (WFI) to ensure that no solids remain. Further add WFI to the API to 3/4 of the required total volume and stir magnetically to dissolve.

3) Bring to volume in a suitable container and finally check the pH to see if it is pH 5.5 (±0.1) and adjust if necessary.

4) The drug solution was clear and slightly beige (N,N-dimethyltryptamine fumarate was used). The color was removed by filtration (step 6), leaving a colorless solution filtrate.

5) Nitrogen is purged through the formulation until the dissolved oxygen level measured is below 5 ppm, preferably below 2 ppm.

6) Filter the solution with a syringe into a suitable glass multi-dose vial, suitably 0.22 μm or 0.2 μm filter into a glass multi-dose vial.

Example formulations comprising co-solvents, surfactants, buffers, pH adjusters or tonicity agents or other excipients.

The formulations of the invention may contain one or more of the excipients listed above.

"DS" refers to an optionally substituted dimethyltryptamine compound used in the formulations of the present invention.

Example 9: N,N-dimethyltryptamine pH-solubility

pH solubility samples were prepared in 0.5M Britton Robinson (BR) buffer. Prior to adding N,N-dimethyltryptamine, an amount of NaOH was added to the BR buffer as needed to ensure the desired pH. For each pH tested (pH 4, 5, 6, 7, 8, 9, and 10), the total volume of BR buffer plus the required amount of NaOH was 5 mL. 150 mg of N,N-dimethyltryptamine was then added and the pH was checked before shaking overnight at ambient temperature.

As shown in the following table and Figure 3, the solubility of N,N-dimethyltryptamine was measured at different pH values at 25°C:

pH Actual data (mg/mL) 4.05 104.6 4.98 126.3 6.05 92.6 7.08 68.6 8.07 88.4 8.91 17.1 10.01 1.14

Solubility above 90 mg/mL was observed at pH between about 4 to about 6, with maximum solubility observed at a pH of about 5.

It is desirable to allow about 2-3 times the solubility headspace to reduce the risk of precipitation during long-term storage and/or temporary storage at temperatures below the recommended storage temperature. These data support a 100 mg/2.5 mL (40 mg/ml) dose at a pH of about 5 to about 6.5 while achieving the desired 2-3 times solubility headspace at 25°C.

Example 10: Example Formulation

The example formulations of the present invention are shown in the following table.

Components Unit volume (per mL) Function DMT fumarate or deuterated analogs 25 mg (free base form) Active ingredients Trisodium citrate dihydrate 1.47mg Buffer Sodium hydroxide q.s. to pH 6 Alkali hydrochloric acid q.s. to pH 6 pH Adjusters Water for Injection q.s. to 1.0mL Solvents Nitrogen q.s. Antioxidants

q.s. means sufficient quantity

Example 11: Stability

Formulations of DMT fumarate (Example 2) and deuterated DMT fumarate (Example 2) prepared according to Example 10 were evaluated for stability after storage for 3 months at 2-8°C, at 25°C/60% RH and at 40°C/75% RH.

For formulations containing DMT fumarate, no related substances above the limit of quantitation (≥0.05% w/w) were observed at T=0 or after 3 months storage at 2-8°C and 25°C/60% RH. After 3 months storage at 40°C/75% RH, a total of 0.35% w/w of related substances was observed.

For formulations containing deuterated DMT fumarate, no related substances above the limit of quantitation (≥0.05% w/w) were observed at T=0 or after 3 months storage at 2-8°C and 25°C/60% RH. After 3 months storage at 40°C/75% RH, a total of 0.33% w/w of related substances was observed.

These data demonstrate the good stability of the formulations of the present invention, with only small amounts of related substances observed under stress conditions of 40°C/75% RH.

The present invention may be further understood with reference to the following non-limiting items:

1. A pharmaceutical formulation suitable for intramuscular injection and/or nebulizer inhalation, comprising a salt of an optionally substituted dimethyltryptamine compound; and water; wherein the formulation has a pH of about 5 to about 6, a concentration of about 10 mg/ml or more as a free base, and an osmotic pressure of about 250 to about 350 mOsm/Kg.

2. A pharmaceutical formulation suitable for intramuscular injection and/or nebulizer inhalation, comprising a salt of an optionally substituted dimethyltryptamine compound; and water; wherein the formulation has a pH of about 5 to about 6.5, a concentration of about 10 mg/ml or more as free base, and an osmotic pressure of about 250 to about 350 mOsm/Kg.

3. A pharmaceutical formulation suitable for intramuscular injection and/or nebulizer inhalation, comprising a salt of an optionally substituted dimethyltryptamine compound; an alkaline agent, water and optionally a buffer separate from the salt; wherein the formulation has a pH of about 5 to about 6, a concentration of about 10 mg/ml or more as the free base, and an osmotic pressure of about 250 to about 350 mOsm/Kg; and wherein the formulation contains a dose of the optionally substituted dimethyltryptamine compound within an injection or inhalation volume of 5 ml or less.

4. A pharmaceutical formulation suitable for intramuscular injection and/or nebulizer inhalation, comprising a salt of an optionally substituted dimethyltryptamine compound; an alkaline agent, water and optionally a buffer separate from the salt; wherein the formulation has a pH of about 5 to about 6.5, a concentration of about 10 mg/ml or more as the free base, and an osmotic pressure of about 250 to about 350 mOsm/Kg; and wherein the formulation contains a dose of the optionally substituted dimethyltryptamine compound within an injection or inhalation volume of 5 ml or less.

5. The formulation of any preceding item, wherein the formulation comprises an effective dose of an optionally substituted dimethyltryptamine compound for use in psychedelic-assisted therapy in a volume of 5 ml or less.

6. The preparation of any preceding item, wherein the volume is 3 ml or less.

7. The preparation of any preceding item, wherein the volume is 2.5 ml or less.

8. The formulation of any preceding clause, wherein the formulation has an osmotic pressure of about 275 to about 325 mOsm/Kg.

9. The formulation of any preceding item, wherein the salt of the optionally substituted dimethyltryptamine compound comprises a Bronsted acid having a pKa of about 3 to about 5 and a compound of formula I:

in:

R ¹ is independently selected from -R ⁴ , -OH, -OR ⁴ , -O(CO)R ⁴ , monohydrogen phosphate, -F, -Cl, -Br and -I;

n is selected from 0, 1, 2, 3 or 4;

^R2 is C( ^xH ) ₃ ;

R ³ is C( ^x H) ₃ ;

Each R ⁴ is independently selected from C ₁ -C ₄ alkyl; and

Each ^xH and ^yH is independently selected from protium or deuterium.

10. The formulation of any preceding clause, wherein the salt of the optionally substituted dimethyltryptamine compound comprises a Bronsted acid having a pKa of about 3 to about 5 and a compound of Formula IA or Formula IB:

in:

R ^1a is independently selected from -R ^4a , -OH, -OR ^4a , -O(CO)R ^4a , monohydrogen phosphate, -F, -Cl, -Br and -I;

n is selected from 0, 1, 2, 3 or 4;

R ^2a is C( ^xa H) ₃ ;

R ^3a is C( ^xaH ) ₃ ;

Each R ^4a is independently selected from C ₁ -C ₄ alkyl; and

Each ^xa H and ^ya H is independently selected from protium or deuterium;

in:

R ^1b is independently selected from -R ^4b , -OH, -OR ^4b , -O(CO)R ^4b , monohydrogen phosphate, -F, -Cl, -Br and -I;

n is selected from 0, 1, 2, 3 or 4;

R ^2b is C( ^xb H) ₃ ;

R ^3b is C( ^xb H) ₃ ;

Each R ^4b is independently selected from C ₁ -C ₄ alkyl; and

Each of ^xb H, ^yb H and ^z H is independently selected from protium or deuterium.

11. The preparation of item 9 or item 10, wherein the salt of the optionally substituted dimethyltryptamine compound comprises (i) a compound of formula I, wherein n is 0; or n is 1 and R ¹ is at the 4- or 5-position; or (ii) a compound of formula IA, wherein n is 0; or n is 1 and R ^1a is at the 4- or 5-position; or (iii) a compound of formula IB, wherein n is 0; or n is 1 and R ^1b is at the 4- or 5-position.

12. The formulation of any one of items 9 to 11, wherein the salt of the optionally substituted dimethyltryptamine compound comprises (i) a compound of formula I, wherein each R ¹ is independently selected from -OH, -OMe, -OCD ₃ , -OAc, -O(CO)Me and monohydrogen phosphate; or (ii) a compound of formula IA, wherein each R ^1a is independently selected from -OH, -OMe, -OCD ₃ , -OAc, -O(CO)Me and monohydrogen phosphate, or (iii) a compound of formula IB, wherein each R ^1b is independently selected from -OH, -OMe, -OCD ₃ , -OAc, -O(CO)Me and monohydrogen phosphate.

13. The formulation of any of items 9 to 12, wherein the salt of the optionally substituted dimethyltryptamine compound comprises (i) a compound of formula I, wherein R ² is CD ₃ and R ³ is CD ₃ ; or (ii) a compound of formula IA, wherein R ^2a is CD ₃ and R ^3a is CD ₃ , or (iii) a compound of formula IB, wherein R ^2b is CD ₃ and R ^3b is CD ₃ .

14. The formulation of any of items 9 to 12, wherein the salt of the optionally substituted dimethyltryptamine compound comprises (i) a compound of formula I, wherein R ² is CH ₃ and R ³ is CH ₃ ; or (ii) a compound of formula IA, wherein R ^2a is CH ₃ and R ^3a is CH ₃ , or (iii) a compound of formula IB, wherein R ^2b is CH ₃ and R ^3b is CH ₃ .

15. The formulation of any of items 9 to 12, wherein the salt of the optionally substituted dimethyltryptamine compound comprises (i) a compound of formula I, wherein R ² is CH ₃ and R ³ is CD ₃ ; or (ii) a compound of formula IA, wherein R ^2a is CH ₃ and R ^3a is CD ₃ , or (iii) a compound of formula IB, wherein R ^2b is CH ₃ and R ^3b is CD ₃ .

16. The formulation of any one of items 9 to 12, wherein the salt of the optionally substituted dimethyltryptamine compound comprises (i) a compound of formula I, wherein each ^x H is D; or a compound of formula IA, wherein each ^xa H is D; or (iii) a compound of formula IB, wherein each ^xb H is D.

17. The formulation of any one of items 9 to 16, wherein the salt of the optionally substituted dimethyltryptamine compound comprises (i) a compound of formula I, wherein two ^y H are D; or (ii) a compound of formula IA, wherein two ^ya H are D; or (iii) a compound of formula IB, wherein two ^yb H are D.

18. A formulation of any one of items 9 to 16, wherein the salt of an optionally substituted dimethyltryptamine compound comprises (i) a compound of formula I, wherein one ^y H is H and one ^y H is D; or (ii) a compound of formula IA, wherein one ^ya H is H and one ^ya H is D; or (iii) a compound of formula IB, wherein one ^yb H is H and one ^yb H is D.

19. The formulation of any one of items 9 to 16, wherein the salt of the optionally substituted dimethyltryptamine compound comprises (i) a compound of formula I, wherein two ^y H are H; or (ii) a compound of formula IA, wherein two ^ya H are H; or (iii) a compound of formula IB, wherein two ^yb H are H.

20. The formulation of any one of items 10 to 19, wherein the salt of the optionally substituted dimethyltryptamine compound comprises a compound of formula IB, wherein both ^z H are D.

21. The formulation of any one of items 10 to 19, wherein the salt of the optionally substituted dimethyltryptamine compound comprises a compound of formula IB, wherein both ^z H are H.

22. The formulation of any one of items 10 to 19, wherein the salt of the optionally substituted dimethyltryptamine compound comprises a compound of formula IB, wherein one ^z H is H and one ^z H is D.

23. The formulation of any one of items 9 to 11 and 13 to 22, wherein n is 0.

24. The formulation of any one of items 9 to 22, wherein n is 1 and R ¹ or R ^1a or R ^1b is 4-acetoxy.

25. The formulation of any one of items 9 to 22, wherein n is 1 and R ¹ or R ^1a or R ^1b is 5-methoxy or trideuterated 5-methoxy.

26. The formulation of any one of items 1 to 9, wherein the optionally substituted dimethyltryptamine compound is N,N-dimethyltryptamine.

27. The preparation of any one of items 1 to 25, wherein the optionally substituted dimethyltryptamine compound is selected from α,α-dideutero-N,N-dimethyltryptamine (d ₂ -DMT), α,α,β,β-tetradeutero-N,N-dimethyltryptamine (d ₄ -DMT), N,N-di(trideuteromethyl)tryptamine (d ₆ -DMT), α,α-dideutero-N,N-di(trideuteromethyl)tryptamine (d ₈ -DMT), α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine (d ₁₀ -DMT), 5-methoxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine, α,α-dideutero-N,N-di(trideuteromethyl)tryptamine (d ₈ -DMT), α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine (d ₁₀ -DMT), 5-methoxy-N,N-di(trideuteromethyl)tryptamine, 5-methoxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine, 5-methoxy-α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine and mixtures thereof.

28. The formulation of any preceding item, wherein the salt of an optionally substituted dimethyltryptamine compound has an optionally substituted dimethyltryptamine compound and an acid selected from the group consisting of fumaric acid, tartaric acid, citric acid, acetic acid, lactic acid and gluconic acid.

29. The preparation of claim 28, wherein the acid is fumaric acid.

30. The formulation of any preceding clause, comprising a drug substance comprising a salt of an optionally substituted dimethyltryptamine compound having a purity greater than or equal to 99% when measured by HPLC.

31. The formulation of any preceding clause, wherein the concentration of the optionally substituted dimethyltryptamine is from about 10 mg/mL to about 150 mg/mL (as free base equivalent).

32. The formulation of any preceding clause, wherein the concentration of the optionally substituted dimethyltryptamine is from about 15 mg/mL to about 70 mg/mL (as free base equivalent).

33. The formulation of any preceding clause, wherein the concentration of the optionally substituted dimethyltryptamine compound is from about 20 mg/mL to about 40 mg/mL (as free base equivalent).

34. The formulation of any preceding clause, wherein the concentration of optionally substituted dimethyltryptamine is about 20 mg/mL or more (as free base equivalent).

35. The formulation of any preceding clause, wherein the concentration of the optionally substituted dimethyltryptamine compound is about 25 mg/mL or more (as free base equivalent).

36. The formulation of any preceding clause, wherein the formulation further comprises a buffer separate from said salt.

37. The formulation of claim 36, wherein the buffer comprises acetate and acetic acid; or citrate and citric acid; or phosphate and phosphoric acid; or the buffer comprises acetate, citrate or phosphate.

38. The formulation of any preceding item, wherein the alkaline agent is sodium hydroxide or potassium hydroxide.

39. The formulation of any preceding item, wherein the formulation further comprises a tonicity agent.

40. The formulation of any preceding clause, wherein the formulation consists essentially of: a salt of an optionally substituted dimethyltryptamine compound, water and an alkaline agent, and optionally one or more agents selected from the group consisting of tonicity agents, buffers, co-solvents, preservatives and antioxidants.

41. The formulation of any preceding clause, wherein the formulation consists essentially of: a salt of an optionally substituted dimethyltryptamine compound, water, an optional buffer and an optional tonicity agent.

42. The formulation of any preceding clause, wherein the formulation consists essentially of: a salt of an optionally substituted dimethyltryptamine compound, an alkaline agent, water, an optional buffering agent and an optional tonicity agent.

43. The formulation of any one of items 1 to 35 and 39 to 42, wherein the formulation consists of: a salt of an optionally substituted dimethyltryptamine compound, water and an optional tonicity agent.

44. The formulation of any one of items 3 to 35 and 38 to 42, wherein the formulation consists of: a salt of an optionally substituted dimethyltryptamine compound, an alkaline agent, water and optionally a tonicity agent.

45. The formulation of any one of items 39 to 44, wherein the tonicity agent is sodium chloride or dextrose.

46. The formulation of any one of items 1 to 45, having an oxygen content of less than 5 ppm.

47. The formulation of any one of items 1 to 45, having an oxygen content of less than 2 ppm.

48. The formulation of any preceding clause, wherein the formulation has been purged with an inert gas.

49. The preparation of any preceding item, which is stored in a container having a volume of 5 ml or less.

50. The preparation of any preceding item, which is stored in a container having a volume of 4 ml or less.

51. The preparation of any preceding item, which is stored in a container having a volume of 3 ml or less.

52. The preparation of any preceding item, which is stored in a container having a volume of 2 ml or less.

53. The preparation of any preceding item, which is stored in a container having a volume of 1 ml or less.

54. The preparation of any preceding item, which is stored in a container having a volume of 0.5 ml or less.

55. The formulation of any preceding item, wherein the formulation further comprises a pH adjusting agent.

56. The formulation of claim 55, wherein the pH adjuster comprises hydrochloric acid.

57. The formulation of item 56, comprising a salt of an optionally substituted dimethyltryptamine compound, an alkaline agent, water and a pH adjuster.

58. A kit suitable for preparing a formulation of any preceding item, said kit comprising a salt of an optionally substituted dimethyltryptamine compound; an optional tonicity agent; and an optional buffer separate from said salt.

59. A kit suitable for preparing the formulation of any one of items 3 to 57, said kit comprising a salt of an optionally substituted dimethyltryptamine compound; an optional tonicity agent; an alkaline agent and an optional buffering agent separate from said salt.

60. A method for preparing a pharmaceutical formulation as defined in any one of items 1 to 57, comprising contacting a salt of an optionally substituted dimethyltryptamine compound, water and optionally a buffer, and optionally a tonicity agent.

61. A method for preparing a pharmaceutical formulation as defined in any one of items 3 to 57, comprising contacting a salt of an optionally substituted dimethyltryptamine compound, water, an alkaline agent and optionally a buffer separate from the salt, and optionally a tonicity agent.

62. The method of item 60 or item 61, wherein an aqueous solution of a buffer is contacted with a salt of an optionally substituted dimethyltryptamine compound, wherein the aqueous solution has a pH as defined in item 1 or 2.

63. The method of any one of items 60 to 62, wherein the method comprises contacting an optionally substituted dimethyltryptamine compound with a buffer, water and optionally a tonicity agent.

64. The method of any one of items 60 to 63, further comprising adjusting the pH of the formulation.

65. The method of item 64, wherein the pH is adjusted with an alkaline agent, preferably sodium hydroxide or potassium hydroxide.

66. The method of item 64 or item 65, which further comprises adjusting the pH with a pH adjusting agent, preferably hydrochloric acid.

67. The method of any one of items 60 to 66, further comprising purging the formulation with an inert gas.

68. A preparation as defined in any one of items 1 to 57 or a kit according to item 58 or item 59 for use as a medicament or in combination with a psychotherapy (ie for use in pharmacologically assisted psychotherapy).

69. A formulation as defined in any one of items 1 to 57 or a kit as defined in item 58 or item 59 for use in a method of treating a mental or neurological disorder in a patient.

70. The preparation for use according to item 69, wherein the mental or neurological disorder is selected from the group consisting of: (i) obsessive-compulsive disorder, (ii) depressive disorder, (iii) anxiety disorder, (iv) substance abuse and gambling disorder and (v) motivational disorder.

71. A method of treating a mental or neurological disorder comprising administering to a patient in need thereof a formulation as defined in any one of items 1 to 57.

72. The method of item 71, wherein the mental or neurological disorder is as defined in item 70.

73. The method of item 71, wherein the preparation as defined in any one of items 1 to 57 is administered in combination with psychotherapy.

74. A formulation according to any one of items 1 to 57, a formulation for use according to any one of items 68 to 70, or a method according to any one of items 71 to 73, wherein the dose of the optionally substituted dimethyltryptamine compound is in the range of about 5 to about 250 mg.

75. A formulation according to any one of items 1 to 57, a formulation for use according to any one of items 68 to 70, or a method according to any one of items 71 to 73, wherein the dose of the optionally substituted dimethyltryptamine compound is in the range of about 10 to about 150 mg.

76. A formulation according to any one of items 1 to 57, a formulation for use according to any one of items 68 to 70, or a method according to any one of items 71 to 73, wherein the dose of the optionally substituted dimethyltryptamine compound is in the range of about 10 to about 100 mg.

77. A formulation according to any one of items 1 to 57, a formulation for use according to any one of items 68 to 70, or a method according to any one of items 71 to 73, wherein the dose of the optionally substituted dimethyltryptamine compound is in the range of about 20 to about 70 mg.

78. A formulation according to any one of items 1 to 57, a formulation for use according to any one of items 68 to 70, or a method according to any one of items 71 to 73, wherein the dose of the optionally substituted dimethyltryptamine compound is in the range of about 20 to about 50 mg.

79. A preparation according to any one of items 1 to 57, a preparation for use according to any one of items 68 to 70, or a method according to any one of items 71 to 73, wherein the preparation comprises:

a) an optionally substituted dimethyltryptamine compound and a salt of an acid, wherein the optionally substituted dimethyltryptamine compound is selected from α,α-dideutero-N,N-dimethyltryptamine (d ₂ -DMT), α,α,β,β-tetradeutero-N,N-dimethyltryptamine (d ₄ -DMT), N,N-di(trideuteromethyl)tryptamine (d ₆ -DMT), α,α-dideutero-N,N-di(trideuteromethyl)tryptamine (d ₈ -DMT), α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine (d ₁₀ -DMT), 5-methoxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine, 5-methoxy-N,N-di(trideuteromethyl)tryptamine and 5-methoxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine and mixtures thereof, wherein the acid is selected from the group consisting of fumaric acid, tartaric acid, citric acid, acetic acid, lactic acid and gluconic acid;

b) an alkaline agent selected from sodium hydroxide and potassium hydroxide;

c) water;

d) an optional buffer, which is separate from the salt and which comprises acetate and acetic acid; or citrate and citric acid; or phosphate and phosphoric acid; or it comprises acetate, citrate or phosphate;

e) an optional pH adjuster which is hydrochloric acid,

wherein the formulation has a pH of about 5 to about 6.5, or a pH of about 5 to about 6, a concentration of about 15 mg/mL to about 70 mg/mL (as free base equivalent), and an osmotic pressure of about 250 to about 350 mOsm/Kg; and wherein the formulation contains a dose of the optionally substituted dimethyltryptamine compound in the range of about 10 mg to about 100 mg in a volume of 5 ml or less.

Claims (54)

1. A pharmaceutical formulation suitable for intramuscular injection and/or inhalation by a nebulizer comprising a salt of an optionally substituted dimethyltryptamine compound, an alkaline agent, water and optionally a buffer separate from the salt; wherein the formulation has a pH of about 5 to about 6.5, a concentration of about 10mg/ml or more, as free base, and an osmolality of about 250 to about 350 mOsm/Kg; and wherein the formulation comprises a dose of the optionally substituted dimethyltryptamine compound in a volume of less than 5 ml.

2. The formulation of claim 1, wherein the formulation has a pH of about 5 to about 6.

3. The formulation of claim 1 or claim 2, wherein the formulation is suitable for intramuscular injection.

4. A formulation according to any one of the preceding claims, wherein the formulation comprises an effective dose of an optionally substituted dimethyltryptamine compound for use in a magical adjuvant therapy in a volume of less than 5 ml.

5. The formulation of any one of the preceding claims, wherein the volume is 3ml or less.

6. The formulation of any one of the preceding claims, wherein the volume is 2.5ml or less.

7. The formulation of any one of the preceding claims, wherein the formulation has an osmolality of about 275 to about 325 mOsm/Kg.

8. The formulation of any one of claims 1 to 7, wherein the salt of the optionally substituted dimethyltryptamine compound comprises a bronsted acid having a pKa of about 3 to about 5 and a compound of formula IB:

Wherein:

R ^1b is independently selected from the group consisting of-R ^4b、-OH、-OR^4b、-O(CO)R^4b, monohydrogen phosphate, -F, -Cl, -Br, and-I;

n is selected from 0,1, 2, 3 or 4;

R ^2b is C (^xbH)₃;

r ^3b is C (^xbH)₃;

Each R ^4b is independently selected from C ₁-C₄ alkyl; and

Each ^xbH、^yb H and ^z H is independently selected from protium or deuterium.

9. The formulation of claim 8, wherein the salt of an optionally substituted dimethyltryptamine compound comprises a compound of formula IB, wherein n is 0; or n is 1 and R ^1b is in the 4-or 5-position.

10. The formulation of claim 8 or claim 9, wherein the salt of an optionally substituted dimethyltryptamine compound comprises a compound of formula IB, wherein each R ^1b is independently selected from-OH, -OMe, -OCD ₃, -OAc, -O (CO) Me, and monohydrogen phosphate.

11. The formulation of any one of claims 8 to 10, wherein the salt of the optionally substituted dimethyltryptamine compound comprises a compound of formula IB, wherein R ^2b is CD ₃ and R ^3b is CD ₃.

12. The formulation of any one of claims 8 to 11, wherein the salt of an optionally substituted dimethyltryptamine compound comprises a compound of formula IB, wherein each ^yb H is D.

13. The formulation of any one of claims 8, 9, 11 or 12, wherein n is 0.

14. The formulation of any one of claims 8 to 12, wherein n is 1 and R ^1b is 4-acetoxy.

15. The formulation of any one of claims 8 to 12, wherein n is 1 and R ^1b is 5-methoxy or tridentate 5-methoxy.

16. The formulation of any one of claims 1 to 8, wherein the optionally substituted dimethyltryptamine compound is N, N-dimethyltryptamine.

17. The formulation of any one of claims 1-8, wherein the optionally substituted dimethyltryptamine compound is a, a-dideutero-N, N-dimethyltryptamine.

18. The formulation of any one of claims 1 to 17, wherein the salt of an optionally substituted dimethyltryptamine compound has an optionally substituted dimethyltryptamine compound and an acid selected from the group consisting of fumaric acid, tartaric acid, citric acid, acetic acid, lactic acid, and gluconic acid.

19. The formulation of claim 18, wherein the acid is fumaric acid.

20. The formulation of any one of claims 1 to 19, comprising a drug substance comprising a salt of the optionally substituted dimethyltryptamine compound having a purity of greater than or equal to 99% when measured by HPLC.

21. The formulation of any one of claims 1 to 20, wherein the concentration of the optionally substituted dimethyltryptamine is from about 10mg/mL to about 150mg/mL (on a free base equivalent basis).

22. The formulation of any one of claims 1 to 20, wherein the concentration of the optionally substituted dimethyltryptamine is from about 15mg/mL to about 70mg/mL (on a free base equivalent basis).

23. The formulation of any one of claims 1 to 20, wherein the concentration of the optionally substituted dimethyltryptamine compound is from about 20mg/mL to about 40mg/mL (on a free base equivalent basis).

24. The formulation of any one of claims 1 to 20, wherein the concentration of the optionally substituted dimethyltryptamine compound is about 25mg/mL (on a free base equivalent basis).

25. The formulation of any one of the preceding claims, wherein the formulation comprises a buffer separate from the salt.

26. The formulation of claim 25, wherein the buffer comprises acetate and acetic acid; or citrate and citric acid; or phosphate and phosphoric acid; or the buffer comprises acetate, citrate or phosphate.

27. The formulation of any one of the preceding claims, wherein the alkaline agent is sodium hydroxide or potassium hydroxide.

28. The formulation of any one of claims 1 to 27, wherein the formulation further comprises a tonicity agent and/or a pH adjusting agent.

29. The formulation of any one of the preceding claims, wherein the formulation consists essentially of: salts of optionally substituted dimethyltryptamine compounds, water and alkaline agents, and optionally one or more agents selected from the group consisting of pH adjusting agents, tonicity agents, buffers, co-solvents, preservatives and antioxidants.

30. The formulation of any one of the preceding claims, wherein the formulation consists essentially of: salts of optionally substituted dimethylamine compounds, water, alkaline agents, and optionally buffers and/or tonicity agents and/or pH adjusting agents.

31. The formulation according to any one of the preceding claims, wherein the formulation consists of: optionally substituted salts of the dimethyltryptamine compounds, water, a base agent and optionally buffers and/or tonicity agents and/or pH adjusting agents.

32. The formulation of any one of claims 28 to 31, wherein the tonicity agent is sodium chloride or dextrose.

33. The formulation according to any one of claims 1 to 32, having an oxygen content of less than 5ppm, preferably less than 2 ppm.

34. The formulation of any one of claims 1 to 33, stored in a container having a volume of less than 5 ml.

35. The formulation of any one of claims 1 to 33, stored in a container having a volume of less than 2 ml.

36. The formulation of any one of claims 1 to 35, comprising a salt of the optionally substituted dimethyltryptamine compound, an alkaline agent, water, a buffer separate from the salt, and a tonicity agent or pH adjusting agent.

37. The formulation of claim 36, comprising a salt of the optionally substituted dimethyltryptamine compound; an alkaline agent selected from potassium hydroxide and sodium hydroxide; water; buffer as citrate; and tonicity agents or as pH adjusting agents for acids.

38. A kit suitable for preparing a formulation according to any one of claims 1 to 37, the kit comprising a salt of the optionally substituted dimethyltryptamine compound; optionally a tonicity agent and/or a pH adjusting agent; an alkaline agent and optionally a buffer separate from the salt.

39. A process for preparing a pharmaceutical formulation as defined in any one of claims 1 to 37 comprising contacting a salt of the optionally substituted dimethyltryptamine compound, water, a base agent and optionally a buffer separate from the salt, and optionally a tonicity agent and/or a pH adjusting agent.

40. The method of claim 39, wherein an aqueous solution of a buffer is contacted with the salt of the optionally substituted dimethyltryptamine compound, wherein the aqueous solution has a pH as defined in claim 1.

41. The method of claim 39 or 40, wherein the method comprises contacting the optionally substituted dimethyltryptamine compound with water and optionally a buffer and/or tonicity agent and/or a pH adjusting agent.

42. The method of any one of claims 39 to 41, further comprising adjusting the pH of the formulation.

43. A process according to claim 42, wherein the pH is adjusted with an alkaline agent, which is sodium hydroxide or potassium hydroxide.

44. The method of any one of claims 39 to 43, further comprising purging the formulation with an inert gas.

45. A formulation as defined in any one of claims 1 to 37 or a kit according to claim 38 for use as a medicament or in combination with psychotherapy.

46. A formulation as defined in any one of claims 1 to 37 or a kit according to claim 38 for use in a method of treating a mental or neurological disorder in a patient.

47. The formulation for use or the kit for use according to claim 46, wherein the mental or neurological disorder is selected from the group consisting of (i) obsessive-compulsive disorder, (ii) depressive disorder, (iii) anxiety disorder, (iv) substance abuse and gambling disorder, and (v) motivation deficiency disorder.

48. A method of treating a mental or neurological disorder comprising administering to a patient in need thereof a formulation as defined in any one of claims 1 to 37.

49. The method of claim 48, wherein the mental or neurological disorder is as defined in claim 47.

50. The method according to claim 48, wherein the formulation as defined in any one of claims 1 to 37 is administered in combination with psychotherapy.

51. A lyophilized powder formulation comprising a formulation according to any one of claims 1 to 37 which has been lyophilized.

52. A method of preparing a lyophilized powder formulation comprising drying the formulation according to any one of claims 1 to 37 by lyophilization.

53. A method of preparing an aqueous formulation comprising mixing a lyophilized powder formulation as defined in claim 51 or as prepared by the method of claim 52 into water to provide a formulation comprising a salt of an optionally substituted dimethylamine compound, an alkaline agent, water, and optionally a buffer separate from the salt to provide a formulation having a pH of about 5 to about 6.5, a concentration of about 10mg/ml or more in terms of free base, and an osmolality of about 250 to about 350 mOsm/Kg.

54. The method of claim 53, wherein the method provides a formulation having a pH of about 5 to about 6.