KR20240110836A - Injectable and inhaled preparations - Google Patents

Abstract

The present invention relates to aqueous pharmaceutical preparations, methods for their preparation, and uses thereof. Aqueous pharmaceutical formulations include an optionally substituted salt of a dimethyltryptamine compound and water, with a pH of 5 to 6.5, preferably about 5 to about 6, and about 10 mg/ml or more of the optionally substituted free base equivalent. has a concentration of the compound dimethyltryptamine. These formulations may contain an effective dose of an optionally substituted dimethyltryptamine compound for use in psychedelic adjuvant therapy in a volume of 5 ml or less. These preparations are surprisingly both stable, clinically acceptable, suitable for both intramuscular injection and nebulized inhalation, and have potential use in the treatment of psychiatric or neurological disorders.

Description

Injectable and inhaled preparations

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

Conventional hallucinogens have shown preclinical and clinical potential in the treatment of mental disorders (Carhart-Harris and Goodwin, Neuropsychopharmacology 42, 2105-2113 (2017)). In particular, psilocybin demonstrated significant improvements in various depression and anxiety rating scales in a randomized, double-blind study (Griffiths et al. Journal of Psychopharmacology , 30(12), 1181-1197 (2016 )).

N,N-dimethyltryptamine (DMT) is also understood to have therapeutic value as a short-acting hallucinogen. A review of studies on the biosynthesis and metabolism of DMT in the brain and peripheral tissues, methods and results for detection of DMT in body fluids and brain, see SA Barker in Front. Neurosci. , 12, 536, 1-17 (2018)]. Barker et al suggest that ‘ further characterization of DMT cellular distribution, receptors and general biochemistry may lead to more effective pharmaceutical agents and new targets for intervention ’.

Injecting human volunteers with a saline solution of DMT fumarate salt was described in [C. Timmermann et al ., Sci. Rep. , 9, 16324 (2019)]. The effects of DMT fumarate on the power spectrum and signal diversity of human brain activity were recorded via multivariate EEG and compared with the results obtained upon injection of placebo (saline solution). Compared to results obtained with placebo, DMT fumarate was found to suppress alpha power and normalize/increase delta and theta power. Alpha power is associated with high-level psychological functioning, top-down predictive processing and related feedback connectivity, while theta and delta power are associated with conventional REM sleep dreams and related 'visionary hallucinations'. )' is related to the state. These results demonstrate that infusion of DMT fumarate is associated with the experience of feeling deeply immersed in a completely different world.

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

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

Summary of the Invention

The present invention provides an aqueous pharmaceutical formulation suitable for both intramuscular injection and nebulized inhalation, comprising about 10 mg/ml (as free base equivalent) or more of an optionally substituted salt of the dimethyltryptamine compound, and water. wherein the formulation has a pH value of 5 to 6.5 and a typical osmolality of about 250 to about 350 mOsm/Kg. The formulation may have a pH of about 5 to about 6 or a pH of 5 to 6. These formulations are capable of delivering an effective dose of an optionally substituted dimethyltryptamine compound for use in psychedelic-assisted therapy (pharmacological-assisted psychotherapy) in a volume of 5 ml or less, which can be administered by intramuscular injection. and nebulized inhalation. Preferably, the agent is used for psychedelic adjuvant 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. It is possible to deliver an effective dose of an optionally substituted dimethyltryptamine compound to:

The present invention solves the problem of providing pharmaceutical formulations suitable for intramuscular injection or nebulized inhalation with substantially reduced degradation products compared to known formulations when stored under standard or severe conditions. This represents an improved shelf life over these known pharmaceutical formulations. Additionally, deuterated optionally substituted dimethyltryptamine compounds, such as those of Formula IA or IB, exhibit significantly improved exposure and Cmax by intramuscular injection compared to their non-deuterated analogs (Figure 1a and 1b). Accordingly, the present invention provides 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. An aqueous pharmaceutical formulation is provided for the first time with an effective dose (at least for an average body weight human) of an optionally substituted dimethyltryptamine compound via intramuscular injection or nebulized inhalation in volumes of ml or less.

Accordingly, in terms of the first aspect, the invention provides a salt of an optionally substituted dimethyltryptamine compound, a base agent, water; and optionally a salt and a separate buffer; wherein the formulation has a pH of about 5 to about 6.5, a concentration of about 10 mg/ml or greater as free base, and an osmolarity 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.

In some embodiments of the first aspect of the invention, the agent has (as free base equivalent) 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 of an optionally substituted dimethyltryptamine compound. Contains salt. Typically, the formulation contains about 25 mg/ml (as free base equivalent) of an optionally substituted salt of the dimethyltryptamine compound.

In a preferred embodiment of the first aspect of the invention, the pharmaceutical preparation is 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. , comprising an effective dose of an optionally substituted dimethyltryptamine compound for use in psychedelic adjuvant therapy in a volume of 1 ml or less, or 0.5 ml or less.

In terms of a second aspect, the invention provides a kit suitable for preparing the formulation of the first aspect, said kit comprising: an optionally substituted salt of a dimethyltryptamine compound; It includes a base agent, optionally a salt and a separate buffer and optionally an isotonic agent and/or a pH adjusting agent. In a preferred embodiment of the second aspect of the invention, the kit is 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, An effective dose of an optionally substituted dimethyltryptamine compound for use in psychedelic adjuvant therapy in a volume of 1 ml or less, or 0.5 ml or less.

In terms of the third aspect, the invention provides a method for preparing the pharmaceutical preparation of the first aspect, comprising salt, water, a base agent, optionally a buffering agent separated from the salt, and optionally an isotonic agent and/or a pH adjusting agent. In a preferred embodiment of the third aspect of the invention, the formulation is 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, An effective dose of an optionally substituted dimethyltryptamine compound for use in psychedelic adjuvant therapy in a volume of 1 ml or less, or 0.5 ml or less.

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

Due to the known instability of the free base of N,N-dimethyltryptamine in solution, solutions containing optionally substituted dimethyltryptamine compounds are generally prepared immediately prior to or close to the time of use, i.e., optionally Storage of solutions of substituted dimethyltryptamine compounds is avoided. Alternatively, the solution of the optionally substituted dimethyltryptamine compound is frozen. The inventors have found that when a buffering agent separated from the salt is used, the resulting formulation is more stable than a formulation prepared without the use of a buffering agent separated from the salt. Additionally, when containers adapted to prevent penetration of ultraviolet rays are used, the resulting preparations are more stable than when stored in containers capable of transmitting ultraviolet rays.

In terms of a fourth aspect, the invention provides a preparation of the first aspect or a kit of the second aspect for use as a medicine or in combination with psychotherapy.

In terms of the fifth aspect, the invention provides an agent of the first aspect or a kit of the second aspect for use in a method of treating a mental or neurological disorder in a patient.

In view of the sixth aspect, the invention provides a method of treating a mental or neurological disorder, comprising administering the agent of the first aspect to a patient in need of treatment of the mental or neurological disorder.

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

In view of the eighth aspect, the invention comprises a salt comprising a Brønsted acid having a pKa of about 3 to about 5 at 25°C and a compound of formula (IA), and water, at a pH of about 5 to about 6.5, and a concentration of the compound of formula (IA) as the free base equivalent salt of about 10 mg/ml or more:

In the above equation,

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

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

R ^2a is C( ^xa H) ₃ ;

R ^3a is C( ^xa H) ₃ ;

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

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

Preferably, the formulation may have a pH of about 5 to about 6, or a pH of 5 to 6. In a preferred embodiment of the eighth aspect of the invention, the pharmaceutical preparation is 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. , an effective dose of a compound of formula (IA) for use in psychedelic adjuvant therapy in a volume of 1 ml or less, or 0.5 ml or less.

In view of the ninth aspect, the invention comprises a salt comprising a Bronsted acid having a pKa of from about 3 to about 5 at 25° C. and a compound of formula (IB), and water, at a pH of from about 5 to about 6.5, and a concentration of the compound of formula (IB) as the free base equivalent salt of about 10 mg/ml or more:

In the above equation,

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

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

R ^2b is C( ^xb H) ₃ ;

R ^3b is C( ^xb H) ₃ ;

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

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

Preferably, the formulation may have a pH of about 5 to about 6, or a pH of 5 to 6. In a preferred embodiment of the ninth aspect of the invention, the pharmaceutical preparation is 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. , an effective dose of a compound of formula (IB) for use in psychedelic adjuvant therapy in a volume of 1 ml or less, or 0.5 ml or less. For the avoidance of doubt, the embodiments of the eighth aspect of the invention apply mutatis mutandis to the ninth aspect of the invention.

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

In view of the eleventh aspect, the invention provides a process for preparing a lyophilized powder formulation, comprising drying the formulation as defined in the first aspect of the invention by lyophilization.

In view of the twelfth aspect, the invention provides a formulation comprising a salt of an optionally substituted dimethyltryptamine compound, a base agent, water, and optionally a buffering agent separated from the salt, as defined in the tenth aspect in water. or mixing the lyophilized powder formulation as prepared in the method of the eleventh aspect, at a pH of about 5 to about 6.5, a concentration of about 10 mg/ml or more as free base, and a temperature of about 250 to about 350 mOsm/. A method of making an aqueous formulation is provided, comprising providing a formulation having an osmolality of Kg. Preferably, the formulation may have a pH of about 5 to about 6, or a pH of 5 to 6.

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

Additional aspects and embodiments of the invention will become apparent from the discussion that follows.

Figure 1: Figures 1A and 1B are added as cassettes in vivo; After an IM dose of 3.5 mg/kg (for fumarate), mean plasma N,N-dimethyltryptamine (SPL026), d ₂ -N,N-dimethyltryptamine (SPL028i), and d ₈ -N,N- A plot of dimethyltryptamine (SPL028viii) concentration is shown. Figure 1a - Linear plot, Figure 1b - Semi-log plot. All three drug substances achieve Cmax greater than 50 ng/ml, representing therapeutically relevant doses. SPL028i and SPL028viii each show significantly higher plasma levels at 30 minutes compared to non-deuterated DMT.
Figures 2A and 2B show plots of mean plasma d ₂ -DMT (SPL028i) concentrations over time following IM doses of 3.5 mg/kg and 10 mg/kg (for fumarate) in vivo. Figure 2a - Linear plot, Figure 2b - Semilogarithmic plot, SEM error bars.
Figure 3 shows pH-solubility curves for N,N-dimethyltryptamine from pH 4 to pH 10.

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

Unless otherwise stated, measurements are performed at room temperature and pressure, i.e., 20° C. (293.15 K, 68° F.) and 1 atm (14.696 psi, 101.325 kPa), respectively. Unless otherwise stated, ambient conditions refer to room temperature and pressure.

In the following discussion, reference is made to a number of terms which, unless the context clearly indicates to the contrary, are to be understood to have the meanings provided below. The nomenclature used herein for hallucinogenic agents for use in the formulations of the invention is as commonly used in the art. The compounds described herein are also described in the International Union of Pure and Applied Chemistry (IUPAC) for Chemical Compounds, specifically in the IUPAC Compendium of Chemical Terminology (Gold Book) (A. D. Jenkins et al., Pure & Appl. Chem., 1996, 68, 2287-2311]. For the avoidance of doubt, if the rules of the IUPAC organization conflict with the definitions provided herein, the definitions herein shall prevail.

References herein to singular nouns include plural nouns and vice versa, unless the context suggests otherwise.

Throughout this specification, the word "comprise", or variants such as "comprises" or "comprising", refers to a referenced element, integer or step, or element, integer or step. will be understood to mean including a group of, but does not exclude any other element, integer or step, or group of elements, integer or step. The term 'comprising' includes within its scope the terms 'consisting of' or 'consisting essentially of'.

The term 'consisting of' or variations thereof includes the mentioned element, integer or step, or group of elements, integers or steps, and includes any other element, integer or step, or group of elements, integers or steps. It should be understood as meaning exclusion.

The term 'consisting essentially of' or variations thereof includes a referenced element, integer or step, or group of elements, integers or steps, as well as additional ingredients, which substantially affect the essential properties of the agent, composition, or compound. It should be understood to mean that only things that do not affect can exist.

As used herein, the term 'about', when defining a number or value, is used to refer to a value that is within ±5% of the specified value. For example, if the osmolality range is specified to be from about 250 to about 350 mOsm/Kg, values from 238 to 367 are included; When the pH range is specified as about 5 to about 6, values from 4.75 to 6.3 are included. For the avoidance of doubt, where a number or value is specified herein without the term 'about', the number or value is to be construed in accordance with standard numeric rounding rules to decimal places. For example, an integer such as 6 is understood to include values ≥ 5.5 and < 6.5. Likewise, numbers specified with one decimal place, such as 5.3, are understood to include values ≥ 5.25 and < 5.35.

The term 'aqueous' as used herein relates to formulations that contain water and may also contain additional solvents.

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

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

As used herein, the term 'in combination with psychotherapy' relates to the treatment of mental disorders by psychological means, enhanced by the administration of the agents of the invention. The terms 'psychedelic-assisted therapy' and 'medication-assisted therapy' are used herein to refer to treatment in combination with psychotherapy.

The term 'treatment' defines curative treatment of a patient that reduces the rate of progression of the disorder or stops it, or improves or cures the disorder. Prevention of disability as a result of treatment is also included. References to prevention do not require complete prevention of the disorder: it is intended herein that its onset may instead be prevented through treatment according to the invention. Typically, treatment is not prophylactic and agents are administered to patients diagnosed or suspected of having a disorder.

As understood in the art, a mental or neurological disorder is a disorder that may be associated with one or more cognitive impairments. As used herein, the term 'mental disorder' refers to the occurrence in an individual of a person experiencing pain (e.g., painful symptoms) or impairment (i.e., impairment of one or more important areas of functioning) or death, pain, or capacity. A clinically significant behavioral or psychological syndrome or pattern that is associated with a significantly increased risk of suffering disability or significant loss of freedom.

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

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

As used herein, the term 'obsessive-compulsive disorder' (OCD) is defined as the presence of obsessions or compulsions, but usually both. Symptoms can cause significant functional impairment and/or distress. Obsessions are defined as unwanted, intrusive thoughts, impressions, or impulses that enter a person's mind repeatedly. Compulsions are repetitive behavioral or mental actions that a person feels they must perform. Typically, OCD manifests as one or more obsessions that lead to the adoption of compulsive behaviors. For example, an obsession with germs may lead to a compulsive cleaning, or an obsession with food may lead to compulsions of overeating, eating too little, or vomiting after eating (i.e., eating too little). Obsession with eating can itself manifest itself as an eating disorder). Compulsions may be overt, such as checking whether a door is locked, or covert mental acts that cannot be observed, such as the repetition of certain phrases in a person's mind, and can be observed by another person.

As used herein, the term 'eating disorder' is defined as a serious and persistent disturbance of eating behavior and associated distressing thoughts and feelings. The term 'eating disorder' includes anorexia nervosa and bulimia nervosa, binge eating disorder, avoidant restrictive food intake disorder, certain other feeding and eating disorders, pica and rumination disorders.

Eating disorders often co-occur with anxiety disorders, and obsessive-compulsive disorders. Neziroglu and Sandler distinguish between OCD and eating disorders as follows: ' Patients with eating disorders are primarily driven by concerns about their appearance, and as a result they change their eating accordingly in order to lose weight. Change the pattern. People with OCD may restrict their eating for very different reasons than body shape 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 to keep body 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), then intentionally getting sick, using laxatives, eating very little and/or exercising too much to prevent weight gain. Symptoms of BED include regularly eating large amounts of food until you feel 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 patients in the later stages of the disease.

As used herein, the term 'major depressive disorder' (also referred to as MDD, major depression or clinical depression) refers to a disorder that occurs during most of the day, over a period of two weeks or more (also referred to herein as a 'major depressive episode'). , defined as the presence of five or more of the following symptoms almost daily:

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

· Significantly reduced interest or inability to enjoy all or most activities;

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

· Insomnia or increased need to sleep;

· Restlessness or slowed down behavior that may be observed by others;

· Fatigue or loss of energy;

· Feelings of worthlessness or excessive or inappropriate guilt;

· Difficulty making decisions, or thinking or concentrating;

· Recurrent thoughts of death or suicide, or suicide attempts.

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

Persistent depressive disorder, also known as dysthymia, is defined as patients exhibiting the following two characteristics:

A. Feeling depressed most of the time, most days, for at least two years. Children and adolescents may have irritable moods for at least a year.

B. While depressed, a person experiences at least two of the following symptoms:

· Overeating or loss of appetite.

· Sleeping too much or having difficulty sleeping.

· Fatigue, lack of energy.

· Low self-esteem.

· Difficulty concentrating or making decisions.

As used herein, the term 'treatment-resistant major depressive disorder' describes MDD that fails to achieve an adequate response to appropriate treatment using standard treatment regimens.

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

There are two defined subcategories of bipolar disorder; All of these include marked changes in mood, energy, and activity level. These moods range from periods of excited, extremely 'high' and energetic behavior (known as manic episodes, defined further below) to periods of very sad, 'off' or hopeless (depressive episodes). (known as). Less severe manic periods are known as hypomanic episodes.

Bipolar I disorder - defined as a manic episode lasting at least 7 days, or manic symptoms so severe that a person requires immediate hospital treatment. Usually, depressive episodes also occur and usually last at least two weeks. Depressive episodes with mixed features (having both depressive and manic symptoms) are also possible.

Bipolar II Disorder - Defined by a pattern of depressive episodes and hypomanic episodes rather than full-blown manic episodes as described above.

As used herein, 'bipolar depression' is defined as an individual experiencing depressive symptoms in conjunction with a prior or co-existing episode of manic symptoms, but not meeting clinical criteria for bipolar disorder.

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

'Generalized anxiety disorder' (GAD), as used herein, refers to a chronic disorder characterized by long-lasting anxiety that causes inability to focus on any one object or situation. People with GAD experience non-specific persistent fears and worries and become excessively concerned about everyday problems. GAD is characterized by excessive and persistent worrying accompanied by three or more of the following symptoms: restlessness, fatigue, concentration problems, irritability, muscle tension, and trouble sleeping.

A 'phobia' is defined as a persistent fear of an object or situation that the affected person goes to great lengths to avoid and is usually disproportionate to the actual danger that poses it. If the feared object or situation cannot be completely avoided, the affected person will endure severe distress and significant interference in social or occupational activities.

Patients suffering from 'panic disorder' are defined as those who suffer from one or more episodic attacks of intense fear and anxiety (also referred to as panic attacks), often accompanied by tremors, tremors, confusion, dizziness, nausea and/or difficulty breathing. A panic attack is defined as a feeling of fear or discomfort that comes on suddenly and peaks within 10 minutes.

'Social anxiety disorder' is defined as an extreme fear and avoidance of negative public scrutiny, public embarrassment, humiliation, or social interaction. Social anxiety often presents with specific physical symptoms, including flushing, sweating, and difficulty speaking.

‘Post-traumatic stress disorder’ (PTSD) is an anxiety disorder that arises from traumatic experiences. Post-traumatic stress can be caused by extreme situations such as combat, natural disasters, rape, hostage situations, child abuse, bullying, or even serious accidents. Common symptoms include hypervigilance, flashbacks, avoidance behavior, anxiety, anger, and depression.

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

As used herein, the term 'substance abuse' means drug use where the user exhibits a pattern of consuming the drug in amounts or in a manner that is harmful to themselves or others.

As used herein, the term 'gambling disorder' refers to persistent and repetitive problem gambling behavior that results in clinically significant impairment or distress. This disorder has similarities to drug abuse.

As used herein, the term 'avolition disorder' refers to a disorder whose symptoms include decreased motivation to initiate and perform self-directed purposeful activities.

The invention provides salts of optionally substituted dimethyltryptamine compounds; base preparation; water; and optionally salts and separate buffering agents; wherein the formulation has a pH of about 5 to about 6.5, and an osmolarity 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.

In a preferred embodiment of the invention, the pharmaceutical preparation is administered 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. An effective dose of an optionally substituted dimethyltryptamine compound for use in psychedelic adjuvant therapy in a volume of less than, or 0.5 ml or less.

The inventors found that the formulation was surprisingly more stable than formulations prepared at higher pH (specifically, at a pH matching that of human serum, i.e., at a pH of about 7.4). The greater stability of the inventive formulations compared to isotonic formulations is discussed in more detail in the Examples section.

Osmolarity is formally defined as the quotient of the rational activity of water and the negative natural logarithm of the molar mass of water, as expressed in the equation:

In the above equation, is the partial vapor pressure of water in solution, is the partial vapor pressure of pure water. Simply put, osmolarity is the number of osmotically active particles (number of solute particles) in 1 kg of solution. Therefore, osmolarity is a function of the number of particles alone and is not related to particle molecular weight, size, shape or charge (for a review of measurements of serum osmolality, see DK Faria et al ., ME Mendes and NM Sumita , J. Bras. Med. Lab. , 53, 1, 38-45). For example, 1 mole of an undissociated substance (e.g., DMT as the free base) dissolved in 1 kg of water has an osmolarity of 1 Osm/kg (1000 mOsm/kg), while One mole of a substance (e.g., DMT fumarate) dissociated into two separate species in solution in water has an osmolality of 2 Osm/kg (2000 mOsm/kg).

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

The inventive formulations are suitable for nebulized inhalation. Typically, the particles present in nebulized inhalation formulations are about 0.1 to about 10 μm, preferably about 0.3 to about 8 μm, preferably about 0.3 to about 7 μm, more preferably about 0.5 to about 5 μm. or has a mean aerodynamic diameter (MMAD) of about 3 to about 7 μm. MMAD will be selected depending on the type of nebulizer such as jet nebulizer, mesh nebulizer or ultrasonic nebulizer. Suitably, a multistage cascade impactor (CI) device may be used to size the aerosol with respect to its aerodynamic particle size distribution (APSD). MMAD is calculated from APSD and is defined as the diameter at which 50% of aerosol particles are larger and 50% are smaller by mass.

The formulation (i.e. the formulation of the invention) is suitable for intramuscular injection, meaning that it complies with the pharmacopeia requirements for sterility, contaminants and pyrogens (see, for example, The United States Pharmacopeial Convention, General Requirements / <1> Injections, page 33]). Sometimes, the formulation includes microbial growth inhibitors (e.g., antimicrobial preservatives) and/or antioxidants.

Formulations suitable for parenteral administration generally have a pH of about 3 to 9 and an osmolality of about 250 to about 600 mOsm/Kg. pH values greater than 9 are as described in I. Usach et al. in Adv. Ther. , 36, 2986-2996 (2019)], it was recorded to be associated with tissue necrosis (cell death within tissues), while values below 3 were recorded to cause pain and phlebitis (inflammation of veins). However, Usach et al. reported that ' a pH that approximates physiological pH is recommended to minimize pain, irritation, and tissue damage ' (emphasis added). Osmolality values above 600 mOsm/Kg have also been reported to cause pain. Usach et al also recommended that parenteral preparations should be formulated as isotonic solutions (osmolality of approximately 300 mOsm/Kg) and suggest an upper limit of 600 mOsm/Kg to minimize pain.

The formulations (i.e. formulations of the invention) are also suitable for inhalation, especially nebulized inhalation.

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

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

In some embodiments, the dimethyltryptamine compound is substituted with acetoxy or methoxy at position 4 or 5 or with monohydrogen phosphate at position 4. 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 the formula HPO ₄ derived from phosphoric acid by removing a proton from two of the three OH, and thus represents a substituent of the formula -OP(O)(OH)O ^- .

If the dimethyltryptamine compound is substituted at position 4 with monohydrogen phosphate, this results in psilocybin in water (also known as [3-(2-dimethylaminoethyl)-1 H -indol-4-yl] dihydrogen phosphate ) generally reflects having a 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. The monohydrogen phosphate-containing form of psilocybin is further understood to exist as a zwitterion (i.e., internal salt) in which the nitrogen atom of the dimethylamino moiety is protonated. In this form, psilocybin is considered to be a salt of the compound dimethyltryptamine substituted at position 4 with monohydrogen phosphate.

For the avoidance of doubt, positions 4 and 5 of the optionally substituted dimethyltryptamine salt relate to the positions labeled in the structure below (substitutions not shown).

.

The formulation optionally includes a salt and a separate buffering agent, 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), the amount of buffering agent required is at least and in excess of the buffering effect provided by the fumarate salt. It can be The term 'buffer' is well known in the art and refers to a chemical substance included in a formulation that resists changes in pH upon addition of an acid or base to the formulation. As used herein, the term 'buffer' refers to a buffering system or buffering agent. Buffering agents suitable for use in the formulations of the invention include weak acids and their conjugate bases. Suitable buffering systems include acids with pKa values 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 a pKa value greater than 1 (i.e., each molecule of the acid can donate more than one proton), at least one of the pKa values is within the desired pH range so that the buffer is suitable.

The weak acid and its conjugate base in a buffer system are in equilibrium with each other. According to Le Chatelier's principle (if a constraint (such as a change in the concentration of a reactant) is applied to a system in equilibrium, the equilibrium will shift to cancel out the effect of the constraint), the acid or The addition of a base shifts the equilibrium position in favor of the mate base or weak acid, respectively. As a result, the concentration of free protons (and therefore pH) in the formulation remains relatively unchanged.

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

In some embodiments, the formulation includes a buffering agent. In some embodiments, the buffering agent is separated from the salt.

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

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

Sometimes, the buffering system includes acetate and acetic acid; or citrate and citric acid.

In some embodiments, the buffering system includes acetate and acetic acid, often sodium acetate and acetic acid, or potassium acetate and acetic acid.

As used herein, the term 'buffer' refers to a weak acid or base. Any pharmaceutically acceptable buffering agent may be used in the formulations of the invention, including phosphoric acid, citric acid, acetic acid, phosphate, citrate, and acetate. In some embodiments, the buffering agent includes sodium phosphate, sodium citrate, or sodium acetate.

Preferably, the pharmaceutical formulation comprises an effective dose of an optionally substituted dimethyltryptamine compound for use as a medicine or for use in hallucinogenic adjuvant therapy, wherein the formulation contains dimethyltryptamine in the dosage range that produces a hallucinogenic experience in average weight human patients. Includes salts of tryptamine compounds. Typically, the dosage range is from about 5 to about 250 mg (in free base equivalents), or from about 10 to about 150 mg, suitably from about 10 to about 100 mg, suitably from about 20 to about 100 mg. In some embodiments, the dosage range is from about 20 to about 70 mg, or from about 20 to about 50 mg. For example, a suitable dose is about 9 mg, or about 12 mg, or about 17 mg, or about 21.5 mg, or about 24 mg, or about 30.5 mg, or about 34 mg, or about 33 mg, or about 36 mg. , or about 38.5 mg, or about 43 mg, or about 51 mg, or about 52 mg, or about 55 mg, or about 60 mg, or about 64.5 mg. The dosage ranges and suitable dosages provided in this paragraph relate to free base equivalent dosages.

The concentration of buffering agent in the formulation is sufficient to resist significant pH changes in the formulation upon storage of the formulation, typically for two weeks, while also ensuring that the osmolality of the formulation is within the preferred range of about 250 to about 350 mOsm/Kg. (i.e., the pH typically varies by less than about 0.1 pH units). The skilled person can achieve this by evaluating suitable buffer concentrations. Often, the concentration of the buffer is from about 15mM to about 75mM, such as about 20mM to about 30mM. In some embodiments, the concentration of buffer is about 25 mM.

As described above, the formulation includes an optionally substituted salt of the dimethyltryptamine compound at a concentration of about 10 mg/ml or more as organic base equivalent.

The salt comprises an acid and an optionally substituted dimethyltryptamine compound, or the salt preferably comprises a dimethyltryptamine compound substituted at position 4 of the indole ring system with monohydrogen phosphate. An example of a salt containing an acid and a dimethyltryptamine compound is N,N-dimethyltryptamine fumarate, which is the fumarate salt of N,N-dimethyltryptamine. PH Stahl and CG Wermuth , Handbook of Pharmaceutical Salts: Properties, Selection and Use , Weinheim/ ] provides an overview of the pharmaceutical salts and acids contained therein. The acids described in this review are acids suitable for inclusion in salts of the agent.

The salts are 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-acetic acid. Amidobenzoic acid, 4-aminosalicylic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphor acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, Cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, galactaric acid, gentisic 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. Fonic 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 and undecided. It may include an acid selected from the group consisting of silenic acid.

In some embodiments, when the salt includes an acid and a dimethyltryptamine compound, the acid is a Bronsted acid with a pKa of about 3 to about 5 at 25°C in water. In this embodiment, Brønsted acid can serve both as a counterion for the dimethyltryptamine compound and as a buffering agent. Accordingly, the formulation can be stabilized to a greater extent, i.e. the decomposition of the dimethyltryptamine compound can be further improved if the salt contains such an acid.

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

In the above equation,

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

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

R ^2a is C( ^xa H) ₃ ;

R ^3a is C( ^xa H) ₃ ;

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

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

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

In the above equation,

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

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

R ^2b is C( ^xb H) ₃ ;

R ^3b is C( ^xb H) ₃ ;

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

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

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

Formula IA will be recognized as a sub-formula of IB wherein each ^z H is hydrogen.

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

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

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

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

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

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

In some embodiments, the compound is of Formula (IA) or (IB) where n is 0.

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

In some embodiments, the compound is (i) Formula IA according to any preceding embodiment wherein both ^ya H are light hydrogens; or (ii) of formula IB according to any of the preceding embodiments, wherein both ^yb H are light hydrogen.

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

In some embodiments, the compound is of Formula I B where both ^z H are deuterium. In some embodiments, the compound is of Formula I B where both ^z H are light hydrogen. In some embodiments, the compound is of Formula I B wherein one ^z H is light hydrogen and one ^z H is deuterium.

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

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

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

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

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

In some embodiments, C ₁ -C ₄ alkyl can be deuterated C ₁ -C ₄ alkyl, for example CD ₃ .

For the avoidance of doubt, certain optionally substituted dimethyltryptamine compounds encompassed by the present invention include compounds known by more than one name in the art, including:

The compound N,N-dimethyltryptamine (DMT) may also be known as N,N-dimethyl-1H-indole-3-ethanamine (CAS No. 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 No. 1019-45-0) It may be known as

The compound 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT) can also be used as 4-acetoxy-N,N-dimethyltryptamine, O-acetylsilosine, cilacetin, or [3-[2 -(dimethylamino)ethyl]-1H-indol-4-yl] acetate (CAS number 92292-84-7).

Compound 4-hydroxy-N,N-dimethyltryptamine-d ₆ can also be used as psilocin-d ₆ or 3-(2-( bis (methyl-d ₃ )amino)ethyl)-1H-indol-4-ol. It may be known.

The compound N,N-di(trideuteromethyl)tryptamine may also be known as N,N -hexadeuterio-dimethyltryptamine or _D6 -DMT.

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

The compound N- mono(trideuteromethyl)tryptamine may also be known as N -methyl-tryptamine-D ₃ (CAS number 1794745-39-0).

Compound α,α-dideutero-N,N-dimethyltryptamine is also known as D ₂ -DMT, or 2-(1H-indol-3-yl)-N,N-dimethylethane-1-amine-1,1- It may be known as d ₂ .

Compound α,α,β,β-tetradeutero-N,N-dimethyltryptamine is also known as D ₄ -DMT, or 2-(1H-indol-3-yl)-N,N-dimethylethane-1-amine It may be known as -1,1,2,2-d ₄ .

Compound α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine can also be used as D ₁₀ -DMT, or 2-(1H-indol-3-yl)-N,N- It may be known as bis(methyl-d ₃ )ethane-1-amine-1,1,2,2-d ₄ .

In some embodiments, the optionally substituted dimethyltryptamine compound is N,N-dimethyltryptamine. In some embodiments, the optionally substituted dimethyltryptamine compound is 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- It is a deuterated dimethyltryptamine compound containing di(trideuteromethyl)tryptamine.

Salts of deuterated N,N -dimethyltryptamine compounds, which can be synthesized according to the synthetic schemes disclosed in WO 2020/245133 A1, WO 2021/116503 and WO 2021/089873 A1 (all Small Pharma Ltd) as defined above This has been found to be a particularly advantageous drug substance for the formulations of the invention. Deuterated N,N -dimethyltryptamine compounds as described hereinabove have been found to exhibit a kinetic isotope effect that can be used to extend their half-life in biological systems. The inventors have now shown that in vivo the formulations of the invention comprising deuterated N,N -dimethyltryptamine compounds and deuterated substituted N,N -dimethyltryptamine compounds are significantly more effective than their non-deuterated analogs. It was found to have high Cmax and exposure (see Figures 1A and 1B).

If desired, the composition may be prepared for use in a formulation of the invention comprising an amount of N,N-dimethyltryptamine and a deuterated N,N-dimethyltryptamine compound, wherein deuterated (as defined above) The relative ratio of N,N-dimethyltryptamine to the digested N,N-dimethyltryptamine compound can be divided into lithium aluminum hydride and lithium aluminum deuterium in the reducing agent, as described for example in WO 2021/116503 (Small Pharma Ltd). It can be adjusted by changing the ratio of cargo.

Compositions comprising an amount of N,N-dimethyltryptamine and/or a deuterated N,N-dimethyltryptamine compound can be used to provide salts of optionally substituted dimethyltryptamine compounds, so that the formulations are described herein. and one or more optionally substituted dimethyltryptamine compounds, each in salt form as described.

The composition included in the formulation is 90% or more, 95% or more, preferably 97% or more, more preferably 98% or more, most preferably 99% or more by weight of the composition. may contain excess amounts of α,α-dideutero-N,N-dimethyltryptamine.

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

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

In some embodiments, the composition comprised in the formulation comprises a) 90% or more of the α,α-dideutero-N,N-dimethyltryptamine compound, b) 10% or less of the α- a prothio-α-deutero-N,N-dimethyltryptamine compound, and c) 2% or less of N,N-dimethyltryptamine, wherein α,α-deutero-N,N The weight of -dimethyltryptamine compound, α-prothio-α-detero-N,N-dimethyltryptamine compound, and N,N-dimethyltryptamine is 100% total.

In some embodiments, the composition comprised in the formulation comprises, by weight of the composition, a) 95% or more of the α,α-dideutero-N,N-dimethyltryptamine compound, b) 5% or less of the α- a prothio-α-deutero-N,N-dimethyltryptamine compound, and c) 1% or less of N,N-dimethyltryptamine, wherein α,α-deutero-N,N The weight of -dimethyltryptamine compound, α-prothio-α-detero-N,N-dimethyltryptamine compound, and N,N-dimethyltryptamine is 100% total.

For the avoidance of doubt, N,N-dimethyltryptamine may be absent, or present in the composition in trace amounts, or in an amount of 2% or less by weight of the composition, or 1% by weight of the composition. % or less may be present in the composition. In the case of 4-, 5-, 6-, or 7-substituted dimethyltryptamine compounds, 2% or less, or 1% or less of the N,N-dimethyltryptamine mentioned above is not deuterated, for example. It should be understood as including 4-, 5-, 6- or 7-substituted N,N-dimethyltryptamine such as 5-methoxy-N,N-dimethyltryptamine. For example, in a composition comprising 5-methoxy-α,α-dideutero-N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine may be absent or present in trace amounts in the composition. or may be present in the composition in an amount of 2% or less, or 1% or less by weight of the composition.

As used herein, the term 'α,α-dideutero-N,N-dimethyltryptamine compound' refers to the compound α,α-dideutero-N,N-dimethyltryptamine (d ₂ -DMT) as well as other positions. α,α-dideutero-N,N-dimethyltryptamine compounds comprising deuteration in 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 tamine (d ₁₀ -DMT), and substituted α,α-dideutero-N,N-dimethyltryptamine compounds such as 5-methoxy-α,α-dideutero-N,N-di(trideuteromethyl) Contains tryptamine.

As used herein, the term 'α-Prothio-α-detero-N,N-dimethyltryptamine compound' refers to the compound α-Prothio-α-detero-N,N-dimethyltryptamine (d ₁ - DMT) as well as α-proteo-α-deutero-N,N-dimethyltryptamine compounds containing deuterocation at other positions, such as α-proteo-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 substituted α-prothio-α-detero-N,N-dimethyltryptamine compounds such as 5 -methoxy-α-proteo-α-deutero-N,N-di(trideuteromethyl)tryptamine. In some embodiments, the composition comprised in the formulation may comprise a) 90% or more, preferably 95% or more of an optionally substituted N,N-di(trideuteromethyl)tryptamine compound. . Optionally substituted N,N-di(trideuteromethyl)tryptamine compounds include 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-meth Toxy-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 of an optionally substituted dimethyltryptamine compound and an acid selected from the group consisting of fumaric acid, tartaric acid, citric acid, acetic acid, lactic acid, and gluconic acid, typically fumaric acid.

Therefore, the salt is

N,N-dimethyltryptamine, α-monodeutero-N,N-dimethyltryptamine, α,α-dideutero-N,N-dimethyltryptamine, α,β-dideutero-N,N-dimethyltryptamine Tamamine, 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) any one or a combination; or

4-acetoxy-N,N-dimethyltryptamine, 4-acetoxy-α-monodeutero-N,N-dimethyltryptamine, 4-acetoxy-α,α-dideutero-N,N-dimethyltryptamine tamamine, 4-acetoxy-N,N-di(trideuteromethyl)tryptamine, 4-acetoxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine, and 4- Any one or a combination of acetoxy-α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine; or

5-methoxy-N,N-dimethyltryptamine, 5-methoxy-α-monodeutero-N,N-dimethyltryptamine, 5-methoxy-α,α-dideutero-N,N-dimethyltryptamine Tamin. 5-methoxy-N,N-di(trideuteromethyl)tryptamine, 5-methoxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine, and 5-methoxy -Any one or a combination of -α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine; or

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)tryptic acid any one or a combination of tamamine and 4-monohydrogen phosphate-α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine; and

It may include acids 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 is an optionally substituted dimethyltryptamine compound comprising dimethyltryptamine and fumaric acid.

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

It is particularly advantageous to prepare the formulations of the invention using a drug substance comprising an optionally substituted dimethyltryptamine compound or salt thereof with a purity of greater than 99%. A drug substance, as understood in the art, is intended to provide pharmacological activity or other direct effects in the diagnosis, cure, alleviation, treatment, or prevention of disease, or is associated with any function or structure in the patient. means an active ingredient intended to exert an effect, but does not include intermediates used in the synthesis of such ingredient. It will be understood that a drug substance may comprise one or more of these active ingredients.

Preferred embodiments of any aspect of the invention include drug substances comprising an optionally substituted dimethyltryptamine compound or salt thereof having a purity of greater than or equal to 99% as determined by HPLC. A particularly preferred embodiment comprises an optionally substituted dimethyltryptamine compound or salt thereof having a purity of greater than or equal to 99.5%, even more preferably 99.7%, even more preferably 99.9%, as determined by HPLC. Contains drug substances that

The concentration of the salt of the optionally substituted dimethyltryptamine compound in the formulation can be any desired concentration to achieve a free base-equivalent of equal to or greater than 10 mg/ml, provided that the osmolarity of the formulation is between about 250 and 250 mg/ml. It is about 350 mOsm/Kg. The dimethyltryptamine compound may be present in concentrations greater than 20 mg/mL. A concentration of 28 mg/mL of dimethyltryptamine provides approximately 148 mOsm/kg (approximately 296 mOsm/kg considering the counter ion). This can provide an additional 54 mOsm/kg by other components of the formulation, such as any buffering agents. The salt of the Dimethyltryptamine Compound has (by free base equivalent) greater than 20 mg/mL, greater than 25 mg/mL, greater than 30 mg/mL, greater than 40 mg/mL, greater than 50 mg/mL, greater than 60 mg/mL, or 70 mg/mL. It may be present in concentrations exceeding mg/m. Additionally, or alternatively, the optionally substituted Dimethyltryptamine Compound has a weight (as free base equivalent) of about 10 mg/ml to about 150 mg/ml, about 10 mg/ml to about 100 mg/ml, about 10 mg/ml It may be present in a concentration of from about 80 mg/ml, from about 15 mg/ml to about 70 mg/ml, from about 15 mg/ml to about 50 mg/ml, or from about 20 mg/ml to about 40 mg/ml. Typically, the optionally substituted dimethyltryptamine compound may be present at a concentration of about 25 mg/ml (as free base equivalent).

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

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

Sometimes, the concentration of optionally substituted dimethyltryptamine salt and optional buffering agent in the formulation results in the desired osmolality. Alternatively, the desired osmolality can be achieved by including one or more isotonic agents in the formulation. Accordingly, in some embodiments, the formulation further comprises an isotonic agent. Isotonic agents are defined herein as chemicals that, when included in a formulation, increase the osmolality of the formulation. As described above, osmolarity is the number of osmotically active particles (number of solute particles) in 1 kg of solution. Accordingly, chemicals that act as solutes when incorporated into a formulation are within the definition of an isotonic agent.

If the formulation further comprises an isotonic agent, the concentration of the isotonic agent depends on the concentration of other ingredients in the formulation, such as optionally substituted dimethyltryptamine and buffering agents. For example, if a formulation without an isotonic agent has an osmolality of about 60 mOsm/kg, at least about 190 mOsm/kg will be provided by the isotonic agent (e.g., 95 mM sodium chloride). MF Powell, T. Nguyen and L. Baloian, PDA J. Pharm. Sci. Technol. , 52, 238-311 (1998) provides a review of excipients suitable for parenteral administration (administration other than oral or gastrointestinal). All soluble excipients listed in this review article that can be given by the intravenous route will contribute to the osmolarity when added to the formulation and can therefore be considered isotonic agents.

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

Some excipients can act as cosolvents. Suitable solvents or co-solvents for use in the formulations of the 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, if the optionally substituted salt of the Dimethyltryptamine Compound is a fumarate, for example N,N-dimethyltryptamine fumarate or α,α-dideutero-N,N-dimethyltryptamine fumarate, the formulation is commonly used. Does not include hawks.

Suitable buffering agents for use in the formulations of the 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 will be understood that some excipients may have more than one function. For example, citric acid can be used as a buffering ingredient, flavoring agent, or as an antioxidant. pH adjusting agents, such as hydrochloric acid, can also act as tonicity agents.

In some embodiments, the isotonic agent is dextrose, sodium chloride; phosphoric acid; Phosphates such as 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 any one or combination selected from the group consisting of hydrochloric acid.

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

In some embodiments, the formulation includes an isotonic agent, such as sodium chloride, at a concentration of about 120mM to about 140mM, such as about 125mM to about 135mM. Sometimes, the concentration of isotonic agent, such as 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 buffer, and optionally an isotonic agent and/or pH adjuster. This means, for example, that the presence of additional ingredients in the preparation is permitted, provided that the amount of these additional ingredients does not substantially affect the essential properties of the preparation in a detrimental way. The formulation is intended to contain optionally substituted dimethyltryptamine salts, water, base preparations, optional buffering agents and optional isotonic agents and/or pH adjusting agents and is suitable for both intramuscular injection and nebulizer inhalation and is suitable for storage at least Given that producing a pharmaceutical formulation of optionally substituted dimethyltryptamine that is stable for several weeks, the stability of the formulation or its suitability for injection (e.g., its osmolarity or pH) may be substantially affected in a detrimental manner. Inclusion of ingredients that affect the formulation will be understood as exclusion from the formulation. On the other hand, the presence of any ingredients that do not substantially affect in a deleterious manner the stability of the formulation or its suitability for injection will be understood to be included. These ingredients include antioxidants and antimicrobial preservatives. For a review of pharmaceutical excipients and their properties, including those with antioxidant and antimicrobial properties, see PJ Sheskey, WG Cook and CG Cable, Handbook of Pharmaceutical Excipients , Eighth Edition, Pharmaceutical Press, London 2017. do.

The base preparation adjusts the pH of the preparation to the required pH range, for example pH 5 to pH 6. The pH of formulations comprising optionally substituted dimethyltryptamine salts, water, and buffering agents are often low, for example, below pH 5, and thus pH adjustment using base agents may be necessary. The skilled artisan can evaluate suitable base agents to adjust the pH of the solution without risk of 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 for use in the formulations of the invention include citric acid, sodium metabisulfite, and mixtures thereof.

In some embodiments, the formulation further comprises an antimicrobial preservative. Suitable antimicrobial preservatives for use in the formulations of the invention include propylparaben ( 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, such as 0.1 ppm to 2 ppm. The skilled person will be able to use the present technique, for example, using a dissolved oxygen meter (e.g. the Jenway 970 Enterprise dissolved oxygen meter, available from Keison Products: http://www.keison.co.uk/products/jenway/970.pdf ). The oxygen content of the formulation can be determined using any technique known to be suitable in the field.

The formulation may be stored in any suitable container. In some embodiments, the container may 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 degradation of the formulation, the formulation is stored in a container adapted to prevent transmission of ultraviolet light, such as an amber glass vial. In other words, the container in which the formulation is stored is not adapted to have the protection against ultraviolet radiation provided, if desired, by secondary packaging (e.g. packaging in which the container containing the formulation may be placed) (e.g. For example, it can be made of transparent glass). Often, the container is closed and the preparation is stored under an inert atmosphere, such as nitrogen or argon, typically nitrogen. The formulation may be stored at room temperature, for example, from about 20 to about 30 degrees Celsius, or at a lower temperature, for example, from about 2 to about 8 degrees Celsius. Alternatively, to further improve the breakdown of the formulation, it may be stored in a freezer.

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

In view of the second aspect, the invention provides a kit suitable for preparing the formulation of the first aspect, the kit comprising: an optionally substituted salt of the dimethyltryptamine compound; Base preparations, optionally salts and separate buffers; and optionally tonicity agents and/or pH adjusting agents. In a preferred embodiment of the second aspect of the invention, the kit is 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, Includes an effective dose of an optionally substituted dimethyltryptamine compound for use in drug-assisted psychotherapy (hallucinogen-assisted therapy) in a volume of 1 ml or less, or 0.5 ml or less.

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

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

- a second composition comprising a base agent and optionally a buffering agent separated from the salt, and/or an isotonic agent, and/or a pH adjusting agent,

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

For the avoidance of doubt, the embodiments of the first aspect of the invention as defined herein and the embodiments relating to the optionally substituted dimethyltryptamine salt and buffering agent as well as other features 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 be acetate. and acetic acid.

The optionally substituted dimethyltryptamine salt in the kit may be a solid, for example in powder or crystalline form. To improve the decomposition of optionally substituted dimethyltryptamine salts in solid form, the salts may be lyophilized (freeze-dried) prior to incorporation into the kit. Freeze-drying of a salt involves freezing it in the presence of a solvent (usually water) and separating the solvent from the salt by subtraction.

If the kit additionally comprises an isotonic agent, the embodiments relating to any isotonic agent of the first aspect of the invention as defined herein apply mutatis mutandis to the second aspect. For example, the isotonic agent may be any one or combination selected from the groups listed above.

In terms of the third aspect, the invention provides a method for preparing the pharmaceutical formulation of the first aspect. The method includes contacting an optionally substituted dimethyltryptamine salt, a base agent, optionally a buffer, and optionally an isotonic agent and/or pH adjusting agent with water. In a preferred embodiment of the third aspect of the invention, the optionally substituted dimethyltryptamine salt is administered in a volume of 5 ml or less, preferably 4 ml or less, 3 ml or less, 2.5 ml or less, Includes an effective dose of an optionally substituted dimethyltryptamine compound for use in drug-assisted psychotherapy (psychedelic-assisted therapy) in a volume of 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 dimethyltryptamine fumarate; Buffering agents may include acetic acid and acetate or phosphoric acid and phosphate; Isotonic agents may include sodium chloride.

It will be understood that the contacting step of the above method may be accomplished in a variety of ways. Often, the optionally substituted dimethyltryptamine salt is dissolved in water to form a first solution in which the base agent and optional buffering agents are added and dissolved to form a second solution. If an isotonic agent or pH adjuster is used, it is often added to the second solution to dissolve it. Additional solvents or co-solvents may be added to the first or second solution.

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

The optionally substituted dimethyltryptamine salt in the formulation comprises an amount of a suitable buffering agent to stabilize the pH of the optionally substituted dimethyltryptamine as the free base and to act as a counterion for the optionally substituted dimethyltryptamine when protonated. It can be formed by contact with an aqueous solution. Accordingly, the method of the invention may include contacting optionally substituted dimethyltryptamine in its free base form with a buffer, water, and optionally an isotonic agent.

The method further includes using a base agent to adjust the pH of the solution resulting from the contact. Since the pH of the solution resulting from the contact step is generally low, a subsequent pH adjustment step is necessary. Adjusting pH often involves contacting the solution with a suitable base agent, such as a strong base agent. The skilled person can evaluate which base is suitable for adjusting the pH of the solution resulting from the contact without risk of decomposition of the optionally substituted dimethyltryptamine salt. The pH of the solution resulting from contact is adjusted with a suitable alkaline, preferably base agent, which may be sodium hydroxide or potassium hydroxide.

In some embodiments, the pH is further adjusted using a pH adjuster to achieve the desired pH. The pH adjusting agent is selected from suitable acids such as acetic acid, aspartic acid, benzene sulfonic acid, benzoic acid, citric acid, hydrochloric acid, hydrobromic acid, methane sulfonic acid, propionic acid, tartaric acid, fumaric acid, lactic acid, phosphoric acid, maleic acid and sulfuric acid, or mixtures thereof. It could be a mountain. Preferably, the pH adjusting agent is selected from acetic acid, aspartic acid, benzene sulfonic acid, benzoic acid, citric acid, hydrochloric acid, hydrobromic acid, methane sulfonic acid, tartaric acid, fumaric acid, maleic acid and sulfuric acid, or mixtures thereof. Preferably, the formulation of the invention comprises a pH adjusting agent which is hydrochloric acid.

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

As described above, dimethyltryptamine has a possible therapeutic role in the treatment of depression, obsessive-compulsive disorder, and substance abuse disorders (see (S. A. Barker, 2018), supra. In view of the fourth aspect, accordingly, The invention provides a preparation 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 preparation is 5 ml or less. Drug-assisted in a volume of less than, 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. It contains an effective dose of an optionally substituted dimethyltryptamine compound for use in psychotherapy, or psychedelic adjuvant therapy.

In terms of the fifth aspect, the invention provides an agent of the first aspect or a kit of the second aspect for use in a method of treating a mental or neurological disorder in a patient. In a preferred embodiment of the fifth aspect of the invention, the formulation is 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, An effective dose of an optionally substituted dimethyltryptamine compound for use in drug-assisted psychotherapy or psychedelic-assisted therapy in a volume of 1 ml or less, or 0.5 ml or less.

Often, the mental or neurological disorder is selected from the group consisting of (i) obsessive-compulsive disorder, (ii) depressive disorder, (iii) anxiety disorder, (iv) substance abuse and gambling disorder, and (v) alexithymia disorder. Often, the disorder is selected from the group consisting of major depressive disorder, treatment-resistant major depressive disorder, postnatal depression, obsessive-compulsive disorder, and eating disorders such as compulsive eating disorder.

In view of the sixth aspect, the invention provides a method of treating a mental or neurological disorder, comprising administering the agent of the first aspect to a patient in need of treatment of the mental or neurological disorder. In a preferred embodiment of the sixth aspect of the invention, the formulation is 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, An effective dose of an optionally substituted dimethyltryptamine compound for use in drug-assisted psychotherapy or psychedelic-assisted therapy in a volume of 1 ml or less, or 0.5 ml or less. The mental or neurological disorder may be any of those described in connection with the fifth aspect. For example, the disorder may be selected from the group consisting of major depressive disorder, treatment-resistant major depressive disorder, postnatal depression, obsessive-compulsive disorder, and eating disorders such as compulsive eating disorder.

In a sixth aspect of the invention, the agent of the first aspect can be administered in combination with psychotherapy (i.e., in drug-assisted psychotherapy).

To treat a disorder, the agent contains an effective amount of the dimethyltryptamine compound, i.e., an amount sufficient to reduce or halt the rate of progression of the disorder, or to ameliorate or cure the disorder, thereby producing the desired therapeutic or inhibitory effect. Includes.

The formulation is suitable for intramuscular injection, so that its administration to a patient involves injection of the formulation.

The formulation may be suitable for bolus injection, in which separate amounts of optionally substituted dimethyltryptamine salts are administered in a single injection to rapidly increase the concentration of optionally substituted dimethyltryptamine in the body.

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

The formulation is also suitable for nebulized inhalation, so that its administration to a patient may involve inhalation of the formulation using a nebulizer.

The agents of the invention are deuterated N,N-dimethyltryptamine compounds, such as α,α-dideutero-N,N-dimethyltryptamine (d ₂ -DMT), α,α,β,β-tetradyu. tero-N,N-dimethyltryptamine (d ₄ -DMT), N,N-di(trideuteromethyl)tryptamine (d ₆ -DMT), α,α-dideutero-N,N-di(tri Deuteromethyl)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 inventive formulations suitable for lower dosage volumes. This has the advantage of allowing the IM formulation to be administered over a wider range of injection sites. The higher concentrations and lower dose volumes of the present formulation may also allow the use of a wider range of nebulizer equipment and allow for shorter inhalation times.

In a tenth aspect, the invention provides a lyophilized powder formulation comprising the formulation as defined in the first aspect of the invention, which is lyophilized (i.e. freeze-dried).

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

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

In a twelfth aspect, the invention provides a preparation comprising a salt of an optionally substituted dimethyltryptamine compound, a buffering agent separated from the salt, a base agent and water, as defined in the tenth aspect or the compound of the eleventh aspect in water. The lyophilized powder formulation as prepared in the method is mixed to achieve 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. A method for producing an aqueous formulation is provided, comprising providing a formulation having. 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, the embodiments associated with each aspect of the invention apply mutatis mutandis to other aspects of the invention. Each and every reference mentioned herein is herein incorporated by reference in its entirety as if the entire contents of each reference were set forth herein in its entirety.

PCT/EP2021/073189, UK Patent Application No. 2119021.0 and US Patent Application No. 17/574,424 and any validly claimed priority documents are incorporated herein by reference in their entirety.

The synthesis of compounds for use in the preparations 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 extent 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 free base) was prepared as N,N-DMT fumarate using the chemicals disclosed in Scheme 2 and Examples section of WO 2021/089873. An additional 4-6 g of six partially deuterated mixtures were also produced using modified conditions.

Example 2: Deuterated N,N-dimethyltryptamine

Synthesis of deuterated mixtures of DMT compounds

Using a solid LiAlH ₄ /LiAlD ₄ mixture using 1.8 equivalents of LiAlH ₄ /LiAlD ₄ for 0.9 equivalents of LiAlH ₄ using the process described above for N,N-dimethyltryptamine as disclosed in WO 2021/089873. A modified synthesis was adopted. Deuterated dimethyltryptamine compounds include α-prothio, α-deutero-dimethyltryptamine and α,α-dideutero-dimethyltryptamine.

Data for the six deuterated reactants are shown in the table below:

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

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

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

Synthesis of α,α-dideutero-5-methoxydimethyltryptamine

Step 1:

A 100 mL 3-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 N ₂ . EDC.HCl (4.459 g, 23.261 mmol) was then charged in portions at <30°C over 15 minutes. The reaction mixture was stirred at ambient temperature for 1 hour before being charged with 2M dimethylamine (14.54 mL, 29.078 mmol) dropwise over 15 minutes at <25°C. After stirring for 1 hour, HPLC showed no SM remaining. The reaction mixture was then charged with 10% K ₂ CO ₃ (20 mL), stirred for 5 minutes and then allowed to separate. The lower aqueous layer was removed and extracted again with DCM (10 mL x 2). The organic extracts were combined, washed with saturated brine (10 mL) then dried over MgSO ₄ and filtered. The filtrate was concentrated in vacuo at 45° C. to give 3.898 g active product (yield=87%), 95.7% pure by HPLC.

Step 2:

A 100 mL 3-neck flask was charged with Stage 1 methoxy derivative (3.85 g, 16.586 mmol) and THF (19.25 ml) under N ₂ . 2.4 M LiAlD ₄ in THF (6.22 mL, 14.927 mmol) was then charged dropwise over 30 minutes at <40°C. The reaction mixture was heated to 60° C. for 1 hour, where HPLC showed 0.1% SM remaining. The reaction mixture was then cooled to ambient temperature and quenched with Rochelle salt (38.5 mL) by dropwise addition over 30 minutes at <30°C. The resulting suspension was stirred for 1 hour before separation. The lower aqueous layer was then removed and the upper organic layer was washed with saturated brine (9.6 mL). The organics were then dried over MgSO ₄ , filtered and concentrated in vacuo before applying to the azeotrope from EtOH (10 mL x 2). This gave 3.196 g active product (yield=88%), 91.5% pure by HPLC.

Step 3:

A 50 mL 3-neck flask 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) under N ₂ . The mixture was then heated to 75°C for 1 hour, which did not produce a solution as expected, and the mixture was further heated to reflux (78°C), which still failed to give a solution. The suspension was thus cooled to 0-5°C, filtered and washed with EtOH (8 mL x 2) before drying at 50°C overnight. This gave 3.165 g material (yield=65%) with 99.9% purity by HPLC.

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

Example 4: d ₆ -Dimethyltryptamine

Synthesis of d ₆ -DMT

Step 1

EDC.HCl (15.7 g, 81.90 mmol) was added to 3-indoleacetic acid (12.0 g, 68.50 mmol) and HOBt.H ₂ O (1.16 g, 75.75 mmol) in DCM (108 mL) at room temperature. The reaction was stirred for 1 hour, then N,N -diisopropylethylamine (DIPEA) (35.6 mL, 205.75 mmol) and d ₆ -dimethylamine.HCl (9.0 g, 102.76 mmol) were added (temperature was 30 maintained below ℃). The reaction was stirred at room temperature for 1 hour, after which analysis by HPLC showed 65.6% product with 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 x 30 mL). The combined organics were washed with brine (2 x 30 mL) followed by aqueous citric acid (20 w/w%, 50 mL), dried over MgSO ₄ and filtered. The filtrate was removed and the resulting solid was slurried in TBME (120 mL) and isolated by filtration. Purification by flash column chromatography yielded 8.34 g of the desired product (58% yield). The identity of the product was confirmed by ¹ H NMR.

Step 2

LiAlH ₄ (1 M in THF, 17.3 mL, 17.28 mmol) was added to the suspension of Step 1 (4.0 g, 19.20 mmol) in THF (10 mL) at <30°C. The resulting reaction was heated to 60-65°C and stirred for 2 hours. HPLC analysis showed complete consumption of step 1 and 97.3% product formed. The reaction was cooled to room temperature and quenched with aqueous Rossel's salt (10 g in 30 mL water) at <30°C. After stirring for 1 hour, the phases were separated. The aqueous phase was extracted with THF (20 mL). The combined organics were washed with brine (20 mL), dried over MgSO ₄ , filtered, and removed (azeotroped with ethanol, 20 mL) to give the desired product (3.97 g) as an amber oil. ¹ H NMR confirmed the identity of the product and showed that 8.5% ethanol was present (no THF) and 3.63 g, 97% yield of active material was obtained.

Step 3

d ₆ -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. (the solid crystallized during heating and did not redissolve). The resulting suspension was cooled to 0-5°C and stirred for 1 hour. The solid was isolated by filtration, washed with ethanol (2 x 7 mL) and pulled dry. Additional drying in a vacuum oven at 50°C yielded the desired d ₆ -DMT fumarate (4.98 g, 87%).

Example 5: d ₈ -Dimethyltryptamine

Synthesis of d ₈ -DMT

Step 1 (coupling of 3-indoleacetic acid and d ₆ -dimethylamine) was carried out according to the process described in Example 4, Step 1 above.

Step 2

LiAlD ₄ (1 M in THF, 17.3 mL, 17.28 mmol) was added to the suspension of the product of step 1 (4.0 g, 19.20 mmol) in THF (10 mL) at <30°C. The resulting reaction was heated to 60-65°C and stirred for 2 hours. HPLC analysis showed complete consumption of step 1 and 97.3% product formed. The reaction was cooled to room temperature and quenched with aqueous Rossel's salt (10 g in 30 mL water) at <30°C. After stirring for 1 hour, the phases were separated. The aqueous phase was extracted with THF (20 mL). The combined organics were washed with brine (20 mL), dried over MgSO ₄ , filtered, and removed (azeotroped with ethanol, 20 mL) to give the desired product (4.01 g) as an amber oil. ¹ H NMR confirmed the identity of the product and showed that 8.6% ethanol was present (no THF) and 3.66 g, 97% yield of active material was obtained.

Step 3

d ₈ -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. (the solid crystallized during heating and did not redissolve). The resulting suspension was cooled to 0-5°C and stirred for 1 hour. The solid was isolated by filtration, washed with ethanol (2 x 7 mL) and dried by suction. Additional drying in a vacuum oven at 50°C yielded the desired d ₈ -DMT fumarate (4.62 g, 81%).

Example 6: d ₆ -5-methoxydimethyltryptamine

Synthesis of d ₆ -5-MeO-DMT

Step 1

The coupling of 5-methoxy-3-indoleacetic acid and d ₆ -dimethylamine was carried out on a 20 g scale by a process similar to that described in Step 1 of Example 4 above. Purification by flash column chromatography yielded a light brown solid (87%) that was 97.8% pure by HPLC. Molecular Weight: 238.32.

Step 2

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

Step 3

The fumarate salt of d ₆ -5-MeO-DMT was produced following the process described for step 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 indicated that the hemi-salt was isolated. Molecular weight: (as half salt) 564.74.

Example 7: d ₈ -5-methoxydimethyltryptamine

Synthesis of d ₈ -5-MeO-DMT

Step 1

The coupling of 5-methoxy-3-indoleacetic acid and d ₆ -dimethylamine was carried out on a 20 g scale by a process similar to that described in Step 1 of Example 4 above. Purification by flash column chromatography yielded a light brown solid (87%) that was 97.8% pure by HPLC. Molecular Weight: 238.32.

Step 2

The product of Example 7, Step 1 was reacted with LiAlD ₄ in THF at a 9 g scale following the process described in Step 2 of Example 5. Purification yielded 8.12 g (7.58 g active, 88.7%) of product d ₈ -5-MeO-DMT as an amber oil with 97.9% purity by HPLC. Molecular Weight: 226.35.

Step 3

The fumarate salt of d ₈ -5-MeO-DMT was produced according to the process described for step 3 of Example 4. 9.6 g of product d ₈ -5-MeO-DMT fumaric acid was obtained with 99.71% purity by HPLC. Molecular Weight: 342.42.

Degree of deuteration.

D ₆ -5-hydroxydimethyltryptamine and d ₈ -5-hydroxydimethyltryptamine were obtained by a process similar to that described in Examples 6 and 7, respectively, using 5-hydroxy-3-indoleacetic acid as starting material. can be manufactured. Alternatively, d ₆ -5-hydroxydimethyltryptamine and d ₈ -5-hydroxydimethyltryptamine can be prepared from d , respectively, by demethylation of the 5-methoxy group using standard procedures, for example BBr ₃ demethylation. It can be prepared from ₆ -5-methoxydimethyltryptamine and d ₈ -5-methoxydimethyltryptamine.

Example 8: Pharmacokinetic (PK) profile in vivo testing

N,N-dimethyltryptamine (DMT, SPL026), α,α,-bis-deuterium-N,N-dimethyltryptamine (d ₂ -DMT, SPL028i) and α,α,bis after intramuscular (IM) administration. In vivo examination of the pharmacokinetic (PK) profile of -deuterio-N,N-hexadeuterio-dimethyltryptamine (d ₈ -DMT, SPL028viii) was performed in rats.

test compound

method

Twelve male (7-8 week old) Sprague Dawley rats (250 - 300 g body weight) received the following doses:

Kennels and breeding

Dosage regimen

Cassette doses of 3.5 mg/kg SPL026 fumarate and 3.5 mg/kg SPL028viii fumarate were administered as a single IM dose to four different male animals to allow direct comparison between animals of SPL026 and SPL028viii, thereby reducing the variability between animals. The confounding effect of was avoided. 3.5 mg/kg and 10 mg/kg SPL028i fumarate were administered as a single IM dose to four different male animals.

Administration Procedure

Animals were weighed on the morning of dosing, and doses were administered based on body weight and specified dose 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 distributed directly into the thigh muscles.

PK sampling

After administration, serial whole blood samples (approximately 200 μL) will be collected from the lateral tail vein via an indwelling cannula into individual K ₂ EDTA treated containers. Samples were collected at the following time points post-dose:

IM 5, 10, 25, 30, 45, 60, 90, 120, and 180 minutes prior to administration.

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

bioanalysis

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

Concentrations of DMT and d ₈ -DMT were quantified using 20.0 μL of rat plasma with a target lower limit of quantitation (LLOQ) of DMT, d ₈ -DMT, and d ₂ -DMT of approximately 0.310 ng/mL using the following method: It was verified by:

· Assay Linearity - Calibration curve prepared in duplicate containing ≥8 concentration levels as well as a control blank and zero (IS only). Acceptance criteria - At least 75% of the calibration standards (non-zero samples) should have a relative error (RE) of ≤±20% of their prepared nominal concentration (≤±25% RE at the lower limit of quantification).

· Sensitivity - Minimum signal to noise should be 5:1 at LLOQ concentration.

· Precision and accuracy - single assay batch with QC at low, medium and high concentrations, repeated (n=6). Acceptance criteria - within-batch precision (CV) and accuracy (RE) ≤20%.

· Selectivity - Qualitative evaluation of chromatograms of control blank matrices from at least one source for the presence of potential interfering peaks. Acceptance Criteria - The response of any co-elution interference should be ≤25% of the peak area of the LLOQ calibration standard. The response of any co-elution interference should be less than 5% of the zero sample peak area relative to the internal standard.

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

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

PK parameters

Pharmacokinetic parameters of DMT (SPL026), d ₈ -DMT (SPL028viii) and d ₂ -DMT (SPL028i) in plasma were derived by non-compartmental analysis using the plasma concentration-time profile for each animal.

result

The results are presented in Figure 1. These data indicate that d ₈ -DMT(SPL028viii) and d ₂ -DMT(SPL028i) have greater overall exposure compared to DMT (SPL026) after IM administration at 3.5 mg/kg.

Figures 1A and 1B are linear plots of mean DMT (SPL026), d ₈ -DMT (SPL028viii) and d ₂ -DMT (SPL028i) concentrations over time following 3.5 mg/kg fumarate IM administration (added as a cassette) in vivo. and semilogarithmic plots. Figure 1a - Linear plot, Figure 1b - Semilogarithmic plot, SEM error bars.

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

ANOVA with pairwise comparisons was performed to analyze the effect of dose group on PK parameters. Statistically significant differences in the mean area under the curve (AUC _0-inf ) from time 0 to time extrapolated to infinity between the SPL026 and SPL028viii groups and between the SPL026 and SPL028i groups after administering equivalent IM doses to both groups. There was a significantly higher total systemic exposure of SPL028viii and SPL028i compared to SPL026 after a single IM administration.

Cmax was found to be significantly higher for d ₈ -DMT (SPL028viii) and d ₂ -DMT (SPL028i) compared to DMT (SPL026) after IM administration (p = 0.005**).

There was a 144% increase in Cmax and a 237% increase in AUC _0-inf of d ₂ -DMT (SPL028i) at the 10 mg/kg dose compared to the 3.5 mg/kg dose level. The differences in the dose response relationship levels of Cmax and AUC _0-inf are significantly different from each other (p<0.05* and p<0.001***, respectively), indicating a significant dose-response relationship.

The invention is further illustrated by the following embodiments.

Development of formulation

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

Detailed description of experiment

The stability of the N,N-dimethyltryptamine (DMT) fumarate formulation was evaluated at a concentration of 20 mg/mL and pH 4, 5, 6, 7, 8, and 9. The pH was varied using a Britton-Robinson (B-R) buffer system (also known as universal buffer). The B-R buffer system typically consists of a mixture of 0.04 M boric acid, 0.04 M phosphoric acid, and 0.04 M acetic acid, and is titrated to the desired pH using 0.2 M sodium hydroxide. The system can change pH while maintaining the osmolality constant.

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

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

pH stability

The pH-stability of DMT fumarate at a nominal concentration of 2.5 mg/mL was assessed in 40 mM Britton-Robinson buffer over the buffer solution range of pH 4 to 9 (nominal). The pH of each formulation was measured at the time of manufacture after 7 days of storage at 40°C, followed by an additional 3 days at 40°C and 7 days of additional storage at 50°C (for a total of 10 additional days of storage). Analysis of these preparations was performed for content (assay) and related substances at the time of manufacture and after subsequent 7 and 17 days of storage.

For further testing, two additional aliquots of the pH 7 (nominal) solution were taken, one sparged with nitrogen and the second irradiated with 1 ICH unit (200 watt-hour UVA, 600,000 luxhours) for 4 hours. A harsh test of intense UV light corresponding to was applied.

During the preparation of each formulation, there was a decrease in pH ranging from 0.14 units (pH 4 formulation) to 1.29 units (pH 9 formulation), which was due to the acidic nature of the drug substance. Once manufactured, the pH of each formulation remained stable over two subsequent stability time points (Table 1).

The concentration of DMT fumarate was determined by HPLC at the time of preparation and at two subsequent stability time points (Table 2). All results confirmed that the product was manufactured correctly without significant concentration changes on the 7th and 17th days. The only significant change over the course of the experiment was a drop in concentration after light stress testing on aliquots of the nominal pH 7 preparation. This was accompanied by a significant increase in the observed decomposition products.

For related substances, only peaks exceeding 0.05% of the total peak area were recorded. Summary relevant material data is shown in Table 3 and individual values are in Table 4 (storage for 7 days at 40°C) and Table 5 (storage for 10 days at 40°C and an additional 7 days at 50°C).

Upon preparation, no relevant material peaks were present. On day 7, only the pH 9 formulation contained a peak at a relative retention time of 1.11. After 7 days of extended storage, only minimal additional peaks were observed and the formulation was further subjected to stress testing (with increasing storage temperature over time) and when analyzed after 17 days of storage, the pH increased. Additional peaks were present in several formulations with a clear trend of increasing peak number and peak area as the concentration increased, ranging from no peak (pH 4) to 3 peaks with a total peak area of 0.61% (pH 9). It reaches. The nitrogen sparged formulation (pH 7) was significantly more robust than its unsparged equivalent, thereby confirming that oxidation was the degradation pathway. The formulation subjected to the accelerated illumination test was the most degraded sample with a total related substances value of 1.68%.

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

It can be seen from Table 2 that the concentration of DMT fumarate in solutions with a nominal pH > 7 decreased over 17 days.

Table 3 clearly shows that the amount of related substances increased with increasing pH, indicating reduced stability.

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

As described above, when developing an injectable formulation, it is common to match the pH of the formulation with the pH of the patient's serum. Human serum has a pH of about 7.4. As a result, reliable formulations of salts of optionally substituted dimethyltryptamine compounds are those with a pH of about 7.4. The greater stability of preparations of these salts prepared at pH values below 7.0 was unexpected.

Formulation manufacturing

Details of each individual exemplary formulation are shown in the table below. Each formulation can be prepared by a process similar to the examples below.

Aliquots of each agent may be taken for assay/relevant substances and osmolality determination. The remainder of each preparation was filtered into clear glass multi-dose vials (filter size 0.2 μm), sparged with nitrogen, and capped.

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

One) The required amount of drug substance is weighed into a suitable container (glass weigh boat). Ensure that the mass of drug substance taken includes corrections for salt and purity.

2) Carefully transfer the weighed drug substance into the beaker. Rinse the weighing vessel with water for injection (WFI) to ensure that no solid material remains. Add additional WFI to the drug substance, up to ¾ of the total volume required, and magnetically stir to dissolve.

3) Fill a suitable container to a certain volume, and finally check that the pH is pH 5.5 (±0.1) and adjust if necessary.

4) The drug product solution is transparent with a very slightly beige color (using N,N-dimethyltryptamine fumarate). This color is removed by filtration (step 6), leaving a colorless filtered solution.

5) Nitrogen is bubbled through the formulation until the measured dissolved oxygen content is less than 5 ppm, preferably less than 2 ppm.

6) The solution is injected by syringe filtration into a suitable glass multi-dose vial, suitably at 0.22 μm or 0.2 μm.

Exemplary agents include cosolvents, surfactants, buffers, pH adjusters or isotonic agents, or other excipients.

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

'DS' refers to an optionally substituted dimethyltryptamine compound for use in the formulations of the invention.

Example 9: N,N-dimethyltryptamine pH-stability

pH solubility samples were prepared in 0.5M Britton Robinson (BR) buffer. Before adding N,N-dimethyltryptamine, the required amount of NaOH was added to the BR buffer to ensure the required pH. The total volume of BR buffer plus 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 then added and the pH checked before shaking overnight at ambient temperature.

The solubility of N,N-dimethyltryptamine was determined at various pH at 25°C as shown in the following table and Figure 3:

Solubilities of 90 mg/mL or greater were observed at a pH of about 4 to about 6, with the highest solubility being observed at a pH of approximately 5.

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

Example 10: Exemplary Formulations

Exemplary formulations of the invention are shown in the table below.

Example 11: Stability

A preparation of DMT fumarate prepared according to Example 10 (Example 2) and a preparation of deuterated DMT fumarate (Example 2) were incubated at 25°C/60% RH and 40°C/75% RH for 3 months. Stability was evaluated after storage at -8°C.

For preparations containing DMT fumarate, no substances above the limit of quantification (≥0.05% w/w) were observed at T=0 or after 3 months storage at 2-8°C and 25°C/60% RH. didn't After 3 months storage at 40°C/75% RH, a total of 0.35% w/w related substances were observed.

For preparations containing deuterated DMT fumarate, relevant substances exceeding the limit of quantitation (≥0.05% w/w) are stored for 3 months at T=0, or at 2-8°C and 25°C/60% RH. not observed after. After 3 months storage at 40°C/75% RH, a total of 0.33% w/w related substances were observed.

These data indicate good stability for the formulation of the invention, with small amounts of relevant substances observed only under the harsh conditions of 40°C/75% RH.

The invention may be further understood by reference to the following non-limiting provisions:

One. salts of optionally substituted dimethyltryptamine compounds; and water; as pharmaceutical preparations suitable for intramuscular injection and/or nebulizer inhalation; wherein the formulation has a pH of about 5 to about 6, a free base concentration of about 10 mg/ml or greater, and an osmolality of about 250 to about 350 mOsm/Kg.

2. Salts of optionally substituted dimethyltryptamine compounds; and water; as pharmaceutical preparations suitable for intramuscular injection and/or nebulizer inhalation; wherein the formulation has a pH of about 5 to about 6.5, a free base concentration of about 10 mg/ml or greater, and an osmolality of about 250 to about 350 mOsm/Kg.

3. Salts of optionally substituted dimethyltryptamine compounds; As a pharmaceutical preparation suitable for intramuscular injection and/or nebulizer inhalation comprising a base preparation, water, and optionally a buffer separated from the salt; wherein the formulation has a pH of about 5 to about 6, a concentration of about 10 mg/ml or greater as free base, and an osmolarity of about 250 to about 350 mOsm/K; A pharmaceutical formulation comprising a dose of an optionally substituted dimethyltryptamine compound in a volume of 5 ml or less for injection or inhalation.

4. salts of optionally substituted dimethyltryptamine compounds; As a pharmaceutical preparation suitable for intramuscular injection and/or nebulizer inhalation comprising a base preparation, water, and optionally a buffer separated from the salt; wherein the formulation has a pH of about 5 to about 6.5, a concentration of about 10 mg/ml or greater as free base, and an osmolarity of about 250 to about 350 mOsm/Kg; A pharmaceutical formulation comprising a dose of an optionally substituted dimethyltryptamine compound in a volume of 5 ml or less for injection or inhalation.

5. The formulation of any one of clauses 1 to 4, wherein the formulation comprises an effective dose of an optionally substituted dimethyltryptamine compound for use in psychedelic adjuvant therapy in a volume of 5 ml or less.

6. The preparation according to any one of clauses 1 to 5, wherein the volume is 3 ml or less.

7. The preparation according to any one of clauses 1 to 6, wherein the volume is 2.5 ml or less.

8. The formulation of any one of clauses 1 to 7, wherein the formulation has an osmolarity of about 275 to about 325 mOsm/Kg.

9. The formulation of any one of clauses 1 to 8, 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 above equation,

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;

R ² is C( ^xH ) ₃ ;

R ³ is C( ^xH ) ₃ ;

each R ⁴ is independently selected from C ₁ -C ₄ alkyl;

Each ^x H and ^y H is independently selected from light hydrogen or deuterium.

10. The formulation of any one of clauses 1 to 9, wherein the salt of the optionally substituted dimethyltryptamine compound comprises a Bronsted acid having a pKa of about 3 to about 5 and a compound of Formula (IA) or Formula (IB):

In the above equation,

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

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

R ^2a is C( ^xa H) ₃ ;

R ^3a is C( ^xa H) ₃ ;

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

each ^xa H and ^ya H is independently selected from light hydrogen or deuterium;

In the above equation,

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

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

R ^2b is C( ^xb H) ₃ ;

R ^3b is C( ^xb H) ₃ ;

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

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

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

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

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

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

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

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

17. The salt of any of clauses 9 to 16, wherein the salt of the optionally substituted dimethyltryptamine compound is (i) a compound of formula (I) wherein both ^y H are D; or (ii) a compound of formula (IA) wherein both ^ya H are D; or (iii) a preparation comprising a compound of formula (IB) wherein both ^yb H are D.

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

19. The salt of any of clauses 9 to 16, wherein the salt of the optionally substituted dimethyltryptamine compound is (i) a compound of formula (I) wherein both ^y H are H; or (ii) a compound of formula (IA) wherein both ^ya H are H; or (iii) a preparation comprising a compound of formula (IB) wherein both ^yb H are H.

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

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

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

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

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

25. The preparation according to 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. The formulation of any one of clauses 1 to 9, wherein the optionally substituted dimethyltryptamine compound is N,N-dimethyltryptamine.

27. The method of any one of clauses 1 to 25, wherein the optionally substituted dimethyltryptamine compound is α,α-dideutero-N,N-dimethyltryptamine (d ₂ -DMT), α,α,β,β-tetra Deutero-N,N-dimethyltryptamine (d ₄ -DMT), N,N-di(trideuteromethyl)tryptamine (d ₆ -DMT), α,α-dideutero-N,N-di( Trideuteromethyl)tryptamine (d ₈ -DMT), α,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine (d ₁₀ -DMT), 5-methoxy -α,α-dideutero-N,N-di(trideuteromethyl)tryptamine, α,α-dideutero-N,N-di(trideuteromethyl)tryptamine (d ₈ -DMT), α ,α,β,β-tetradeutero-N,N-di(trideuteromethyl)tryptamine (d ₁₀ -DMT), 5-methoxy-N,N-di(trideuteromethyl)tryptamine, 5-methoxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine, 5-methoxy-α,α,β,β-tetradeutero-N,N-di(trideutero) Deuteromethyl)tryptamine and mixtures thereof.

28. The salt of any of clauses 1 to 27, wherein the salt of the optionally substituted dimethyltryptamine compound is of the optionally substituted dimethyltryptamine compound and an acid selected from the group consisting of fumaric acid, tartaric acid, citric acid, acetic acid, lactic acid and gluconic acid. Jeje.

29. The formulation of clause 28, wherein the acid is fumaric acid.

30. The formulation of any one of clauses 1 to 29, comprising a drug substance comprising a salt of an optionally substituted dimethyltryptamine compound with a purity of greater than or equal to 99% as determined by HPLC.

31. The formulation of any one of clauses 1 to 30, wherein the concentration of the optionally substituted dimethyltryptamine is from about 10 mg/mL to about 150 mg/mL (as free base equivalents).

32. The formulation of any one of clauses 1 to 31, wherein the concentration of the optionally substituted dimethyltryptamine is from about 15 mg/mL to about 70 mg/mL (as free base equivalents).

33. The formulation of any one of clauses 1 to 32, wherein the concentration of the optionally substituted dimethyltryptamine compound is from about 20 mg/mL to about 40 mg/mL (as free base equivalents).

34. The formulation of any one of clauses 1-33, wherein the concentration of the optionally substituted dimethyltryptamine is about 20 mg/mL (as free base equivalent) or greater.

35. The formulation of any of clauses 1-34, wherein the concentration of the optionally substituted dimethyltryptamine compound is about 25 mg/mL (as free base equivalent) or greater.

36. The formulation according to any one of clauses 1 to 35, wherein the formulation further comprises a salt and a separate buffering agent.

37. The method of clause 36, wherein the buffering agent is acetate and acetic acid; or citrate and citric acid; or contains phosphates and phosphoric acid; or a formulation wherein the buffering agent includes acetate, citrate, or phosphate.

38. The formulation of any one of clauses 1 to 37, wherein the base agent is sodium hydroxide or potassium hydroxide.

39. The formulation according to any one of clauses 1 to 38, wherein the formulation further comprises an isotonic agent.

40. The method of any one of clauses 1 to 39, wherein the agent is comprised of salts of optionally substituted dimethyltryptamine compounds, water, and base agents, and optionally one or more agents selected from isotonic agents, buffers, cosolvents, preservatives, and antioxidants. A preparation that is essentially done.

41. The formulation according to any one of clauses 1 to 40, wherein the formulation consists essentially of a salt of an optionally substituted dimethyltryptamine compound, water, optionally a buffer and optionally an isotonic agent.

42. The formulation according to any one of clauses 1 to 41, wherein the formulation consists essentially of an optionally substituted salt of the dimethyltryptamine compound, a base agent, water, optionally a buffer and optionally an isotonic agent.

43. The formulation according to any one of clauses 1 to 35 and 39 to 42, wherein the formulation consists of a salt of an optionally substituted dimethyltryptamine compound, water, and optionally an isotonic agent.

44. The formulation according to any one of clauses 3 to 35 and 38 to 42, wherein the formulation consists of an optionally substituted salt of the dimethyltryptamine compound, a base agent, water, and optionally an isotonic agent.

45. The formulation according to any one of clauses 39 to 44, wherein the isotonic agent is sodium chloride or dextrose.

46. The formulation according to any one of clauses 1 to 45, wherein the formulation has an oxygen content of less than 5 ppm.

47. The formulation according to any one of clauses 1 to 45, wherein the formulation has an oxygen content of less than 2 ppm.

48. The formulation of any one of clauses 1 to 47, wherein the formulation is sparged with an inert gas.

49. The preparation according to any one of clauses 1 to 48, wherein the preparation is stored in a container having a volume of 5 ml or less.

50. The preparation according to any one of clauses 1 to 49, wherein the preparation is stored in a container having a volume of 4 ml or less.

51. The preparation according to any one of clauses 1 to 50, wherein the preparation is stored in a container having a volume of 3 ml or less.

52. The preparation according to any one of clauses 1 to 51, wherein the preparation is stored in a container having a volume of 2 ml or less.

53. The preparation according to any one of clauses 1 to 52, wherein the preparation is stored in a container having a volume of 1 ml or less.

54. The preparation according to any one of clauses 1 to 53, wherein the preparation is stored in a container having a volume of 0.5 ml or less.

55. The formulation according to any one of clauses 1 to 54, wherein the formulation further comprises a pH adjusting agent.

56. 55. The formulation of clause 55, wherein the pH adjusting agent comprises hydrochloric acid.

57. 56. 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 the formulation of any one of clauses 1 to 57, said kit comprising an optionally substituted salt of a dimethyltryptamine compound; optionally isotonic; and optionally a salt and a separate buffer.

59. A kit suitable for preparing the formulation of any one of clauses 3 to 57, said kit comprising an optionally substituted salt of a dimethyltryptamine compound; optionally isotonic; A kit comprising a base agent and optionally a buffer separated from the salt.

60. A process for preparing a pharmaceutical preparation as defined in any one of clauses 1 to 57, comprising contacting a salt of an optionally substituted dimethyltryptamine compound, water and optionally a buffer, and optionally an isotonic agent.

61. A process for the preparation of a pharmaceutical preparation as defined in any one of clauses 3 to 57, comprising contacting a salt of an optionally substituted dimethyltryptamine compound, water, a base preparation and optionally a buffering agent separated from the salt, and optionally an isotonic agent. .

62. The method of clause 60 or 61, wherein an aqueous solution of the 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. The method of any one of clauses 60 to 62, wherein the method comprises contacting the optionally substituted dimethyltryptamine compound with a buffer, water and optionally an isotonic agent.

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

65. Method according to clause 64, wherein the pH is adjusted using a base agent, preferably sodium hydroxide or potassium hydroxide.

66. The method according to clause 64 or clause 65, further comprising adjusting the pH using a pH adjuster, preferably hydrochloric acid.

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

68. A preparation as defined in any of Articles 1 to 57 or a kit of Articles 58 or 59 for use as a medicine or in combination with psychotherapy (i.e. in medication-assisted psychotherapy).

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

70. Clause 69, wherein the mental or neurological disorder is selected from the group consisting of (i) obsessive-compulsive disorder, (ii) depressive disorder, (iii) anxiety disorder, (iv) substance abuse and gambling disorder, and (v) aphrodisiac disorder. Preparations for use in lice.

71. A method of treating a mental or neurological disorder comprising administering to a patient in need of treatment an agent as defined in any one of clauses 1 to 57.

72. A method of treatment according to clause 71, wherein the mental or neurological disorder is as defined in clause 70.

73. The method of treatment according to clause 71, wherein the agent as defined in any one of clauses 1 to 57 is administered in combination with psychotherapy.

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

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

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

77. The formulation, formulation, or method for use therein according to any one of clauses 1 to 57, 68 to 70, or 71 to 73, wherein the dosage of the optionally substituted dimethyltryptamine compound is in the range of about 20 to about 70 mg. .

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

79. The method of any of clauses 1 to 57, 68 to 70, or 71 to 73, wherein the agent is

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 and 5-methoxy-α,α-dideutero-N,N-di(trideuteromethyl)tryptamine, and Salts of optionally substituted dimethyltryptamine compounds selected from mixtures thereof, and acids selected from the group consisting of fumaric acid, tartaric acid, citric acid, acetic acid, lactic acid and gluconic acid;

b) base agents selected from sodium hydroxide and potassium hydroxide;

c) water;

d) Optionally separated from salts, acetate and acetic acid; or citrate and citric acid; or contains phosphates and phosphoric acid; or a buffering agent including acetate, citrate, or phosphate;

e) pH adjuster, optionally hydrochloric acid

Includes,

wherein the formulation has a pH of about 5 to about 6.5, or a pH of about 5 to about 6, a concentration (as free base equivalent) of about 15 mg/mL to about 70 mg/mL, and a concentration of about 250 to about 350 mOsm/Kg. has an osmolality; A formulation, formulation, or method for use therein, wherein the formulation comprises a dose of an optionally substituted dimethyltryptamine compound ranging from about 10 mg to about 100 mg in a volume of 5 ml or less.

Claims (54)

A pharmaceutical preparation suitable for intramuscular injection and/or nebulizer inhalation comprising an optionally substituted salt of a dimethyltryptamine compound, a base preparation, water and optionally a buffering agent separated from the salt; has a pH of about 5 to about 6.5, a concentration of free base greater than about 10 mg/ml, and an osmolarity of about 250 to about 350 mOsm/Kg; A pharmaceutical preparation comprising a dose of an optionally substituted dimethyltryptamine compound in a volume of 5 ml or less. 2. The formulation of claim 1, having a pH of about 5 to about 6. A preparation according to claim 1 or 2 suitable for intramuscular injection. 4. A preparation according to any one of claims 1 to 3, comprising an effective dose of an optionally substituted dimethyltryptamine compound for use in psychedelic adjuvant therapy in a volume of 5 ml or less. The preparation according to any one of claims 1 to 4, wherein the volume is 3 ml or less. The preparation according to any one of claims 1 to 5, wherein the volume is 2.5 ml or less. 7. The formulation of any one of claims 1 to 6, wherein the formulation has an osmolality 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):

In the above equation,
R ^1b is independently selected from -R ^4b , -OH, -OR ^4b , -O(CO)R ^4b , monohydrogen phosphate, -F, -Cl, -Br and -I;
n is selected from 0, 1, 2, 3 or 4;
R ^2b is C( ^xb H) ₃ ;
R ^3b is C( ^xb H) ₃ ;
each R ^4b is independently selected from C ₁ -C ₄ alkyl;
Each of ^xb H, ^yb H and ^z H is independently selected from light hydrogen or deuterium. 9. The method of claim 8, wherein salts of the optionally substituted dimethyltryptamine compounds include compounds of formula IB, wherein n is 0; or n is 1 and R ^1b is present at the 4-position or 5-position. 10. The method of claim 8 or 9, wherein the salts of the optionally substituted dimethyltryptamine compounds include compounds of formula IB, wherein each R ^1b is independently -OH, -OMe, -OCD ₃ , -OAc, - An agent selected from O(CO)Me, and monohydrogen phosphate. 11. The formulation of any one of claims 8-10, wherein the salts of the optionally substituted dimethyltryptamine compounds include compounds of formula IB, wherein R ^2b is CD ₃ and R ^3b is CD ₃ . 12. The formulation of any one of claims 8 to 11, wherein the salts of the optionally substituted dimethyltryptamine compounds include compounds of formula IB, wherein each ^yb H is D. The formulation of claim 8, 9, 11 or 12, wherein n is 0. 13. The formulation according to any one of claims 8 to 12, wherein n is 1 and R ^1b is 4-acetoxy. 13. The preparation according to any one of claims 8 to 12, wherein n is 1 and R ^1b is 5-methoxy or trideutero-5-methoxy. The formulation of any one of claims 1 to 8, wherein the optionally substituted dimethyltryptamine compound is N,N-dimethyltryptamine. The formulation of any one of claims 1 to 8, wherein the optionally substituted dimethyltryptamine compound is α,α-dideutero-N,N-dimethyltryptamine. 18. The method of any one of claims 1 to 17, wherein the salt of the optionally substituted dimethyltryptamine compound is an optionally substituted dimethyltryptamine compound and a salt selected from the group consisting of fumaric acid, tartaric acid, citric acid, acetic acid, lactic acid and gluconic acid. An agent that is a salt of an acid. 19. The formulation of claim 18, wherein the acid is fumaric acid. 20. A formulation according to any one of claims 1 to 19, comprising a drug substance comprising a salt of an optionally substituted dimethyltryptamine compound with a purity of at least 99% as determined by HPLC. 21. The formulation of any one of claims 1-20, wherein the concentration of optionally substituted dimethyltryptamine is from about 10 mg/mL to about 150 mg/mL (as free base equivalents). 21. The formulation of any one of claims 1-20, wherein the concentration of optionally substituted dimethyltryptamine is from about 15 mg/mL to about 70 mg/mL (as free base equivalents). 21. The formulation of any one of claims 1-20, wherein the concentration of the optionally substituted dimethyltryptamine compound is from about 20 mg/mL to about 40 mg/mL (as free base equivalents). 21. The formulation of any one of claims 1-20, wherein the concentration of the optionally substituted dimethyltryptamine compound is about 25 mg/mL (as free base equivalents). 25. A formulation according to any one of claims 1 to 24, comprising a salt and a separate buffering agent. 26. The method of claim 25, wherein the buffering agent is acetate and acetic acid; or citrate and citric acid; or contains phosphates and phosphoric acid; or a formulation wherein the buffering agent includes acetate, citrate, or phosphate. 27. The preparation according to any one of claims 1 to 26, wherein the base agent is sodium hydroxide or potassium hydroxide. 28. The formulation according to any one of claims 1 to 27, further comprising an isotonic agent and/or a pH adjusting agent. 29. The method of any one of claims 1 to 28, selected from salts of the optionally substituted dimethyltryptamine compound, water, and base agents, and optionally pH adjusters, isotonic agents, buffers, cosolvents, preservatives, and antioxidants. A preparation that essentially consists of one or more preparations. 30. A preparation according to any one of claims 1 to 29, which consists essentially of a salt of an optionally substituted dimethyltryptamine compound, water, a base preparation and optionally a buffer and/or isotonic agent and/or pH adjuster. 31. The preparation 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 isotonic agent and/or pH adjuster. 32. The formulation according to any one of claims 28 to 31, wherein the isotonic agent is sodium chloride or dextrose. 33. The preparation according to any one of claims 1 to 32, having an oxygen content of less than 5 ppm, preferably less than 2 ppm. 34. The preparation according to any one of claims 1 to 33, stored in a container having a volume of 5 ml or less. 34. The preparation according to any one of claims 1 to 33, stored in a container having a volume of 2 ml or less. 36. The formulation according to any one of claims 1 to 35, comprising an optionally substituted salt of the dimethyltryptamine compound, a base agent, water, a buffer separated from the salt, and an isotonic agent or pH adjusting agent. 37. A salt of the optionally substituted dimethyltryptamine compound according to claim 36; base agents selected from potassium hydroxide and sodium hydroxide; water; a buffering agent that is citrate; and a formulation comprising a pH adjusting agent that is an isotonic agent or acid. A kit suitable for preparing the agent of any one of claims 1 to 37, comprising: an optionally substituted salt of a dimethyltryptamine compound; optionally tonicity agents and/or pH adjusting agents; A kit comprising a base agent and optionally a buffer separated from the salt. 38. The method of any one of claims 1 to 37, comprising contacting a salt of the optionally substituted dimethyltryptamine compound, water, a base agent and optionally a buffering agent separated from the salt, and optionally an isotonic agent and/or a pH adjusting agent. A process for preparing a pharmaceutical preparation as defined. 40. A process according to claim 39, wherein an aqueous solution of the buffer is contacted with a salt of an optionally substituted dimethyltryptamine compound, wherein the aqueous solution has a pH as defined in claim 1. 41. A process according to claims 39 or 40, comprising contacting the optionally substituted dimethyltryptamine compound with water and optionally a buffer and/or isotonic agent and/or pH adjusting agent. 42. The method according to any one of claims 39 to 41, further comprising adjusting the pH of the formulation. 43. The method of claim 42, wherein the pH is adjusted using a base agent that is sodium hydroxide or potassium hydroxide. 44. The method according to any one of claims 39 to 43, further comprising sparging the formulation with an inert gas. A preparation as defined in any one of claims 1 to 37 or a kit of claim 38 for use as a medicine or in combination with psychotherapy. An agent as defined in any one of claims 1 to 37 or the kit of claim 38 for use in a method of treating a mental or neurological disorder in a patient. 46. The method of claim 46, wherein the mental or neurological disorder is divided into (i) obsessive-compulsive disorder, (ii) depressive disorder, (iii) anxiety disorder, (iv) substance abuse and gambling disorder, and (v) avolition disorder. A formulation or kit selected from the group consisting of: 38. A method of treating a mental or neurological disorder comprising administering to a patient in need of treatment an agent as defined in any one of claims 1 to 37. 49. The method of claim 48, wherein the mental or neurological disorder is as defined in claim 47. 49. The method of claim 48, wherein the agent as defined in 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, wherein the formulation is lyophilized. A method for producing a lyophilized powder formulation, comprising drying the formulation according to any one of claims 1 to 37 by lyophilization. as defined in claim 51 or as prepared by the method of claim 52 to provide a formulation comprising a salt of an optionally substituted dimethyltryptamine compound, a base agent, water, and optionally a buffering agent separated from the salt. Mixing the lyophilized powder formulation in water to provide a formulation having a pH of about 5 to about 6.5, a concentration of at least about 10 mg/ml as free base, and an osmolality of about 250 to about 350 mOsm/Kg. A method for producing an aqueous formulation. 54. The method of claim 53, providing a formulation having a pH of about 5 to about 6.