GB2596884A

GB2596884A - Pharmaceutical composition

Info

Publication number: GB2596884A
Application number: GB2019241.5A
Authority: GB
Inventors: Feilding-Mellen Cosmo
Original assignee: Beckley Psytech Ltd
Current assignee: Beckley Psytech Ltd
Priority date: 2020-06-12
Filing date: 2020-12-07
Publication date: 2022-01-12
Anticipated expiration: 2040-12-07
Also published as: GB202008961D0; GB2596884B8; GB2596884A8; GB202019241D0; GB2596884B

Abstract

A composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5-methoxy-N,N-dimethyltryptamine (5MeODMT). The composition may be used as a medicament. The composition may comprise 5MeODMT benzoate at 1.25% concentration. The composition may comprise a dosage amount of 5MeODMT in the range 0.05 – 100 mg. The composition may be formulated for oral, transdermal, inhalable, intravenous, or rectal administration. The composition may be formulated as a tablet, capsule, granules, powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, or suppository dosage form. Most preferably, the preparation may be suitable for administration by inhalation, via a dispenser selected from a dry powder inhaler, a nasal inhaler, or a pressurised metered dose inhaler. The composition may comprise one or more pharmaceutically acceptable carriers or excipients, and may comprise one or more of a mucoadhesive enhancer, a penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.

Description

Pharmaceutical Composition

Field of the invention

This invention relates to pharmaceutically acceptable salts of 5-methoxy-N,N-dimethyltrypta mine. In particular, though not exclusively, the invention relates to formulations and uses of the same as a medicament.

Background of the invention

5-methoxy-N,N-dimethyltryptamine (hereafter 5Me0DMT) is a pharmacologically active compound of the tryptamine class and has the chemical formula: 5Me0DMT is a psychoactive/psychedelic substance found in nature and is believed to act mainly through serotonin receptors. It is also believed to have a high affinity for the 5-HT2 and 5-HTIA subtypes, and/or inhibits monoamine reuptake.

However, 5Me0DMT is not well understood and uses of this compound have not been well explored. Further, 5Me0DMT is not easy to handle, and there are challenges in formulating it for effective delivery in pharmaceutically useful compositions.

There remains a need in the art for improved formulations and uses of 5Me0DMT. Summary of the invention Herein disclosed, there is provided a composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable salt of 5-methoxy-N,N-dimethyltrypta mine (5Me0DMT).

Herein disclosed, the salt anion is an aryl carboxylate. In an embodiment, the aryl carboxylate is substituted with one to three R groups.

In an embodiment the one or more R groups are selected from: allcynyl, carbonyl, aldehyde, haloformyl, alkyl, halide, hydroxy, alkoxy, carbonate ester, carboxylate, carboxyl, carboalkoxy, methoxy, hydroperoxy, peroxy, ether, hemiacetal, hem iketal, acetal, ketal, orthoester, methylenedioxy, orthocarbonate ester, carboxylic anhydride, carboxamide, secondary, tertiary or quaternary amine, primary or secondary ketimine, primary or secondary aldimine, imide, azide, azo, cyanate, isocyanate, nitrate, nitrile, isonitrile, nitrosooxy, nitro, nitroso, oxime, pyridyl, carbamate, sulfhydryl, sulfide, disulfide, sulfinyl, sulfonyl, sulfino, sulfo, thiocyanate, isothiocyanate, carbonothioyl, carbothioic S-acid, carbothioic 0-acid, thiolester, thionoester, carbodithioic acid, carbodithio, phosphino, phosphono, phosphate, borono, boronate, borino or borinate.

In an embodiment the one or more R groups are selected from C1 -C6 alkyl, C1 -C6 alkoxy, C1 -C6 alkenyl or C1 -CG alkynyl, and where each of these may be optionally substituted with one to three R groups as previously described.

In a first aspect of the invention, there is provided a composition comprising a pharmaceutically 5 effective amount of a pharmaceutically acceptable benzoate salt of 5-methoxy-N,N-dimethyltryptamine (5Me0DMT).

The invention provides for improved formulations and uses of 5Me0DMT salts.

In an embodiment the composition comprises a dosage amount of 5Me0DMT in the range of 0.05mg to 100mg.

In an embodiment the composition comprises a dosage amount of 5Me0DMT in the range of 0.1mg to 50mg.

In an embodiment the composition comprises a dosage amount of 5Me0DMT in the range of 0.5mg to 25mg.

In an embodiment the composition comprises a dosage amount of 5Me0DMT in the range of 0.5mg to 10mg.

In an embodiment the composition comprises a dosage amount of 5Me0DMT in the range of lmg to 10mg.

In an embodiment the composition comprises a dosage amount of 5Me0DMT in the range of lmg to 8mg.

In an embodiment the composition comprises a dosage amount of 5Me0DMT in the range of 3mg to 15mg.

In an embodiment the composition comprises a dosage amount of 5Me0DMT in the range of 0.005mg to 100mg.

In an embodiment the composition comprises a dosage amount of 5Me0DMT in the range of 0.001mg to 100mg.

In an embodiment the composition comprises a dosage amount of 5Me0DMT in the range of 0.0005mg to 100mg.

The level of the active agent can be adjusted as required by need for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.

In an embodiment the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, or rectal dosage form.

It is advantageous to be able to deliver the active agent in different forms, for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.

In an embodiment the composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, or suppository dosage form.

In an embodiment the powder is suitable for administration by inhalation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler.

In an embodiment the powder comprises particles, the particles having a median diameter of less than 20001.tm, 1000gm, 500gm, 250gm, 100gm, 50gm, or 1 gm.

In an embodiment the powder comprises particles, the particles having a median diameter of 10 greater than 500gm, 250gm, 100um, 50gm, 1gm or 0.5gm.

In an embodiment the powder comprises particles, and wherein the powder has a particle size distribution of d10=20-60gm, and/or d50=80-1201.tm, and/or d90=130-300gm.

The nature of the powder can be adjusted to suit need. For example, if being made for nasal inhalation, then the particles may be adjusted to be much finer than if the powder is going to be formulated into a gelatine capsule, or differently again if it is going to be compacted into a tablet.

In an embodiment the 5Me0DMT salt is amorphous or crystalline.

In an embodiment the 5Me0DMT salt is in a polymorphic crystalline form, optionally 5Me0DMT salt is Polymorph A. In an embodiment the 5Me0DMT salt is a benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt, optionally the salt is the chloride, benzoate or fumarate salt.

In an embodiment the 5Me0DMT salt is formulated into a composition for mucosal delivery. In an embodiment, the 5Me0DMT salt is a benzoate salt.

For the salt, the dosage amount is the equivalent amount of the free base delivered when the salt is taken. So 100 mg dosage amount of 5Me0DMT corresponds to 117mg of the hydrochloride salt (i.e. both providing the same molar amount of the active substance). The greater mass of the salt needed is due to the larger formula weight of the hydrogen chloride salt (i.e. 218.3 g/mol for the free base as compared to 254.8 g/mol for the salt). Similarly, for the deuterated or triturated version of 5Me0DMT (also considered within the scope of the invention), a slight increase in mass can be expected due to the increased formula weight of these isotopic compounds.

Amorphous and crystalline substances often show different chemical/physical properties, e.g. improved rate of dissolution in a solvent, or improved thermal stability. Similarly, different polymorphs may also show different and useful chemical/physical properties.

In an embodiment the composition comprises one or more pharmaceutically acceptable carriers or excipients.

In an embodiment the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.

In an embodiment the composition comprises one or more of: chitosan, chitosan derivatives (such as N,N,N-trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl (QuatHexyl)-N,N-dimethyl chitosan, chitosan chloride), B-cyclodextrin, clostridium perFringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholat, palmitic acid, palmitoleic acid, stearic acid, °leyl acid, oleyl alchohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phophatidyl choline, soybean lecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose, and citric acid.

In an embodiment the composition defined herein above for use in a method of treatment of a human or animal subject by therapy.

In an embodiment the method of treatment is a method of treatment of: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), conditions benefiting from anti-inflammatory treatment depression, anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorders, obsessive-compulsive disorders, or body dysmorphic disorders, optionally the condition is SUNCT and/or SUNA.

Treatment of the above conditions may be beneficially improved by taking the invention.

In an embodiment the method of treatment is a method of treatment of more than one of the above conditions, for example, the method of treatment may be a method of treatment of depression and anxiety.

In an embodiment the composition is administered one or more times a year.

In an embodiment the composition is administered one or more times a month.

In an embodiment the composition is administered one or more times a week.

In an embodiment the composition is administered one or more times a day.

In an embodiment the composition is administered at such a frequency as to avoid tachyphylaxis.

In an embodiment the composition is administered together with a complementary treatment and/or with a further active agent.

In an embodiment the further active agent is a psychedelic compound, optionally a tryptamine.

In an embodiment the further active agent is lysergic acid diethylamide (LSD), psilocybin, psilocin or a prodrug thereof.

In an embodiment the complementary treatment is psychotherapy.

In an embodiment, there is provided a composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5 methoxy N,N dimethyltryptamine (5Me0DMT) for use in a method of treatment of treatment resistant depression.

In an embodiment, there is provided a nasal inhalation composition comprising a pharmaceutically 20 effective amount of a pharmaceutically acceptable benzoate salt of 5 methoxy N,N dimethyltryptamine (5Me0DMT) for use in a method of treatment of treatment resistant depression.

Treatment of the above conditions may be beneficially improved by taking the invention together with some complementary treatments; also these treatments may occur much less regularly than some other treatments that require daily treatments or even multiple treatments a day.

The present invention will now be further described with reference to the following, and the accompanying drawings, of which:

Brief description of the drawings

Figure 1 is a schematic route for the synthesis of 5Me0DMT.

Figure 2 is a further schematic route for the synthesis of 5Me0DMT.

Figure 3 is a schematic route for the preparation of a powder form of 5Me0DMT.

Figure 4 is an overview of the slug mucosa! irritation (SMI) test. (A) First 15 minute contact period between slug and test item. (B) Slug is transferred onto a wet paper towel in a new Petri dish for 1 hour. (C) Second 15 minute contact period between slug and test item. (D) Slug is transferred onto a wet paper towel in a new Petri dish for 1 hour. (E) Third 15 minute contact period between slug and test item.

Detailed description of the invention

Figure 1 shows a one-step synthesis of 5Me0DMT from the reaction of 4-methoxyphenylhydrazine hydrochloride with (NN)-dimethylamino)butanal dimethyl acetal.

Figure 2 shows a three step synthesis of 5Me0DMT. The first step involves the reaction of 5-methoxyindole with oxalyl chloride. The resultant product is aminated with dimethylamine and then is reduced with lithium aluminium hydride.

Figure 3 shows the schematic route for the formation of a powder form of 5Me0DMT using a spray drying process.

Examples

Example 1: Synthesis of SMe0DMT (the free base) in on step (the free base) A schematic representation of this reaction is shown in Figure 1.

Hydrazine (1.0 eq), diethyl acetal (1.2 eq), and aqueous sulfuric acid (0.1 eq) where heated together at 65-75°C for 18 hours. MTBE (10 vol) was added, followed by adjustment to about pH10 using 12% caustic (about 1.1eq.). The layers were separated and the aqueous fraction back extracted with MTBE (10vol). The combined organic fractions were washed with water (10vol) twice, then evaporated to dryness under vacuum. Yield 100%.

Example 2: Synthesis of SMe0DMT (the free base) in three steps A schematic representation of this reaction is shown in Figure 2.

Step 1-Add methyl tert-butyl ether (MTBE) (15vol) into the reaction vessel and cool to -20 to -30°C, before adding oxalyl chloride (1.5 eq), maintaining the temperature at no more than -20°C. Add a solution of 5-methoxyindole (1.0 eq) in THE (lvol) to the reaction vessel, maintaining the temperature at no more than -20°C. Allow the reaction to warm to 0-5°C and stir for at least 1 hour, ensuring that no more than 2% of the starting material indole remains.

Cool the reaction to between -20 to -30°C and add a solution of methanol (1vol) and MTBE (1vol), maintaining the temperature at no more than -20°C. Allow the reaction to warm to 0-5°C over no less than 30 minutes and stir for at least 1 hour.

Filter and wash the solids with MTBE cooled to 0-5°C. Add the washed filtered solids and methanol (20vol) to a reaction vessel. Heat to 60-65°C and stir for no more than 30 minutes. Cool to 0-5°C over no less than 2 hours and stir for no less than 2 hours. Filter and wash the solids with MTBE cooled to 0-5°C. Dry the solids obtained at no more than 40°C for no less than 12 hours. Yield 95%.

Step 2 -Add the compound obtained in step 1 (1.0 eq) to a reaction vessel together with dimethylamine hydrochloride (3.0 eq) and methanol (2vol). Add 25% Na0Me in methanol (3.5 eq), to the reaction maintaining the temperature at no more than 30°C. Warm to and stir for no less than 5 hours, ensuring that no more than 0.5% of the starting material from step 1 remains. Adjust the temperature to 0-5°C over no less than 2 hours, then add water (5vol) over no less than 1 hour with stirring at 0-5°C for no less than 1 hour.

Filter and wash the solids with water cooled to 0-5°C, and dry the solids obtained at no more than 40°C for no less than 12 hours. Yield 85%.

Step 3-Add the compound obtained in step 2 (1.0 eq) to a reaction vessel. Add 1M LiAIH4 in THF (1.5 eq) in THF (8vol) to the reaction maintaining no more than 40°C. Heat at reflux for no less than 4 hours ensuring that no more than 2% of the starting material from step 2 remains.

Adjust to 0-5°C and add water (0.25vol) in THF (0.75vol) over no less than 30 minutes, maintaining no more than 10°C. Then add 15% caustic (0.25vo1) maintaining the temperature at no more than 10°C. Add water (0.65vo1) maintaining the temperature at no more than 10°C. Add THF (0.25vo1) as a vessel rinse and stir the contents at 0-5°C for no less than 30 minutes. Add sodium sulfate (100wt%) and stir contents at 0-5°C for no less than 30 minutes.

Filter and wash the solids with toluene (2x1Ovol) and keep liquors separate. Recharge THF liquors to a clean vessel and distil under vacuum to minimum stir. Charge toluene liquors and distil under vacuum to about 10vol. Then add water (5vol) and stir for no less than 15 minutes. Stop, settle and remove aqueous layer to waste. Charge with 4% HCI to a pH of between 1-2 (about 4vol) and stir for no less than 15 minutes. Stop, settle and remove organic layer to waste. Charge MTBE (15vol).

Charge with 15% caustic to a pH between 11-13 (about 0.9vol). Stir for no less than 15 minutes.

Stop, settle and remove aqueous layer to waste. Charge with water (5vol). Stir for no less than 15 minutes. Stop, settle and remove the aqueous layer to waste.

Example 3: Synthesis of SMe0DMT hydrochloride salt 5Me0DMT (the free base) is dissolved in toluene (1.0 to 2.5vol). Isopropyl alcohol (IPA) was then added (2.5vol) followed by 1.25M HCI in IPA (1.0 eq) and the temperature adjusted to 0-5°C over 1 hour.

If no precipitation/crystallization occurs, toluene (6.25vo1) is added over 30 minutes. The mixture was then stirred at 0-5°C for 2 hours. The resultant solid is filtered, washed with toluene (3.8vol). The solid was dried under vacuum at ambient temperature. Yield 58%.

Example 4: Synthesis of SMe0DMT benzoate salt 5Me0DMT (the free base) is dissolved in toluene (1 eq) and benzoic acid (1 eq) in toluene (10vol) is added over a period of 20 minutes and stirred at room temperature for 2 hours. The resultant precipitation/crystallization was filtered and washed with toluene (2.5vol) and dried under vacuum at room temperature.

Isopropyl acetate (IPAc) (15.8vol) was added to the solids obtained above and the temperature was raised to about 73°C until the solid dissolved. The solution was allowed to cool to 0-5°C over 2 hours and this temperature was maintained for 1 hour with stirring. The resultant benzoate salt was filtered and vacuum dried at room temperature. Yield 68%.

Example 5: Synthesis of 5Me0DMT fumarate salt 5Me0DMT (the free base) is added to a solution of fumaric acid (0.5 eq) in IPA over 15 minutes at 40-45°C. The resultant solution was cooled at room temperature and stirred for 16 hours. The solution was then cooled to 0-5°C with stirring for 2 hours. The resulting precipitation/crystallization was filtered and was rinsed with toluene (2.5vol). Yield 68%.

Example 6: 5Me0DMT powder A schematic route for the preparation of a powder form of 5Me0DMT (or the salt thereof) is shown in Figure 3. The three main steps in the process are: 1. Spray drying a solution containing the substance(s) of interest (e.g. 5Me0DMT, or the salt, thereof inclusive of any excipients). This can be done via an atomizing nozzle such as with rotary atomizers, pressure atomizers, twin fluid nozzles, ultrasonic atomizers, four-fluid nozzles. This is done so as to form droplets capable of generating co-formed particles in the desired particle size range.

2. Drying of the atomized droplets (e.g. with nitrogen gas, optionally at an elevated temperature).

3. Separating and collecting the dried particles from the gas stream (e.g. using a cyclone separator to capture the required size fraction).

Example 7: Slug Mucosal Irritation assay The Slug Mucosa! Irritation (SMI) assay was initially developed at the Laboratory of Pharmaceutical Technology (UGent) to predict the mucosal irritation potency of pharmaceutical formulations and ingredients. The test utilizes the terrestrial slug Anion lusitanicus. The body wall of the slugs is a mucosal surface composed of different layers. The outer single-layered columnar epithelium that contains cells with cilia, cells with micro-villi and mucus secreting cells covers the subepithelial connective tissue. Slugs that are placed on an irritating substance will produce mucus. Additionally tissue damage can be induced which results in the release of proteins and enzymes from the mucosal surface. Several studies have shown that the SMI assay is a useful tool for evaluating the local tolerance of pharmaceutical formulations and ingredients. A classification prediction model that distinguishes between irritation (mucus production) and tissue damage (release of proteins and enzymes) has been developed. Furthermore, several studies with ophthalmic preparations have shown that an increased mucus production is related to increased incidence of stinging, itching and burning sensations. In 2010 a clinical trial was set up to evaluate the stinging and burning sensations of several diluted shampoos. A 5% shampoo dilution or artificial tears were instilled in the eye and the discomfort was scored by the participants on a 5 point scale during several time points up to 30 min after instillation. The same shampoos were tested in the SMI assay using the Stinging, Itching and Burning (SIB) protocol. This study showed that an increased mucus production was related with an increased incidence of stinging and burning sensations in the human eye irritation test. The relevance of the assay to reliably predict nasal irritation and stinging and burning sensations was demonstrated using several OTC nasal formulations, isotonic, and hypertonic saline.

Furthermore, the test was validated using reference chemicals for eye irritation (ECETOC eye reference data bank). These studies have shown that the SMI assay can be used as an alternative to the in vivo eye irritation tests. Moreover, a multi-center prevalidation study with four participating laboratories showed that the SMI assay is a relevant, easily transferable and reproducible alternative to predict the eye irritation potency of chemicals.

The purpose of this assay was to assess the stinging, itching or burning potential of the test item(s) defined below. Using the objective values obtained for the mucus production the stinging, itching or burning potential of the test item(s) can be estimated by means of the prediction model that is composed of four categories (no, mild, moderate and severe).

Control items: * Negative control -Name: Phosphate buffered saline (PBS) * Positive control -Name: 1% (w/v) Benzalkonium chloride in PBS Test items: Compound 1 Name: 10% (w/v) Disodium fumarate in PBS CASRN: 17013-01-3 Batch: KBSJ-P0

Description: colourless solution

Storage condition: room temperature (compounded on the day of the experiment) Compound 2 Name: 10% (w/v) Sodium phosphate monobasic in PBS CASRN: 7558-80-7 Batch: 2A/220991

Description: colourless solution

Storage condition: room temperature (compounded on the day of the experiment) Compound 3 Name: 10% (w/v) Sodium acetate in PBS CASRN: 127-09-3 Batch: 5A/233258

Description: colourless solution

Storage condition: room temperature (compounded on the day of the experiment) Compound 4 Name: 10% (w/v) Sodium citrate in PBS CASRN: 68-04-2 Batch of vial: 5A/241516

Description: colourless solution

Storage condition: room temperature (compounded on the day of the experiment) Test System: Slugs (Anon lusitanicus); 3 slugs per treatment group. The parental slugs of Anion lusitanicus collected in local gardens along Gent and Aalter (Belgium) are bred in the laboratory in an acclimatized room (18-20°C). The slugs are housed in plastic containers and fed with lettuce, cucumber, carrots and commercial dog food.

Test Design: A single study was performed. Treatment time was 15 minutes three times on the same day.

Preparation of Slugs: Slugs weighing between 3 and 6 g were isolated from the cultures two days before the start of an experiment. The body wall was inspected carefully for evidence of macroscopic injuries. Only slugs with clear tubercles and with a foot surface that shows no evidence of injuries were used for testing purposes. The slugs were placed in a plastic box lined with paper towel moistened with PBS and were kept at 18 -20°C. Daily the body wall of the slugs was wetted with 300 pl PBS using a micropipette.

Test Procedure: The stinging, itching or burning potency of the test item(s), was evaluated by placing 3 slugs per treatment group 3 times a day on 100 uiL of test item in a Petri dish for 15 ± 1 min. After each 15-min contact period the slugs were transferred for 60 min into a fresh Petri dish on paper towel moistened with 1 ml PBS to prevent desiccation. An overview of this can be seen in Figure 4.

Mucus Production: The amount of mucus produced during each contact period was measured by weighing the Petri dishes with the test item before and after each 15-min contact period. The mucus production was expressed as % of the body weight. The slugs were weighed before and after each 15-min contact.

Classification prediction model Based on the endpoint of the SMI assay the stinging, itching or burning potency of the test item(s) was estimated using a classification prediction model.

The evaluation of the test results was based upon the total amount of mucus production during 3 repeated contact periods with the test item.

For each slug, the mucus production was expressed in % of the body weight by dividing the weight of the mucus produced during each contact period by the body weight of the slug before the start of that contact period. The total mucus was calculated for each slug and then the mean per treatment group was calculated. The classification prediction model shown in Table 1 was used to classify the compounds.

Table 1 Cut-off values for classification -potency for nasal mucosa! discomfort Total Mucus production in % Stinging, Itching and Burning (SIB) <5.5% No 5.5 and < 10% Mild and < 17.5% Moderate 17.5% Severe Acceptance criteria Before a test was considered valid, the following criteria must be met: * the negative control should be classified as causing no stinging, itching and burning (Total mucus production < 5.5%) * the positive control item should be classified as causing severe stinging, itching and burning (Total mucus production 17.5%) Irritation Potential Table 2 Amount of mucus produced (MP) during each 15-min contact period (CP) and total amount of mucus produced Formulation MP CP11 (%) MP CP21 (%) MP CP31 DO Total MP1 (50 SIB Category2 NC-PBS -0.2 + 0.3 -0.6 + 0.1 0.3 + 0.6 -0.5 + 0.7 No PC -1% BAC 9.2 + 1.5 8.4 + 1.2 5.9 + 3.1 23.4 + 3.6 Severe Disodium fumarate, 5.0 + 2.5 4.7 + 1.7 3.6 + 0.8 13.3 + 1.8 Moderate Sodium phosphate, 10% 3.3 + 0.9 5.6 + 0.3 6.2 + 1.3 15.2 + 1.8 Moderate Sodium acetate, 10% 3.3 + 0.2 3.9 + 0.4 3.9 + 0.2 11.0 + 0.8 Moderate Sodium citrate, 10% 4.2 + 0.5 4.2 + 0.3 4.1 + 1.1 12.5 + 1.4 Moderate NC: negative control; PC: positive control; BAC: benzalkonium chloride 'Mean ± SD, n=3 2 No: total MP < 5.5%; Mild: 5.5% 5 total MP < 10%; Moderate: 10%5 total MP < 17.5%; Severe: total MP 17.5% The average amount of mucus produced during each 15-min contact period and total mucus production (total MP) is presented in Table 2. According to the classification prediction model of the SMI test, the negative control (untreated slugs) did not induce reactions in the slugs (mean total MP < 5.5%). The positive control on the other hand (DDWM/SLS 80/20) induced a high mucus production during each contact period (mean total MP 17.5%) resulting in a classification as severe stinging, itching, and burning (SIB) reactions. The acceptance criteria were met and the experiment was considered valid.

In total, 4 different solutions were tested. The amount of mucus produced during each 15-min contact period was between 10% and 17.5%, indicating moderate SIB reactions. The test items can be ranked according to increasing total mucus production: sodium acetate (10% w/v) < sodium citrate (10% w/v)< disodium fumarate (10% w/v) < sodium phosphate (10% w/v).

Numerical Data Treatment Replicate MP CPI MP CP2 MP CP3 Total MP 1 -0.32 -0.59 0.97 0.06 NC 2 -OM -0.57 -0.32 -1.33 3 0.14 -0.70 0.35 -0.21 1 8.08 7.91 9.29 25.28 PC 2 10.82 9.71 5.23 25.77 3 8.59 7.49 3.17 19.25 1 7.83 3.56 3.14 14.53 Disodium fumarate, 10% 2 4.39 6.64 3.11 14.14 3 2.87 3.84 4.47 11.17 1 4.33 5.34 7.41 17.07 Sodium phosphate, 10% monobasic 2 2.93 5.69 6.40 15.02 3 2.74 5.83 4.89 13.46 1 3.47 424 4.10 11.80 Sodium acetate, 10% 2 3.44 3.93 3.81 11.18 3 3.06 3.43 3.69 10.17 1 4.16 4.01 3.78 11.95 Sodium citrate, 10% 2 4.75 4.03 5.33 14.12 3 3.68 4.55 3.25 11.48 Table 3 Amount of mucus produced (MP) during each 15-min contact period (CP) and total amount of mucus produced Formulation MP CP11 MP CP21 MP CP31 Total MP1 SIB (%) (%) (%) (%) Category2 NC-PBS -0.2 ± 0.3 -0.6 ± 0.1 0.3 + 0.6 -0.5 ± 0.7 No PC -1% BAC 9.2 ± 1.5 8.4 + 1.2 5.9 + 3.1 23.4 ± 3.6 Severe Disodium fumarate, 5.0 + 2.5 4.7 + 1.7 3.6 + 0.8 13.3 + 1.8 Moderate Sodium phosphate, 10% 3.3 + 0.9 5.6 + 0.3 6.2 + 1.3 15.2 + 1.8 Moderate Sodium acetate, 10% 3.3 + 0.2 3.9 + 0.4 3.9 + 0.2 11.0 + 0.8 Moderate Sodium citrate, 10% 4.2 + 0.5 4.2 + 0.3 4.1 + 1.1 12.5 ± 1.4 Moderate NC: negative control; PC: positive control; BAC: benzalkonium chloride 1Mean ± SD, n=3 2 No: total MP < 5.5%; Mild: 5.5% total MP < 10%; Moderate: 10% total MP < 17.5%; Severe: total MP 17.5% Table 4 Amount of mucus produced (MP) during each 30-min contact period (CP) and total amount of mucus produced (Code 00E04) Treatment CP1 30-min CP2 30-min Total MP PBS -1.0 ± 0.6 -1.1 ± 0.8 -2.2 ± 0.6 BAC (1%) 13.2 ± 4.2 18.6 ± 9.8 31.8 ± 12.6 Sodium oxalate (1%) 4.5 ± 1.3 6.6 ± 1.0 11.1 ± 2.0 Table 5 Amount of mucus produced (MP) during each 60-min contact period (CP) and total amount of mucus produced Treatment Day 1 Day 2 Total MP CP1 60-min CP2 60-min PBS -0.2 ± 0.7 -0.7 ± 0.5 -0.9 ± 0.5 BAC (1% CP1 & 3.5% CP2) 21.9 ± 4.8 9.7 ± 3.2 31.6 ± 2.5 Sodium oxalate (1% CP1 & 3.5% CP2) 11.2 ± 3.9 16.0 ± 4.0 27.1 ± 2.3 Table 6 Amount of mucus produced (MP) during a 60-min contact period (CP) Treatment CP1 60-min PBS -0.2 ± 1.0 BAC (1%) 15.0 ± 1.9 Sodium benzoate (1%) 2.6 ± 0.3 Sodium benzoate (10%) 6.9 ± 11 Results The total MP for a 60-min treatment (historical data) was compared with the total MP of the SIB protocol (3x 15-min treatment; current data). In the table below a ranking is proposed from least SIB reactions to highest SIB reactions: Compound Concentration Treatment time Total MP (% body weight) Sodium benzoate 1% 60-min 2.6 Sodium benzoate 10% 60-min 6.9 Sodium acetate 10% 45-min (3x 15-min) 11.0 Sodium citrate 10% 45-min (3x 15-min) 12.5 Disodium fumarate 10% 45-min (3x 15-min) 13.3 Sodium phosphate 10% 45-min (3x 15-min) 15.2 Sodium oxalate 1% 60-min 11.2 Sodium oxalate appears to be the most irritating salt since a 1% concentration results in 11.2% total MP after 1 hour of contact. Sodium benzoate is the least irritating salt.

Example 8: Further slug mucosa! irritation (SMI)testing 5Me0DMT as a freebase compound is known to be highly irritating to the mucosal lining; therefore, it is commonly prepared as a salt for insufflation. The hydrochloride (HCI) salt of 5Me0DMT is most commonly used due to ease of crystallisation. However, it is known that the HCI salt of 5Me0DMT is still quite irritating to the mucosa! lining.

Following the results above indicating that sodium benzoate is the least irritating salt of those studied; further SMI testing was performed on 5Me0DMT benzoate and the common SMe0DMT HCI salt according to the previously described methods (of Example 7). The results of this are shown below:

S

Compound Concentration (w/y) Total MP (lo body weight) 5Me0DMT benzoate 10% 7.38 5Me0DMT HC1 10% 10.27 Benzylkonium (positive control) 10% 17.56 PBS (negative control) 10% -0.77 The 5Me0DMT benzoate produced 'mild' irritation compared to the 5Me0DMT HCI which scored as 'moderate' on testing.

Example 9: Permeation data The use of ovine nasal epithelium to study nasal drug absorption is a technique which is well known to the person skilled in the art.

The permeation of 5Me0DMT benzoate and 5Me0DMT HCI has been studied by the current applicants. Dosing solutions corresponding to 1.25% concentration were prepared in water and applied to ovine nasal epithelium. The average cumulative (g/cm2) of permeation of the benzoate and hydrochloride salt are shown in the table below (mean ± SD, n=5): T4ne (min) 9.9 10.0 20.0 30.0 40.0 505 605 75.0 50.0 Cuenti1a(Ne 5-Mea-DNIT Benzoate 0,00 0.20 3.46 930 ¶546 21 51 27.30 33.34 39.77 amount) (0.35) (3.07) (6.46) (10.00) (11.42) (13.73) 14.81) (1.1)07.m2 (cD)) 1- * 5-Kle0-DIAT Hydrochtride 0Th] 0.33 330 826 13.33 18.77 23.43 29.52 3535 (f) 00) (0 52) (3.51) (810) 8) (1 CI 75) 111.38) (1277) (1329) The cumulative amount of 5Me0DMT benzoate and 5Me0DMT hydrochloride which permeated through ovine nasal epithelium per unit area following application of 1.25% dosing solutions prepared in water (mean ± SD, n=5) can be seen in Figure 5.

As can clearly be seen, the benzoate salt has higher permeation across the epithelium.

The above data obtained in the above test show that the 5Me0DMT benzoate salt gives higher permeation with less mucosal irritation than the commonly used HCI salt; and so this combination of properties makes the benzoate salt an ideal candidate for mucosa! delivery. For example, less 5Me0DMT benzoate salt may be needed by inhalation to provide the same benefit as the HCI salt and the benzoate salt is less irritating, and so provides a synergistic benefit. Smaller amounts of compound also make inhalation easier to accomplish.

Claims

Claims 1. A composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5-methoxy-N,N-dimethyltryptamine (5Me0DMT).
2. The composition of claim 1, wherein the composition comprises a dosage amount of 5Me0DMT in the range of 0.05mg to 100mg.
3. The composition of any one of the preceding claims, wherein the composition comprises a dosage amount of 5Me0DMT in the range of 0.1mg to 50mg.
4. The composition of any one of the preceding claims, wherein the composition comprises a dosage amount of 5Me0DMT in the range of 0.5mg to 25mg.
5. The composition of any one of the preceding claims, wherein the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, or rectal dosage form.
6. The composition of any one of the preceding claims, wherein the composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, or suppository dosage form.
7. The composition of claim 6, wherein the powder is suitable for administration by inhalation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler.
8. The composition of claim 6 or 7, wherein the powder comprises particles, the particles having a median diameter of less than 2000um, 1000um, 5001.Lm, 250pm, 10011m, 50um, or him.
9. The composition of any one of claims 6 to 8, wherein the powder comprises particles, the particles having a median diameter of greater than 500pm, 250pm, 100pm, 50p.m, lpm or 0.5p.m.
10. The composition of any one of claims 6 to 9, wherein the powder comprises particles, and wherein the powder has a particle size distribution of d10=20-60urn, and/or d50=80-120p.m, and/or d90=130-300um.
11. The composition of any one of the preceding claims, wherein the 5Me0DMT benzoate salt is amorphous or crystalline.
12. The composition of any one of the preceding claims, wherein the 5Me0DMT benzoate salt is in a polymorphic crystalline form.
13. The composition of any one of the preceding claims, wherein the 5Me0DMT benzoate composition is formulated for mucosal delivery.
14. The composition of any one of the preceding claims, wherein the composition comprises one or more pharmaceutically acceptable carriers or excipients.
15. The composition of any one of the preceding claims, wherein the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.
16. The composition of any one of the preceding claims for use in a method of treatment of a human or animal subject by therapy.
17. The composition of claim 16, wherein the method of treatment is a method of treatment of: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), conditions benefiting from anti-inflammatory treatment, depression, anxiety, substance use disorder, addictive disorder, gambling disorder eating disorders, obsessive-compulsive disorders, or body dysmorphic disorders.
18. The composition of claim 16 or 17, wherein the composition is administered one or more times a year.
19. The composition of any one of claims 16 to 18, wherein the composition is administered one or more times a month.
20. The composition of any one of claims 16 to 19, wherein the composition is administered one or more times a week.
21. The composition of any one of claims 16 to 20, wherein the composition is administered one or more times a day.
22. The composition of any one of claims 16 to 21, wherein the composition is administered together with a complementary treatment and/or with a further active agent.
23. The composition of any one of claims 16 to 22, wherein the further active agent is a psychedelic compound, optionally a tryptamine, further optionally the further active agent is lysergic acid diethylamide (LSD), psilocybin, psilocin or a prodrug thereof.
24. The composition of any one of claims 16 to 23, wherein the complementary treatment is psychotherapy.
25. A nasal inhalation composition comprising a pharmaceutically effective amount of a pharmaceutically acceptable benzoate salt of 5-methoxy-N,N-dimethyltryptamine (5Me0DMT) for use in a method of treatment of treatment resistant depression.