JP2024540527A - Injectable and inhaled preparations - Google Patents

Abstract

The present invention relates to an aqueous pharmaceutical formulation, a method for its preparation and its use. The aqueous pharmaceutical formulation comprises a salt of an optionally substituted dimethyltryptamine compound and water, has a pH of 5 to 6.5, preferably about 5 to about 6, and has a concentration of the optionally substituted dimethyltryptamine compound of about 10 mg/ml or more as free base equivalent. These formulations can contain an effective amount of the optionally substituted dimethyltryptamine compound for use in psychedelic assisted therapy in a volume of 5 ml or less. Such formulations are surprisingly suitable for both intramuscular injection and inhalation by nebulizer, are stable and clinically tolerated, and have the potential to be used in the treatment of psychiatric or neurological disorders.
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Description

FIELD OF THEINVENTION

The present invention relates to an aqueous pharmaceutical formulation, a method for its preparation and its use. The aqueous pharmaceutical formulation comprises a salt of an optionally substituted dimethyltryptamine compound and water, has a pH of 5 to 6.5 and a concentration of the optionally substituted dimethyltryptamine compound of about 10 mg/ml or more as free base equivalent. The formulation can have a pH of about 5 to about 6, or a pH of 5 to 6. These formulations contain an effective amount of the optionally substituted dimethyltryptamine compound for use in psychedelic assisted therapy in a volume of 5 ml or less. Such formulations are surprisingly suitable for both intramuscular (IM) injection and inhalation by nebulizer, are stable and clinically tolerated, and may be used to treat psychiatric or neurological disorders.

2. Background of the Invention

Classical psychedelics have shown preclinical and clinical promise in the treatment of psychiatric disorders (Carhart-Harris and Goodwin, Neuropsychopharmacology 42, 2105-2113 (2017)). In particular, psilocybin (also called psilocybin) has shown significant improvements in a range of depression and anxiety assessment measures in randomized double-blind trials (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 studies on the biosynthesis and metabolism of DMT in brain and peripheral tissues, and methods and results of DMT detection in body fluids and brain is given by S. A. Barker in Front. Neurosci., 12, 536, 1-17 (2018). Barker et al. suggest that "further characterization of DMT's cellular distribution, receptors, and general biochemistry may lead to more effective pharmaceutical agents and new targets for intervention."

Saline injections of DMT fumarate in human volunteers have been described by C. Timmermann et al. in 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 with placebo (saline) injections. The results showed that DMT fumarate suppressed alpha power and normalized/increased delta and theta power compared with the results obtained with placebo. Alpha power is associated with higher psychological functioning, top-down predictive processing, and related feedback connectivity, while theta and delta power are classically associated with REM dreaming sleep and related "visionary" states. These results are explained as being related to the fact that DMT fumarate injections cause the experience of a sensation of being deeply immersed in a completely different world.

Silviera et al. (Molecules, 2020, 25, 2072) discuss the stability profile of ayahuasca. Piries et al. (Phytochem. Anal. 2009, 20, 149-153) discuss a method for the simultaneous determination of the main active components in ayahuasca tea samples.

According to the Human Metabolome Database (HMDB), N,N-dimethyltryptamine degrades relatively quickly in solution (see, for example, http://www.hmdb.ca/metabolites/HMDB0005973). Thus, there is a need in the art for an injectable solution of DMT that is stable over longer periods, is clinically tolerated, and is formulated in a manner that minimizes the discomfort and costs associated with administration of dimethyltryptamine-based medications. The present invention addresses this need.

The present invention relates to an aqueous pharmaceutical formulation suitable for both intramuscular injection and nebulized inhalation, comprising at least about 10 mg/ml (as free base equivalent) of an optionally substituted dimethyltryptamine compound salt and water, wherein the formulation has a pH value of about 5 to about 6.5 and a typical osmolality of about 250 to about 350 mOsm/Kg. The formulation can have a pH of about 5 to about 6, or a pH of 5 to 6. These formulations are capable of delivering an effective amount of an optionally substituted dimethyltryptamine compound for use in psychedelic-assisted therapy (pharmacologically-assisted psychotherapy) in a volume of 5 ml or less, and are particularly suitable for both intramuscular injection and nebulized inhalation. Preferably, the formulation can deliver an effective amount of an optionally substituted dimethyltryptamine compound for use in psychedelic-assisted therapy 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 present invention addresses the problem of providing a pharmaceutical formulation suitable for intramuscular injection or nebulized inhalation, which has substantially reduced degradation products when stored under standard or stress conditions compared to known formulations. This represents an improved shelf life over such known pharmaceutical formulations. Furthermore, deuterated optionally substituted dimethyltryptamine compounds, such as the deuterated compounds of formula IA or IB, show significantly improved exposure and Cmax by intramuscular injection compared to their non-deuterated analogs (see Figures 1A and 1B). Thus, the present invention provides for the first time an aqueous pharmaceutical formulation having an effective amount (at least for a human of average body weight) of an optionally substituted dimethyltryptamine compound by intramuscular injection or nebulized inhalation in a volume of 5 ml or less, preferably 4 ml or less, or 3 ml or less, or 2.5 ml or less, or 2 ml or less, or 1 ml or less, or 0.5 ml or less.

Thus, in a first aspect, the present invention provides a pharmaceutical formulation suitable for both intramuscular injection and nebulization, comprising a salt of an optionally substituted dimethyltryptamine compound, a base agent, water; and optionally a buffer separate from said salt; wherein the formulation has a pH of about 5 to about 6.5, a concentration of about 10 mg/ml or more as a free base, and an osmolality of about 250 to about 350 mOsm/Kg. The formulation can 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 (as free base equivalent) of the salt of the optionally substituted dimethyltryptamine compound. Typically, the formulation contains about 25 mg/ml (as free base equivalent) 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 amount of an optionally substituted dimethyltryptamine compound for use in 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.

In a second aspect, the present invention provides a kit suitable for preparing the formulation of the first aspect, the kit comprising a salt of an optionally substituted dimethyltryptamine compound; a base agent, optionally a buffering agent other than the salt, and optionally a tonicity agent and/or a pH adjusting agent. In a preferred embodiment of the second aspect of the invention, the kit comprises an effective amount of an optionally substituted dimethyltryptamine compound for use in 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.

Viewed from a third aspect, the present invention provides a method of preparing the pharmaceutical formulation of the first aspect, comprising contacting a salt, water, a base agent, optionally a buffer other than said salt, and optionally a tonicity agent and/or a pH adjusting agent. In a preferred embodiment of the third aspect of the invention, the formulation comprises an effective amount of an optionally substituted dimethyltryptamine compound for use in psychedelic assisted therapy in a volume of 5ml or less, preferably 4ml or less, 3ml or less, 2.5ml or less, 2ml or less, 1ml or less, or 0.5ml or less.

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

Due to the known instability of N,N-dimethyltryptamine free base in solution, solutions containing optionally substituted dimethyltryptamine compounds are generally prepared immediately or close to the time of use (i.e., storage of solutions of optionally substituted dimethyltryptamine compounds is avoided). Alternatively, solutions of optionally substituted dimethyltryptamine compounds are frozen. The inventors have found that when a buffer separate from the salt is used, the resulting formulation is more stable than a formulation prepared without a buffer separate from the salt. Furthermore, when a container that prevents the transmission of ultraviolet light is used, the resulting formulation is more stable than a formulation stored in a container that permits the transmission of ultraviolet light.

In a fourth aspect, the present invention provides a formulation according to the first aspect or a kit according to the second aspect for use as a pharmaceutical or in combination with psychotherapy (psychotherapy).

In a fifth aspect, the present invention provides a formulation of the first aspect or a kit of the second aspect for use in a method of treating a psychiatric or neurological disorder (psychiatric or neurological disease) in a patient.

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

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

In an eighth aspect, the present invention provides an aqueous pharmaceutical formulation comprising a salt with a Bronsted acid having a pKa (at 25° C.) of about 3 to about 5, a compound of formula IA, and water, the formulation having a pH of about 5 to about 6.5 and a concentration of the compound of formula IA of about 10 mg/ml or more as the free base equivalent salt:
(Wherein,
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( ^xaH ) 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 can 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 amount of a compound of formula IA for use in 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.

In a ninth aspect, the present invention provides an aqueous pharmaceutical formulation comprising a salt comprising a Bronsted acid having a pKa (at 25° C.) of about 3 to about 5, a compound of formula IB, and water, the formulation having a pH of about 5 to about 6.5 and a concentration of the compound of formula IB of about 10 mg/ml or more as the free base equivalent salt:
(Wherein,
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;
^R2b is C( ^xbH ) ₃ ;
R ^3b is C( ^xbH ) ₃ ;
each R ^4b is independently selected from C ₁ -C ₄ alkyl; and each ^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 preferred embodiments of the ninth aspect of the invention, the pharmaceutical formulation comprises an effective amount of a compound of formula IB for use in psychedelic assisted therapy in a volume of 5ml or less, preferably 4ml or less, 3ml or less, 2.5ml or less, 2ml or less, 1ml or less, or 0.5ml 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.

In a tenth aspect, the present invention provides a lyophilized powder formulation comprising a lyophilized formulation as defined in the first aspect of the present invention.

In an eleventh aspect, the present invention provides a method for preparing a lyophilized powder formulation, comprising drying a formulation 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 a lyophilized powder formulation prepared by the method of the eleventh aspect in water, to provide a formulation comprising a salt of an optionally substituted dimethyltryptamine compound, a base agent, water, and optionally a buffer other than the salt, to provide a formulation having a pH of about 5 to about 6, a concentration of about 10 mg/ml or more as a free base, and an osmolality of about 250 to about 350 mOsm/Kg. Preferably, the formulation can 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 relating to each aspect of the invention apply mutatis mutandis to other aspects of the invention.

Further aspects and embodiments of the present invention will become apparent from the description that follows.

FIG. 1A and FIG. 1B show plots of mean plasma concentrations of N,N-dimethyltryptamine (SPL026), _d2 -N,N-dimethyltryptamine (SPL028i) and _d8 -N,N-dimethyltryptamine (SPL028viii) over time after IM administration of 3.5 mg/kg (as fumarate salt) (in vivo, added as cassette). FIG. 1A - Linear plot, FIG. 1B - Semi-log plot. All three drugs achieved Cmax above 50 ng/ml, indicating therapeutically relevant doses. SPL028i and SPL028viii each show significantly higher plasma concentrations at 30 minutes compared to non-deuterated DMT.

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

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

Detailed Description of the Invention

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

Unless otherwise noted, measurements are taken at room temperature and pressure, i.e., 20°C (293.15 K, 68°F) and 1 atmosphere pressure (14.696 psi, 101.325 kPa), respectively. Ambient conditions refer to room temperature and pressure, unless otherwise noted.

In the following description, reference will be made to a number of terms which shall be understood to have the meanings set forth below unless the context clearly indicates to the contrary. The nomenclature used herein for the psychedelic agents used in the formulations of the present invention is that commonly used in the art. The compounds described herein may also be referred to by nomenclature in accordance with the International Union of Pure and Applied Chemistry (IUPAC) rules for chemical compounds, specifically the "IUPAC Compendium of Chemical Terminology (Gold Book)" (see A. D. Jenkins et al., Pure & Appl. Chem., 1996, 68, 2287-2311). For the avoidance of doubt, in the event that the rules of the IUPAC organization are contrary to the definitions set forth herein, the definitions herein shall control.

In this specification, a reference to the singular form of a noun includes the plural form of that noun (and vice versa), unless the context requires otherwise.

Throughout this specification, the word "comprise" or variations thereof such as "comprises" or "comprising" are understood to mean the inclusion of a stated element, integer or step, or a plurality of elements, integers or steps, but not the exclusion of other elements, integers or steps, or other plurality of elements, integers or steps. The term "comprise" includes within its scope the terms "consisting of" or "consisting essentially of".

The term "consisting of" or variations thereof are understood to mean the inclusion of a stated element, integer or step, or a plurality of elements, integers or steps, and the exclusion of any other element, integer or step, or a plurality of other elements, integers or steps.

The term "consisting essentially of" or variations thereof is understood to mean the inclusion of a recited element, integer or step, or a plurality of elements, integers or steps, and that additional ingredients may be present, but only those that do not materially affect the essential characteristics of the formulation, composition, or compound.

As used herein, the term "about" when modifying a number or value is used to refer to a value that is within ±5% of the specified value. For example, if an osmolality range is specified as about 250 to about 350 mOsm/Kg, values from 238 to 367 are included, and if a pH range is specified as about 5 to about 6, values from 4.75 to 6.3 are included. For the avoidance of doubt, if a number or value is specified herein without the term "about," the number or value is to be understood according to standard numerical rounding practices according to the number of decimal places. For example, an integer such as 6 is understood to include values equal to or greater than 5.5 and less than 6.5. Similarly, a number specified to one decimal place, such as 5.3, is understood to include values equal to or greater than 5.25 and less than 5.35.

As used herein, the term "aqueous" refers to a formulation that contains water and may contain additional solvents.

The formulations of the present invention are useful for treatment and can be administered to a patient 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 domestic mammals. The term does not include laboratory mammals.

As used herein, the term "effective amount" refers to the dose that produces, on average, a clinical response, i.e., an improvement in symptoms.

As used herein, the term "combined with psychotherapy" refers to the treatment of a psychiatric disorder by psychological means, which is augmented by administration of the formulation of the present 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 to reduce or stop the rate of progression of a disorder (disease) or to improve or cure the disorder. Prevention of the disorder as a result of treatment is also included. Reference to prevention is intended herein not to require complete prevention of the disorder: instead, its onset may be prevented (delayed) by treatment according to the invention. Typically, the treatment is not prophylactic and the formulation is administered to a patient diagnosed with or suspected of having the disorder.

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

The diagnostic criteria for the psychiatric or neurological disorders referred to herein are set out 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 psychological therapeutic intervention provided in conjunction with a psychedelic therapeutic formulation (e.g., including any formulation defined in the present invention).

As used herein, the term obsessive-compulsive disorder (OCD) is defined by the presence of either obsessions or compulsions, but commonly both. The symptoms can cause significant impairment or distress. Obsessions are defined as recurring, unwanted, intrusive thoughts, images, or urges. Compulsions are recurring behaviors or mental acts that a person feels they must perform. Typically, OCD manifests as one or more obsessions that drive a person to perform the compulsions. For example, an obsession with germs can cause a cleaning compulsion, and an obsession with food can cause a compulsion to overeat, undereat, or puke after eating (i.e., an obsession with food can manifest as an eating disorder). Compulsions can be either obvious and observable to others, such as checking that the door is locked, or covert mental acts that cannot be observed, such as repeating a phrase in one's head.

As used herein, the term "eating disorder" is defined as a severe and persistent disturbance in eating behavior and associated distressing thoughts and feelings. The term "eating disorder" includes anorexia nervosa, bulimia nervosa, binge eating disorder, avoidant restrictive food intake disorder, other specified eating behavior 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: Patients with eating disorders are primarily concerned about their physical appearance and, as a result, change their eating patterns in order to lose weight. Patients with OCD may restrict their eating for reasons quite different from body image concerns (https://iocdf.org/expert-opinions/expert-opinion-eating-disorders-and-ocd/).

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

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 known as major depression or clinical depression" is defined as the presence of five or more of the following symptoms, most of the time, almost every day, for a period of two weeks or more (also referred to herein as a "major depressive episode"):
- depressed mood, e.g. feeling sad, empty or tearful (in children and teenagers, depressed mood may manifest as persistent irritability);
- markedly decreased interest or pleasure in all or most activities;
significant weight loss in the absence of dietary therapy, weight gain, or decreased or increased appetite (in children, failure to gain weight as expected);
- insomnia or increased desire to sleep;
- Observable restlessness or slowness of movement;
- fatigue or reduced energy;
Feelings of worthlessness or excessive or inappropriate guilt;
- Difficulty making decisions, thinking or concentrating;
-Recurrent thoughts of death or suicide, or suicide attempts
At least one of the symptoms must be either depressed mood or loss of interest or pleasure.

Persistent depressive disorder, also known as dysthymia, is defined as a patient who exhibits two characteristics:
A. Having a depressed mood almost every day for at least two years. Children and adolescents may experience episodes of irritable mood for at least one year.
B. During a depression, you experience at least two of the following symptoms:
-Eating too much or having a lack of appetite -Sleeping too much or having trouble sleeping -Fatigue, loss of energy -Loss of self-esteem -Difficulty concentrating or making decisions

As used herein, the term "treatment-resistant major depressive disorder" refers to MDD that does not respond adequately to adequate treatment with standard of care therapies.

As used herein, "bipolar disorder," also known as manic depression, is a disorder characterized by abnormal changes in mood, energy, activity level, and ability to carry out daily tasks.
There are two defined subcategories of bipolar disorder, all of which involve pronounced changes in mood, energy, and activity levels. These moods range from periods of extremely "up," elated, and energetic behavior (known as manic episodes and further defined below), to periods of very sadness, "down," or hopelessness (known as depressive episodes). Less severe manic periods are known as hypomanic episodes.

Bipolar I disorder is defined by a manic episode lasting at least 7 days or by manic symptoms severe enough to require immediate hospital treatment. Depressive episodes usually also occur, typically lasting at least 2 weeks. Depressive episodes with mixed features (simultaneous depressive and manic symptoms) may also occur.

Bipolar II disorder is defined by a pattern of depressive and hypomanic episodes, but without the terminal manic episodes described above.

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

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

As used herein, "generalized anxiety disorder (GAD)" means a chronic disorder characterized by long-lasting anxiety that is not specific to one object or situation. People with GAD experience persistent, non-specific fear and anxiety and become excessively concerned about everyday, mundane things. GAD is characterized by chronic, excessive anxiety accompanied by three or more of the following symptoms: restlessness, fatigue, difficulty concentrating, irritability, muscle tension, and sleep disorders.

A "phobia" is defined as a persistent fear of an object or situation, which the affected person goes to great lengths to avoid (typically disproportionate to the actual danger posed). If the feared object or situation cannot be avoided completely, the affected person will endure it with significant distress and serious impairment in social or occupational functioning.

A patient suffering from "panic disorder" is defined as someone who experiences one or more brief attacks of intense fear and anxiety (also called panic attacks), often characterized by trembling, shaking, confusion, dizziness, nausea, and/or difficulty breathing. A panic attack is defined as a sudden feeling of fear or discomfort that peaks within 10 minutes.

"Social anxiety disorder" is defined as intense fear and avoidance of negative public scrutiny, public embarrassment, embarrassing situations, or social interactions. Social anxiety often manifests with specific physical symptoms, including blushing, sweating, and difficulty speaking.

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

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

As used herein, the term "substance abuse" means a patterned use of a drug in which the user takes the substance in amounts or in ways that are harmful to themselves or others.

As used herein, the term "gambling disorder" means persistent, recurrent, problematic gambling behavior that results in clinically significant impairment or distress. The disorder is similar to substance abuse.

As used herein, the term "avolition disorder" refers to a disorder whose symptoms include reduced motivation to initiate and carry out purposeful activities independently.

The present invention provides an aqueous pharmaceutical formulation suitable for either intramuscular injection and/or nebulized inhalation comprising a salt of an optionally substituted dimethyltryptamine compound; a base; water; and optionally a buffer separate from said salt, wherein said formulation has a pH of about 5 to about 6.5 and an osmolality of about 250 to about 350 mOsm/Kg. The formulation can have a pH of about 5 to about 6, or a pH of 5 to 6.

In a preferred embodiment of the invention, the pharmaceutical formulation comprises an effective amount of an optionally substituted dimethyltryptamine compound for use in 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.

The inventors have found that the formulations are surprisingly more stable than formulations prepared at higher pHs (specifically formulations prepared at a pH consistent with human blood serum, i.e., about 7.4). The greater stability of the formulations of the present invention (compared to isotonic formulations) is described in more detail in the Examples section.

Osmolarity is formally defined as the quotient of the negative natural logarithm of the theoretical activity of water and the molar mass of water, and is given by the formula:
where p is the partial pressure of water vapor in the solution and p* is the partial pressure of pure water vapor. More simply, osmolality is the number of osmotically active particles (number of solute particles) in 1 kg of solution. Thus, osmolality is a function of the number of particles only, and not their molecular weight, size, shape, or charge (for a review of serum osmolality measurements, see DK Faria et al., ME Mendes and NM Sumita, J. Bras. Patol. Med. Lab., 53, 1, 38-45 (2017)). For example, the osmolality of 1 mole of a non-dissociated substance (e.g., DMT as free base) dissolved in 1 kg of water is 1 Osm/kg (1000 mOsm/kg), whereas the osmolality of a substance that dissociates into two separate species in solution (e.g., DMT fumarate) dissolved in 1 kg of water is 2 Osm/kg (2000 mOsm/kg).

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

The formulations of the present invention are suitable for nebulized inhalation. Typically, the particles present in the formulation for nebulized inhalation have a mass mean aerodynamic diameter (MMAD) of about 0.1 to about 10 μm, preferably about 0.3 to about 8 μm, more preferably about 0.3 to about 7 μm, even more preferably about 0.5 to about 5 μm or about 3 to about 7 μm. The MMAD is selected depending on the type of nebulizer, such as a jet nebulizer, a mesh nebulizer or an ultrasonic nebulizer. Suitably, a multistage cascade impactor (multistage CI) device can be used to size fractionate the aerosol in terms of aerodynamic particle size distribution (APSD). The MMAD is calculated from the APSD and is defined as the diameter above and below which 50% of the particles of the aerosol are larger and smaller by mass, respectively.

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

Formulations suitable for parenteral administration generally have a pH of about 3 to about 9 and an osmolality of about 250 to about 600 mOsm/Kg. pH values above 9 have been reported by I. Usach et al. in Adv. Ther., 36, 2986-2996 (2019) to be associated with tissue necrosis (death of cells in tissue), while values below 3 have been reported to cause pain and phlebitis (inflammation of veins). However, Usach et al. report that " a pH close to physiological is recommended to minimize pain, irritation, and tissue damage." Osmolality above 600 mOsm/Kg has also been reported to cause pain. Usach et al. also recommend that parenteral formulations be formulated as isotonic solutions (osmolality of about 300 mOsm/Kg) and suggest an upper limit of 600 mOsm/Kg to minimize pain.

The formulation (i.e., the formulation of the present invention) is also suitable for inhalation, particularly inhalation by nebulizer.

The formulation comprises a salt of an optionally substituted dimethyltryptamine compound. The formulation according to the invention may comprise one or more salts of an optionally substituted dimethyltryptamine compound. For the avoidance of doubt, if the formulation comprises an ion of an optionally substituted dimethyltryptamine compound and an ion (counterion) opposite in charge to the optionally substituted dimethyltryptamine ion, the formulation comprises an optionally substituted dimethyltryptamine salt. Thus, the optionally substituted dimethyltryptamine salt in the formulation may be formed, for example, by contacting the optionally substituted dimethyltryptamine as a free base with an aqueous solution comprising an excess of buffer relative to the molar amount of the optionally substituted dimethyltryptamine.

The dimethyltryptamine compounds are optionally substituted with deuterium, where a deuterium atom is a hydrogen atom with a neutron added.

In some embodiments, the dimethyltryptamine compound is substituted at the 4- or 5-position with acetoxy or methoxy, or substituted at the 4-position with monohydrogen phosphate. The term "acetoxy" (often abbreviated as OAc) defines a monovalent group derived from acetic acid by removing a hydrogen atom from the OH moiety. The term "methoxy" (often abbreviated as OMe) defines a monovalent group derived from methanol by removing a hydrogen atom from the OH moiety. The term monohydrogen phosphate defines a divalent group of formula _HPO4 , derived from phosphoric acid by removing protons from two of the three OH moieties, thus indicating a substituent of formula -OP(O)(OH)O- ^.

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

For the avoidance of doubt, the 4- and 5-positions of the optionally substituted dimethyltryptamine salts refer to the positions labeled in the following structure (substituents not shown).

The formulation optionally contains a buffering agent separate from the salt (i.e., the buffering agent is not simply a counterion to the optionally substituted dimethyltryptamine). For example, if the salt is N,N-dimethyltryptamine fumarate (i.e., the fumarate salt of N,N-dimethyltryptamine), an amount of buffering agent may be required in addition to the buffering effect provided by the fumarate salt. The term "buffer" is well known in the art and refers to a chemical substance that is included in a formulation to resist changes in pH due to the addition of an acid or base to the formulation. As used herein, the term "buffer" refers to a buffer system or buffering agent. A buffering system suitable for use in the formulations of the present invention includes a weak acid and its conjugate base. A suitable buffering system includes an acid having a pKa value within ±1 of the desired pH of the formulation. For example, if the desired pH of the formulation is about 5.0, a suitable buffering system includes a weak acid having a pKa value of about 4.0 to about 6.0. If the acid in the buffer system has multiple pKa values (i.e., each molecule of the acid can donate multiple protons), at least one of the pKa values must be within the desired pH range for the buffer to be suitable.

The weak acid and conjugate base in a buffer system are in equilibrium with each other. According to Le Châtelier's principle (which states that when a constraint (such as a change in the concentration of a reactant) is imposed on a system in equilibrium, the equilibrium shifts in a way that offsets the effect of the constraint), adding an acid or base to the formulation shifts the position of equilibrium in favor of the conjugate base or weak acid, respectively. As a result, the concentration of free protons in the formulation (i.e., pH) remains relatively unchanged.

As discussed above, the formulations of the present invention have a pH of about 5 to about 6.5, preferably about 5 to about 6, more 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 about 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 includes a buffer. In some embodiments, the buffer is separate from the salt.

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

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

Buffer systems may include acetate and acetic acid; or citrate and citric acid.
In some embodiments, the buffer system comprises acetate and acetic acid, often sodium acetate and acetic acid, or potassium acetate and acetic acid.

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

Preferably, the pharmaceutical formulation comprises an effective amount of an optionally substituted dimethyltryptamine compound for use as a medicine or for use in psychedelic-assisted therapy. This means that the formulation contains a salt of a dimethyltryptamine compound in a dose range that induces a psychedelic experience in a human patient of average weight. Typically, the dose range is about 5 to about 250 mg, or about 10 to about 150 mg, preferably about 10 to about 100 mg, preferably about 20 to about 100 mg (as free base equivalent). In some embodiments, the dose range is about 20 to about 70 mg, or about 20 to about 50 mg. For example, suitable doses are 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 dose ranges and suitable doses described in this paragraph refer to free base equivalent doses.

The concentration of the buffering agent in the formulation is typically sufficient to resist significant pH change of the formulation upon storage of the formulation for 2 weeks (i.e., pH fluctuations are typically less than about 0.1 pH units) while ensuring that the osmolality of the formulation is within the desired range of about 250 to about 350 mOsm/Kg. One of skill in the art can assess and achieve the appropriate buffering agent concentration. Often, the buffering agent concentration is about 15 mM to about 75 mM, e.g., about 20 mM to about 30 mM. In some embodiments, the buffering agent concentration is about 25 mM.

As noted above, the formulation contains a salt of an optionally substituted dimethyltryptamine compound at a concentration of about 10 mg/ml or greater as the free base equivalent.

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

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, octanoic acid, carbonic acid, cinnamic acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, galactaric acid, gentisic acid acid), glucoheptonic 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, nicotinic acid, 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, undecylenic acid.

In some embodiments, when the salt includes 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 may act as a counterion to the dimethyltryptamine compound and as a buffering agent. Thus, when the salt includes such an acid, the formulation may be more stabilized, i.e., degradation of the dimethyltryptamine compound may 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:
(Wherein,
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( ^xaH ) 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.
(Wherein,
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;
^R2b is C( ^xbH ) ₃ ;
R ^3b is C( ^xbH ) ₃ ;
each R ^4b is independently selected from C ₁ -C ₄ alkyl; and each ^xb H, ^yb H and ^z H is independently selected from protium or deuterium.

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

Formula IA is a subformula of IB, it being recognized that each ^zH in the formula is hydrogen.
In some embodiments, the compound has (i) formula IA, where R ^4a is methyl, or (ii) formula IB, where R ^4b is methyl.

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

In some embodiments, the compound is (i) of formula IA according to any preceding embodiment, where n is 0; or n is 1 and R ^1a is in the 4th or 5th position; or the compound is (ii) of formula IB according to any preceding embodiment, where n is 0; or n is 1 and R ^1b is in the 4th or 5th position.

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

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

In some embodiments, the compound has formula IA or IB, where n is 0.
In some embodiments, the compound has (i) formula IA according to any preceding embodiment, where both ^ya H are deuterium, or (ii) formula IB according to any preceding embodiment, where both ^yb H are deuterium.

In some embodiments, the compound has (i) formula IA according to any preceding embodiment, where both ^ya H are protium, or (ii) formula IB according to any preceding embodiment, where both ^yb H are protium.

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

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

In some embodiments, the compound is (i) formula IA according to any preceding embodiment, where each ^xaH is D, or (ii) formula IB according to any preceding embodiment, where each ^xbH is D. In some embodiments, the compound is (i) formula IA according to any preceding embodiment, where ^R2a and ^R3a are both C( ^xaH ) ₃ , or (ii) formula IB according to any preceding embodiment, where ^R2b and ^R3b are both C( ^xbH ) ₃ .

In some embodiments, the compound has (i) formula IA according to any preceding embodiment, where both C( ^xaH ) ₃ are the same, or (ii) formula IB according to any preceding embodiment, where both C( ^xbH ) ₃ are the same.

In some embodiments, the compound has (i) formula IA according to any preceding embodiment, where both ^R2a and ^R3a are _CD3 , or (ii) formula IB according to any preceding embodiment, where both ^R2b and ^R3b are _CD3 .

In some embodiments, the compound has (i) formula IA according to any preceding embodiment, where both ^R2a and ^R3a are _CH3 , or (ii) formula IB according to any preceding embodiment, where both ^R2b and ^R3b are _CH3 .

In some embodiments, the compound has (i) formula IA according to any preceding embodiment, where ^R2a is _CD3 and ^R3a is _CH3 , or (ii) formula IB according to any preceding embodiment, where ^R2b is _CD3 and ^R3b is _CH3 .

In some embodiments, the _C1 - _C4 alkyl may be a deuterated _C1 - _C4 alkyl, such as _CD3 .

For the avoidance of doubt, certain optionally substituted dimethyltryptamine compounds encompassed by the present invention include compounds known in the art by more than one name:
The compound N,N-dimethyltryptamine (DMT) is also known as N,N-dimethyl-1H-indole-3-ethanamine (CAS number 61-50-7).
The compound 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is also known as 5-methoxy-N,N-dimethyl-1H-indole-3-ethanamine (CAS number 1019-45-0).
The compound 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT) is also known as 4-acetoxy-N,N-dimethyltryptamine, O-acetylpsilocin, psilacetin, or [3-[2-(dimethylamino)ethyl]-1H-indol-4-yl]acetate (CAS number 92292-84-7).
The compound 4-hydroxy-N,N-dimethyltryptamine-d ₆ is also known as psilocin (psilocin)-d ₆ or 3-(2-(bis(methyl-d ₃ )amino)ethyl)-1H-indol-4-ol.
The compound N,N-di(trideuteromethyl)tryptamine is also known as N,N-hexadeuterio-dimethyltryptamine or D ₆ -DMT.
The compound 5-hydroxy-N-mono(trideuteromethyl)tryptamine is also known as N-methyl-serotonin-D ₃ (CAS number 1794811-18-9).
The compound N-mono(trideuteromethyl)tryptamine is also known as N-methyl-tryptamine-D ₃ (CAS number 1794745-39-0).
The compound α,α-dideutero-N,N-dimethyltryptamine is also known as D ₂ -DMT, or 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d ₂ .
The compound α,α,β,β-tetradeutero-N,N-dimethyltryptamine is also known as D ₄ -DMT, or 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1,2,2-d ₄ .
The compound α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine is also known as D ₁₀ -DMT or 2-(1H-indol-3-yl)-N,N-bis(methyl-d ₃ )ethan-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.

The salts of the deuterated N,N-dimethyltryptamine compounds defined above can be synthesized according to the synthesis schemes disclosed in WO 2020/245133 A1, WO 2021/116503, and WO 2021/089873 A1 (all to Small Pharma Ltd) and have been found to be particularly advantageous drug substances for the formulations of the present invention. The above deuterated N,N-dimethyltryptamine compounds have been found to exhibit kinetic isotope effects that can be used to extend half-life in biological systems. The inventors have found that formulations of the present invention comprising deuterated N,N-dimethyltryptamine compounds and deuterated substituted N,N-dimethyltryptamine compounds have significantly higher Cmax and exposure in vivo compared to their non-deuterated analogues (see Figures 1A and 1B).

If desired, compositions for use in the formulations of the invention can be prepared that contain an amount of N,N-dimethyltryptamine and a deuterated N,N-dimethyltryptamine compound, where the relative proportion of N,N-dimethyltryptamine to deuterated N,N-dimethyltryptamine compound (as defined above) can be controlled by varying the ratio of lithium aluminum hydride to 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 deuterated N,N-dimethyltryptamine compounds can be used to provide salts of optionally substituted dimethyltryptamine compounds (such that the formulations each contain one or more optionally substituted dimethyltryptamine compounds in the salt form 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, and most preferably 99% or more by weight of the composition.

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

The composition contained in the formulation may contain α-protio-α-deutero-N,N-dimethyltryptamine in an amount of 5% or less, preferably 2% or less, more preferably 1% or less, and most preferably 0.5% or less by weight of the composition.

In some embodiments, the composition contained in the formulation may contain, by weight of the composition, a) 90% or more of an α,α-dideutero-N,N-dimethyltryptamine compound, b) 10% or less of an α-prothio-α-deutero-N,N-dimethyltryptamine compound, and c) 2% or less of N,N-dimethyltryptamine, where the weights of the α,α-dideutero-N,N-dimethyltryptamine compound, the α-prothio-α-deutero-N,N-dimethyltryptamine compound, and the N,N-dimethyltryptamine total 100%.

In some embodiments, the composition contained in the formulation may contain, by weight of the composition, a) 95% or more of an α,α-dideutero-N,N-dimethyltryptamine compound, b) 5% or less of an α-prothio-α-deutero-N,N-dimethyltryptamine compound, and c) 1% or less of N,N-dimethyltryptamine, where the weights of the α,α-dideutero-N,N-dimethyltryptamine compound, the α-prothio-α-deutero-N,N-dimethyltryptamine compound, and the N,N-dimethyltryptamine compound total 100%.

For the avoidance of doubt, N,N-dimethyltryptamine may be absent from the composition, or may be present in trace amounts in the composition, or may be present in the composition in an amount of 2% or less by weight of the composition, or may be present 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-mentioned 2% or less or 1% or less of N,N-dimethyltryptamine should be understood to include non-deuterated 4, 5, 6 or 7-substituted N,N-dimethyltryptamines, such as 5-methoxy-N,N-dimethyltryptamine. By way of example, in a composition comprising 5-methoxy-α,α-dideutero-N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine may be absent from the composition, or may be present in trace amounts in the composition, or may be present in an amount of 2% or less or 1% or less by weight of the composition.

The term "α,α-dideutero-N,N-dimethyltryptamine compound" as used herein includes the compound α,α-dideutero-N,N-dimethyltryptamine (d ₂ -DMT) as well as α,α-dideutero-N,N-dimethyltryptamine compounds that are deuterated at other positions, such as α,α,β,β-tetradeutero-N,N-dimethyltryptamine (d ₄ -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), 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-prothio-α-deutero-N,N-dimethyltryptamine compound" refers to the compound α-prothio-α-deutero-N,N-dimethyltryptamine (d ₁ -DMT) as well as α-prothio-α-deutero-N,N-dimethyltryptamine compounds that are deuterated at other positions, such as α-prothio-α,β,β-trideutero-N,N-dimethyltryptamine (d ₃ -DMT), α-prothio-α-deutero-N,N-di(trideuteromethyl)tryptamine (d ₇ -DMT), α-prothio-α,β,β-trideutero-N,N-di(trideuteromethyl)tryptamine (d ₉ -DMT), and the like. -DMT), and substituted α-prothio-α-deutero-N,N-dimethyltryptamine compounds, such as 5-methoxy-α-prothio-α-deutero-N,N-di(trideuteromethyl)tryptamine. In some embodiments, the composition contained in the formulation may comprise: a) 90% or more, preferably 95% or more, of an optionally substituted N,N-di(trideuteromethyl)tryptamine compound. The optionally substituted N,N-di(trideuteromethyl)tryptamine compound may be 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-N,N-di(trideuteromethyl)tryptamine, 5-methoxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine, and 5-methoxy-α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine.

In some embodiments, the salt is a salt of an optionally substituted dimethyltryptamine compound with 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, the salts can include:
any one or combination of N,N-dimethyltryptamine, α-monodeutero-N,N-dimethyltryptamine, α,α-dideutero-N,N-dimethyltryptamine, α,β-dideutero-N,N-dimethyltryptamine, α,α,β-trideutero-N,N-dimethyltryptamine, α,β,β-trideutero-N,N-dimethyltryptamine, α,α,β,β-tetradeutero-N,N-dimethyltryptamine, N,N-di(trideuteromethyl)tryptamine (d ₆ -DMT), and α,α-dideutero-N,N-di(trideuteromethyl)tryptamine (d ₈ -DMT); or
Any one or combination of 4-acetoxy-N,N-dimethyltryptamine, 4-acetoxy-α-monodeutero-N,N-dimethyltryptamine, 4-acetoxy-α,α-dideutero-N,N-dimethyltryptamine, 4-acetoxy-N,N-di(trideuteromethyl)tryptamine, 4-acetoxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine, and 4-acetoxy-α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine; or
Any one or combination of 5-methoxy-N,N-dimethyltryptamine, 5-methoxy-α-monodeutero-N,N-dimethyltryptamine, 5-methoxy-α,α-dideutero-N,N-dimethyltryptamine, 5-methoxy-N,N-di(trideuteromethyl)tryptamine, 5-methoxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine, and 5-methoxy-α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine; or
Any one or combination of 4-monohydrogen phosphate-N,N-dimethyltryptamine, 4-monohydrogen phosphate-α-monodeutero-N,N-dimethyltryptamine, 4-monohydrogen phosphate-α,α-dideutero-N,N-dimethyltryptamine, 4-monohydrogen phosphate-N,N-di(trideuteromethyl)tryptamine, 4-monohydrogen phosphate-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine, and 4-monohydrogen phosphate-α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine; 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).

In some embodiments, the salt is dimethyltryptamine fumarate, i.e., it contains dimethyltryptamine and fumaric acid as an optionally substituted dimethyltryptamine compound.

Dimethyltryptamine compounds (used interchangeably herein with optionally substituted dimethyltryptamine compounds) can have a purity of about 80-100%. Sometimes the purity is about 90-100%, e.g., about 95-100%. Typically, dimethyltryptamine compounds have a purity of about 99-100%, i.e., a purity of 99% or greater. Purity percentages herein are as determined by HPLC.

The formulations of the invention are particularly advantageously prepared using a drug substance comprising an optionally substituted dimethyltryptamine compound or salt thereof of greater than 99% purity. Drug substance means an active ingredient intended to provide pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure or any function of the patient, as understood in the art, but does not include intermediates used in the synthesis of such ingredients. It is understood that a drug substance may contain one or more such active ingredients.

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

The concentration of the optionally substituted salt of the dimethyltryptamine compound in the formulation may be any desired concentration to achieve 10 mg/mL or more in free base equivalent, provided that the osmolality of the formulation is about 250 to about 350 mOsm/Kg. The dimethyltryptamine compound may be at a concentration of more than 20 mg/mL. A concentration of 28 mg/mL of dimethyltryptamine provides about 148 mOsm/kg (about 296 mOsm/kg, taking into account the counterion). This allows for an additional 54 mOsm/kg to be provided by other components of the formulation, such as any buffering agents. The salt of the dimethyltryptamine compound may be at a concentration of more than 20 mg/mL, more than 25 mg/mL, more than 30 mg/mL, more than 40 mg/mL, more than 50 mg/mL, more than 60 mg/mL, or more than 70 mg/mL (as free base equivalent). Additionally or alternatively, the optionally substituted dimethyltryptamine compound may be at a concentration of 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 (as free base equivalent). Typically, the optionally substituted dimethyltryptamine compound may be at a concentration of about 25 mg/ml (as free base equivalent).

The total dosage of the salt of an optionally substituted dimethyltryptamine compound used in any of the fourth to sixth aspects of the present 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 discussed above, the formulations of the present invention have an osmolality of about 250 to about 350 mOsm/Kg. In some embodiments of the present invention, the osmolality of the formulations of the present invention is about 250 to about 400 mOsm/Kg. In some embodiments, the osmolality of the formulations of the present invention is about 275 to about 325 mOsm/Kg, e.g., about 280 to about 310 mOsm/Kg. Typically, the osmolality of the formulations is about 295 to about 305 mOsm/Kg.

Sometimes, the concentration of the optionally substituted dimethyltryptamine salt and optional buffer in the formulation produces the desired osmolality. Alternatively, the desired osmolality may be achieved by including one or more tonicity agents in the formulation. Thus, in some embodiments, the formulation further comprises an isotonicity agent. As used herein, an isotonicity agent is defined as a chemical that, when contained within the formulation, increases the osmolality of the formulation. As discussed above, osmolality is the number of osmotically active particles (number of solute particles) in 1 kg of solution. Thus, chemicals that act as solutes when incorporated into the formulation are included in the definition of an isotonicity agent.

If the formulation further comprises an isotonicity agent, the concentration of the isotonicity agent will depend on the concentration of other components in the formulation, such as optionally substituted dimethyltryptamine and buffering agents. For example, if the formulation without the isotonicity agent has an osmolality of about 60 mOsm/kg, at least about 190 mOsm/kg will be provided by the isotonicity agent (e.g., 95 mM sodium chloride). M. F. Powell, T. Nguyen, and L. Baloian provide a review of excipients suitable for parenteral administration (administration other than by mouth or digestive tract) in PDA J. Pharm. Sci. Technol., 52, 238-311 (1998). All of the soluble excipients that can be administered intravenously that are described in this review contribute to the osmolality 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 the group consisting of ethanol, citric acid, trisodium citrate, benzalkonium chloride, microcrystalline cellulose, sodium carboxymethylcellulose, chlorobutanol, disodium edetate, glycerin, hydrochloric acid, methylparaben, polyethylene glycol, propylene glycol, propylparaben, sodium saccharin, sodium hydrogen carbonate, sodium hydrogen sulfate, sodium hydrogen sulfite, sodium chloride, sodium hydroxide, sodium metabisulfite, sodium phosphate, sodium citrate, sulfuric acid, trisodium citrate, tromethamine, and mixtures thereof.

Some additives act as co-solvents. Solvents or co-solvents suitable for use in the formulations of the present invention may be selected from ethanol, polyethylene glycol, propylene glycol, and mixtures thereof. In some embodiments, the formulation includes a co-solvent. In some embodiments, the formulation does not include a co-solvent. In particular, when the salt of the optionally substituted dimethyltryptamine compound is a fumarate salt, such as N,N-dimethyltryptamine fumarate or α,α-dideutero-N,N-dimethyltryptamine fumarate, the formulation does not include a co-solvent.

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

It is understood that some additives may have multiple functions. For example, citric acid may be utilized as a buffer component, a flavoring agent, or an antioxidant. pH adjusters, such as hydrochloric acid, may also function as tonicity agents.

In some embodiments, the tonicity agent is any one or combination selected from the group consisting of: dextrose (glucose), sodium chloride; phosphoric acid; phosphate salts, e.g., sodium phosphate or potassium phosphate; acetic acid; ethanol; citric acid; citrate salts, 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 mentioned above can be used to buffer the formulation (e.g. acetate, acetic acid, citrate, citric acid, phosphate, phosphoric acid). For the avoidance of doubt, if one of the tonicity agents listed above is used as a buffering agent, it is not also a defined tonicity agent, i.e. if the formulation further comprises an isotonicity agent, the tonicity agent is different from the buffering agent. Typically the isotonicity agent is sodium chloride or dextrose.

In some embodiments, the formulation includes a tonicity agent, such as sodium chloride, at a concentration of about 120 mM to about 140 mM, e.g., about 125 mM to about 135 mM. Sometimes, the concentration of the tonicity agent (e.g., sodium chloride) in the formulation is about 130 mM.

In some embodiments, the formulation consists essentially of an optionally substituted dimethyltryptamine salt, water, a base agent, optionally a buffering agent, and optionally a tonicity agent and/or a pH adjusting agent. This means, for example, that the presence of additional components in the formulation is permitted, but the amount of such additional components does not substantially affect the essential properties of the formulation in a detrimental manner. Given that the intention of including the optionally substituted dimethyltryptamine salt, water, a base agent, optionally a buffering agent, and optionally a tonicity agent and/or a pH adjusting agent in the formulation is to produce a pharmaceutical formulation of optionally substituted dimethyltryptamine that is suitable for both intramuscular injection and nebulized inhalation and is stable on storage for at least several weeks, it is understood that the inclusion of components that substantially affect the stability or injectability of the formulation in a detrimental manner (e.g., its osmolality or pH) is excluded from the formulation. On the other hand, the presence of components that do not substantially affect the stability or injectability of the formulation in a detrimental manner is understood to be 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, Eighth Edition, Pharmaceutical Press, London 2017.

The base agent adjusts the pH of the formulation to the required pH range, e.g., pH 5 to pH 6. The pH of a formulation containing an optionally substituted dimethyltryptamine salt, water, and a buffer is often low, e.g., below pH 5, and therefore pH adjustment with a base agent may be necessary. One skilled in the art can evaluate an appropriate base agent to adjust the pH of the solution without risking decomposition of the optionally substituted dimethyltryptamine salt. The base agent may be sodium hydroxide or potassium hydroxide.

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

In some embodiments, the formulation further comprises an antimicrobial preservative. Antimicrobial preservatives suitable for use in the formulations of the present invention include n-propyl parahydroxybenzoate, benzalkonium chloride, and mixtures thereof.

Preferably, the formulation has an oxygen content of less than 5 ppm, preferably less than 2 ppm, for example between 0.1 ppm and 2 ppm. A person skilled in the art can determine the oxygen content of a formulation using any technique known to be suitable 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).

The formulation can be stored in any suitable container. In some embodiments, the container can have a volume of 10 ml or less, 5 ml or less, 4 ml or less, 2 ml or less, 1 ml or less, or 0.5 ml or less. In some embodiments, to further improve the degradation of the formulation, the formulation is stored in a container adapted to prevent the transmission of ultraviolet light (such as an amber glass vial). In other embodiments, the container in which the formulation is stored is not so adapted (e.g., it may be made of clear glass), and protection against ultraviolet light is optionally provided by a secondary package (e.g., a package into which the container containing the formulation may be placed). In many cases, the container is airtight and the formulation is stored under an inert atmosphere, e.g., under nitrogen or argon, typically under nitrogen. The formulation can be stored at room temperature, e.g., about 20 to about 30° C., or at a lower temperature, e.g., about 2 to about 8° C. Alternatively, it may be stored in a freezer to further improve the degradation of the formulation.

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

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

There is also provided 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 a base agent and, optionally, a buffering agent (separate from said salt), and/or a tonicity agent, and/or a pH adjusting agent,
Here, 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 buffering agent, as well as other features and embodiments of the first aspect of the invention 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 buffering agent may comprise acetate and acetic acid.

The optionally substituted dimethyltryptamine salt in the kit may be in solid, e.g., powdered or crystalline form. To improve degradation of the optionally substituted dimethyltryptamine salt in solid form, the salt may be lyophilized (freeze-dried) prior to incorporation into the kit. Lyophilization of the salt involves freezing the salt in the presence of a solvent (typically water) and separating the solvent from the salt by sublimation.

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

In a third aspect, the present invention provides a method of preparing the pharmaceutical formulation of the first aspect. The method comprises contacting an optionally substituted dimethyltryptamine salt, a base agent, optionally a buffering agent, and optionally a tonicity agent and/or a pH adjusting agent with water. In a preferred embodiment of the third aspect of the invention, the optionally substituted dimethyltryptamine salt comprises an effective amount of the optionally substituted dimethyltryptamine compound for use in pharmacologically assisted psychotherapy (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. For the avoidance of doubt, the embodiments of the first aspect of the invention apply mutatis mutandis to the third aspect. For example, the salt may be a fumarate salt of dimethyltryptamine; the buffering agent may comprise acetic acid and acetate salts or phosphoric acid and phosphate salts; and the tonicity agent may comprise sodium chloride.

It will be appreciated that the contacting of the present method can be accomplished in a variety of ways. Often, the optionally substituted dimethyltryptamine salt is dissolved in water to form a first solution, to which a base agent and optionally a buffering agent are added and dissolved to form a second solution. If an isotonicity agent or pH adjusting agent is used, it is often added and dissolved in the second solution. Additional solvents or co-solvents may be added to the first solution or the second solution.

In some embodiments, an aqueous solution of a buffering agent is contacted with the salt, where the aqueous solution of the buffering agent has a pH of about 5 to about 6.5, e.g., a pH of about 5 to about 6, or a pH of about 5.3 to about 6, or a pH of about 5.5 to about 6. In some embodiments, the aqueous solution of the buffering agent may have a pH of 5 to 6. In some embodiments, the aqueous solution of the buffering agent has a pH of about 5.5 or about 6.

The optionally substituted dimethyltryptamine salt in the formulation can be formed by contacting the optionally substituted dimethyltryptamine as a free base with an aqueous solution containing a suitable amount of a buffer to stabilize the pH and act as a counterion to the optionally substituted dimethyltryptamine when protonated. Thus, the method of the invention can include contacting the optionally substituted dimethyltryptamine in the free base form with a buffer, water, and optionally an isotonicity agent.

The method further comprises using a base agent to adjust the pH of the solution resulting from said contacting. The pH of the solution resulting from the contacting step is usually low, so a subsequent pH adjustment step is necessary. The pH adjustment often comprises contacting the solution with a suitable base agent, e.g. a strong base agent. A person skilled in the art can assess which base is suitable to adjust the pH of the solution resulting from said contacting without risking decomposition of the optionally substituted dimethyltryptamine salt. The pH of the solution resulting from said contacting is adjusted with a base agent, which may be a suitable alkali, preferably sodium hydroxide or potassium hydroxide.

In some embodiments, the pH is further adjusted with a pH adjuster to achieve the desired pH. The pH adjuster may 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 adjuster 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 formulation of the present invention includes a pH adjuster that is hydrochloric acid.

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

As mentioned above, dimethyltryptamine may have a therapeutic role in the treatment of depression, obsessive-compulsive disorder, and substance abuse disorders (S. A. Barker, 2018, supra). Thus, in a fourth aspect, the invention provides a formulation of the first aspect or a kit of the second aspect for use as a medicine or in combination with psychotherapy. In a preferred embodiment of the fourth aspect of the invention, the formulation comprises an effective amount 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.

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

Often, the psychiatric 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) anorexia (avoidant disorder). Often, the disorder is selected from the group consisting of major depressive disorder, treatment-resistant major depressive disorder, postpartum depression, obsessive-compulsive disorder, and eating disorders (such as compulsive eating disorder).

In a sixth aspect, the present invention provides a method of treating a psychiatric or neurological disorder comprising administering to a patient in need thereof a formulation of the first aspect. In a preferred embodiment of the sixth aspect of the invention, the formulation comprises an effective amount of an optionally substituted dimethyltryptamine compound for use in pharmacologically assisted psychotherapy or psychedelic assisted therapy in a volume of 5ml or less, preferably 4ml or less, 3ml or less, 2.5ml or less, 2ml or less, 1ml or less, or 0.5ml or less. The psychiatric or neurological disorder may be any of those described in relation to the fifth aspect. For example, the disorder may be selected from the group consisting of major depressive disorder, treatment-resistant 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 (i.e., in pharmacologically assisted psychotherapy).

To treat a disorder (disease), the formulation contains an effective amount of a dimethyltryptamine compound, i.e., an amount sufficient to reduce or stop the rate of progression of the disorder or to ameliorate or cure the disorder, thereby producing the desired therapeutic or inhibitory effect.

Administration to a patient typically involves injection of the formulation, as the formulation is suitable for intramuscular injection.
The formulation may be suitable for bolus injection, where a discrete amount of the optionally substituted dimethyltryptamine salt is administered in a single injection to rapidly raise the concentration of the optionally substituted dimethyltryptamine in the body.

Typically, IM injections are administered at a dose of 5 ml or less using a 19-27 needle gauge, more typically a 20-25 needle gauge. The concentrated formulations of the present invention may use a higher needle gauge, preferably a 22-27, allowing for administration of smaller volumes and reducing pain associated with the injection. Injection volumes can be from about 0.5 to about 4 ml, from about 0.5 to about 3 ml, or from about 0.5 to about 2.5 ml.

The formulation is also suitable for inhalation by nebulizer, so administration to a patient may include inhalation of the formulation using a nebulizer.

When the formulations of the present 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 present invention particularly suitable for low doses (volumes). This has the advantage that the IM formulations can be administered to a wider range of injection sites. The high concentration and low dose of the formulations may also allow the use of a wider range of nebulizer devices and allow 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 that has been lyophilized (i.e. freeze-dried).

Lyophilization (also known as freeze-drying or cryodesiccation) is a drying process carried out at low temperatures. Lyophilization generally involves lowering the temperature and pressure below the triple point of the substance and removing the frozen solvent (e.g., water ice) by sublimation. For aqueous compositions as disclosed herein, lyophilization can be carried out at temperatures of about -50°C to -80°C, preferably about -70°C, and pressures 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, the method comprising drying a 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 a lyophilized powder formulation prepared by the method of the eleventh aspect with water to provide a formulation comprising a salt of an optionally substituted dimethyltryptamine compound, a buffer separate from said salt, a base and water to provide a 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 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. For the avoidance of doubt, the embodiments of the first aspect of the invention apply mutatis mutandis to the tenth, eleventh and twelfth aspects of the invention.

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

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

Synthesis of compounds for use in the formulations of the 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 Small Pharma Ltd). For deuterated compounds, the degree of deuteration was 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
220.9 g of N,N-DMT (as the free base) was prepared as the N,N-DMT fumarate salt using the chemistry disclosed in Scheme 2 and the Examples section of WO 2021/089873. Six additional partially deuterated mixtures of 4-6 g were also prepared using varying conditions.

Example 2: Deuterated N,N-dimethyltryptamine
Synthesis of Deuterated Mixtures of DMT Compounds A modified synthesis method using a solid _LiAlH4 / _LiAlD4 mixture was employed in which 1.8 equivalents of _LiAlH4 / _LiAlD4 were used (for 0.9 equivalents of _LiAlH4 , using the process described above for N,N-dimethyltryptamine as disclosed in WO 2021/089873). Deuterated dimethyltryptamine compounds include α-protio,α-deutero-dimethyltryptamine and α,α-dideutero-dimethyltryptamine.

Data for the six deuteration reactions are shown in the table below:

5- and 4-substituted dimethyltryptamine and deuterated dimethyltryptamine compounds can be prepared by a similar process 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 synthesis of α,α-dideutero-5-methoxydimethyltryptamine below) or 4-methoxyindole-3-acetic acid, respectively, both of which are commercially available (for 5-methoxyindole-3-acetic acid, see e.g. Sigma-Aldrich (code M14935-1G) and for 4-methoxyindole-3-acetic acid, see e.g. 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 number 520-52-5) are also commercially available.

Example 3: Synthesis of α,α-dideutero-5-methoxydimethyltryptamine
Stage 1:
A 100 mL three-neck 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) under _N2 . EDC.HCl (4.459 g, 23.261 mmol) was then charged in portions over 15 min at <30 °C. The reaction mixture was stirred at ambient temperature for 1 h, then 2 M dimethylamine (14.54 mL, 29.078 mmol) was added dropwise over 15 min at <25 °C. After stirring for 1 h, HPLC showed no SM remained. The reaction mixture was charged with 10% _K2CO3 (20 mL) and stirred for 5 min before being allowed to separate. 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), dried over _MgSO4 , and filtered. The filtrate was concentrated under reduced pressure at 45 °C to give 3.898 g (yield = 87%) of the active product with a purity of 95.7% by HPLC.

Stage 2:
A 100 mL three-neck flask was charged with the stage 1 methoxy derivative (3.85 g, 16.586 mmol) and THF (19.25 mL) under _N2 . 2.4 M _LiAlD4 in THF (6.22 mL, 14.927 mmol) was then added dropwise over 30 min at <40 °C. The reaction mixture was heated to 60 °C for 1 h and HPLC showed 0.1% SM remaining. The reaction mixture was then cooled to ambient temperature and quenched by dropwise addition of 25% Rochelle's salt (38.5 mL) over 30 min at <30 °C. The resulting suspension was stirred for 1 h and then separated. The lower aqueous layer was removed and the upper organic layer was washed with saturated brine (9.6 mL). The organics were then dried over _MgSO4 , filtered, concentrated under reduced pressure and azeotroped from EtOH (10 mL x 2). This gave 3.196 g of active product (yield=88%) with a purity of 91.5% by HPLC.

Stage 3:
A 50 mL three-neck flask under _N2 was charged with a solution of fumaric acid (1.675 g, 14.430 mmol) and stage 2 methoxy derivative (3.15 g, 14.299 mmol) in EtOH (37.8 mL). The mixture was then heated to 75 °C for 1 h, but as expected no solution was obtained, and the mixture was further heated to reflux (78 °C), but again no solution was obtained. Thus, the suspension was cooled to 0-5 °C, filtered, washed with EtOH (8 mL x 2), and then dried at 50 °C overnight. This afforded 3.165 g (yield = 65%) of material with a purity of 99.9% by HPLC.

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

Example 4: d6 _- Dimethyltryptamine
Synthesis of _d6 -DMT
Stage 1

EDC.HCl (15.7 g, 81.90 mmol) was added to 3-indoleacetic acid (12.0 g, 68.50 mmol) and _HOBt.H2O (1.16 g, 75.75 mmol) in DCM (108 mL) at room temperature. The reaction was stirred for 1 hour, then N,N-diisopropylethylamine (DIPEA) (35.6 mL, 205.75 mmol) and _d6 -dimethylamine.HCl (9.0 g, 102.76 mmol) were added (temperature kept below 30°C). The reaction was stirred at room temperature for 1 hour, then analyzed by HPLC, which showed 65.6% product and 28.9% 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 showed no change in conversion. Aqueous potassium carbonate (6.0 g in 54 mL water) was added and the phases were separated. The aqueous phase was extracted with DCM (2×30 mL). The combined organics were washed with brine (2×30 mL), then aqueous citric acid (20% w/w, 50 mL), dried over _MgSO4 , and filtered. The filtrate was removed and the resulting solid was slurried with TBME (120 mL) and isolated by filtration. Purification by flash column chromatography afforded 8.34 g of the desired product (58% yield). ¹ H NMR confirmed the identity of the product.

Stage 2

_LiAlH4 (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 h. HPLC analysis indicated 97.3% product formed and stage 1 was completely consumed. The reaction was cooled to room temperature and quenched with aqueous Rochelle's salt (10 g, in 30 mL water) at <30°C. After stirring for 1 h, the phases were separated. The aqueous phase was extracted with THF (20 mL). The combined organics were washed with brine (20 mL), dried over _MgSO4 , filtered and stripped (azeotroped with ethanol, 20 mL) to give the desired product as an amber oil (3.97 g). ¹ H NMR confirmed the identity of the product and showed 8.5% ethanol present (THF not included) giving an active yield of 3.63 g (97%).

Stage 3

_d6 -DMT free base (3.6 g active, 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 (a solid crystallized during heating and did not redissolve). The resulting suspension was cooled to 0-5°C and stirred for 1 h. The solid was isolated by filtration, washed with ethanol (2 x 7 mL) and dried. Further drying in a vacuum oven at 50°C afforded the desired _d6 -DMT fumarate salt (4.98 g, 87%).

Example 5: d8 _- Dimethyltryptamine
Synthesis of d ₈ -DMT Stage 1 (coupling of 3-indoleacetic acid with d ₆ -dimethylamine) was carried out according to the process described for Stage 1 of Example 4 above.

Stage 2

_LiAlD4 (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 h. HPLC analysis indicated that 97.3% product had formed and stage 1 was completely consumed. The reaction was cooled to room temperature and quenched with aqueous Rochelle's salt (10 g, in 30 mL water) at <30°C. After stirring for 1 h, the phases were separated. The aqueous phase was extracted with THF (20 mL). The combined organics were washed with brine (20 mL), dried over _MgSO4 , filtered and stripped (azeotroped with ethanol, 20 mL) to give the desired product as an amber oil (4.01 g). ¹ H NMR confirmed the identity of the product and showed the presence of 8.6% ethanol (THF not included) giving an active yield of 3.66 g (97%).

Stage 3

_d8 -DMT free base (3.6 g active, 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 (a solid crystallized during heating and did not redissolve). The resulting suspension was cooled to 0-5°C and stirred for 1 h. The solid was isolated by filtration, washed with ethanol (2 x 7 mL) and dried. Further drying in a vacuum oven at 50°C afforded the desired _d8 -DMT fumarate salt (4.62 g, 81%).

Example 6: d6-5 _- Methoxydimethyltryptamine
Synthesis of _d6-5 -MeO-DMT
Stage 1
Coupling of 5-methoxy-3-indoleacetic acid with _d6 -dimethylamine was carried out on a 20 g scale by a process similar to that described for Stage 1 of Example 4 above. Purification by flash column chromatography gave a light brown solid (87%) with a purity of 97.8% by HPLC. Molecular weight: 238.32.

Stage 2
The product of Stage 1 of Example 6 was reacted with _LiAlH4 in THF according to the process described for Stage 2 of Example 4. The reaction was carried out on a 9 g scale to produce _d6-5 -MeO-DMT as an amber oil in 8.22 g yield (activity 7.40 g, 87.3%) with 98.4% purity by HPLC. Molecular weight: 224.34.

Stage 3
The fumarate salt of _d6-5 -MeO-DMT was prepared according to the process described for stage 3 of Example 4. 6.04 g (65%) of an off-white solid was obtained with a purity of 99.61% by HPLC. NMR and XRPD data showed that the hemi-salt was isolated. Molecular weight: 564.74 (as hemi-salt).

Example 7: d8-5 _- Methoxydimethyltryptamine
Synthesis of _d8-5 -MeO-DMT
Stage 1
Coupling of 5-methoxy-3-indoleacetic acid with _d6 -dimethylamine was carried out on a 20 g scale by a process similar to that described for Stage 1 of Example 4 above. Purification by flash column chromatography gave a light brown solid (87%) with a purity of 97.8% by HPLC. Molecular weight: 238.32.

Stage 2
The product of Stage 1 of Example 7 was reacted with _LiAlD4 in THF on a 9 g scale according to the process described for Stage 2 of Example 5. Purification afforded 8.12 g (7.58 g activity, 88.7%) of the product _d8-5 -MeO-DMT as an amber oil with a purity of 97.9% by HPLC. Molecular weight: 226.35.

Stage 3
The fumarate salt of _d8-5 -MeO-DMT was prepared according to the process described for stage 3 of Example 4. 9.6 g of product _d8-5 -MeO-DMT fumaric acid was obtained with a purity of 99.71% by HPLC. Molecular weight: 342.42

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

Example 8: In vivo pharmacokinetic (PK) profile study
The pharmacokinetic (PK) profiles of N,N-dimethyltryptamine (DMT, SPL026), α,α-bis-deuterio-N,N-dimethyltryptamine (d ₂ -DMT, SPL028i), and α,α-bis-deuterio-N,N-hexadeuterio-dimethyltryptamine (d ₈ -DMT, SPL028viii) following intramuscular administration were investigated in vivo in rats.

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

To directly compare SPL026 and SPL028viii between animals and to avoid confounding effects from between-animal variability, cassette doses of 3.5 mg/kg SPL026 fumarate and 3.5 mg/kg SPL028viii fumarate were administered IM as a single dose to four different male animals. 3.5 mg/kg and 10 mg/kg SPL028i fumarate were administered IM as a single dose to four different male animals.

Dosing Procedure On the morning of dosing, animals were weighed and dosed based on body weight and specific dosing volume.
The IM administration device consisted of an appropriately sized insulin syringe. The injection site was shaved the morning of administration. During administration, the dose was injected directly into the thigh muscle.

PK Sampling After dosing, serial whole blood samples (approximately 200 μL) are collected from a lateral tail vein via an indwelling cannula into separate _K2EDTA -treated containers. Samples were collected at the following times post-dose:
IM: Pre-dose, 5, 10, 25, 30, 45, 60, 90, 120, 180 min. Blood samples were placed in a cooling block and then centrifuged at 10,000g for 2 min at approximately 4°C, and the resulting plasma was withdrawn. All samples were stored at approximately -80°C.

Bioanalysis of DMT, _d8 -DMT and _d2 -DMT in rat _K2EDTA plasma was performed using LC-MS/MS. The following table details the two methods that were qualified:

The concentrations of DMT and _d8 -DMT were quantified using 20.0 μL of rat plasma at a target lower limit of quantification (LLOQ) of approximately 0.310 ng/mL for DMT, _d8- DMT, and _d2- DMT, and were characterized by the following method:
- Linearity of the assay
A calibration curve is prepared in duplicate containing 8 or more concentration levels and a control blank and zero (IS only).
Acceptance Criteria: At least 75% of the calibration standards (non-zero samples) must have a relative error (RE) of less than ±20% of the prepared nominal concentration (less than ±25% RE at the lower limit of quantitation).
·sensitivity
Minimum signal to noise at LLOQ concentration is 5:1.
・Precision and Accuracy
A single analytical batch containing low, medium, and high concentration QCs was replicated (n = 6).
Acceptance criteria: Within-batch precision (CV) and accuracy (RE) ≤ 20%
Selectivity
Qualitatively evaluate chromatograms of control blank matrices from at least one source to identify the presence of potential interfering peaks.
Acceptance Criteria: The response of coeluting interferences must be less than or equal to 25% of the LLOQ calibration standard peak area. The response of coeluting interferences must be less than 5% of the internal standard zero sample peak area.
Stability
Stability of QC Med in matrix in replicates (minimum n=3) is assessed for DMT alone at the sample processing temperature for at least 2 hours.
Acceptance criteria: precision (CV) and accuracy (RE) ≤ 20%.
・Carryover
The upper limit of quantification (ULOQ) is assessed in at least one control blank matrix sample (carry-over blank) analyzed immediately after the calibration standards.
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.

PK parameters
Plasma pharmacokinetic parameters of DMT (SPL026), d ₈ -DMT (SPL028viii), and d ₂ -DMT (SPL028i) were derived by non-compartmental analysis using the plasma concentration-time profiles of each animal.

Results The results are shown in Figure 1. These data demonstrate that overall exposure was greater with _d8 -DMT (SPL028viii) and _d2 -DMT (SPL028i) compared to DMT (SPL026) after IM administration of 3.5 mg/kg.
1A and 1B are linear and semi-log plots showing the time course of mean DMT (SPL026), _d8- DMT (SPL028viii), and _d2 -DMT (SPL028i) concentrations following IM administration of 3.5 mg/kg fumarate (added as a cassette) in vivo.
Fig. 1A - Linear plot, Fig. 1B - Semi-log plot, SEM error bars

2A and 2B are linear and semi-log plots showing the time course of mean d ₂ -DMT (SPL028i) concentrations in vivo following IM administration of 3.5 mg/kg and 10 mg/kg of the fumarate salt.
Fig. 2A - Linear plot, Fig. 2B - Semi-log plot, SEM error bars

Pairwise ANOVA was performed to analyze the effect of dose group on PK parameters.Statistically significant differences were observed in the mean areas under the curve from time 0 to estimated infinity ( _AUC0-inf ) between SPL026 and SPL028viii and between SPL026 and SPL028i after administration of equivalent IM doses in both groups, indicating that SPL028viii and SPL028i had significantly higher systemic exposure after a single IM dose compared to SPL026.

Compared to DMT (SPL026), d ₈ -DMT (SPL028viii) and d ₂ -DMT (SPL028i) had significantly higher Cmax following IM administration (p=0.005 ^** ).
The Cmax and _AUC0-inf of _d2- DMT (SPL028i) at 10 mg/kg were increased by 144% and 237%, respectively, compared with the 3.5 mg/kg dose. The dose-response relationship levels for Cmax and AUC0 _-inf were significantly different from each other (p<0.05 ^* and p<0.001 ^*** , respectively), suggesting a significant dose-response relationship.

The present invention is further described by the following embodiments.

FORMULATION DEVELOPMENTAll concentrations listed below are expressed as the free base (i.e., without the fumarate counterion present) and to do so, a correction factor of 1.59 has been applied to the particular batch of drug substance supplied.

Experimental details
The stability of N,N-dimethyltryptamine (DMT) fumarate formulations was evaluated at a concentration of 20 mg/mL at pH 4, 5, 6, 7, 8, and 9. To vary the pH, the Britton-Robinson (BR) buffer system (also known as the universal buffer) was used. The BR buffer system typically consists of a mixture of 0.04 M boric acid, 0.04 M phosphoric acid, and 0.04 M acetic acid, titrated to the desired pH with 0.2 M sodium hydroxide. This system allows the pH to be varied while keeping the osmolarity constant.

Seven solutions containing DMT fumarate at a nominal concentration of 20 mg/mL were prepared in Britton-Robinson (B-R) buffer. DMT fumarate was dissolved in each test formulation (DMT fumarate was highly soluble and only required swirling and shaking for each test formulation), and the pH of each test formulation was adjusted to pH 4, 5, 6, 7, 8, and 9 with 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 overnight storage under ambient conditions, the pH of each solution was measured and 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 precipitate was present) contained approximately the same content of DMT fumarate.

pH Stability The pH stability of DMT fumarate at a nominal concentration of 2.5 mg/mL was evaluated in 40 mM Britton-Robinson buffer over the buffer pH range of 4 to 9 (nominal). The pH of each formulation was measured upon preparation, after 7 days of storage at 40°C, and after an additional 3 days at 40°C and 7 days at 50°C (i.e., a total of 10 additional days of storage). The formulations were analyzed for content (assay) and related substances upon preparation, after the subsequent 7 days of storage, and after 17 days of storage.

For further testing, two extra aliquots of the pH 7 (nominal) solution were taken, one sparged with nitrogen and the other exposed to intense UV light for 4 hours, equivalent to 1 ICH unit (200 watt-hours UVA, 600,000 luxhours).

Upon preparation of each formulation, a decrease in pH ranging from 0.14 units (pH 4 formulation) to 1.29 units (pH 9 formulation) was observed, due to the acidic nature of the formulation ingredients. Once prepared, the pH of each formulation remained stable at two subsequent stability time points (Table 1).

The concentration of DMT fumarate was measured by HPLC at the time of preparation and at two subsequent stability times (Table 2). All results confirmed correct preparation with no significant concentration changes on either days 7 or 17. The only significant change over the course of the experiment was a decrease in concentration after light stressing an aliquot of the nominal pH 7 formulation. This was accompanied by a significant increase in observed degradants.

For related substances, only peaks greater than 0.05% of the total peak area are reported. A summary of related substances data is given in Table 3, with individual values given in Tables 4 (storage at 40°C for 7 days) and 5 (storage at 40°C for 10 days followed by storage at 50°C for 7 days).

Upon preparation, no related substance peaks were present. At 7 days, only the pH 9 formulation showed a peak at a relative retention time of 1.11. Very few additional peaks were observed after 7 days of elevated temperature storage, but when the formulations were further stressed (storage temperature was increased over time) and analyzed after 17 days of storage, additional peaks were present in some formulations, with a clear trend of increasing number and peak area with increasing pH (from no peaks (pH 4) to three peaks with a total peak area of 0.61% (pH 9)). The nitrogen sparged formulation (pH 7) was significantly more robust than the unsparged equivalent formulation, confirming oxidation as the degradation pathway. The light stressed formulation was the most degraded sample, with a total related substances value of 1.68%.

表１は、pH安定性がpHの上昇とともに低下することを示している(特にpH≧7の製剤について)。

Table 1 shows that pH stability decreases with increasing pH (especially for formulations with pH > 7).

表２からわかるように、公称pH≧7の溶液中のDMTフマル酸塩濃度は、17日にわたり減少した。

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

表３は、関連物質の量がpHの上昇とともに増加し、安定性が低下していることを明確に示している。

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

加速条件下では、17日後の関連物質の総量は、pH7以上の製剤で増加することがわかった。

Under accelerated conditions, the total amount of related substances after 17 days was found to be increased in formulations at pH 7 and above.

The data presented in Tables 1-5 above clearly show that the stability of the tested formulations decreases with increasing pH. In particular, the stability was found to improve for formulations with a pH below 7.

As mentioned above, when developing an injectable formulation, it is common to match the pH of the formulation to the patient's serum pH. In humans, the serum pH is about 7.4. Thus, 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 such salt formulations prepared at pH values below 7.0 was unexpected.

Preparation of Formulations Details of the individual formulation examples are provided in the table below. Each formulation can be prepared by a process similar to the examples below.
An aliquot of each formulation can be taken for assay/related substances and osmolality checks. The remainder of each formulation is filtered (0.2 μm filter size) into clear glass multi-dose vials, sparged with nitrogen, and capped.

Preparation of Example Formulation (25 mg/mL, pH 5.5) 1) Weigh the required amount of drug substance into a suitable container (glass weighing boat). Ensure that the mass of drug substance taken includes corrections for salts and purity.
2) Carefully transfer the weighed drug substance into a beaker. Rinse the weighing vessel with water for injection (WFI) to ensure no solids remain. Add additional WFI to the drug substance up to 3/4 of the total required amount and dissolve with magnetic stirring.
3) Bring to volume in a suitable container and finally check that the pH is pH 5.5 (± 0.1) and adjust if necessary.
4) The formulation solution is clear with a very slight beige color (N,N-dimethyltryptamine fumarate was used). This color is removed by filtration (step 6), leaving a colorless solution filtrate.
5) Nitrogen is bubbled through the formulation until the dissolved oxygen level is measured to be less than 5 ppm, preferably less than 2 ppm.
6) Syringe filter the solution into a suitable glass multi-dose vial, preferably either 0.22 μm or 0.2 μm into a glass multi-dose vial.

本発明の製剤は、上掲の添加剤の一種又は二種以上を含むことができる。
「DS」は、本発明の製剤に使用される任意に置換されたジメチルトリプタミン化合物を指す。 Exemplary formulations include co-solvents, surfactants, buffers, pH adjusters or tonicity agents, or other additives.

The formulations of the present invention may contain one or more of the additives 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. The amount of NaOH required to ensure the required pH was added to the BR buffer prior to the addition of N,N-dimethyltryptamine. The total volume of BR buffer and the required amount of NaOH was 5 ml for each pH tested (pH 4, 5, 6, 7, 8, 9, 10). 150 mg of N,N-dimethyltryptamine was added and the pH was checked before shaking overnight at ambient temperature.

pH約4～約6にて90mg/mL以上の溶解度が観察され、pH5付近で最も高い溶解度が観察された。 The solubility of N,N-dimethyltryptamine was measured at varying pH at 25° C. as shown in the table below and in FIG. 3:

Solubilities of greater than 90 mg/mL were observed at pH values from about 4 to about 6, with the highest solubility observed near pH 5.

A solubility headspace of approximately 2-3 times is ideally acceptable 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 dose of 100 mg/2.5 mL (40 mg/ml) at a pH of about 5 to about 6.5 while achieving the desired solubility headspace of 2-3 times at 25°C.

EXAMPLES: FORMULATION EXAMPLES Formulation examples of the present invention are as shown in the following table.

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 three months at 2-8°C, 25°C/60% RH, and 40°C/75% RH.

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

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

These data indicate that the formulation of the present invention has good stability, with low amounts of related substances observed only under stress conditions of 40°C/75% RH.

式中、
R¹は、独立して、-R⁴、-OH、-OR⁴、-O(CO)R⁴、リン酸一水素、-F、-Cl、-Br及び-Iから選択される；
nは、0、1、2、3又は4から選択される；
R²は、C(^xH)₃である；
R³は、C(^xH)₃である；
各R⁴は、独立して、C₁-C₄アルキルから選択される；及び
^xH及び^yHは、それぞれ独立して、プロチウム又は重水素から選択される。
（１０）
任意に置換されたジメチルトリプタミン化合物の塩が、約3～約5のpKaを有するブレンステッド酸と、式IA又は式IBの化合物とを含む、先行する条項のいずれか１項に記載の製剤：
(式中、
R^1aは、独立して、-R^4a、-OH、-OR^4a、-O(CO)R^4a、リン酸一水素、-F、-Cl、-Br、及び-Iから選択される；
nは、0、1、2、3又は4から選択される；
R^2aは、C(^xaH)₃である；
R^3aは、C(^xaH)₃である；
各R^4aは、独立して、C₁-C₄アルキルから選択される；及び
各^xaH及び^yaHは、独立して、プロチウム又は重水素から選択される)
(式中、
R^1bは、独立して、-R^4b、-OH、-OR^4b、-O(CO)R^4b、リン酸一水素、-F、-Cl、-Br、及び-Iから選択される；
nは、0、1、2、3又は4から選択される；
R^2bは、C(^xbH)₃である；
R^3bは、C(^xbH)₃である；
各R^4bは、独立して、C₁-C₄アルキルから選択される；及び
各^xbH、^ybH、及び^zHは、独立して、プロチウム又は重水素から選択される)。
（１１）
任意に置換されたジメチルトリプタミン化合物の塩が、
(i) 式Iの化合物(式中、nは0であり；又はnは1であり、そしてR¹は4位又は5位である)、又は
(ii) 式IAの化合物(式中、nは0であり；又はnは1であり、そしてR^1aは4位又は5位である)、又は
(iii) 式IBの化合物(式中、nは0であり；又はnは1であり、そしてR^1bは4位又は5位である)
を含む、条項９又は条項１０に記載の製剤。
（１２）
任意に置換されたジメチルトリプタミン化合物の塩が、
(i) 式Iの化合物(式中、各R¹は、-OH、-OMe、-OCD₃、-OAc、-O(CO)Me、及びリン酸一水素から独立して選択される)；又は
(ii) 式IAの化合物(式中、各R^1aは、-OH、-OMe、-OCD₃、-OAc、-O(CO)Me、及びリン酸一水素から独立して選択される)；又は
(iii) 式IBの化合物(式中、各R^1bは、-OH、-OMe、-OCD₃、-OAc、-O(CO)Me、及びリン酸一水素から独立して選択される)
を含む、条項９～１１のいずれか１項に記載の製剤。
（１３）
任意に置換されたジメチルトリプタミン化合物の塩が、
(i) 式Iの化合物(式中、R²はCD₃であり、R³はCD₃である)、又は
(ii) 式IAの化合物(式中、R^2aはCD₃であり、R^3aはCD₃である)、又は
(iii) 式IBの化合物(式中、R^2bがCD₃であり、R^3bがCD₃である)
を含む、条項９～１２のいずれか１項に記載の製剤。
（１４）
任意に置換されたジメチルトリプタミン化合物の塩が、
(i) 式Iの化合物(式中、R²はCH₃であり、R³はCH₃である)；又は
(ii) 式IAの化合物(式中、R^2aはCH₃であり、R^3aはCH₃である)；又は
(iii) 式IBの化合物(式中、R^2bはCH₃であり、R^3bはCH₃である)
を含む、条項９～１２のいずれか１項に記載の製剤
（１５）
任意に置換されたジメチルトリプタミン化合物の塩が、
(i) 式Iの化合物(式中、R²はCH₃であり、R³はCD₃である)；又は
(ii) 式IAの化合物(式中、R^2aはCH₃であり、R^3aはCD₃である)；又は
(iii) 式IBの化合物(式中、R^2bはCH₃であり、R^3bはCD₃である)
を含む、請求項９～１２のいずれか１項に記載の製剤。
（１６）
任意に置換されたジメチルトリプタミン化合物の塩が、
(i) 式Iの化合物(式中、各^xHはDである)；又は
(ii) 式IAの化合物(式中、各^xaHはDである)；又は
(iii) 式IBの化合物(式中、各^xbHはDである)
を含む、条項９～１２のいずれか１項に記載の製剤。
（１７）
任意に置換されたジメチルトリプタミン化合物の塩が、
(i) 式Iの化合物(式中、両方の^yHはDである)；又は
(ii) 式IAの化合物(式中、両方の^yaHはDである)；又は
(iii) 式IBの化合物(式中、両方の^ybHはDである)
を含む、条項９～１６のいずれか１項に記載の製剤。
（１８）
任意に置換されたジメチルトリプタミン化合物の塩が、
(i) 式Iの化合物(式中、１つの^yHがHであり、１つの^yHがDである)；又は
(ii) 式IAの化合物(式中、１つの^yaHがHであり、１つの^yaHがDである)；又は
(iii) 式IBの化合物(式中、１つの^ybHがHであり、１つの^ybHがDである)
を含む、条項９～１６のいずれか１項に記載の製剤
（１９）
任意に置換されたジメチルトリプタミン化合物の塩が、
(i) 式Iの化合物(式中、^yHは両方ともHである)；又は
(ii) 式IAの化合物(式中、^yaHは両方ともHである)；又は
(iii) 式IBの化合物(式中、^ybHは両方ともHである)、
を含む、条項９～１６のいずれか１項に記載の製剤。
（２０）
任意に置換されたジメチルトリプタミン化合物の塩が、式IBの化合物(式中、^zHは両方ともDである)を含む、条項１０～条項１９項のいずれか１項に記載の製剤。
（２１）
任意に置換されたジメチルトリプタミン化合物の塩が、式IBの化合物(式中、^zHは両方ともHである)を含む、条項１０～１９項のいずれか１項に記載の製剤。
（２２）
任意に置換されたジメチルトリプタミン化合物の塩が、式IBの化合物(式中、１つの^zHはHであり、１つの^zHはDである)を含む、条項１０～１９のいずれか１項に記載の製剤。
（２３）
nが0である、条項９～１１及び１３～２２のいずれか１項に記載の製剤。
（２４）
nが1であり、R¹又はR^1a又はR^1bが、4-アセトキシである、条項９～２２のいずれか１項に記載の製剤。
（２５）
nが1であり、R¹又はR^1a又はR^1bが、5-メトキシ又はトリデューテロ-5-メトキシである、条項９～２２のいずれか１項に記載の製剤。
（２６）
任意に置換されたジメチルトリプタミン化合物が、N,N-ジメチルトリプタミンである、条項１～９のいずれか１項に記載の製剤。
（２７）
任意に置換されたジメチルトリプタミン化合物が、α,α-ジデューテロ-N,N-ジメチルトリプタミン(d₂-DMT)、α,α,β,β-テトラデューテロ-N,N-ジメチルトリプタミン(d₄-DMT)、N,N-ジ(トリデューテロメチル)トリプタミン(d₆-DMT)、α,α-ジデューテロ-N,N-ジ(トリデューテロメチル)トリプタミン(d₈-DMT)、α,α,β,β-テトラデューテロ-N,N-ジ(トリデューテロメチル)トリプタミン(d₁₀-DMT)、5-メトキシ-α,α-ジデューテロ-N,N-ジ(トリデューテロメチル)トリプタミン、α,α-ジデューテロ-N,N-ジ(トリデューテロメチル)トリプタミン(d₈-DMT)、α,α,β,β-テトラデューテロ-N,N-ジ(トリデューテロメチル)トリプタミン(d₁₀-DMT)、5-メトキシ-N,N-ジ(トリデューテロメチル)トリプタミン、5-メトキシ-α,α-ジデューテロ-N,N-ジ(トリデューテロメチル)トリプタミン、5-メトキシ-α,α,β,β-テトラデューテロ-N,N-ジ(トリデューテロメチル)トリプタミン、及びそれらの任意の混合物から選択される、条項１～２５のいずれか１項に記載の製剤。
（２８）
任意に置換されたジメチルトリプタミン化合物の塩が、
任意に置換されたジメチルトリプタミン化合物と、
フマル酸、酒石酸、クエン酸、酢酸、乳酸、及びグルコン酸からなる群より選択される酸との塩である、
先行する条項のいずれか１項に記載の製剤。
（２９）
酸がフマル酸である、条項２８に記載の製剤。
（３０）
任意に置換されたジメチルトリプタミン化合物の塩を、HPLCで測定した場合に99％以上の純度で含有する製剤原料を含む、先行する条項のいずれか１項に記載の製剤。
（３１）
任意に置換されたジメチルトリプタミンの濃度が、約10mg/mL～約150mg/mL(遊離塩基当量として)である、先行する条項のいずれか１項に記載の製剤。
（３２）
任意に置換されたジメチルトリプタミンの濃度が、約15mg/mL～約70mg/mL(遊離塩基当量として)である、先行する条項のいずれか１項に記載の製剤。
（３３）
任意に置換されたジメチルトリプタミン化合物の濃度が、約20mg/mL～約40mg/mL(遊離塩基当量として)である、先行する条項のいずれか１項に記載の製剤。
（３４）
任意に置換されたジメチルトリプタミンの濃度が、約20mg/mL以上(遊離塩基当量として)である、先行する条項のいずれか１項に記載の製剤。
（３５）
任意に置換されたジメチルトリプタミン化合物の濃度が、約25mg/mL以上(遊離塩基当量として)である、先行する条項のいずれか１項に記載の製剤。
（３６）
製剤が、前記塩とは別個の緩衝剤をさらに含む、先行する条項のいずれか１項に記載の製剤。
（３７）
緩衝剤が、酢酸塩及び酢酸；又はクエン酸塩及びクエン酸；又はリン酸塩及びリン酸を含む；又は
緩衝剤が、酢酸塩、クエン酸塩、又はリン酸塩を含む、条項３６に記載の製剤。
（３８）
塩基剤が、水酸化ナトリウム又は水酸化カリウムである、先行する条項のいずれか１項に記載の製剤。
（３９）
製剤がさらに等張化剤を含む、先行する条項のいずれか１項に記載の製剤。
（４０）
製剤が、任意に置換されたジメチルトリプタミン化合物の塩、水、及び塩基剤、及び任意で、等張化剤、緩衝剤、共溶媒、保存剤(防腐剤)、及び酸化防止剤から選択される１つ又は複数の剤から本質的になる、先行する条項のいずれか１項に記載の製剤。
（４１）
製剤が、任意に置換されたジメチルトリプタミン化合物の塩、水、任意で緩衝剤、及び任意で等張化剤から本質的になる、先行する条項のいずれか１項に記載の製剤。
（４２）
製剤が、任意に置換されたジメチルトリプタミン化合物の塩、塩基剤、水、任意で緩衝剤、及び任意で等張化剤から本質的になる、先行する条項のいずれか１項に記載の製剤。
（４３）
製剤が、任意に置換されたジメチルトリプタミン化合物の塩、水、及び任意で等張化剤からなる、条項１～３５及び３９～４２のいずれか１項に記載の製剤。
（４４）
製剤が、任意に置換されたジメチルトリプタミン化合物の塩、塩基剤、水、及び任意で等張化剤からなる、条項３～３５及び３８～４２のいずれか１項に記載の製剤。
（４５）
等張化剤が塩化ナトリウム又はデキストロースである、条項３９～４４のいずれか１項に記載の製剤。
（４６）
5ppm未満の酸素含有量を有する、条項１～４５のいずれか１項に記載の製剤。
（４７）
2ppm未満の酸素含有量を有する、条項１～４５のいずれか１項に記載の製剤。
（４８）
製剤が不活性ガスでスパージされたものである、先行する条項のいずれか１項に記載の製剤。
（４９）
5ml以下の容積を有する容器に保存される、先行する条項のいずれか１項に記載の製剤。
（５０）
4ml以下の容積を有する容器に保存される、先行する条項のいずれか１項に記載の製剤。
（５１）
3ml以下の容積を有する容器に保存される、先行する条項のいずれか１項に記載の製剤。
（５２）
2ml以下の容積を有する容器に保存される、先行する条項のいずれか１項に記載の製剤。
（５３）
1ml以下の容積を有する容器に保存される、先行する条項のいずれか１項に記載の製剤。
（５４）
0.5ml以下の容積を有する容器に保存される、先行する条項のいずれか１項に記載の製剤。
（５５）
製剤がpH調節剤をさらに含む、先行する条項のいずれか１項に記載の製剤。
（５６）
pH調節剤が塩酸を含む、条項５５に記載の製剤。
（５７）
任意に置換されたジメチルトリプタミン化合物の塩、塩基剤、水、及びpH調節剤を含む、条項５６に記載の製剤。
（５８）
先行する条項のいずれか１項に記載の製剤を調製するのに適したキットであって、任意に置換されたジメチルトリプタミン化合物の塩；任意で等張化剤；及び任意で前記塩とは別の緩衝剤を含む、キット。
（５９）
条項３～５７のいずれか１項に記載の製剤を調製するのに適したキットであって、任意に置換されたジメチルトリプタミン化合物の塩；任意で等張化剤；塩基剤、及び任意で前記塩とは別の緩衝剤を含む、キット。
（６０）
任意に置換されたジメチルトリプタミン化合物の塩、水、任意で緩衝剤、任意で等張化剤を接触させることを含む、条項１～５７のいずれか１項に記載の医薬製剤を調製する方法。
（６１）
任意に置換されたジメチルトリプタミン化合物の塩、水、塩基剤、任意で前記塩とは別の緩衝剤、及び任意で等張化剤を接触させることを含む、条項３～５７のいずれか１項に記載の医薬製剤を調製する方法。
（６２）
緩衝剤の水溶液を、任意に置換されたジメチルトリプタミン化合物の塩と接触させる、条項６０又は６１に記載の方法であって、ここで、水溶液が条項１又は２に定義されるpHを有する、方法。
（６３）
任意に置換されたジメチルトリプタミン化合物を、緩衝剤、水、及び任意で等張化剤と接触させることを含む、条項６０～６２のいずれか１項に記載の方法。
（６４）
製剤のpHを調整することをさらに含む、条項６０～６３のいずれか１項に記載の方法。
（６５）
pHが、好ましくは水酸化ナトリウム又は水酸化カリウムである塩基剤で調整される、条項６４に記載の方法。
（６６）
好ましくは塩酸であるpH調節剤で、pHを調整することをさらに含む、条項６４又は６５に記載の方法。
（６７）
製剤を不活性ガスでスパージングすることをさらに含む、条項６０～６６のいずれか１項に記載の方法。
（６８）
医薬品として、又は心理療法と組み合わせて(すなわち、薬理学的支援心理療法において)使用するための、条項１～５７のいずれか１項に記載の製剤、又は条項５８もしくは条項５９に記載のキット。
（６９）
患者の精神障害又は神経障害を治療する方法に使用するための、条項１～５７のいずれか１項に記載の製剤、又は条項５８もしくは５９に記載のキット。
（７０）
精神障害又は神経障害が、(i)強迫性障害、(ii)うつ病性障害、(iii)不安障害、(iv)物質乱用及びギャンブル障害、ならびに(v)意欲消失障害からなる群より選択される、条項６９に記載の使用のための製剤。
（７１）
精神障害又は神経障害を治療する方法であって、それを必要とする患者に、条項１～５７のいずれか１項に記載の製剤を投与することを含む、方法。
（７２）
条項７１に記載の方法であって、精神障害又は神経障害が条項７０に定義されたものである、方法。
（７３）
条項１～５７のいずれか１項に記載の製剤が、心理療法と組み合わせて投与される、条項７１に記載の方法。
（７４）
任意に置換されたジメチルトリプタミン化合物の用量が、約5～約250mgの範囲である、条項１～５７のいずれか１項に記載の製剤、条項６８～７０のいずれか１項に記載の使用のための製剤、又は条項７１～７３のいずれか１項に記載の方法。
（７５）
任意に置換されたジメチルトリプタミン化合物の用量が、約10～約150mgの範囲である、条項１～５７のいずれか１項に記載の製剤、条項６８～７０のいずれか１項に記載の使用のための製剤、又は条項７１～７３のいずれか１項に記載の方法。
（７６）
任意に置換されたジメチルトリプタミン化合物の用量が、約10～約100mgの範囲である、条項１～５７のいずれか１項に記載の製剤、条項６８～７０のいずれか１項に記載の使用のための製剤、又は条項７１～７３のいずれか１項に記載の方法。
（７７）
任意に置換されたジメチルトリプタミン化合物の用量が、約20～約70mgの範囲である、条項１～５７のいずれか１項に記載の製剤、条項６８～７０のいずれか１項に記載の使用のための製剤、又は条項７１～７３のいずれか１項に記載の方法。
（７８）
任意に置換されたジメチルトリプタミン化合物の用量が、約20～約50mgの範囲である、条項１～５７のいずれか１項に記載の製剤、条項６８～７０のいずれか１項に記載の使用のための製剤、又は条項７１～７３のいずれか１項に記載の方法。
（７９）
条項１～５７のいずれか１項に記載の製剤、条項６８～７０のいずれか１項に記載の使用のための製剤、又は条項７１～７３のいずれか１項に記載の方法であって、製剤が以下を含み：
ａ）α,α-ジデューテロ-N,N-ジメチルトリプタミン(d₂-DMT)、α,α,β,β-テトラデューテロ-N,N-ジメチルトリプタミン(d₄-DMT)、N,N-ジ(トリデューテロメチル)トリプタミン(d₆-DMT)、α,α-ジデューテロ-N,N-ジ(トリデューテロメチル)トリプタミン(d₈-DMT)、α,α,β,β-テトラデューテロ-N,N-ジ(トリデューテロメチル)トリプタミン(d₁₀-DMT)、5-メトキシ-α,α-ジデューテロ-N,N-ジ(トリデューテロメチル)トリプタミン、5-メトキシ-N,N-ジ(トリデューテロメチル)トリプタミン、5-メトキシ-α,α-ジデューテロ-N,N-ジ(トリデューテロメチル)トリプタミン、及び、それらの混合物から選択される、任意に置換されたジメチルトリプタミン化合物と、
フマル酸、酒石酸、クエン酸、酢酸、乳酸、及びグルコン酸からなる群より選択される酸との塩；
ｂ）水酸化ナトリウム及び水酸化カリウムから選択される塩基剤；
ｃ）水；
ｄ）任意で、前記塩とは別の緩衝剤であって、
酢酸塩と酢酸；又はクエン酸塩とクエン酸；又はリン酸塩とリン酸を含む；又は、
酢酸塩、クエン酸塩、又はリン酸塩を含む、緩衝剤；
ｅ）任意で、塩酸であるpH調節剤
ここで、前記製剤は、約5～約6.5のpH、又は約5～約6のpH、約15mg/mL～約70mg/mL(遊離塩基当量として)の濃度、及び約250～約350mOsm/Kgの浸透圧を有し；及び、前記製剤は、5ml以下の容積内の、約10mg～約100mgの範囲の任意に置換されたジメチルトリプタミン化合物の用量を含む。 The present invention will be further understood by reference to the following non-limiting clauses:
(1)
1. A pharmaceutical formulation suitable for intramuscular injection and/or nebulized inhalation comprising a salt of an optionally substituted dimethyltryptamine compound; and water,
A pharmaceutical formulation, wherein the formulation has a pH of about 5 to about 6, a concentration of about 10 mg/ml or greater as a free base, and an osmolality of about 250 to about 350 mOsm/Kg.
(2)
1. A pharmaceutical formulation suitable for intramuscular injection and/or nebulized inhalation comprising a salt of an optionally substituted dimethyltryptamine compound; and water,
A pharmaceutical formulation, wherein the formulation has a pH of about 5 to about 6.5, a concentration of about 10 mg/ml or greater as a free base, and an osmolality 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; a base, water, and optionally a buffer other than said salt;
the formulation has a pH of about 5 to about 6, a concentration of about 10 mg/ml or greater as a free base, and an osmolality of about 250 to about 350 mOsm/Kg;
A pharmaceutical formulation, wherein the formulation comprises a dose of an optionally substituted dimethyltryptamine compound in an injectable or inhalable 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; a base, water, and optionally a buffer other than said salt,
the formulation has a pH of about 5 to about 6.5, a concentration of about 10 mg/ml or greater as a free base, and an osmolality of about 250 to about 350 mOsm/Kg;
A pharmaceutical formulation, wherein the formulation comprises a dose of an optionally substituted dimethyltryptamine compound in an injectable or inhalable volume of 5 ml or less.
(5)
A formulation according to any one of the preceding clauses, wherein the formulation comprises an effective dose of an optionally substituted dimethyltryptamine compound for use in psychedelic assisted therapy in a volume of 5ml or less.
(6)
10. The formulation of any one of the preceding clauses, having a volume of 3 ml or less.
(7)
10. The formulation of any one of the preceding clauses, having a volume of 2.5 ml or less.
(8)
The formulation of any one of the preceding clauses, wherein the formulation has an osmolality of about 275 to about 325 mOsm/Kg.
(9)
The formulation of any one of the preceding clauses, 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 the formula,
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 ;
^R3 is C( ^xH ) ₃ ;
Each ^R4 is independently selected from _C1 - _C4 alkyl; and
^xH and ^yH are each independently selected from protium or deuterium.
(10)
The formulation of any one of the preceding clauses, 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:
(Wherein,
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( ^xaH ) 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.
(Wherein,
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;
^R2b is C( ^xbH ) ₃ ;
R ^3b is C( ^xbH ) ₃ ;
each R ^4b is independently selected from C ₁ -C ₄ alkyl; and each ^xb H, ^yb H, and ^z H is independently selected from protium or deuterium.
(11)
The salt of an optionally substituted dimethyltryptamine compound is
(i) a compound of formula I, wherein n is 0; or n is 1 and R ¹ is in the 4- or 5-position, or
(ii) a compound of formula IA, wherein n is 0; or n is 1 and R ^1a is in the 4- or 5-position; or
(iii) A compound of formula IB, wherein n is 0; or n is 1 and R ^1b is in the 4- or 5-position.
11. The formulation of clause 9 or clause 10 comprising:
(12)
The salt of an optionally substituted dimethyltryptamine compound is
(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.
12. The formulation according to any one of clauses 9 to 11, comprising:
(13)
The salt of an optionally substituted dimethyltryptamine compound is
(i) a compound of formula I, wherein ^R2 is _CD3 and ^R3 is _CD3 , or
(ii) a compound of formula IA, wherein ^R2a is _CD3 and ^R3a is _CD3 ; or
(iii) A compound of formula IB, wherein ^R2b is _CD3 and ^R3b is _CD3 .
13. The formulation according to any one of clauses 9 to 12, comprising
(14)
The salt of an optionally substituted dimethyltryptamine compound is
(i) a compound of formula I, wherein ^R2 is _CH3 and ^R3 is _CH3 ; or
(ii) a compound of formula IA, wherein ^R2a is _CH3 and ^R3a is _CH3 ; or
(iii) A compound of formula IB, wherein ^R2b is _CH3 and ^R3b is _CH3 .
The formulation (15) according to any one of clauses 9 to 12, comprising
The salt of an optionally substituted dimethyltryptamine compound is
(i) a compound of formula I, wherein ^R2 is _CH3 and ^R3 is _CD3 ; or
(ii) a compound of formula IA, wherein ^R2a is _CH3 and ^R3a is _CD3 ; or
(iii) Compounds of formula IB, wherein ^R2b is _CH3 and ^R3b is _CD3 .
The formulation according to any one of claims 9 to 12, comprising:
(16)
The salt of an optionally substituted dimethyltryptamine compound is
(i) a compound of formula I, wherein each ^xH is D; or
(ii) a compound of formula IA, wherein each ^xa H is D; or
(iii) A compound of formula IB, wherein each ^xb H is D.
13. The formulation according to any one of clauses 9 to 12, comprising
(17)
The salt of an optionally substituted dimethyltryptamine compound is
(i) a compound of formula I, wherein both ^yH are D; or
(ii) a compound of formula IA, wherein both ^ya H are D; or
(iii) A compound of formula IB, wherein both ^yb H are D.
17. The formulation according to any one of clauses 9 to 16, comprising:
(18)
The salt of an optionally substituted dimethyltryptamine compound is
(i) a compound of formula I, wherein one ^yH is H and one ^yH is D; or
(ii) a compound of formula IA, wherein one ^yaH is H and one ^yaH is D; or
(iii) A compound of formula IB, wherein one ^ybH is H and one ^ybH is D.
The formulation (19) according to any one of clauses 9 to 16, comprising
The salt of an optionally substituted dimethyltryptamine compound is
(i) a compound of formula I, wherein ^y H are both H; or
(ii) a compound of formula IA, wherein both ^ya and H are H; or
(iii) a compound of formula IB, wherein both ^yb H are H;
17. The formulation according to any one of clauses 9 to 16, comprising:
(20)
The formulation of any one of clauses 10 to 19, wherein the salt of the optionally substituted dimethyltryptamine compound comprises a compound of formula IB, wherein ^z H are both D.
(21)
The formulation of any one of clauses 10-19, wherein the salt of the optionally substituted dimethyltryptamine compound comprises a compound of formula IB, wherein ^z H are both H.
(22)
20. The formulation of any one of clauses 10-19, 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)
23. The formulation according to any one of clauses 9 to 11 and 13 to 22, wherein n is 0.
(24)
23. The formulation of any one of clauses 9-22, wherein n is 1 and R ¹ or R ^1a or R ^1b is 4-acetoxy.
(25)
23. The formulation of any one of clauses 9 to 22, wherein n is 1 and R ¹ or R ^1a or R ^1b is 5-methoxy or trideutero-5-methoxy.
(26)
10. The formulation of any one of clauses 1 to 9, wherein the optionally substituted dimethyltryptamine compound is N,N-dimethyltryptamine.
(27)
Optionally substituted dimethyltryptamine compounds include 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 26. The formulation of any one of clauses 1 to 25, wherein the 5-methoxy-N,N-di(trideuteromethyl)tryptamine ( _d10- DMT), α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine (d10-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 any mixture thereof.
(28)
The salt of an optionally substituted dimethyltryptamine compound is
an optionally substituted dimethyltryptamine compound;
A salt with an acid selected from the group consisting of fumaric acid, tartaric acid, citric acid, acetic acid, lactic acid, and gluconic acid.
A formulation according to any one of the preceding clauses.
(29)
29. The formulation of clause 28, wherein the acid is fumaric acid.
(30)
The formulation of any one of the preceding clauses, comprising a drug substance containing a salt of an optionally substituted dimethyltryptamine compound in a purity of 99% or greater as measured by HPLC.
(31)
The formulation of any one of the preceding clauses, 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 one of the preceding clauses, 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 one of the preceding clauses, 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 one of the preceding clauses, wherein the concentration of the optionally substituted dimethyltryptamine is about 20 mg/mL or more (as free base equivalent).
(35)
The formulation of any one of the preceding clauses, 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 one of the preceding clauses, wherein the formulation further comprises a buffering agent separate from the salt.
(37)
37. The formulation of clause 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 one of the preceding clauses, wherein the base agent is sodium hydroxide or potassium hydroxide.
(39)
The formulation of any one of the preceding clauses, wherein the formulation further comprises an isotonicity agent.
(40)
The formulation of any one of the preceding clauses, wherein the formulation consists essentially of a salt of an optionally substituted dimethyltryptamine compound, water, and a base agent, and optionally one or more agents selected from an isotonicity agent, a buffering agent, a cosolvent, a preservative, and an antioxidant.
(41)
The formulation of any one of the preceding clauses, wherein the formulation consists essentially of the salt of the optionally substituted dimethyltryptamine compound, water, optionally a buffering agent, and optionally a tonicity agent.
(42)
The formulation of any one of the preceding clauses, wherein the formulation consists essentially of a salt of the optionally substituted dimethyltryptamine compound, a base agent, water, optionally a buffering agent, and optionally a tonicity agent.
(43)
43. The formulation of any one of clauses 1-35 and 39-42, wherein the formulation consists of a salt of the optionally substituted dimethyltryptamine compound, water, and optionally an isotonicity agent.
(44)
43. The formulation of any one of clauses 3-35 and 38-42, wherein the formulation consists of a salt of the optionally substituted dimethyltryptamine compound, a base agent, water, and optionally an isotonicity agent.
(45)
45. The formulation of any one of clauses 39-44, wherein the isotonicity agent is sodium chloride or dextrose.
(46)
46. The formulation of any one of clauses 1-45, having an oxygen content of less than 5 ppm.
(47)
46. The formulation of any one of clauses 1-45, having an oxygen content of less than 2 ppm.
(48)
10. The formulation of any one of the preceding clauses, wherein the formulation is sparged with an inert gas.
(49)
13. The formulation according to any one of the preceding clauses, stored in a container having a volume of 5 ml or less.
(50)
13. The formulation according to any one of the preceding clauses, stored in a container having a volume of 4 ml or less.
(51)
13. The formulation according to any one of the preceding clauses, stored in a container having a volume of 3 ml or less.
(52)
2. The formulation according to any one of the preceding clauses, stored in a container having a volume of 2 ml or less.
(53)
13. The formulation of any one of the preceding clauses, stored in a container having a volume of 1 ml or less.
(54)
13. The formulation of any one of the preceding clauses, stored in a container having a volume of 0.5 ml or less.
(55)
The formulation of any one of the preceding clauses, wherein the formulation further comprises a pH adjuster.
(56)
56. The formulation of clause 55, wherein the pH adjuster comprises hydrochloric acid.
(57)
57. The formulation of clause 56, comprising a salt of an optionally substituted dimethyltryptamine compound, a base agent, water, and a pH adjusting agent.
(58)
A kit suitable for preparing a formulation according to any one of the preceding clauses, comprising a salt of an optionally substituted dimethyltryptamine compound; optionally a tonicity agent; and optionally a buffer separate from the salt.
(59)
58. A kit suitable for preparing a formulation according to any one of clauses 3 to 57, comprising a salt of an optionally substituted dimethyltryptamine compound; optionally an isotonicity agent; a base agent, and optionally a buffering agent separate from said salt.
(60)
58. A method for preparing a pharmaceutical formulation according to any one of clauses 1 to 57, comprising contacting a salt of an optionally substituted dimethyltryptamine compound, water, optionally a buffering agent, and optionally a tonicity agent.
(61)
58. A method for preparing a pharmaceutical formulation according to any one of clauses 3 to 57, comprising contacting a salt of an optionally substituted dimethyltryptamine compound, water, a basic agent, optionally a buffer other than said salt, and optionally an isotonicity agent.
(62)
62. The method of claim 60 or 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 clause 1 or 2.
(63)
63. The method of any one of clauses 60 to 62, comprising contacting the optionally substituted dimethyltryptamine compound with a buffer, water, and optionally a tonicity agent.
(64)
64. The method of any one of clauses 60 to 63, further comprising adjusting the pH of the formulation.
(65)
65. The method of claim 64, wherein the pH is adjusted with a base agent, preferably sodium hydroxide or potassium hydroxide.
(66)
66. The method of claim 64 or 65, further comprising adjusting the pH with a pH adjusting agent, preferably hydrochloric acid.
(67)
67. The method of any one of clauses 60-66, further comprising sparging the formulation with an inert gas.
(68)
A formulation according to any one of clauses 1 to 57, or a kit according to clause 58 or clause 59, for use as a medicament or in combination with psychotherapy (i.e. in pharmacologically assisted psychotherapy).
(69)
60. A formulation according to any one of clauses 1 to 57, or a kit according to clause 58 or 59, for use in a method of treating a psychiatric or neurological disorder in a patient.
(70)
70. The formulation for use according to clause 69, wherein the psychiatric 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) anorexia disorder.
(71)
A method for treating a psychiatric or neurological disorder comprising administering to a patient in need thereof a formulation according to any one of clauses 1 to 57.
(72)
72. The method according to clause 71, wherein the psychiatric or neurological disorder is as defined in clause 70.
(73)
The method of claim 71, wherein the formulation of any one of clauses 1 to 57 is administered in combination with psychotherapy.
(74)
74. The formulation of any one of clauses 1 to 57, the formulation for use of any one of clauses 68 to 70, or the method of any one of clauses 71 to 73, wherein the dose of the optionally substituted dimethyltryptamine compound is in the range of about 5 to about 250 mg.
(75)
74. The formulation of any one of clauses 1 to 57, the formulation for use of any one of clauses 68 to 70, or the method of any one of clauses 71 to 73, wherein the dose of the optionally substituted dimethyltryptamine compound is in the range of about 10 to about 150 mg.
(76)
74. The formulation of any one of clauses 1 to 57, the formulation for use of any one of clauses 68 to 70, or the method of any one of clauses 71 to 73, wherein the dose of the optionally substituted dimethyltryptamine compound is in the range of about 10 to about 100 mg.
(77)
74. The formulation of any one of clauses 1 to 57, the formulation for use of any one of clauses 68 to 70, or the method of any one of clauses 71 to 73, wherein the dose of the optionally substituted dimethyltryptamine compound is in the range of about 20 to about 70 mg.
(78)
74. The formulation of any one of clauses 1 to 57, the formulation for use of any one of clauses 68 to 70, or the method of any one of clauses 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 formulation according to any one of clauses 1 to 57, a formulation for use according to any one of clauses 68 to 70, or a method according to any one of clauses 71 to 73, wherein the formulation comprises:
a) 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, 5-methoxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine, and mixtures thereof;
Salts with an acid selected from the group consisting of fumaric acid, tartaric acid, citric acid, acetic acid, lactic acid, and gluconic acid;
b) a base agent selected from sodium hydroxide and potassium hydroxide;
c) water;
d) optionally a buffering agent separate from said salt,
Acetate and acetic acid; or citrate and citric acid; or phosphate and phosphoric acid; or
a buffering agent, including acetate, citrate, or phosphate;
e) optionally, a pH adjusting agent that 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 osmolality 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 nebulizer inhalation, comprising:
a salt of an optionally substituted dimethyltryptamine compound, a base, water, and optionally a buffer other than the salt;
having a pH of about 5 to about 6.5, a concentration of about 10 mg/ml or greater as a free base, and an osmolality of about 250 to about 350 mOsm/Kg; and
containing a dose of an optionally substituted dimethyltryptamine compound in a volume of 5 ml or less,
Pharmaceutical preparations. The formulation of claim 1, having a pH of about 5 to about 6. The formulation according to claim 1 or 2, which is suitable for intramuscular injection. A formulation according to any one of claims 1 to 3, comprising an effective amount of an optionally substituted dimethyltryptamine compound for use in psychedelic-assisted therapy in a volume of 5 ml or less. The formulation according to any one of claims 1 to 4, having a volume of 3 ml or less. The formulation according to any one of claims 1 to 5, having a volume of 2.5 ml or less. The formulation according to any one of claims 1 to 6, having an osmotic pressure of about 275 to about 325 mOsm/Kg. 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 -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;
^R2b is C( ^xbH ) ₃ ;
R ^3b is C( ^xbH ) ₃ ;
each R ^4b is independently selected from C ₁ -C ₄ alkyl; and each ^xb H, ^yb H, and ^z H is independently selected from protium or deuterium. 9. The formulation of claim 8, wherein the salt of the optionally substituted dimethyltryptamine compound comprises a compound of formula IB, wherein n is 0; or n is 1 and R ^1b is at the 4- or 5-position. The formulation of claim 8 or 9, wherein the salt of the 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. 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 _CD3 and R ^3b is _CD3 . The formulation of any one of claims 8 to 11, wherein the salt of the optionally substituted dimethyltryptamine compound comprises a compound of formula IB, wherein each ^yb H is D. The formulation according to any one of claims 8, 9, 11 or 12, wherein n is 0. The formulation of any one of claims 8 to 12, wherein n is 1 and R ^1b is 4-acetoxy. The formulation of any one of claims 8 to 12, wherein n is 1 and R ^1b is 5-methoxy or trideutero-5-methoxy. The formulation according to any one of claims 1 to 8, wherein the optionally substituted dimethyltryptamine compound is N,N-dimethyltryptamine. The formulation according to any one of claims 1 to 8, wherein the optionally substituted dimethyltryptamine compound is α,α-dideutero-N,N-dimethyltryptamine. The formulation according to any one of claims 1 to 17, wherein the salt of the optionally substituted dimethyltryptamine compound is a salt of the optionally substituted dimethyltryptamine compound with an acid selected from the group consisting of fumaric acid, tartaric acid, citric acid, acetic acid, lactic acid, and gluconic acid. The formulation of claim 18, wherein the acid is fumaric acid. The formulation according to any one of claims 1 to 19, comprising a pharmaceutical ingredient containing a salt of an optionally substituted dimethyltryptamine compound with a purity of 99% or more as measured by HPLC. The formulation according to any one of claims 1 to 20, wherein the concentration of the optionally substituted dimethyltryptamine is from about 10 mg/mL to about 150 mg/mL (as free base equivalent). The formulation according to any one of claims 1 to 20, wherein the concentration of the optionally substituted dimethyltryptamine is from about 15 mg/mL to about 70 mg/mL (as free base equivalent). The formulation according to any one of claims 1 to 20, wherein the concentration of the optionally substituted dimethyltryptamine compound is from about 20 mg/mL to about 40 mg/mL (as free base equivalent). The formulation according to any one of claims 1 to 20, wherein the concentration of the optionally substituted dimethyltryptamine compound is about 25 mg/mL (as free base equivalent). The formulation according to any one of claims 1 to 24, further comprising a buffer other than 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. The formulation according to any one of claims 1 to 26, wherein the base agent is sodium hydroxide or potassium hydroxide. The formulation according to any one of claims 1 to 27, further comprising an isotonicity agent and/or a pH adjusting agent. The formulation of any one of claims 1 to 28, consisting essentially of a salt of an optionally substituted dimethyltryptamine compound, water, a base agent, and optionally one or more agents selected from a pH adjusting agent, an isotonicity agent, a buffering agent, a cosolvent, a preservative, and an antioxidant. The formulation according to any one of claims 1 to 29, consisting essentially of a salt of an optionally substituted dimethyltryptamine compound, water, a base agent, and optionally a buffer and/or a tonicity agent and/or a pH adjusting agent. The formulation according to any one of claims 1 to 30, comprising a salt of an optionally substituted dimethyltryptamine compound, water, a base agent, and optionally a buffer and/or an isotonicity agent and/or a pH adjusting agent. The formulation according to any one of claims 28 to 31, wherein the isotonicity agent is sodium chloride or dextrose. The formulation according to any one of claims 1 to 32, having an oxygen content of less than 5 ppm, preferably less than 2 ppm. The formulation according to any one of claims 1 to 33, stored in a container having a volume of 5 ml or less. The formulation according to any one of claims 1 to 33, stored in a container having a volume of 2 ml or less. The formulation according to any one of claims 1 to 35, comprising a salt of an optionally substituted dimethyltryptamine compound, a base agent, water, a buffer other than the salt, and an isotonicity agent or a pH adjusting agent. 37. The formulation of claim 36, comprising a salt of an optionally substituted dimethyltryptamine compound; a base selected from potassium hydroxide and sodium hydroxide; water; a buffering agent that is a citrate salt; and an isotonicity agent or pH adjusting agent that is an acid. A kit suitable for preparing the formulation according to any one of claims 1 to 37, comprising an optionally substituted salt of a dimethyltryptamine compound; optionally an isotonicity agent and/or a pH adjusting agent; a base agent, and optionally a buffering agent separate from the salt. A method for preparing the pharmaceutical formulation of any one of claims 1 to 37, comprising contacting a salt of an optionally substituted dimethyltryptamine compound, water, a base agent, and optionally a buffer other than the salt, and optionally a tonicity agent and/or a pH adjusting agent. 39. The method of claim 39, 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 claim 1. The method of claim 39 or 40, comprising contacting an optionally substituted dimethyltryptamine compound with water and, optionally, a buffer and/or a tonicity agent and/or a pH adjusting agent. The method of any one of claims 39 to 41, further comprising adjusting the pH of the formulation. The method of claim 42, wherein the pH is adjusted with a base agent that is sodium hydroxide or potassium hydroxide. The method of any one of claims 39 to 43, further comprising sparging the formulation with an inert gas. A formulation according to any one of claims 1 to 37 or a kit according to claim 38 for use as a medicine or in combination with psychotherapy. A formulation according to any one of claims 1 to 37 or a kit according to claim 38 for use in a method for treating a psychiatric or neurological disorder in a patient. The formulation for use or kit for use according to claim 46, wherein the psychiatric 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) anorexia disorder. A method for treating a psychiatric or neurological disorder, comprising administering to a patient in need thereof a formulation according to any one of claims 1 to 37. The method of claim 48, wherein the psychiatric or neurological disorder is as described in claim 47. The method according to claim 48, wherein the formulation according to any one of claims 1 to 37 is administered in combination with psychotherapy. A lyophilized powder formulation comprising the formulation according to any one of claims 1 to 37 that has been lyophilized. A method for preparing a lyophilized powder formulation, comprising drying the formulation according to any one of claims 1 to 37 by lyophilization. 53. A method for preparing an aqueous formulation comprising mixing the lyophilized powder formulation of claim 51 or the lyophilized powder formulation prepared by the method of claim 52 with water,
A method for preparing an aqueous formulation comprising providing a formulation comprising a salt of an optionally substituted dimethyltryptamine compound, a base agent, water, and optionally a buffer agent other than said salt, and providing 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 osmolality of about 250 to about 350 mOsm/Kg. The method of claim 53, wherein the formulation has a pH of about 5 to about 6.

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