BR112022022198B1 - INJECTABLE FORMULATION - Google Patents

Abstract

INJECTABLE FORMULATION. Pharmaceutical formulations, methods for their production and their uses are provided in this document. Pharmaceutical formulations comprise a salt of an optionally substituted dimethyltryptamine compound, a buffer, which is separated from the salt, and water. The formulations have pH values of about 3.5 to about 6.5 and osmolalities of about 250 to about 350 mOsm/Kg. Such formulations are optionally suitable for injection, are stable and clinically acceptable, and have potential uses in the treatment of psychiatric or neurological disorders.

Description

FIELD OF INVENTION

[001] The present invention relates to pharmaceutical formulations, methods for their production and uses thereof. Pharmaceutical formulations comprise a salt of an optionally substituted dimethyltryptamine compound, a buffer, which is separated from the salt, and water. The formulations have pH values of about 3.5 to about 6.5 and osmolalities of about 250 to about 350 mOsm/Kg. Optionally, such formulations are suitable for injection, are stable and clinically acceptable, and have potential uses in the treatment of psychiatric or neurological disorders.

BACKGROUND OF THE INVENTION

[002] Classic psychedelics have shown preclinical and clinical promise in the treatment of psychiatric disorders (Carhart-Harris and Goodwin, Neuropsychopharmacology 42, 2105-2113 (2017)). In particular, psilocybin has demonstrated significant improvement in a number of depression and anxiety rating scales in randomized double-blind studies (Griffiths et al. Journal of Psychopharmacology, 30(12),1181-1197 (2016)).

[003] N,N-dimethyltryptamine (DMT) is also understood to have therapeutic value as a psychedelic. A review of research on the biosynthesis and metabolism of DMT in the brain and peripheral tissues, methods and results for detection of DMT in body fluids and the brain, new sites of action for DMT, and new data on possible physiological and therapeutic roles of DMT are provided by S. A. Barker in Front. Neurosci., 12, 536, 1-17 (2018). In this review, DMT is described as having a possible therapeutic role in the treatment of depression, obsessive-compulsive disorder, and substance abuse disorders.

[004] The injection of saline solutions of DMT fumarate salts into human volunteers is described in C. Timmermann et al., Sci. Rep., 9, 16324 (2019). The effect of DMT fumarate on the power spectrum and signal diversity of human brain activity was recorded using multivariate EEG and compared with the results obtained from the injection of a placebo (saline solution). In relation to the results obtained with placebo, DMT fumarate suppressed alpha power and normalized/increased delta and theta power. Alpha power has been associated with high-level psychological functioning, top-down predictive processing, and related feedback connectivity, while theta and delta power are classically associated with REM sleep dreaming and related “visionary” states. These results are reported to link DMT fumarate injection to the experience of feeling deeply immersed in an entirely different world.

[005] According to the Human Metabolome Database (HMDB - Human Metabolome DataBase), dimethyltryptamine degrades relatively quickly in solution (see specifically http://www.hmdb.ca/metabolites/HMDB0005973). There is a need in the art for injectable DMT solutions that are stable for long periods of time, and are clinically acceptable. The present invention meets this need.

SUMMARY OF THE INVENTION

[006] The present invention relates to pharmaceutical formulations, optionally suitable for injection, comprising a salt of an optionally substituted dimethyltryptamine compound, a buffer, which is separated from the salt, and water, wherein the formulations have pH values of about 3.5 to about 6.5 and typical osmolalities of about 250 to about 350 mOsm/Kg. Human blood serum has a pH of about 7.4 (typically ranging from 7.35 to 7.45, see G. K. Shwalfenberg, J. Environ. Public Health, 2012; 2012:727630), and the obvious salt formulation of optionally substituted dimethyltryptamine compounds is isotonic at a pH of 7.4. It has now been found that the formulations described in the prior art or adapted therefrom have a non-optimal shelf life when stored under ambient conditions. The present invention addresses this problem of providing pharmaceutical formulations, optionally suitable for injection, with substantially reduced degradation products compared to known formulations when stored under stress conditions. This is indicative of increased shelf life relative to such pharmaceutical formulations described in the prior art.

[007] Consequently, viewed from a first aspect, the invention provides a pharmaceutical formulation, optionally suitable for injection, comprising a salt of a dimethyltryptamine compound optionally substituted with deuterium and optionally substituted in position 4 or 5 with acetoxy or methoxy or position 4 with monohydrogen phosphate; a buffer that is separated from the salt; and water, wherein the formulation has a pH of about 3.5 to about 6.5 and an osmolality of about 250 to about 350 mOsm/kg.

[008] Seen from a second aspect, the invention provides a kit suitable for preparing a formulation of the first aspect, said kit comprising a salt of a dimethyltryptamine compound optionally substituted with deuterium and optionally substituted in the 4 or 5 position with acetoxy or methoxy or position 4 with monohydrogen phosphate; and a buffer that is separated from the salt.

[009] Viewed from a third aspect, the invention provides a method of preparing a pharmaceutical formulation of the first aspect, comprising contacting salt, buffer, water and optionally a tonicity agent. In some embodiments, the formulation or composition of the first and second aspect comprises a tonicity agent.

[0010] Due to the instability of dimethyltryptamine in solution, solutions comprising dimethyltryptamine are generally prepared immediately before or close to the time of use, that is, storage of dimethyltryptamine solutions is avoided. Alternatively, dimethyltryptamine solutions are frozen. The inventors have found that when a buffer, which is separated from the salt, is used, the resulting formulations are more stable than formulations prepared without a buffer separate from the salt. In addition, when using a container adapted to prevent the penetration of ultraviolet light, the resulting formulations are more stable than those stored in containers that allow the penetration of ultraviolet light.

[0011] Seen from a fourth aspect, therefore, the present invention provides the use of a buffer to improve the degradation of an injectable pharmaceutical formulation of a salt of a dimethyltryptamine compound optionally substituted with deuterium and optionally substituted in the 4 or 5 position with acetoxy or methoxy or position 4 with monohydrogen phosphate.

[0012] Viewed from a fifth aspect, the invention provides a formulation of the first aspect for use in therapy.

[0013] Viewed from a sixth aspect, the invention provides a formulation of the first aspect for use and a method of treating a psychiatric or neurological disorder in a patient.

[0014] Viewed from a seventh aspect, the invention provides a method of treating a psychiatric or neurological disorder comprising administering to a patient in need of a formulation of the first aspect.

[0015] Other aspects and embodiments of the present invention will be evident from the discussion that follows below.

DETAILED DESCRIPTION OF THE INVENTION

[0016] Throughout this specification, one or more aspects of the invention may be combined with one or more characteristics described in the specification to define distinct embodiments of the invention.

[0017] In the discussion that follows, reference is made to several terms, which are to be understood as having the meanings given below, unless a context expressly indicates otherwise. The nomenclature used in this document to define compounds, in particular the compounds described in this document, is intended to be in accordance with the International Union of Pure and Applied Chemistry (IUPAC) rules for chemical compounds, specifically the Compendium of Terminology IUPAC Chemistry (IUPAC - Compendium of Chemical Terminology) (Gold Book) (see A. D. Jenkins et al., Pure & Appl. Chem., 1996, 68, 2287-2311). For the avoidance of doubt, if a rule of the IUPAC organization is contrary to a definition provided in this document, the definition in this document shall control.

[0018] References in this document to a singular of a noun encompass the plural of the noun, and vice versa, unless the context indicates otherwise.

[0019] Throughout this specification the word "comprises", or variations such as "comprise" or "comprising", will be understood as implying the inclusion of a declared element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integer or step.

[0020] The term “consisting” or variants thereof shall be understood as implying the inclusion of a declared element, integer or step, or group of elements, integers or steps, and the exclusion of any other element, integer or step or group of elements, integers or steps.

[0021] The term “about” in this document, when qualifying a number or value, is used to refer to values that lie within ± 5% of the specified value. For example, if a pH range is specified to be about 3.5 to about 6.5, pH values of 3.3 to 6.8 are included.

[0022] The formulations of the invention are useful in therapy and can be administered to a patient in need of them. As used herein, the term “patient” preferably refers to mammal. Typically for mammal is a human, but can also refer to a domestic mammal. The term does not cover laboratory mammals.

[0023] The term "treatment" defines the therapeutic treatment of a patient, so as to reduce or stop the rate of progression of a disorder, or improve or cure the disorder. Prophylaxis of a disorder as a result of treatment is also included. References to prophylaxis in this document are not intended to require complete prevention of a disorder: its development can, instead, be prevented by treatment in accordance with the invention. Typically, treatment is not prophylactic, and the formulation is administered to a patient with a diagnosed or suspected disorder.

[0024] As understood in the art, psychiatric or neurological disorders are disorders that may be associated with one or more cognitive impairments. As used herein, the term “psychiatric disorder” is a clinically significant behavioral or psychological syndrome or pattern that occurs in an individual and that is associated with present distress (e.g., a painful symptom) or disability (i.e., impairment in a or more areas of functioning) or with a significantly increased risk of suffering death, pain, disability, or a significant loss of freedom.

[0025] The diagnostic criteria for psychiatric or neurological disorders referred to in this document are provided in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5).

[0026] As used in this document, the term “obsessive-compulsive disorder” (OCD) is defined by the presence of obsessions or compulsions, but usually both. Symptoms can cause significant functional impairment and/or distress. An obsession is defined as an intrusive thought, image, or desire that repeatedly enters a person's mind. Compulsions are repetitive behaviors or mental acts that a person feels driven to perform. Typically, OCD manifests as one or more obsessions, which drive the adoption of a compulsion. For example, an obsession with germs may lead to a compulsion to clean, or an obsession with food may lead to a compulsion to eat too much, eat too little, or vomit after eating (i.e., an obsession with food may manifest as a disorder to feed). A compulsion can be overt and observable by others, such as checking to see if a door is locked, or a covert mental act that cannot be observed, such as repeating a certain phrase in the mind.

[0027] 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 “periodic 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 your weight as low as possible. Symptoms of bulimia include eating too much food for too short a period of time (i.e., bingeing) and then being deliberately sick, using laxatives, eating too little, and/or exercising too much to avoid weight gain. Symptoms of BED include regularly eating large portions of food until uncomfortably full and consequently feeling upset or guilty.

[0028] As used herein the term “depressive disorder” includes major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression and depression in terminally ill patients.

[0029] As used herein, the term “major depressive disorder” (MDD, also referred to as major depression or clinical depression) is defined as the presence of five or more of the following symptoms over a period of two weeks or more (also referred to in this document as a “major depressive episode”), for most of the day, almost every day: • depressed mood, such as feeling sad, empty, or tearful (in children and adolescents, depressed mood may appear as constant irritability); • significantly reduced interest or no pleasure in all or most activities; • significant weight loss when not dieting, weight gain, or decreased or increased appetite (in children, failure to gain weight as expected); • insomnia or increased desire to sleep; • restlessness or slow behavior that may be observed by others; • fatigue or loss of energy; • feelings of worthlessness or excessive or inappropriate guilt; • difficulty making decisions or difficulty thinking or concentrating; • recurring thoughts of death or suicide, or attempted suicide

[0030] At least one of the symptoms must be a depressed mood or a loss of interest or pleasure.

[0031] Persistent depressive disorder, also known as dysthymia, is defined as a patient presenting the following two characteristics: A. has a depressed mood most of the time almost every day for at least two years. Children and adolescents may have irritable moods and the duration is at least one year. B. While depressed, a person experiences at least two of the following symptoms: • Overeating or lack of appetite. • Sleeping too much or having difficulty sleeping. • Fatigue, lack of energy. • Low self-esteem. • Difficulty concentrating or making decisions.

[0032] As used herein the term “treatment-resistant major depressive disorder” describes MDD that fails to achieve an adequate response to adequate treatment with standard of care therapy.

[0033] As used herein, “bipolar disorder,” also known as manic-depressive illness, is a disorder that causes unusual changes in mood, energy, activity levels, and the ability to perform day-to-day tasks.

[0034] There are two defined subcategories of bipolar disorder; They all involve clear changes in mood, energy, and activity levels. These moods range from periods of extremely “up,” elated, and energized behavior (known as manic episodes and defined further below) to periods of very sad, “down,” or hopeless (known as depressive episodes). Less severe manic periods are known as hypomanic episodes.

[0035] Bipolar I Disorder - defined by manic episodes that last at least 7 days, or by manic symptoms that are so severe that the person needs immediate hospital care. Depressive episodes usually also occur, usually lasting at least 2 weeks. Episodes of depression with mixed features (having depression and manic symptoms at the same time) are also possible.

[0036] Bipolar II Disorder - defined by a pattern of depressive episodes and hypomanic episodes, but not the full-blown manic episodes described above.

[0037] As used herein, "bipolar depression" is defined as an individual who presents with depressive symptoms with a prior or coexisting episode of manic symptoms, but does not meet the clinical criteria for bipolar disorder.

[0038] As used herein, the term 'anxiety disorder' includes generalized anxiety disorder, phobia, panic disorder, social anxiety disorder and post-traumatic stress disorder.

[0039] “Anxiety Disorder” (GAD) as used herein means a chronic disorder characterized by long-lasting anxiety that is not focused on any object or situation. Those suffering from GAD experience non-specific persistent fear and worry and become excessively worried about everyday matters. GAD is characterized by chronic excessive worrying accompanied by three or more of the following symptoms: restlessness, fatigue, concentration problems, irritability, muscle tension, and sleep disturbances.

[0040] “Phobia” is defined as a persistent fear of an object or situation that the affected person will do anything to avoid, normally disproportionate to the actual danger represented. If the feared object or situation cannot be avoided entirely, the affected person will endure it with marked suffering and significant interference with social or occupational activities.

[0041] A patient suffering from a “panic disorder” is defined as one who experiences one or more brief attacks (also called panic attacks) of intense terror and apprehension, often marked by tremors, tremors, confusion, dizziness , nausea and/or difficulty breathing. A panic attack is defined as a fear or discomfort that comes on abruptly and peaks in less than ten minutes.

[0042] “Social anxiety disorder” is defined as an intense fear and avoidance of negative public scrutiny, public embarrassment, humiliation, or social interaction. Social anxiety often manifests specific physical symptoms, including flushing, sweating, and difficulty speaking.

[0043] “Post-traumatic stress disorder” (PTSD) is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as combat, a natural disaster, rape, hostage situations, child abuse, bullying, or even a serious accident. Common symptoms include hypervigilance, flashbacks, avoidant behaviors, anxiety, anger, and depression.

[0044] As used herein, the term “postpartum depression” (PPD - Post-Partum Depression, also known as postnatal depression) is a form of depression experienced by either parent of a newborn baby. Symptoms usually develop within 4 weeks after the baby is born and often include extreme sadness, fatigue, anxiety, loss of interest or pleasure in hobbies and activities, irritability, and changes in sleeping or eating patterns.

[0045] As used herein, the term “substance abuse” means a patterned use of a drug in which the user consumes the substance in quantities or with methods that are harmful to themselves or others.

[0046] As used herein, the term “an avolition disorder” refers to a disorder that includes as a symptom decreased motivation to initiate and perform intentional self-directed activities.

[0047] The invention provides a pharmaceutical formulation, optionally suitable for injection, comprising a salt of a dimethyltryptamine compound (DMT) optionally substituted with deuterium and optionally substituted in position 4 or 5 with acetoxy or methoxy or position 4 with monohydrogen phosphate; the buffer which is separated from the salt; and water, wherein the formulation has a pH of about 3.5 to about 6.5 and an osmolality of about 250 to about 350 mOsm/kg.

[0048] The inventors have found that the formulation is surprisingly more stable than formulations prepared at a higher pH (specifically those prepared at a corresponding human blood serum pH, i.e., at a pH of about 7.4). . The greater stability of the initial formulation is discussed in more detail in the examples section.

[0049] Osmolality is formally defined as the quotient of the negative natural logarithm of the rational activity of water and the molar mass of water, as represented by the formula: where p is the partial vapor pressure of water in the solution and p* is the partial vapor pressure of pure water. In simpler terms, osmolality is the number of osmotically active particles (the number of solute particles) in 1 kg of a solution. Thus, osmolality is a function of particle number only, and is not related to particle molecular weight, size, shape or charge (see DK Faria et al., ME Mendes and NM Sumita, J. Bras. Patol. Med. Lab ., 53, 1, 38-45 (2017) for a review of measuring serum osmolality). For example, one mole of a non-dissociating substance (e.g. DMT as a free base) dissolved in 1 kg of water has an osmolality of 1 Osm/kg (1000 mOsm/kg), while one mole of a substance that dissociates and two separate species in solution (e.g. DMT fumarate) dissolved in 1 kg of water have an osmolality of 2 Osm/kg (2000 mOsm/kg).

[0050] When a first solution is defined in this document to be isotonic with a second solution, the solutions have the same osmolality. For example, when a formulation is defined to be isotonic with human blood serum, the formulation has the same osmolality as the human blood serum. Human blood serum typically has an osmolality of about 275 to about 300 mOsm/kg (L. Hooper et al., BMJ Open, 2015; 5(10): e008846).

[0051] The formulation (i.e., the invention) is optionally suitable for injection, meaning that it complies with pharmacological requirements for sterility, contaminants and pyrogens (see for example the United States Pharmacopeial Convention, General Requirements / ( 1) Injections, page 33). Sometimes the formulation contains inhibitors of the growth of microorganisms (e.g. antimicrobial preservatives) and/or antioxidants.

[0052] Formulations suitable for injection have a pH of about 3 to 9 and an osmolality of about 250 to about 600 mOsm/Kg. pH values above 9 are reported by I. Usach et al. in Adv. Ther., 36, 2986-2996 (2019) relate to tissue necrosis (death of cells within the tissue), while values below 3 are reported to cause pain and phlebitis (inflammation of the veins). Osmolality values greater than 600 mOsm/Kg are also reported to cause pain. The pH and osmolality of the formulation of the invention fall within the range reported as suitable for injection.

[0053] The formulation comprises a salt of a DMT compound optionally substituted with deuterium and optionally substituted at position 4 or 5 with acetoxy or methoxy or position 4 with monohydrogen phosphate, referred to herein as “the DMT Compound”. The formulations according to this invention may comprise one or more than one DMT compound. For the avoidance of doubt, formulations comprise an optionally substituted DMT salt when they comprise ions of optionally substituted DMT and ions that counter the charge of the optionally substituted DMT ions (counterions). Consequently, the optionally substituted DMT salt within the formulation may be formed, e.g. example, by contacting optionally substituted DMT as a free base with an aqueous solution comprising an excess of buffer relative to the molar amount of optionally substituted DMT.

[0054] The DMT Compound is optionally replaced with deuterium, wherein a deuterium atom is a hydrogen atom with an additional neutron. The DMT compound is also optionally substituted at position 4 or 5 with acetoxy or methoxy or position 4 with monohydrogen phosphate. The term “acetoxy” (often abbreviated to OAc) defines a univalent group derived from acetic acid by removing a hydrogen atom from the OH moiety. The term “methoxy” (often abbreviated to OMe) defines a univalent group derived from methanol by removing a hydrogen atom from the OH moiety. The term monohydrogen phosphate defines a divalent group of formula HPO4, derived from phosphoric acid by removing a proton from two of the three OH moieties, and thus denotes a substituent of formula -OP(O)(OH)O-.

[0055] In some embodiments, the dimethyltryptamine compound is optionally substituted at position 5 with methoxy or position 4 with acetoxy or monohydrogen phosphate.

[0056] When the DMT compound is replaced at position 4 with monohydrogen phosphate, this is to reflect that psilocybin (also known as [3-(2-Dimethyllaminoethyl)-1H-indol-4-yl] dihydrogen phosphate) in water generally has monohydrogen phosphate at position 4, with sine being generally understood to be the predominant form because the pKa values of the two terminal phosphate oxygen atoms are estimated to be 1.3 and 6.5. It is further understood that the monohydrogen phosphate-containing form of psilocybin exists as a zwitterion (i.e., an internal salt) in which the nitrogen atom of the dimethyl amino moiety is protonated. This form is therefore, and psilocybin should be considered as, a salt of a DMT compound substituted at position 4 with monohydrogen phosphate.

[0057] In some embodiments, the dimethyltryptamine compound is optionally substituted with deuterium at one or more selected positions of the α, β and dimethyl carbon atoms. In additional embodiments, the dimethyltryptamine compound is optionally substituted at one or more selected positions of the α and β carbon atoms, such as the α carbon.

[0058] For the avoidance of doubt, positions 4, 5, α and β of the optionally substituted DMT salt refer to the positions marked in the structure below (substitution not shown).

[0059] The formulation comprises a buffer, which is separated from the salt, that is, the buffer is not merely a counterion for the optionally substituted DMT. For example, when the salt is dimethyltryptamine fumarate (i.e., the fumaric acid salt of dimethyltryptamine), an amount of buffer in addition to the buffer provided by the fumarate is required. The term “buffer” is well known in the art and refers to a chemical that, when included within a formulation, resists a pH change upon addition of acid or base to the formulation. Within the formulation, a buffer comprises a weak acid and its conjugate base. A suitable buffer comprises an acid with a pKa value that is within ±1 of the desired pH of the formulation. For example, if the desired pH of the formulation is about 4.0, a suitable buffer comprises a weak acid with a pKa value of about 3.0 to about 5.0. If the acid in a buffer has more than one pKa value (that is, each molecule of the acid is capable of donating more than one proton), for the buffer to be suitable, at least one of the pKa values is within the range of desired pH.

[0060] The weak acid and the conjugate base of the buffer are in equilibrium with each other. According to Le Chatelier's principle [if a restriction (such as a change in the concentration of a reactant) is applied to a system at equilibrium, the equilibrium will shift so as to neutralize the effect of the restriction], adding acid or base to the formulation shifts the equilibrium position in favor of the conjugate base or weak acid, respectively. Consequently, the concentration of free protons in the formulation (and therefore the pH) is relatively unchanged.

[0061] As described above, the formulation of the invention has a pH of about 3.5 to about 6.5. In some embodiments, the buffer comprises an acetate and acetic acid salt (pKa = 4.75); to citrate salt and citric acid (pKa = 3.13, 4.76 and 6.40); a salt of ascorbate and ascorbic acid (pKa = 4.17 and 11.6); a salt of benzoate and benzoic acid (pKa = 4.20); to phosphate salt and phosphoric acid (pKa = 2.14, 7.20 and 12.37); a salt of oxalate salt and oxalic acid (pKa = 1.25 and 4.14); or a formate salt and formic acid (pKa = 3.75). The pKa values cited in this document are those reported at 25°C in water. Typically, the buffer comprises only one of the pairs listed above, that is, an acid and its conjugate base.

[0062] In some embodiments, the buffer comprises an acetate salt and acetic acid; a salt of citrate and citric acid; a salt of ascorbate and ascorbic acid; a salt of benzoate and benzoic acid; or a salt of phosphate and phosphoric acid.

[0063] In some embodiments, the pH of the formulation is from about 3.75 to about 6.5, such as from about 3.75 to about 5.75. Often, the pH of the formulation is about 3.75 to about 4.25, typically about 4.0. In such embodiments, the buffer typically comprises an acetate salt and acetic acid; a salt of citrate and citric acid; a salt of ascorbate and ascorbic acid; a salt of benzoate and benzoic acid; u oxalate salt and oxalic acid; or a salt of formate and formic acid. Sometimes the buffer comprises an acetate salt and acetic acid; a salt of citrate and citric acid; a salt of ascorbate and ascorbic acid; or a salt of benzoate and benzoic acid.

[0064] In some embodiments, the buffer comprises a salt of acetate and acetic acid, typically sodium acetate and acetic acid, or potassium acetate and acetic acid.

[0065] The buffer concentration within the formulation is typically large enough to withstand significant pH changes of the formulation upon storage of the formulation for two weeks (i.e., the pH typically fluctuates less than about 0.1 pH unit) , and is small enough that the osmolality of the formulation remains within the desired range. Those skilled in the art are able to evaluate appropriate buffer concentrations and achieve what is desired. Often, the buffer concentration is from about 15 mM to about 75 mM, such as about 20 mM to about 30 mM. In some embodiments, the buffer concentration is about 25 mM.

[0066] As described above, the formulation comprises the salt of a DMT compound optionally substituted with deuterium and optionally substituted in position 4 or 5 with acetoxy or methoxy or position 4 with monohydrogen phosphate.

[0067] The salt comprises an acid and the DMT compound, or the salt comprises a DMT compound substituted at position 4 with monohydrogen phosphate. An example of a salt comprising an acid and the compound DMT is dimethyltryptamine fumarate, which is the fumaric acid salt of dimethyltryptamine. P. H. Stahl and C. G. Wermuth provide an overview of pharmaceutical salts and the acids contained in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zürich:Wiley-VCH/VHCA, 2002. The acids described in this review are suitable acids for inclusion within the formulation salt.

[0068] The salt may comprise an acid selected from the group consisting of fumaric acid, tartaric acid, citric acid, acetic acid, lactic acid, gluconic acid, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2 - hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, acid octanoic acid, carbonic acid, cinnamic acid, cyclamic acid, dodecylsulfuric acid, 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, nicotinic acid, d-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, acid thiocyanic acid, toluenesulfonic acid and undecylenic acid.

[0069] In some embodiments, where the salt comprises an acid and the compound DMT, the acid is a Br0nsted acid having a pKa at 25 °C in water of about 3 to about 5. In these embodiments, the Br0nsted acid can act both as a counterion to the DMT compound and to the buffer. Thus, the formulation can be stabilized to a greater extent, i.e., the degradation of the DMT compound can be further improved, when the salt comprises such an acid.

[0070] In some embodiments, the salt comprises a Bronsted acid having a pKa at 25°C of about 3 to about 5, and a compound of Formula I I, characterized in that: R4 and R5 are both H and each xH and each YH is independently selected from H and D, or one of R4 and R5 is H and the other is acetoxy or methoxy, each YH is H and each xH is independently selected from H and D, or the salt comprises a compound of formula I wherein R4 is monohydrogen phosphate, R5 is H and each YH and each xH is H.

[0071] In some embodiments, R4 and R5 are both H. In these embodiments, the DMT compound is any one or a combination of N,N-dimethyltryptamine, α-monodeutero-N,N-dimethyltryptamine, α,α-dideutero-N ,N-dimethyltryptamine, α,β-dideutero-N,N-dimethyltryptamine, α,α,β-trideutero-N,N-dimethyltryptamine, α,β,β-trideutero-N,N-dimethyltryptamine and α,α,β ,β-tetradeutero-N,N-dimethyltryptamine. Often, the DMT compound is N,N-dimethyltryptamine.

[0072] In some embodiments, R4, R5 and each YH are H and each xH is independently selected from H and D. In these embodiments, the DMT compound is any one or a combination of N,N-dimethyltryptamine, α-monodeutero-N ,N-dimethyltryptamine, and α,α-dideutero-N,N-dimethyltryptamine.

[0073] Partially deuterated and deuterated N,N-dimethyltryptamine compounds can be synthesized following the reaction schemes (synthetic schemes) provided in Schemes 1 and 2 below. The chemistry described in the schemes was reported by PE Morris and C Chiao (Journal of Labeled Compounds And Radiopharmaceuticals, Vol. XXXIII, No. 6, 455-465 (1993)). Partially deuterated and deuterated N,N-dimethyltryptamine compounds can also be synthesized following the synthetic scheme described in Scheme 3.

[0074] In this document, the terms α,α-dideutero-N,N-dimethyltryptamine compounds and α-prothio, α-deutero-N,N-dimethyltryptamine compounds are referred to as deuterated (or fully deuterated) N,N-dimethyltryptamine and partially deuterated N,N-dimethyltryptamine respectively. A deuterated (or fully deuterated) N,N-dimethyltryptamine compound thus strictly refers to an N,N-dimethyltryptamine compound with both protons in the α position replaced by deuterium atoms. The term partially deuterated N,N-dimethyltryptamine compound strictly refers to an N,N-dimethyltryptamine compound in which one of the two protons in the α position is replaced by a deuterium atom. A deuterated N,N-dimethyltryptamine compound herein is any N,N-dimethyltryptamine compound substituted by two deuterium atoms at the α position and a partially deuterated N,N-dimethyltryptamine compound is any N,N-dimethyltryptamine compound with one atom of hydrogen and a deuterium atom in the α position.

[0075] If desired, compositions comprising amounts of N,N-dimethyltryptamine and deuterated N,N-dimethyltryptamine compounds, with the relative proportions of N,N-dimethyltryptamine versus deuterated N,N-dimethyltryptamine compounds and N,N compounds - Partially deuterated dimethyltryptamine can be controlled by varying the proportion of lithium aluminum hydride and lithium aluminum deuteride in the reducing agent. It should be understood that in such compositions, R4, R5 and each YH are H and each xH is independently selected from H and D, i.e., the DMT compound is any one or a combination of N,N-dimethyltryptamine, α-monodeutero- N,N-dimethyltryptamine and α,α-dideutero-N,N-dimethyltryptamine. The relative proportions can be further varied by adding one or more of N,N-dimethyltryptamine, α,α-dideutero-N,N-dimethyltryptamine and α,α,β,β-tetradeutero-N,N-dimethyltryptamine to the compositions described above. . Scheme 1 Synthetic route for the production of partially deuterated dimethyltryptamine Scheme 2: Synthetic route for the production of partially deuterated N,Ndimethyltryptamine compounds Scheme 3: Synthetic route for the production of partially deuterated N,N-dimethyltryptamine compounds

[0076] The identification of the compositions resulting from the reduction step in Schemes 1 and 2 can be achieved, if desired, by chromatographic separation of the components of the mixtures by conventional means available to those skilled in the art in combination with spectroscopic and/or spectrometric analysis of pasta.

[0077] Alternative compositions are obtained by mixing N,N-dimethyltryptamine, obtained by Scheme 1 or Scheme 2 when the reducing agent is exclusively lithium aluminum hydride, with a deuterated N,N-dimethyltryptamine compound obtained from Scheme 1 or Scheme 2 when the reducing agent is exclusively lithium aluminum deuteride.

[0078] The compositions described above can be further modified by the addition of one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds. Stocks of these deuterated or partially deuterated N,N-dimethyltryptamine compounds can be obtained, for example, from the chromatographic separation described above.

[0079] In some embodiments, R4 is acetoxy and R5 is H, or R5 is acetoxy and R4 is H. According to some embodiments, R4 is acetoxy and R5 is H, therefore, the DMT compound is any one or a combination of 4-acetoxy-N,N-dimethyltryptamine, 4-acetoxy-α-monodeutero-N,N-dimethyltryptamine and 4-acetoxy-α,α-dideutero-N,N-dimethyltryptamine. For example, the compound DMT is 4-acetoxy-N,N-dimethyltryptamine.

[0080] In some embodiments, R4 is H and R5 is methoxy, or R5 is H and R4 is methoxy. According to some embodiments, R4 is H and R5 is methoxy, therefore, the DMT compound is any one or a combination of 5-methoxy-N,N-dimethyltryptamine, 5-methoxy-α-monodeutero-N,N-dimethyltryptamine and 5- methoxy-a,a- dideutero-N,N-dimethyltryptamine. For example, the compound DMT is 5-methoxy-N,N-dimethyltryptamine.

[0081] Scheme 4 represents schemes known in the art for synthesizing DMT compounds, in which the when is different from hydrogen, as defined in Formula I; each R2 is methyl and HX refers to acids described herein with which the DMT compounds described herein can form salts. Scheme 4: Synthetic route for the production of optionally substituted N,N-dimethyltryptamine compounds

[0082] Mixtures of compounds of Formula I comprising controllable proportions of optionally R4- or R5- substituted DMT and the same DMT optionally substituted by R4- or R5- but with α-mono- and/or a,a—di—deuteration can , if desired, be prepared by reducing 2-(3-indolyl)-N,N-dimethyl acetamide with a desired ratio of lithium aluminum hydride and lithium aluminum deuteride.

[0083] For more details on the synthesis of DMT compounds, see the examples section in this document.

[0084] 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.

[0085] Therefore, the salt may comprise: any one or a combination of N,N-dimethyltryptamine, α-monodeutero-N,N-dimethyltryptamine, α,α-dideutero-N,N-dimethyltryptamine, α,β-dideutero -N,N-dimethyltryptamine, α,α, β-trideutero-N,N-dimethyltryptamine, α,β,β-trideutero-N,N-dimethyltryptamine and α,α,β,β- tetradeutero-N,N-dimethyltryptamine ; or any one or a combination of 4-acetoxy-N,N-dimethyltryptamine, 4-acetoxy-α-monodeutero-N,N-dimethyltryptamine and 4-acetoxy-α,α-dideutero-N,N-dimethyltryptamine; or any one or a combination of 5-methoxy-N,N-dimethyltryptamine, 5-methoxy-α-monodeutero-N,N-dimethyltryptamine and 5-methoxy-α,α-dideutero-N,N-dimethyltryptamine; 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.

[0086] In some embodiments, the salt is DMT fumarate, that is, it comprises DMT and fumaric acid.

[0087] The DMT compound 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 DMT compound has a purity of about 99 to 100%, that is, a purity that is greater than or equal to 99%. Purity percentages in this document are as determined by HPLC.

[0088] It is particularly advantageous to prepare the formulations of the present invention with the drug comprising the optionally substituted DMT compound or its salt with a purity greater than 99%. By pharmacological substance is meant, as understood in the art, an active ingredient intended to provide pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure or any function of the patient in question, but does not include intermediates used in the synthesis of such ingredients. It will be understood that the pharmacological substance may comprise one or more of such active ingredients.

[0089] Formulations made with lower purity pharmacological substances have higher rates of related substances, which is indicative of a shorter shelf life. Accordingly, preferred embodiments of any aspect of the present invention comprise a drug substance comprising an optionally substituted dimethyltryptamine compound or salt thereof having a purity of greater than or equal to 99% when measured by HPLC. Particularly preferred embodiments comprise a drug substance comprising an optionally substituted dimethyltryptamine compound or salt thereof having a purity of greater than or equal to 99.5%, even more preferably 99.7%, and even more preferably 99.9%, when measured by HPLC. The concentration of the DMT compound in the formulation can be any desired concentration, as long as the osmolality of the formulation is about 250 to about 350 mOsm/Kg. The DMT compound can be in a concentration of about 0.001 to about 28 mg/ml, such as about 2.5 mg/ml to about 28 mg/ml. Accordingly, in some embodiments, the formulation of the invention comprises the DMT compound at a concentration of 2.5 mg/ml to 28 mg/ml, including any integer value within this range. A concentration of 28 mg/ml DMT provides approximately 148 mOsm/kg (approximately 296 mOsm/kg with counterions taken into account). This allows an additional 54 mOsm/kg to be delivered by other components of the formulation, such as the buffer.

[0090] In some embodiments, the concentration of the DMT compound within the formulation is about 2.5 mg/ml, which provides approximately 13.2 mOsm/kg (approximately 26.4 mOsm/kg with counterions taken into account ).

[0091] As described above, the formulation of the invention has an osmolality of about 250 to about 350 mOsm/Kg. As described above, to be injectable, a formulation may have an osmolality of about 250 to about 600 mOsm/kg. In some embodiments of the invention, the osmolality of the formulation is about 250 to about 500 mOsm/Kg or 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. In some embodiments, the formulation is isotonic with human blood serum.

[0092] Sometimes, the concentration of the salt and buffer and optionally substituted DMT buffer in the formulation gives rise to the desired osmolality. Alternatively, the desired osmolality can be achieved by including one or more tonicizing agents in the formulation. Thus, in some embodiments, the formulation additionally comprises a tonicity agent. A tonicity agent is defined herein as a chemical that, when included in a formulation, increases the osmolality of the formulation. As described above, osmolality is the number of osmotically active particles (the number of solute particles) in 1 kg of a solution. Thus, a chemical that acts as a solute when incorporated into the formulation is within the definition of a tonicity agent.

[0093] If the formulation additionally comprises a tonicity agent, the concentration of the tonicity agent depends on the concentration of other components within the formulation, such as DMT and optionally substituted buffer. For example, where the formulation without tonicity agent has an osmolality of about 60 mOsm/kg, at least about 190 mOsm/kg would be provided by a tonicity agent (e.g. 95 mM sodium chloride). The inclusion of a tonicity agent is often preferable in low concentration formulations useful for intravenous administration, for example in formulations comprising about 2.5 mg/ml of the DMT compound. In higher concentration formulations, for example those comprising the DMT compound in concentrations greater than about 5 mg/ml, the tonicity agent may be less preferable or absent.

[0094] M. F. Powell, T. Nguyen and L. Baloian provide a review of excipients suitable for parenteral administration (administration other than through the mouth or alimentary canal) in PDA J. Pharm. Sci. Technol., 52, 238-311 (1998). All soluble excipients listed in this review article that can be administered intravenously will, when added to the formulation, contribute to osmolality and therefore can be considered tonicizing agents.

[0095] In some embodiments, the tonicity agent is any one or a combination selected from the group consisting of potassium chloride; dextrose; glucose; mannitol; phosphoric acid; lactose; sorbitol; sucrose; a phosphate salt such as sodium phosphate or potassium phosphate; Acetic Acid; an acetate salt such as sodium acetate, potassium acetate or ammonium acetate; alanine; ethanol; Citric acid; a citrate salt such as sodium citrate or potassium citrate; arginine; Ascorbic acid; an ascorbate salt such as potassium ascorbate or sodium ascorbate; Benzilic alcohol; calcium chloride; creatinine; Acetic Acid; an acetate salt such as sodium acetate or calcium acetate; glycine; glycerol; histidine; lactic acid; magnesium chloride; polyethylene glycol; propylene glycol; Sodium bicarbonate; sodium hydroxide; hydrochloric acid; lactic acid; lactate salts such as potassium lactate or sodium lactate; tartaric acid and tartrate salts such as sodium tartrate or potassium tartrate.

[0096] Some of the tonicizing agents listed above can be used as a formulation buffer (for example, acetate salt, acetic acid, citrate salt, citric acid, ascorbate salt, ascorbic acid, phosphate salt, phosphoric acid). For the avoidance of doubt, when one of the tonicity agents listed above is used as the buffer, it is not also the defined tonicity agent, that is, when the formulation additionally comprises a tonicity agent, the tonicity agent is different from the buffer.

[0097] Often, the tonicizing agent is any one or a combination selected from the group consisting of sodium chloride, potassium chloride, dextrose, glucose, mannitol, lactose, sorbitol and sucrose. Typically, the tonicizing agent is sodium chloride.

[0098] In some embodiments, the formulation comprises sodium chloride and a concentration of about 120 mM to about 140 mM, such as about 125 mM to about 135 mM. Sometimes the concentration of sodium chloride in the formulation is about 130 mM.

[0099] In some embodiments, the formulation consists essentially of the optionally substituted DMT salt, the buffer, water, and optionally a tonicity agent. This means, for example, that the presence of additional components in the formulation is permitted, provided that the amounts of such additional components do not materially adversely affect the essential characteristics of the formulation. Since the intention behind including the optionally substituted DMT salt, buffer, water, and optional tonicity agent in the formulation is to produce a pharmaceutical formulation of optionally substituted DMT, optionally suitable for injection, and stable for at least several weeks when stored, it will be understood that the inclusion of components that materially and detrimentally affect the stability of the formulation or its suitability for injection (e.g., its osmolality or pH), are excluded from the formulation. On the other hand, it will be understood that the presence of any components that do not materially adversely affect the stability of the formulation or its suitability for injection is included. Such components include antioxidants and antimicrobial preservatives. For an overview of pharmaceutical excipients and their properties, including those with antioxidant and antimicrobial properties, see P. J. Sheskey, W G Cook and C G Cable, Handbook of Pharmaceutical Excipients, Eighth Edition, Pharmaceutical Press, London 2017.

[00100] Antioxidants commonly used in aqueous injectable formulations include ascorbic acid, citric acid, tartaric acid, sodium metabisulfite and thiol derivatives.

[00101] Antimicrobial preservatives commonly used in injectable formulations include methylparaben (methyl parahydroxybenzoate), ethylparaben (ethyl parahydroxybenzoate) and propylparaben (n-propyl parahydroxybenzoate), benzoic acid, benzyl alcohol, chlorobutanol, phenol and sodium benzoate.

[00102] In specific embodiments, the formulation consists of salt, buffer, water and optionally a tonicity agent, that is, the presence of any other components is excluded.

[00103] Often, the formulation has an oxygen content of less than 2ppm, such as between 0.1 ppm and 2 ppm. One skilled in the art is able to determine the oxygen content of the formulation using any technique known in the art to be suitable, such as the use of a dissolved oxygen meter (e.g., a Jenway 970 Enterprise Dissolved Oxygen Meter, available from Keison Products: http://www.keison.co.uk/produtos/jenway/970.pdf).

[00104] The formulation can be stored in any suitable container. In some embodiments, to further improve degradation of the formulation, the formulation is stored in a container adapted to prevent the penetration of ultraviolet light, such as an amber glass bottle. In others, the container within which the formulation is stored is not so adapted (and may be, for example, made of clear glass) with protection against ultraviolet light, if desired, provided by secondary packaging (e.g. packaging within which the container containing the formulation can be placed). Often, the container is airtight and the formulation is stored under an inert atmosphere, such as under nitrogen or argon, typically nitrogen. The formulation can be stored at room temperature, for example at about 20 to about 30°C or at lower temperatures, for example at about 2 to about 8°C. Alternatively, to further improve formulation degradation, it can be stored in a freezer.

[00105] Seen from a second aspect, the invention provides a kit suitable for preparing a formulation of the first aspect, said kit comprising a salt of a DMT compound optionally substituted with deuterium and optionally substituted in the 4 or 5 position with acetoxy or methoxy or position 4 with monohydrogen phosphate; and a buffer, which is separated from the salt.

[00106] A kit is also provided for generating a formulation of the first aspect, the kit comprising: - a first composition comprising a salt of a DMT compound optionally substituted with deuterium and optionally substituted in position 4 or 5 with acetoxy or methoxy or position 4 with monohydrogen phosphate; and - a second composition comprising a buffer, which is separated from the salt, characterized in that: the first and second compositions are mixed with water and optionally a tonicity agent, and the resulting mixture generates the formulation of the first aspect.

[00107] For the avoidance of doubt, the embodiments relating to the optionally substituted DMT salt and buffer of the first aspect of the invention, as defined herein, apply mutatis mutandis to the second aspect. For example, the optionally substituted DMT salt of the kit may comprise Bronsted acid having a pKa at 25°C of about 3 to about 5, and a compound of Formula I and/or the buffer may comprise an acetate and acid salt. acetic.

[00108] The optionally substituted DMT salt within the kit can be a solid, for example, and a powder or crystalline form. To improve degradation of the optionally substituted DMT salt in solid form, the salt can be freeze-dried (freeze-dried) prior to incorporation into the kit. Freeze-drying salt involves freezing it in the presence of a solvent (typically water) and separating the solvent from the salt by sublimation.

[00109] The kit may additionally comprise a tonicity agent. When the kit additionally comprises a tonicizing agent, the embodiments relating to the optional tonicizing agent of the first aspect of the invention as defined herein apply mutatis mutandis to the second aspect. For example, the tonicity agent may be any one or a combination selected from the group consisting of sodium chloride, potassium chloride, dextrose, glucose, mannitol, lactose, sorbitol and sucrose.

[00110] Viewed from a third aspect, the invention provides a method of preparing a pharmaceutical formulation of the first aspect, which is typically a solution. The method comprises contacting the optionally substituted DMT salt, buffer, water and optionally a tonicity agent. 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 DMT, the buffer may comprise acetic acid and an acetate salt, and/or sodium chloride may be used as a tonicity agent.

[00111] It will be understood that method contact can be achieved in several ways. Often, the optionally substituted DMT salt is dissolved in water to form a first solution to which the buffer is added and dissolved, forming a second solution. If a tonicity agent is used, it is often added and dissolved in the second solution.

[00112] In some embodiments, an aqueous solution of the buffer is contacted with the salt, wherein the aqueous solution has a pH of about 3.5 to about 6.5, such as a pH of about 3.75 to about 6.5. Sometimes the aqueous solution has a pH of about 3.75 to about 5.75, such as a pH of about 3.75 to about 4.25. In some embodiments, the aqueous solution has a pH of about 4.0.

[00113] The optionally substituted DMT salt within the formulation can be formed by contacting optionally substituted DMT with a free base with an aqueous solution comprising an amount of buffer suitable to stabilize the pH and act as a counterion for the optionally substituted DMT when protonated. Accordingly, the method of the invention may comprise contacting the optionally substituted dimethyltryptamine in free base form with the buffer, water and optionally a tonicity agent.

[00114] In some embodiments, the method additionally comprises adjusting the pH of the solution resulting from the contact. Since the pH of the solution resulting from contact is generally low, adjusting the pH usually involves contacting the solution with a suitable base. One skilled in the art is able to evaluate which bases are suitable for adjusting the pH of the solution resulting from contact without risk of degradation of the optionally substituted DMT salt.

[00115] Often, the pH of the solution resulting from contact is adjusted with any one selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide, calcium hydroxide and magnesium hydroxide. In some embodiments, the pH is adjusted with sodium hydroxide or potassium hydroxide.

[00116] As described above, to further improve degradation of the formulation, it may be desirable to minimize the total oxygen content within the container in which the formulation is stored, the oxygen within the container balanced between the formulation and the headspace (if there is) inside the container. Accordingly, it may be desirable to store the formulation under an inert atmosphere, for example, purging the headspace to reduce its oxygen content from about 20% normally found in air, to as little as, for example, 0.5%. Additionally or alternatively, and some embodiments, the method further comprises sparging the solution resulting from contact with an inert gas, such as nitrogen or argon, typically nitrogen.

[00117] Seen from a fourth aspect, there is provided the use of a buffer to improve the degradation of an injectable pharmaceutical formulation of a salt of a dimethyltryptamine compound optionally substituted with deuterium and optionally substituted in the 4 or 5 position with acetoxy or methoxy or position 4 with monohydrogen phosphate.

[00118] For the avoidance of doubt, the embodiments of the first aspect of the invention apply mutatis mutandis to the fourth aspect. Specifically, the embodiments of the first aspect with respect to the buffer and the optionally substituted DMT salt apply mutatis mutandis to the fourth aspect. For example, the buffer of the fourth aspect may comprise an acetate and acetic acid salt; a salt of phosphate and phosphoric acid; a salt of citrate and citric acid; a salt of ascorbate and ascorbic acid; or a salt of benzoate and benzoic acid; and/or the optionally substituted DMT salt of the fourth aspect may comprise a Bronsted acid having a pKa at 25°C of about 3 to about 5.

[00119] As described above, DMT has a possible therapeutic role in the treatment of depression, obsessive-compulsive disorder, and substance abuse disorders. (S. A. Barker, 2018, supra). Viewed from a fifth aspect, therefore, the invention provides a formulation of the first aspect for use in therapy.

[00120] Viewed from a sixth aspect, the invention provides a formulation of the first aspect for use in a method of treating a psychiatric or neurological disorder in a patient. Often, the psychiatric or neurological disorder is selected from the group consisting of (i) an obsessive compulsive disorder, (ii) a depressive disorder, (iii) an anxiety disorder, (iv) substance abuse, and (v) avolition disorder. Often, the disorder is selected from the group consisting of major depressive disorder, treatment-resistant major depressive disorder, postpartum depression, an obsessive compulsive disorder, and an eating disorder such as binge eating disorder.

[00121] Viewed from a seventh aspect, the invention provides a method of treating a psychiatric or neurological disorder comprising administering to a patient in need of a formulation of the first aspect. The psychiatric or neurological disorder can be any of those described in relation to the aspect. For example, the disorder may be selected from the group consisting of major depressive disorder, treatment-resistant major depressive disorder, postpartum depression, an obsessive compulsive disorder, and an eating disorder such as a compulsive eating disorder.

[00122] To treat the disorder, the formulation comprises an effective amount of the DMT compound, that is, an amount that is sufficient to reduce or stop the rate of progression of the disorder, or to ameliorate or cure the disorder and thus produce the therapeutic effect. or inhibitor.

[00123] The formulation is optionally suitable for injection, therefore its administration in therapy typically comprises injection of the formulation.

[00124] The formulation may be suitable for bolus injection, in which a discrete amount of an optionally substituted DMT salt is administered in one injection so that the concentration of DMT in the body increases rapidly. Bolus injections are typically administered intravenously (directly into a vein), intramuscularly (into the muscle), intradermal (under the skin), or subcutaneously (into the fat or skin).

[00125] Alternatively, the formulation may be suitable for inhalation, preferably as an aerosol, for example a nasal spray.

[00126] Each and every reference referred to in this document is incorporated by reference in its entirety, as if the entire content of each reference were set forth in this document in its entirety.

[00127] The invention can be better understood with reference to the following non-limiting clauses and examples below:

[00128] Clause - 1 A pharmaceutical formulation, optionally suitable for injection, comprising a salt of a dimethyltryptamine compound optionally substituted with deuterium and optionally substituted in position 4 or 5 with acetoxy or methoxy or position 4 with monohydrogen phosphate; a buffer that is separated from the salt; and water, wherein the formulation has a pH of about 3.5 to about 6.5 and an osmolality of about 250 to about 350 mOsm/kg.

[00129] Clause - 2 The formulation of clause 1, in which the pH is from about 3.75 to about 6.5.

[00130] Clause - 3 The formulation of clause 1, in which the pH is from about 3.75 to about 5.75.

[00131] Clause - 4 The formulation of clause 1, in which the pH is from about 3.75 to about 4.25.

[00132] Clause - 5 The formulation of clause 1, in which the pH is about 40.

[00133] Clause - 6 The formulation of any one of clauses 1 to 5, wherein the formulation has an osmolality of about 275 to about 325 mOsm/Kg.

[00134] Clause - 7 The formulation of any one of clauses 1 to 5, wherein the formulation has an osmolality of about 280 to about 310 mOsm/Kg.

[00135] Clause - 8 The formulation of any one of clauses 1 to 5, wherein the formulation has an osmolality of about 295 to about 305 mOsm/Kg.

[00136] Clause - 9 The formulation of any one of clauses 1 to 8, in which the dimethyltryptamine compound is optionally substituted in position 5 with methoxy or position 4 with acetoxy or monohydrogen phosphate.

[00137] Clause - 10 The formulation of any of clauses 1 to 9, in which the dimethyltryptamine compound is optionally substituted with deuterium at one or more selected positions of the α, β and dimethyl carbon atoms.

[00138] Clause - 11 The formulation of any one of clauses 1 to 9, in which the dimethyltryptamine compound is optionally substituted with deuterium at one or more selected positions of the α and β carbon atoms.

[00139] Clause - 12 The formulation of any one of clauses 1 to 9, in which the dimethyltryptamine compound is optionally substituted with deuterium once or twice at the α-carbon atom.

[00140] Clause - 13 The formulation of any one of clauses 1 to 8, wherein the salt comprises a Bronsted acid having a pKa of about 3 to about 5 and a compound of Formula I characterized in that: R4 and R5 are both H and each xH and each YH is independently selected from H and D, or one of R4 and R5 is H and the other is acetoxy or methoxy, each YH is H and each xH is independently selected from H and D, or the salt comprises a compound of formula I in which R4 is monohydrogen phosphate, R5 is H and each YH and each xH is H.

[00141] Clause - 14 The formulation of clause 13 in which R4 and R5 are both H.

[00142] Clause - 15 The formulation of clause 14, in which each YH is H and each xH is independently selected from H and D.

[00143] Clause - 16 The formulation of clause 13 in which R4 is acetoxy and R5 is H.

[00144] Clause - 17 The formulation of clause 13 in which R4 is H and R5 is methoxy.

[00145] Clause - 18 The formulation of any one of clauses 1 to 14, wherein the optionally substituted dimethyltryptamine compound is dimethyltryptamine.

[00146] Clause - 19 The formulation of any one of clauses 1 to 18, wherein 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, acid lactic acid and gluconic acid.

[00147] Clause - 20 The formulation of clause 19, in which the acid is fumaric acid.

[00148] Clause - 21 The formulation of any one of clauses 1 to 20 in which the optionally substituted dimethyltryptamine compound has a purity greater than 99% by HPLC.

[00149] Clause - 22 The formulation of any one of clauses 1 to 21, wherein the optionally substituted dimethyltryptamine is a concentration of about 0.001 to about 28 mg/ml.

[00150] Clause - 23 The formulation of any one of clauses 1 to 22, wherein the optionally substituted dimethyltryptamine has a concentration of about 2.5 to about 28 mg/ml.

[00151] Clause - 24 The formulation of any one of clauses 1 to 23, wherein the concentration of the optionally substituted dimethyltryptamine is about 2.5 mg/ml.

[00152] Clause - 25 The formulation of any one of clauses 1 to 24, wherein the buffer comprises an acetate salt and acetic acid; a salt of phosphate and phosphoric acid; citrate salt and citric acid; a salt of ascorbate and ascorbic acid; a salt of benzoate and benzoic acid; a salt of oxalate and oxalic acid; or a salt of formate and formic acid.

[00153] Clause - 26 The formulation of any one of clauses 1 to 24, wherein the buffer comprises an acetate salt and acetic acid; to phosphate salt and phosphoric acid; the salt of citrate and citric acid; a salt of ascorbate and ascorbic acid; or to benzoate salt and benzoic acid.

[00154] Clause - 27 The formulation of any one of clauses 1 to 24, wherein the buffer comprises an acetate salt and acetic acid.

[00155] Clause - 28 The formulation of clause 27, in which the buffer comprises sodium acetate and acetic acid, or potassium acetate and acetic acid.

[00156] Clause - 29 The formulation of any one of clauses 1 to 28, wherein the formulation comprises buffer with a concentration of about 15 mM to about 75 mM.

[00157] Clause - 30 The formulation of clause 29, wherein the buffer concentration is about 20 mM to about 30 mM.

[00158] Clause - 31 The formulation of clause 29, in which the buffer concentration is about 25 mM.

[00159] Clause - 32 The formulation of any one of clauses 1 to 31, wherein the formulation additionally comprises a tonicity agent.

[00160] Clause - 33 The formulation of any one of clauses 1 to 32, wherein the formulation consists essentially of the salt, the buffer, water and optionally a tonicity agent.

[00161] Clause - 34 The formulation of any one of clauses 1 to 32, wherein the formulation consists of the salt, the buffer, water and optionally a tonicity agent.

[00162] Clause - 35 The formulation of any of clauses 32 to 34, in which the tonicity agent is sodium chloride.

[00163] Clause - 36 The formulation of clause 35, wherein the formulation comprises sodium chloride with a concentration of about 120 mM to about 140 mM.

[00164] Clause - 37 The formulation of clause 35, in which the concentration of sodium chloride is about 125 mM to about 135 mM.

[00165] Clause - 38 The formulation of clause 35, in which the concentration of sodium chloride is about 130 mM.

[00166] Clause - 39 The formulation of any of clauses 1 to 38, having an oxygen content of less than 2ppm.

[00167] Clause - 40 The formulation of clause 39, having an oxygen content between 0.1 ppm and 2 ppm.

[00168] Clause - 41 The formulation of any of clauses 1 to 40, stored in a container adapted to prevent the penetration of ultraviolet light.

[00169] Clause - 42 The wording of clause 41, where the container is an amber glass bottle.

[00170] Clause - 43 A kit suitable for preparing a formulation of any one of clauses 1 to 42, said kit comprising a salt of a dimethyltryptamine compound optionally substituted with deuterium and optionally substituted at position 4 or 5 with acetoxy or methoxy or position 4 with monohydrogen phosphate; and a buffer that is separated from the salt.

[00171] Clause - 4 A method of preparing the pharmaceutical formulation as defined in any one of clauses 1 to 42, comprising contacting the salt, buffer, water and optionally a tonicity agent.

[00172] Clause - 45 The method of Clause 44 wherein an aqueous solution of the buffer is contacted with the salt, wherein the aqueous solution has a pH as defined in any of clauses 1 to 5.

[00173] Clause - 46 The method of Clause 44 or 45, wherein the method comprises contacting the optionally substituted dimethyltryptamine in free base form with the buffer, water and optionally a tonicity agent.

[00174] Clause - 47 The method of any one of clauses 44 to 46, further comprising adjusting the pH of the solution resulting from contact.

[00175] Clause - 48 The method of Clause 47 in which the pH is adjusted with sodium hydroxide or potassium hydroxide.

[00176] Clause - 49 The method of any one of clauses 44 to 48 further comprising spraying the solution resulting from contact with an inert gas.

[00177] Clause - 50 The method of clause 49 in which the inert gas is nitrogen.

[00178] Clause - 51 Use of a buffer to improve the degradation of an injectable pharmaceutical formulation of a salt of a dimethyltryptamine optionally substituted with deuterium and optionally substituted in position 4 or 5 with acetoxy or methoxy or position 4 with monohydrogen phosphate.

[00179] Clause - 52 Use of clause 51, wherein salt is as defined in any of clauses 13 - 24.

[00180] Clause - 53 A formulation as defined in any of clauses 1 to 42 or the kit of clause 43 for use in therapy.

[00181] Clause - 54 A formulation as defined in any of clauses 1 to 42 or the kit of clause 43 for use in a method of treating a psychiatric or neurological disorder in a patient.

[00182] Clause - 55 A formulation for use of clause 54 in which the psychiatric or neurological disorder is selected from the group consisting of (i) an obsessive compulsive disorder, (ii) a depressive disorder, (iii) an anxiety disorder, ( iv) substance abuse and (v) an avolition disorder.

[00183] Clause - 56 A formulation for use of clause 55, in which the disorder is major depressive disorder.

[00184] Clause - 57 A formulation for use of clause 55, in which the disorder is treatment-resistant major depressive disorder.

[00185] Clause - 58 A formulation for the use of clause 55, where the disorder is postpartum depression.

[00186] Clause - 59 A formulation for the use of clause 55, where the disorder is an obsessive compulsive disorder.

[00187] Clause - 60 A formulation for the use of clause 55, where the disorder is an eating disorder.

[00188] Clause - 61 A formulation for the use of clause 60, in which the eating disorder is a compulsive eating disorder.

[00189] Clause - 62 A method of treating a psychiatric or neurological disorder comprising administering to a patient in need thereof a formulation as defined in any of clauses 1 to 42.

[00190] Clause - 63 The method of clause 62, wherein the psychiatric or neurological disorder is as defined in any of clauses 55 to 61.

EXAMPLES Example 1:

[00191] N,N-DMT 220.9 g (as free base) was prepared as DMT N,N-fumarate, using the chemistry described in Scheme 3 above. An additional 4-6 g of six partially deuterated mixtures were also produced using modified conditions.

[00192] In Scheme 3, the carbodiimide coupling agent EDC.HCl and the additive coupling agent (which increase the reactivity of the coupling agent) HOBt are used. More generally, the combination of two or more coupling agents comprises an agent selected from (i) a phosphonium coupling agent and a carbodiimide coupling agent selected from DCC, EDC and DIC; and (ii) an additive coupling agent selected from HOBt, HOOBt, HOSu, HOAt, Ethyl 2-cyano-2-(hydroxymino)acetate and DMAP. Often, as exemplified below, EDC is used, preferably as the HCl salt. Often, as exemplified below, the additive coupling agent HOBt. Often, as exemplified below, EDC is used, preferably as the HCl salt in combination with the additive coupling agent HOBt.

Stage 1: Coupling of indole-3-acetic acid and dimethylamine

[00193] Into a 5L container under N2 was charged indole-3- acetic acid (257.0 g, 1.467 mol), hydroxybenzotriazole (HOBt, ~20% wet) (297.3 g, 1.760 mol) and dichloromethane (2313ml ) to give a milky white suspension. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl, 337.5 g, 1.760 mol) was then charged in portions over 5 minutes at 16-22°C. The reaction mixture was stirred for 2 hours at room temperature before 2M dimethyllamine in THF (1100 ml, 2,200 mol) was charged dropwise over 20 minutes at 20-30°C. The resulting solution was stirred at room temperature for 1 hour where HPLC indicated 1.1% indole-3-acetic acid and 98.1% target product referred to as Stage 1). The reaction mixture was then charged with 10% K2CO3 (1285 ml) and stirred for 5 minutes. The layers were separated, and the upper aqueous layer extracted with dichloromethane (643 ml x 2). The organic extracts were combined and washed with saturated brine (643 ml). The organic extracts were then dried over MgSO4, filtered and concentrated in vacuum at 45°C. This provided 303.1 g of crude Stage 1 as an off-white sticky solid. The crude material was then slurried and tert-butyl methyl ether (TBME, 2570 ml) at 50°C for 2 hours before being cooled to room temperature, filtered and washed with TBME (514 ml x 2). The filter cake was then dried under vacuum at 50°C to provide 266.2g of Stage 1 (yield=90%) as an off-white solid with a purity of 98.5% by HPLC and >95% by NMR.

Stage 2: DMT Preparation

[00194] Stage 1 (272.5 g, 1.347 mol) and tetrahydrofuran (THF, 1363 ml) were charged to a 5l vessel under N2 to give an off-white suspension. 2.4 M LiAlH4 in THF (505.3 ml, 1.213 mol) was then charged dropwise over 35 minutes at 20-56°C to give an amber solution. The solution was heated to 60°C for 2 hours where HPLC indicated Stage 1 ND, target product range referred to as Stage 2, 92.5%), Impurity 1 (2.6%), Impurity 2 (1.9% ). The completed reaction mixture was cooled to room temperature and then loaded into a 25% solution of Rochelle salts (aq) (2725 mL) dropwise over 30 minutes at 20-30°C. The resulting milky white suspension was allowed to stir at 20-25°C for 1 hour after which the layers were separated and the upper organic layer washed with saturated brine (681 ml). The organic layer was then dried over MgSO4, filtered and concentrated in vacuo at 45°C. The resulting crude oil was subjected to an ethanol azeotrope (545ml x 2). This provided 234.6g (yield=92%) of Stage 2 with a purity of 95.0% by HPLC and >95% by NMR.

Stage 3a (i)-(iii): preparation of DMT fumarate seed crystals

[00195] (i) Stage 2 (100 mg) was taken up in 8 volumes of isopropyl acetate and heated to 50°C before charging fumaric acid (1 equivalent) as a solution in ethanol. The vial was then left to mature at 50°C for 1 hour before cooling to room temperature and shaken overnight, resulting in a white suspension. The solids were isolated by filtration and dried for 4 hours at 50°C to provide 161 mg of product (>99% yield). Purity by HPLC was determined to be 99.5% and by NMR to be >95%.

[00196] (ii) Replacing isopropyl acetate with isopropyl alcohol in method (i) provided a white suspension after stirring overnight. The solids were isolated by filtration and dried for 4 hours at 50°C to provide 168 mg of product (>99% yield). Purity by HPLC was determined to be 99.8% and by NMR to be >95%.

[00197] Replacing isopropyl acetate with tetrahydrofuran in method (i) provided a white suspension after stirring overnight. The solids were isolated by filtration and dried for 4 hours at 50°C to provide 161 mg of product (>99% yield). Purity by HPLC was determined to be 99.4% and by NMR to be >95%.

[00198] Powder X-ray diffraction analysis showed that the products of each of methods (i) to (iii) were the same, which was labeled as Standard A.

Stage 3b: Preparation of DMT Fumarate

[00199] To a 5l flange flask under N2 was charged fumaric acid (152.7 g, 1.315 mol) and Stage 2 (248.2 g, 1.315 mol) as a solution and ethanol (2,928 ml). The mixture was heated to 75°C to give a dark brown solution. The solution was polish filtered into a preheated (80°C) 5L jacketed vessel. The solution was then cooled to 70°C and skeined with Standard A (0.1% by weight), the seed was allowed to mature for 30 minutes before cooling to 0°C at a rate of 5°C/hour. After stirring for an additional 4 hours at 0°C, the batch was filtered and washed with cold ethanol (496 ml x 2) and then dried at 50°C overnight. This provided 312.4 g (yield=78%) of Stage 3 with a purity of 99.9% by HPLC and >95% by NMR. XRPD: Standard A.

[00200] 5-methoxy DMT fumarate was prepared in an analogous way to the DMT fumarate described immediately above except for the use of 5-methoxyindole-3-acetic acid.

Synthesis of Deuterated Mixtures of DMTs

[00201] A modified stage 2 synthesis using solid mixtures of LiAlH4/LiAlD4 was adopted, using 1.8 equivalents of LiAlH4/LiAlD4 versus 0.9 equivalents using the process described above for non-deuterated DMT.

[00202] Six deuteration reactions were carried out

Representative Synthesis of a Deuterated Mixture (using 1:1 LiAlH4:LiAlD4) of DMT Compounds

[00203] To a 250 ml 3-neck flask under N2 was charged LiAlH4 (1.013 g, 26.7 mmol), LiAlD4 (1.120 g, 26.7 mmol) and THF (100 ml). The resulting suspension was stirred for 30 minutes before stage 1 (6g, 29.666 mmol) was loaded in portions over 15 minutes at 20-40°C. The reaction mixture was then heated to reflux (66°C) for 2 hours where HPLC indicated that no stage 1 remained. The mixture was cooled to 0°C and quenched with 25% Rochelle salts (aq) (120 ml ) for 30 minutes at <30°C. The resulting milky suspension was stirred for 1 hour and then left to separate. The lower aqueous layer was removed and the upper organic layer washed with saturated brine (30ml). The organics were then dried over MgSO4, filtered and concentrated in vacuo. This provided 4.3 g of raw material. The crude product was then returned to ethanol (52 ml) and charged with fumaric acid (2.66 g, 22.917 mmol) before heating to 75°C. The resulting solution was left to cool to room temperature overnight before cooling further to 0-5°C for 1 hour. The solids were isolated by filtration and washed with cold ethanol (6.5 ml x 2). The filter cake was dried at 50°C overnight to provide 5.7 g (yield=63%) of product with a purity of 99.9% by HPLC and >95% by NMR.

Assessment of Deuteration Extensions

[00204] This was achieved by LCMS-SIM (SIM = Single Ion Monitoring), the analysis provided a separate ion count for each mass for the three N,N- deuterated compound of dimethyltryptamines (N,N- dimethyltryptamine (D0), α-deutero-N,N-dimethyltryptamine (D1) and α,α-dideutero-N,N-dimethyltryptamine (D2)) in the retention time for N,N-dimethyltryptamine. The percentage of each component was then calculated from these counts. For example, %D0 = [D0/(D0 + D1 + D2)] x 100. HPLC Parameters System: Agilent 1100/1200 series liquid chromatograph or equivalent Column: Triart Phenyl; 150 x 4.6 mm, 3.0 μm particle size (Ex: YMC, part number: TPH12S03-1546PTH) Mobile Phase A: Water: Trifluoroacetic acid (100:0.05%) Mobile Phase B: Acetonitrile: Trifluoroacetic acid (100:0.05%) Mass spectrometry parameters Data for six deuterated reactions are tabulated in Table A below:

[00205] To synthesize 5-methoxy-N,N-dimethyltryptamine or 4-methoxy-N,N-dimethyltryptamine, 3-indole acetic acid (see Scheme 3) can be replaced with 5-methoxyindole-3-acetic acid (see synthesis of □□□-dideutero-5-methoxydimethyltryptamine described below) or 4-methoxyindole-3-acetic acid respectively, both of which are commercially available (for 5-methoxyindole-3-acetic acid, e.g. from Sigma-Aldrich (code M14935- 1G), for 4-methoxyindole-3-acetic acid see e.g. Aaron chemicals (code AR00VTP1)).

[00206] 5-methoxy-N,N-dimethyltryptamine (see Sigma-Aldrich code M-168-1ML), 4-methoxy-N,N-dimethyltryptamine (see Cayman Chemical code 9000895), 4-acetoxy-N,N- dimethyltryptamine (see Cayman Chemical code 14056) and 3-[2-(Dimethylamino)ethyl]-1H-indol-4-yl phosphate (psilocybin, see Sigma-Aldrich CAS Number 520-52-5) are also commercially available.

Synthesis of α,α-dideutero-5-methoxydimethyltryptamine Stage 1:

[00207] To a 100ml 3-neck flask under N2 was charged 5-methoxyindole-3-acetic acid (3.978g, 19.385mmol), HOBt (~20% wet) (3.927g, 23.261mmol) and DCM (40ml ). EDC.HCl (4.459g, 23.261mmol) was then loaded and portioned for 15 minutes at <30°C. The reaction mixture was stirred at room temperature for 1 hour before being charged with 2 M dimethylamine (14.54 ml, 29.078 mmol) dropwise over 15 minutes at <25°C. After stirring for 1 hour HPLC indicated that no SM remained. The reaction mixture was then charged with 10% K2CO3 (20 ml), stirred for 5 minutes 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 MgSO4 and filtered. The filtrate was concentrated in vacuum at 45°C to provide 3.898g (yield=87%) of active product with a purity of 95.7% by HPLC.

Stage 2:

[00208] To a 100 ml 3-neck flask under N2 was charged the methoxy derivative from Stage 1 (3.85g, 16.586mmol) and THF (19.25ml). 2.4 M LiAlD4 in THF (6.22 ml, 14.927 mmol) was then loaded dropwise over 30 minutes at <40°C. The reaction mixture was heated to 60°C for 1 hour where HPLC indicated 0.1% SM remaining. The reaction mixture was then cooled to room temperature and quenched in 25% Rochelles salts (38.5 ml) dropwise for 30 minutes at <30°C. The resulting suspension was stirred for 1 hour before separating. The lower aqueous layer was then removed, and the upper organic layer washed with saturated brine (9.6 ml). The organics were then dried over MgSO4, filtered and concentrated in vacuo before being subjected to an EtOH azeotrope (10 ml x 2). This provided 3.196g (yield=88%) of active product with a purity of 91.5% by HPLC.

Stage 3:

[00209] To a 50 ml 3-neck flask under N2 was charged fumaric acid (1.675 g, 14.430 mmol) and a solution of Stage 2 methoxy derivative (3.15 g, 14.299 mmol) in EtOH (37.8 mL ). The mixture was then heated to 75°C for 1 hour, this did not produce a solution as expected, the mixture was further heated to reflux (78°C) which still failed to provide a solution. The suspension was therefore cooled to 0-5°C, filtered and washed with EtOH (8 mL x 2) before being dried at 50°C overnight. This provided 3.165 g (yield = 65%) of material with a purity of 99.9% by HPLC.

Formulation Development

[00210] A stable isotonic formulation was developed with human blood serum and suitable for intravenous (IV) bolus administration of DMT fumarate. A suitable process for the preparation of such a formulation comprising DMT fumarate at a concentration of 2.5 mg/ml has also been developed. These formulations were prepared and placed under accelerated storage to assess stability over several weeks.

[00211] All concentrations indicated below are expressed in terms of free base (that is, in the absence of the fumarate counterion). For this, a correction factor of 1.59 was applied to the specific batch of pharmacological substance supplied.

Experimental Details Initial Tests

[00212] The solubility of DMT fumarate was evaluated at a concentration of 10 mg/mL in a small selection of aqueous vehicles (water, saline, 20 mM phosphate buffer, and a combination of buffer and saline).

[00213] Phosphate buffer (100 ml) was prepared using 219.53 mg of the dibasic form [HPO4][Na]2 with 183.7 mg of the monobasic form [H2PO4]Na, both dihydrate salts. The solution was adjusted to pH 7.0 with the addition of NaOH (1 M) and then made up to volume. 10 ml of a 10 mg/ml formulation were prepared.

[00214] A phosphate buffer combined with saline was initially tested (20 mM phosphate buffer in 0.45% w/v saline) as a good starting point for a physiologically acceptable formulation without solubility problems. To prepare this, sodium chloride was first dissolved in water to produce saline solution (100 mL, 0.45% w/v). The phosphate salts, in the amounts described above, were then dissolved in the saline solution and the pH was adjusted using NaOH (1 M).

[00215] DMT fumarate was readily soluble in each aqueous vehicle. In terms of appearance, each solution had a light beige color, which by filtration (using 0.2 μm filters) was removed to produce a clear colorless solution. The pH of these solutions was in the range of 34.

[00216] Buffer strength at 30 and 50 mM (such as phosphate buffer, pH 7.4, prepared in 0.45% w/v sodium chloride) was tested to evaluate the effect of the buffer on pH control of formulations comprising concentrations of 2 or 2.5 mg/mL of DMT fumarate. This buffer strength range was chosen to determine the buffer strength to fix the pH of the formulation at about pH 7.4. When developing formulations for injection, it is typical to match the pH of the formulation to that of the patient's blood serum. Human blood serum has a pH of about 7.4. Buffers were prepared as follows. The saline solution was prepared by dissolving 9 g of sodium chloride in 2 liters of water. Phosphate salts (e.g. 30 mM = dibasic dihydrate (4.29 g), monobasic dihydrate (1.43 g), 50 mM = dibasic dihydrate (7.28 g), monobasic dihydrate (2.25 g)) were dissolved in the saline solution, the pH was adjusted to 7.4 using NaOH (1 M). 9g of NaCl in 2 liters of water. Adjust pH to pH 7.4 with 1M NaOH.

[00217] The initial pH of each solution after preparation was below pH 7.4. At 20 mM, the initial pH value of 5.9 continued to drop on overnight storage of the solution in the laboratory, indicating that the buffering capacity of the buffer at the 20 mM concentration was insufficient. At both 30 mM and 50 mM buffer strengths, initial pH values were >6.5 and remained stable.

[00218] A short-term stability assessment was carried out and the data obtained for pH, osmolality and assay are presented in Tables 1 and 2. The data in Table 2 were obtained when storing the formulations between 40 to 50°C. Table 1 Assessment of Short-Term Formulation Stability Table 2 - Assessment of Short-Term Formulation Stability

[00219] Notably, tampons stored under ambient conditions (1 week at 40°C), without N2 sparging or UV light exposure control, contained 1.13% of related substances after 1 week of storage. This is compared to related substances formed under the same conditions for the Britton-Robinson buffered formulations below.

Formulation Development Materials

[00220] Details of the DMT fumarate used for stability purposes are provided in Table 3 and the excipients used are listed in Table 4. Table 3 - DMT Fumarate Used for the Stability Study Table 4 Excipients Used for the Formulation Development Study

Equipment

[00221] The equipment, excluding standard laboratory glass, used in all studies is listed in Table 5. Equipment calibration and verification were performed in accordance with standard operating procedures for all measurements as required. Table 5 — Typical Equipment Used During the Formulation Development Study

Osmolarity Readings

[00222] A single sample syringe was used to introduce the sample into the osmometer, which employed the industry's preferred principles of freezing point depression to determine osmolality with precision and accuracy.

[00223] Instrument verification was performed using calibration standards of 50, 850 and 2000 mOsm/kg H2O prior to analysis, to confirm accuracy.

pH reading

[00224] pH readings were obtained using a Mettler Toledo MP225 pH meter. The electrode probe was inserted into the test solutions, contained in a glass vial, with brief stirring at room temperature.

[00225] Verification of the instrument was performed before and after each use using, as supplied, pH buffer solutions in the range of pH 1.68 to 10.01 to confirm accuracy. High Performance Liquid Chromatography (HPLC) The following HPLC parameters were employed to evaluate the assays and the amount of related substances (substances resulting from the degradation of DMT fumarate) of DMT fumarate solutions that were prepared as part of formulation development. YMC-Triart Phenyl Column; 150 x 4.6 mm, 3 μm, Mobile phase A: Water: trifluoroacetic acid (100:0.05 v/v) Mobile phase B: Acetonitrile:trifluoroacetic acid (100:0.05 v/v) Diluent Acetonitrile:Water (50:50)

Formulation development

[00226] The solubility of DMT fumarate was initially evaluated over a range of different pH values, from pH 4 to pH 10. Formulations were then prepared at the target concentration of 2.5 mg/ml DMT fumarate over a range from pH 4 to pH 9.

Solubility of DMT Fumarate at Different pH Values

[00227] Seven solutions, each containing a concentration of 20 mg/mL of DMT fumarate, were prepared in Britton-Robinson buffer solution (B-R). Upon dissolving the DMT fumarate in each test formulation (DMT fumarate was very soluble, requiring only shaking and stirring in each), the pH of each test formulation was then adjusted to pH 4.5, 6.7, 8 and 9 using sodium hydroxide solution.

[00228] The solubility of a 20 mg/ml concentration of DMT fumarate was confirmed at pH 4, 5, 6 and 7 - these solutions were clear and colorless. The pH 8 sample was cloudy and the pH 9 and pH 10 samples contained a precipitate. After overnight storage at ambient conditions, the pH of each solution was measured and the results showed no changes from the initial pH values. Each sample was then filtered and analyzed for content. Each solution, including the high pH solutions where the precipitate was present, contained approximately the same DMT fumarate content.

pH stability

[00229] The pH stability of DMT fumarate at a concentration of 2.5 mg/ml was evaluated in 40 mM Britton-Robinson buffer solution in the buffer solution range of pH 4 to 9 (nominal). The pH of each formulation was measured at preparation, after 7 days of storage at 40°C and then additional storage for an additional 3 days at 40°C and 7 days at 50°C (i.e., an additional total storage of 10 days). Analysis of these formulations was carried out at preparation, and then after 7 and 17 days of storage for content (assay) and related substances.

[00230] Two extra aliquots of the pH 7 (nominal) solution were taken for further testing, one was sparged with nitrogen and the second was stressed under intense UV light for 4 hours equivalent to 1 ICH unit (200 watt hours UVA, 0.6 million light hours).

[00231] In the preparation of each formulation, there was a drop in pH in the range of 0.14 units (pH 4 formulation) to 1.29 units (pH 9 formulation), due to the acidic nature of the pharmacological substance. Once prepared, the pH of each formulation remained stable at the two subsequent stability time points (Table 6).

[00232] The concentration of DMT fumarate was determined by HPLC in the preparation and on the two subsequent stability occasions (Table 7). All results confirmed accurate preparation with no significant concentration changes on Day 7 or Day 17. The only significant change throughout the experiment was a drop in concentration after mild stress of the aliquot of the nominal pH 7 formulation. significant in the observed degradants.

[00233] In terms of related substances, only peaks greater than 0.05% of the total peak area have been reported. Summary data for related substances are presented in Table 8, with individual values in Table 9 (7 days of storage at 40°C) and Table 10 (10 days of storage at 40°C with an additional 7 days of storage at 50°C). °C).

[00234] In the preparation, no peaks of related substances were present. On Day 7 only the pH 9 formulation contained a peak with a relative retention time of 1.11. With only minimal additional peaks observed after the 7 days of elevated storage, the formulations were further stressed (with an increase in storage temperature over time) and in the analysis after 17 days of storage, additional peaks were present in several of the formulations with a clear trend visible with increasing numbers of peaks and peak area with increasing pH, ranging from no peaks (pH 4) to 3 peaks with a total peak area of 0.61% (pH 9). The nitrogen sprayed formulation (pH 7) was significantly more robust than its non-sprayed counterpart confirming that oxidation is a degradation pathway. The formulation under light stress was the most degraded sample with a total value of related substances of 1.68%. Table 6: pH Stability Measurement for SPL026 in Britton-Robinson Buffer Table 7 — pH Stability for SPL026 in Britton-Robinson Buffer (assay) Table 8: Total pH Stability Related Substances Assay for SPL026 in Britton-Robinson Buffer Table 9: pH Stability Individual Related Substance Assay for SPL026 in Britton-Robinson Buffer, 7 Days Storage at 40°C Table 10: pH pH Stability Individual Related Substance Assay for SPL026 in Britton-Robinson buffer, 10 days storage at 40°C, 7 days storage at 50°C

Comparison of initial formulation stability with B-R buffered formulations

[00235] As described above, DMT fumarate formulations comprising the go-to buffer stored at temperatures of 40 to 50°C, without N2 sparging or UV light exposure control, contained 1.13% of related substances after 1 week of storage. The amounts of related substances that formed in the go-to formulation and B-R formulations upon storage for one week at 40 to 50°C are compared in Table 11. DMT fumarate formulations comprising B-R buffers stored under the same conditions contained less than 0.02% related substances after 1 week of storage (>5.7 x less related substances than the go-to formulation) suggesting greater stability of the B-R formulations.

[00236] As described above, when developing formulations for injection, it is typical to match the pH of the formulation to that of the patient's blood serum. Human blood serum has a pH of about 7.4. Consequently, the obvious go-to formulation of optionally substituted dimethyltryptamine compound salts is that with a pH of 7.4. Greater stability of formulations of such salts prepared at pH values of 7.0 or less was unexpected. Table 11: Short-term Formulation Stability Assessment of the go-to Formulation and Formulations of the Invention

Development of the Candidate Formulation

[00237] Based on the results of the pH stability assessment, the decision was made to set the pH of the formulation at pH 4.0 (after storage for one week, the B-R formulation at pH 4.0 did not contain peaks corresponding to substances related, suggesting that this was the most stable formulation) and to evaluate the use of phosphate and acetate buffer systems at concentrations of 20 mM and 40 mM, as both buffer well at the ideal pH for stability and evaluate both sodium chloride and dextrose as tonic agents.

Formulation preparation

[00238] Details of each individual formulation (numbered 1 to 8) are presented in Table 12 and Table 13. For each formulation, the required acid and tonicity agent were dissolved in 80 ml of water. The pH of this solution was then adjusted to pH 4 (±0.5) with 1 M sodium hydroxide solution. The drug substance was then dissolved, the pH adjusted to pH 4 (±0 with more 1 M sodium hydroxide solution and then topping up the volume with water and final checking the pH and adjusting as required. For each formulation, the volume of sodium hydroxide used was documented. The composition of each formulation is presented below in Table 12 (saline solution) and Table 13 ( dextrose).

[00239] An aliquot of each formulation was taken for testing/related substances and osmolality verification. The remainder of each formulation was filtered (filter size 0.2 μm) into a clear glass multidose vial, sprayed with nitrogen, capped and placed for storage (60°C) for 14 days. The 40 mM phosphate/dextrose formulation (formulation 8) was divided into two aliquots with one aliquot stored in an amber glass multidose vial and one aliquot in a clear glass multidose vial. Table 12: SPL026 Candidate Formulation Preparations (Saline) Table 13: Candidate Formulation Preparations SPL026 (Dextrose)

Results

[00240] Concentration, osmolality and pH results for formulations in preparation and after storage at 60°C are presented in Table 14. Results for related substances after storage are presented in Table 15.

[00241] All formulations in the preparation were clear colorless solutions. No related substances were present in any of the formulations after preparation.

[00242] After removal from storage, all formulations in terms of their appearance were no longer colorless, but acquired to varying degrees a touch of beige, however all remained clear, the color was most pronounced in formulation 5 (acetate buffer 20 mM / dextrose) which had the highest concentration of related substances.

[00243] Osmolality and pH were confirmed as stable for each formulation tested without significant changes.

[00244] The total number of substances listed as peaks of more than 0.05% of the total peak area ranged from 0.07% to 0.52%. These data suggest that for SPL026, saline is the preferred tonicity agent over dextrose.

[00245] All day 14 results for the 40 mM phosphate/dextrose formulation stored in amber glass mirrored the clear glass results, results confirming that clear glass/amber glass storage has no impact on stability in terms of these conditions, but given the previously observed light instability, amber glass should be used as primary packaging. Table 14: Results of Candidate Formulation SPL026, Osmolality and pH Assay Table 15: Related substance testing for SPL026 candidate formulations after storage at 60°C for 14 days

Conclusion

[00246] All candidate formulations after the 14-day stability assessment were stable in terms of osmolality and pH. For formulations 1 to 3 there was no change in the concentration achieved and for formulations 58 the changes (storage losses) were small (<0.1 mg.ml-1). For each candidate formulation, related substances were very low at between 0.07 and 0.52% of the total peak area. More related substances were observed in dextrose formulations than in saline formulations.

[00247] After reviewing the data, the following formulation SPL026 was chosen (in this document referred to as formulation SPL026 - 10). This is based on formulation 1, but the acetate buffer content is slightly increased to ensure robust buffering in the formulation throughout the shelf life, but at a sufficient level to ensure that blood buffering effects are minimal. The sodium chloride levels were reduced slightly to compensate for the additional acetate, but maintain an osmotic solution. This formulation was prepared and analyzed for assay, pH and osmolality in the preparation. Details of the preparation and results achieved are presented below in Table 16. Table 16: SPL026, - Preparation and Results of the 2.5 mg/mL – 10 Formulation

[00248] The clinical technical batches of the formulation have the above composition. Clinical batches are made in accordance with Good Manufacturing Practices (GMP). The technical batch is used to establish stability data prior to clinical batch preparation. Initial technical data helps determine the shelf life of clinical batches, which are made in accordance with GMP.

Overview of recommended process for formulation preparation (batch size 100 ml) Vehicle Preparation

[00249] Preparation of 1M sodium hydroxide solution (100 ml) 1) Weigh 4 g of sodium hydroxide pellets into a suitable size cup. 2) Dispense 80 ml of Water For Injection (WFI) into the beaker. 3) Stir magnetically to achieve dissolution and let the solution cool to laboratory temperature. 4) Add purified water to make 100 ml. 5) Transfer to a type 1 borosilicate glass container.

[00250] Preparation of Formulation 10 (2.5 mg/ml) 1) Accurately weigh 760 mg of sodium chloride in a suitable container 2) Weigh by difference the amount of pharmacological substance in a suitable container (glass weighing boat ). Make sure that the mass of the pharmacological substance taken includes correction for salt and purity. 3) Carefully transfer the heavy drug substance into a glass. Rinse the weighing vessel with WFI, ensuring that no solids remain. Add more WFI to the drug substance up to the total volume required and stir magnetically to dissolve. Add the batch amount of acetic acid (note that acetic acid is volatile and therefore this step should be performed immediately after weighing). 4) Add the pre-weighed sodium chloride. 5) When dissolution is complete, adjust the pH of the formulation to pH 4 (±0.1) with dropwise addition of the freshly prepared 1M sodium hydroxide solution while stirring continuously. 6) Complete the volume in a suitable container and finally check that the pH is pH 4 (±0.1) and adjust if necessary. 7) The drug product solution is clear with a slight touch of beige color. This color is removed in filtration (step 6) to leave a colorless filtration solution. 8) Bubble nitrogen through the formulation until the measured dissolved oxygen content is below 2 ppm. 9) Filter the solution with a 0.22 μm or 0.2 μm syringe into an amber glass multidose vial.

Stability of Formulation 10 (Technical Batch) Appearance and pH

[00251] The appearance and pH results for formulation 10 (technical batch) in preparation and after storage at 28°C, 25°C/60% relative humidity (RH) and 40°/75% RH are presented in Table 17. At T = 0 (initial analysis), pH met specification of 3.8-4.2 and osmolality met specification of 270-330 mOsm/kg (296 mOsm/kg). For T = 9 months, there are no significant changes in appearance on storage at 2-8°C or at 25°C/60% RH. However, at 40°C/75% RH there is an obvious color change in the product at T = 6 months. There was an indication of color change at the 2 and 3 month points in storage at 40°C/75% RH when compared to the other storage conditions, but at 6 months the color change was obvious. There was no change in pH within 9 months of storage at 2-8°C or 25°C/60% RH or within 6 months of storage at 40°C/75% RH. Table 10: Appearance and pH of formulation 10 after Storage under Specified Conditions

Subvisible particles

[00252] The number of subvisible particles in formulation 10 (technical batch) in preparation and after storage at 28°C, 25°C/60% relative humidity (RH) and 40°/75% RH is presented in Table 18. After 6 months of storage at 2-8°C, 25°C/60% RH and 40°C/75% RH there is no significant change in subvisible particles (see Table 18). Table 18: Subvisible particles of formulation 10 after storage under specified conditions 1 Where the filling volume is 10.5 ml 2 Number of particles with diameter ≥10µm per bottle <6000 = PASS and number of particles with diameter ≥25 µm per bottle <600 = PASS

Extractable Volume

[00253] The extractable volume of 6 vials of formulation 10 (technical batch) is presented in Table 19. The density used to calculate the volume was taken from the placebo data used in manufacturing the batch (1.008 g/cm3). The extractable volume meets the specification of NLT 10.0 ml. Table 19: Extractable Volume of Formulation 10

Percentage Recovery

[00254] The percentage recovery of SPL026 (free base, mg/ml) in formulation 10 (technical batch) in preparation and after storage at 2-8°C, 25°C/60% relative humidity (RH) and 40 °/75% RH is presented in Table 20. There were no significant changes in formulation purity after 9 months of storage at 2-8°C or 25°C/60% RH and 6 months of storage at 40°C/75% RH HR. All recoveries versus theoretical concentration and T = 0 are within specification of 90.0 - 105.0% Table 20: Percent recovery of SPL026 from formulation 10 after storage under specified conditions 1 As a percentage of theoretical 2.5 mg/ml. 2 As a percentage of the initial result (T = 0). 3 As a percentage of the pre-filtration result.

Purity/Related Substances

[00255] The purity of SPL026 (free base, mg/mL) and the amount of impurities observed at different retention times in formulation 10 (technical batch) in preparation and after storage at 2-8°C, 25°C/60 % relative humidity (RH) and 40°/75% RH are presented in Table 21, Table 22 and Table 23 respectively. The total impurities observed in the formulations after 9 months of storage at 2-8°C and 25°C/60%RH increased slightly due to the impurity at RRT 1.04 being observed for the first time and above the LOQ limit in both conditions. Increases in total impurity were observed for the sample stored at 40°C/75%RH from 2 months onwards. An increase in impurity observed at RRT 1.60 is observed from T = 2 months at 40°C/75%RH compared to the other storage conditions, which can be attributed to the higher storage temperature of 40° W. Table 21: Purity/Related Substances of SPL026 of Formulation 10 after Storage at 2-8°C 1 SPL026 purity calculated as 100 - total related substances. 2 Sum of related substances >0.05% Table 22: Purity/Related substances of SPL026 fs formulation 10 after Storage at 25°C/60%RH 1 SPL026 purity calculated as 100 - total related substances. 2 Sum of related substances >0.05% Table 23: Purity/related substances of SPL026 of formulation 10 after storage at 40°C/75%RH 1 SPL026 purity calculated as 100 - total related substances. 2 Sum of related substances >0.05%

Stability of Formulation 10 (Clinical Batch)

[00256] At T = 0 (the initial analysis), the pH met the specification of 3.8-4.2, the osmolality met the specification of 270-330 mOsm/kg (being 306 mOsm/kg), and the volume extractable material met the NLT specification of 10.0 ml (being 10.4 ml). Furthermore, at T = 0, the number of sub-visible particles was 4 particles/vial of size >10 μm and 0 particles/vial of size >25 μm, which is well within the specification of no greater than 6,000 particles/ vial of size >10μm and no larger than 600 particles/vial of size >25 μm At T = 0, the UV-vis spectrum of the formulation conformed to the reference spectra (Àmax at 221 ±3 nm and 279 ± 3 nm) , and the signal was observed at ±2% of the reference standard retention time. Finally, at T = 0, the container closure integrity test showed no dye ingress and the formulation was sterile, comprising <0.01 EU/ml of bacterial endotoxins, which is well within the specification of 20.5 EU/ml.

Appearance and pH

[00257] Appearance and pH results for formulation 10 (clinical batch) in preparation and after storage at 2-8°C, 25°C/60% relative humidity (RH) and 40°/75% RH are shown in Table 24. For T = 3 months, there are no significant changes in appearance on storage at 2-8°C, at 25°C/60% RH or at 40°C/75% RH. There was an indication of color change at the 3 month point. There was no change in pH.Table 24: Appearance and pH of formulation 10 after storage under the specified conditions

Percentage Recovery

[00258] The percentage recovery of SPL026 (free base, mg/ml) in formulation 10 (clinical batch) in preparation and storage at 2-8°C, 25°C/60% relative humidity aa(RH) and 40° /75% RH is presented in Table 25. There were no significant changes in the purity of the formulation after 3 months of storage at 2-8°C or 25°C/60% RH and 40°C/75% RH. All recoveries versus theoretical concentration and T = 0 are within specification of 95.0 - 105.0%Table 25: Percent Recovery of SPL026 from Formulation 10 after Storage under Specified Conditions

Purity/Related Substances

[00259] The purity of SPL026 (free base, mg/ml) and the amount of impurities observed at different retention times in formulation 10 (clinical batch) in preparation and after storage at 2-8°C, 25°C/60 % relative humidity (RH) and 40°/75% RH are presented in Table 26, Table 27 and Table 28, respectively. Table 26: Purity/Related Substances of SPL026 of Formulation 10 after Storage at 2-8°C 2 Sum of chemical substances >0.05% Table 27: Purity/Related Substances of SPL026 of formulation 10 after Storage at 25°C/60%RH 2 Sum of related substances >0.05% Table 28. Purity/Related substances of SPL026 of formulation 10 after Storage at 40°C/75%RH 2 Sum of related substances >0.05%

Claims (20)

1. Pharmaceutical formulation, characterized by comprising: a salt of a dimethyltryptamine compound optionally substituted with deuterium and optionally substituted in position 4 or 5 with acetoxy or methoxy or position 4 with monohydrogen phosphate; a buffer that is separated from the salt; and water, where the Formulation has a pH of 3.75 to 6.5 and an osmolality of 250 to 350 mOsm/Kg. 2. Formulation according to claim 1, characterized in that: the pH is 3.75 to 5.75. 3. Formulation according to claim 1, characterized in that: the pH is 3.75 to 4.25. 4. Formulation according to claim 1, characterized in that: The Formulation has an osmolality of 275 to 325 mOsm/Kg. 5. Formulation according to claim 1, characterized in that: the salt comprises a Bronsted acid having a pKa of 3 to 5 and a compound of Formula I wherein: R4 and R5 are both H and each xH and each YH are independently selected from H and D, or one of R4 and R5 is H and the other is acetoxy or methoxy, each YH is H and each xH is independently selected from H and D, or the salt comprises a compound of Formula I, wherein: R4 is monohydrogen phosphate, R5 is H and each YH and each xH is H. 6. Formulation according to claim 5 characterized in that: R4 and R5 are both H; R4 is acetoxy and R5 is H; or R4 is H and R5 is methoxy. 7. Formulation according to claim 1, characterized in that: the optionally substituted dimethyltryptamine compound is dimethyltryptamine. 8. Formulation according to claim 1, characterized in that: 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. 9. Formulation according to claim 1, characterized in that: the salt is of an optionally substituted dimethyltryptamine compound and in which the acid is fumaric acid. 10. Formulation according to claim 1, characterized in that: the salt of the dimethyltryptamine compound has a purity greater than or equal to 99% when measured by HPLC. 11. Formulation according to claim 1, characterized in that: the concentration of the optionally substituted dimethyltryptamine is 2.5 mg/ml. 12. Formulation according to claim 1, characterized in that: the buffer comprises an acetate and acetic acid salt. 13. Formulation according to claim 1, characterized in that: the formulation additionally comprises a tonicity agent. 14. Formulation according to claim 13, characterized in that: the tonicity agent is sodium chloride with a concentration of 120 mM to 140 mM. 15. Formulation according to claim 1, characterized in that: the formulation consists essentially of salt, buffer, water and, optionally, a tonicity agent. 16. Formulation according to claim 1, characterized in that: the formulation has an oxygen content of less than 2 ppm. 17. Pharmaceutical formulation suitable for injection according to claim 1, characterized in that it comprises: a salt of a dimethyltryptamine compound optionally substituted with deuterium and optionally substituted in position 4 or 5 with acetoxy or position 4 with monohydrogen phosphate; a buffer that is separated from the salt; and water, wherein the formulation has a pH of 3.75 to 6.5 and an osmolality of 250 to 350 mOsm/Kg. 18. Pharmaceutical formulation suitable for injection according to claim 1, characterized in that it comprises: a salt of a dimethyltryptamine compound optionally substituted with deuterium; a buffer that is separated from the salt; and water, wherein the formulation has a pH of 3.75 to 6.5 and an osmolality of 250 to 350 mOsm/Kg. 19. Formulation according to claim 1, characterized in that: the pH is 4.0 to 6.5. 20. Formulation according to claim 5, characterized in that: the pH is 4.0 to 6.5.