BR122025016853A2 - Aerosol comprising 5-methoxy-N,N-dimethyltryptamine, its method of formation, and kit. - Google Patents

Abstract

The present invention relates to aerosols of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof that are useful for administration to a patient via an inhalation route. The aerosols have aerosol particle mass densities in the range of about 0.5 mg/l to about 12.5 mg/l.

Description

Field of Technique

[001] The present invention relates to drug aerosols. More particularly, the invention relates to aerosols of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof that are useful for administration to a patient via an inhalation route, whereby 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered to the patient systemically via the lungs.

Background of the Invention

[002] 5-MeO-DMT is a naturally occurring serotonergic tryptamine that acts as a 5-HT1A and 5-HT2A receptor agonist. 5-MeO-DMT and compositions comprising 5-MeO-DMT in addition to other active components have a long history of recreational use, where its ability to induce intensely altered states of consciousness (including euphoria, trance, transcendence of time and space, spiritual experiences, dissolution of self-limits, or even near-death experiences; so-called "psychedelic" effects) has been applied in a spiritual or self-explored context.

[003] The most commonly described route of administration for 5-MeO-DMT in a recreational context is inhalation into the lungs of "vapors" comprising 5-MeO-DMT ultimately leading to absorption of 5-MeO-DMT into the bloodstream and systemic distribution. The "vapors" comprising 5-MeO-DMT are most commonly generated by exposing materials containing 5-MeO-DMT to high temperatures for an extended period of time, for example, in glass tubes using a lighter.

[004] Based on its pharmacological activities, there has recently been interest in the potential medical uses of 5-MeO-DMT, for example, investigating potential medical uses in human clinical trials. For such uses in human clinical trials, and for potential use in a medical product approved for the treatment of patients, administration of high-purity 5-MeO-DMT is required.

[005] The "vaporization" described above would be unsuitable for any medical application. It does not allow for the administration of defined quantities of 5-MeO-DMT. In many cases, even the exact 5-MeO-DMT content of the material subjected to "vaporization" and its purity are unknown.

[006] The proportion of 5-MeO-DMT that is "vaporized" is likewise unknown, and the properties of the "vapors" are poorly defined.

[007] Furthermore, as indicated above, the conditions currently applied in the recreational context involve exposing 5-MeO-DMT to indefinite high temperatures for an extended period of time. This induces the formation of thermal 5-MeO-DMT degradation products, which are also inhaled. Such degradation products have unknown pharmacological effects and are potentially harmful. They can also cause an unpleasant taste. Another disadvantage of the conditions currently applied in the recreational context to generate 5-MeO-DMT "vapors" is that inhalation of those "vapors" can often lead to coughing, which prevents the ingestion of the target dosage of total 5-MeO-DMT in a single inhalation and limits the duration of lung tissue exposure to 5-MeO-DMT and therefore its absorption.

[008] Each of those issues independently and in combination contributes to the inefficient and unpredictable systemic response of 5-MeO-DMT, which is unacceptable in the context of the potential use of 5-MeO-DMT as a medication, as it may lead to suboptimal clinical efficacy and increased risk for side effects. For potential medical uses, for example, for use in human clinical trials or for use in an approved medical product for the treatment of patients, it is important to deliver the near-complete or complete target dosage of 5-MeO-DMT to the patient in a single inhalation (i.e., within one deep breath), because the onset of psychedelic effects is so rapid that the patient will often not be able to accurately perform a second inhalation (i.e., take a second deep breath). 5-MeO-DMT must be provided under reproducible, standardized, and well-controlled conditions. This has not been addressed in the prior art.

[009] While thermally generated condensation aerosols of some drugs and devices for delivering such aerosols have been described, for example, in US 7,090,830 B2, EP1389098B1, and US 8,955,512 B2, the aforementioned patents do not teach and suggest aerosols containing 5-MeO-DMT. For the compounds tested, highly variable results are reported for the amount of degradation products (e.g., degradation product amounts greater than 80% to less than 1%), for the yield (e.g., yield less than 25% to greater than 90%), and for the physical properties (such as the mass-average aerodynamic diameter) of the generated aerosols.

[0010] In this context, there remains a need for a reproducible method for administering 5-MeO-DMT or a pharmaceutically acceptable salt thereof, in particular via an inhalation route. There is a particular need for a 5-MeO-DMT aerosol or a pharmaceutically acceptable salt thereof having an adequate aerosol particle density so that the therapeutically effective dose of the aerosol can be administered via a single inhalation.

Summary of the Invention

[0011] The present invention relates to an aerosol comprising (a) a pharmaceutically acceptable gas; (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has a particle mass density of about 0.5 mg/l to about 12.5 mg/l, preferably about 1.3 mg/l to about 10 mg/l, in particular about 2 mg/l to about 9 mg/l. The pharmaceutically acceptable gas is preferably air.

[0012] The aerosol particles preferably contain less than 1% by weight of impurities, in particular less than 0.5% by weight of impurities. They, moreover, preferably contain less than 0.5% by weight of 5-MeO-DMT degradation products, in particular less than 0.2% by weight of 5-MeO-DMT degradation products resulting from a chemical modification of 5-MeO-DMT as a result of a chemical reaction during aerosol formation.

[0013] In another preferred aspect of the invention, the aerosol essentially consists of (a) air; (b) aerosol particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0014] The aerosol particles preferably contain 5-MeO-DMT in the form of the free base.

[0015] The aerosol is preferably characterized by a mass-means aerodynamic diameter of less than 3 microns and greater than 0.1 micron, in particular by a mass-means aerodynamic diameter of less than 2 microns and greater than 0.1 micron.

[0016] The aerosol can be formed by a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, configured on a solid support, to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT to produce aerosol particles. The thin layer can have a thickness of less than about 10 μm, in particular less than about 7.5 μm. It can have a thickness in the range of about 0.1 μm to about 10 μm, in particular in the range of about 0.3 μm to about 7.5 μm.

[0017] The thin layer of 5-MeO-DMT, configured on a solid support, can be exposed to thermal energy via the passage of air over the thin layer. Alternatively, the thin layer of 5-MeO-DMT, configured on a solid support, can be exposed to thermal energy via the solid support.

[0018] The air passing over the thin layer can have a temperature in the range of about 180°C to about 260°C. The air passing over the thin layer can in particular have a temperature of about 210°C and passes over the thin layer at a rate of about 12 l/min for a duration of about 15 seconds.

[0019] The aerosol particles may be contained in a volume of about 3 liters or less, such as a volume of about 1.5 to about 2 liters, in particular in a volume of about 2 to about 3 liters. The aerosol is particularly for use in therapy. It is preferably administered to a patient via a single inhalation.

Descriptions of the Figures

[0020] Figure 1 is a diagram obtained by a graphical representation of the peak area, determined by HPLC, versus the concentration of 5-MeO-DMT in a sample.

[0021] Figure 2 shows a Next Generation Impactor (NGI) USP <601> Apparatus 6.

[0022] Figure 3 shows a typical dose sampling apparatus USP <601> Apparatus A.

Detailed Description of the Invention

[0023] The present invention aims to provide 5-MeO-DMT or a pharmaceutically acceptable salt thereof in a form suitable for inhalation in a medical context. The invention in particular provides 5-MeO-DMT and its pharmaceutically acceptable salts in the form of aerosols. These aerosols have an appropriate aerosol particle mass density so that a therapeutically effective dose of the aerosol can be administered to a patient via a single inhalation.

[0024] Aerosols useful in the present invention can be formed using thermal energy. When using thermal energy to form an aerosol of a compound, it is very difficult to predict what conditions are suitable for safety, efficacy, and predictable aerosolization, particularly if the aerosol is to be used for systemic delivery of that compound to a patient via the lungs. Relevant variables in this context include a) the dose of the compound, b) the morphological state in which that compound is made available for aerosolization (e.g., in crystal form, or as a thin layer), c) the amount of thermal energy to which the compound is exposed (defined by temperature and duration of exposure), and d) the volume of air introduced to create the aerosol (defined by flow rate and duration of airflow).

[0025] In a general sense, the present invention aims to provide compositions and methods for the safe, effective and predictable delivery of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to a patient via inhalation. In the context of the technical problem, "safety" means that the aerosol particles would contain only a small amount of impurities and degradation products of 5-MeO-DMT, "effective" means that the dosage is aerosolized to a defined extent and preferably almost completely or completely, that the aerosol has desirable physical properties for the delivery of 5-MeO-DMT or a pharmaceutically acceptable salt thereof via the lungs primarily via absorption in the pulmonary alveoli, and that the aerosol can be inhaled by the patient in a single inhalation (i.e., within a deep breath), and "predictable" means that there should be almost no or no variability in the amount of degradation products, the extent of aerosolization, and the physical properties of the aerosol.

[0026] In a more specific sense, the present invention aims to provide specific parameters for a) a dosage quantity of 5-MeO-DMT, b) the morphological state in which 5-MeO-DMT is made available for aerosolization, c) the amount of thermal energy to which 5-MeO-DMT is exposed, and d) the volume of air introduced to create the 5-MeO-DMT aerosol.

[0027] The inventor recognized that a safe, effective, and predictable systemic delivery of 5-MeO-DMT to a patient can be achieved by delivering 5-MeO-DMT in the form of an aerosol. The aerosol of the invention contains a defined mass of 5-MeO-DMT per unit volume, with a defined mass-average aerodynamic diameter, and a defined maximum amount of impurities, such as 5-MeO-DMT degradation products. The aerosol is administered by inhalation into the lungs, preferably in a single inhalation.

[0028] A suitable aerosol can be achieved by a) delivering therapeutically effective amounts of 5-MeO-DMT as a thin layer on a solid support, b) exposing the thin 5-MeO-DMT layer to controlled elevated temperatures for a short duration of time, and c) delivering a controlled amount of air so that an aerosol is formed.

[0029] The present invention provides compositions and methods for delivering aerosols comprising 5-MeO-DMT that are useful in inhalation therapy for patients, wherein the therapeutically effective dosage amount of 5-MeO-DMT contained in a composition is fully or nearly fully aerosolized, the aerosol particles contain only a very small amount of impurities and degradation products of 5-MeO-DMT, the aerosol has desirable physical properties for delivering 5-MeO-DMT systemically via the lungs primarily via absorption in the respiratory pulmonary alveoli, and the aerosol can be inhaled by the patient in a single inhalation, with limited variability in the extent of aerosolization, the amount of degradation products, and the physical properties of the aerosol, all of which has not been achieved in the prior art.

Definitions

[0030] As used in the context of the present invention, unless otherwise noted, the term "5-MeO-DMT" refers to the free base 5-MeO-DMT. It is contemplated that pharmaceutically acceptable salts of 5-MeO-DMT may also be used. An example of such a salt is the hydrochloride. The appropriate weight amount of a salt to be administered can be calculated from the weight amount of the free base, assuming that equimolar amounts are used.

[0031] As used herein, "aerosol" means a stable system consisting of a gaseous medium (a pharmaceutically acceptable gas, such as air) and minute liquid and/or solid particles suspended in the air, also referred to here as droplets.

[0032] As used in the context of the present invention, unless otherwise noted, the term "degradation product" refers to a compound resulting from a chemical modification of 5-MeO-DMT as a result of a chemical reaction during aerosol formation. Such a reaction includes, without limitation, oxidation.

[0033] When a percentage of a "degradation product" is described in the context of the present invention, then this refers to the amount of 5-MeO-DMT degradation products present in a sample divided by the amount of 5-MeO-DMT plus 5-MeO-DMT degradation products present in the sample multiplied by 100%, that is, (Sum of amounts of all 5-MeO-DMT degradation products present in the sample)/((Amount of 5-MeO-DMT present in the sample) + (Sum of amounts of all 5-MeO-DMT degradation products present in the sample)) x 100%.

[0034] As used herein, the term "impurity" refers to undesirable compounds containing a sample of 5-MeO-DMT (or a pharmaceutically acceptable salt thereof). Impurities may be contained in the starting material prior to aerosol formation or may be degradation products.

[0035] As used in the context of the present invention, unless otherwise noted, the term "purity" refers to 100% less the percentage of all 5-MeO-DMT degradation products and all other impurities present, that is, (100% - (Sum of quantities of all 5-MeO-DMT degradation products present + Sum of quantities of all other impurities present)/(Quantity of 5-MeO-DMT present + Sum of quantities of all 5-MeO-DMT degradation products present + Sum of quantities of all other impurities present) x 100%.

[0036] As used in the context of the present invention, a "patient" to be treated is a human individual who has been diagnosed in accordance with accepted medical practice by a licensed professional (e.g., a physician) as suffering from a disease, disorder or condition, and who may seek or need treatment, requires treatment, is receiving treatment, or will receive treatment.

[0037] As used in the context of the present invention, unless otherwise noted, the terms "treating" and "treatment" and "therapy" will include the management and care of a patient for the purpose of combating a disease, condition or disorder and includes the administration of compounds and methods according to the present invention to alleviate the signs and/or symptoms or eliminate the disease, condition or disorder.

[0038] As used in the context of the present invention, unless otherwise noted, the term "therapeutically effective amount" will mean the amount of the active compound or pharmaceutical ingredient that elicits a clinical response in a patient, which includes relief of the signs and/or symptoms of the disease, condition or disorder to be treated.

[0039] As used in the context of the present invention, unless otherwise noted, the term "administration" will mean the introduction of a quantity, which may be a predetermined quantity, of the active compound or pharmaceutical ingredient into a patient via inhalation into the lungs.

[0040] As used in the context of the present invention, unless otherwise noted, the terms "dose" and "dosage" and "dosage amount" will mean the amount of active compound or pharmaceutical ingredient that is administered to a patient in an individual administration.

[0041] As used in the context of the present invention, unless otherwise noted, the term "mass-mean-aerodynamic diameter" (MMAD) is the diameter at which 50% of the particles present in an aerosol are larger than that calculated diameter, and 50% are smaller.

[0042] As used in the context of the present invention, unless otherwise noted, the term "aerosol particle mass density" refers to the mass of aerosol particles per unit volume of aerosol.

[0043] As used in the context of the present invention, unless otherwise noted, the term "aerosol particle formation rate" refers to the aerosolized mass of 5-MeO-DMT per unit time of aerosolization.

[0044] Note that, in this descriptive report, when ranges are indicated, such as "from about 1 mg to about 25 mg", the inventor contemplates all discrete values within that range, some of which are specifically mentioned, but not all of which is simply for the purpose of brevity.

[0045] In one aspect of the composition of the present invention, a composition for delivering a therapeutically effective amount of 5-MeO-DMT comprises an aerosol, wherein the aerosol is formed by a) exposing a thin layer of 5-MeO-DMT, configured on a solid support, to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT; wherein said aerosol has one or more of the following characteristics: 1) contains aerosol particles that are characterized by a mass-mean aerodynamic diameter of less than 3 microns, 2) contains aerosol particles that are characterized by less than 1% by weight of impurities and less than 0.5% of 5-MeO-DMT degradation products, 3) can be administered to a patient via a single inhalation.

[0046] In one aspect of the method of the present invention, a therapeutically effective quantity of 5-MeO-DMT is delivered to a patient via an inhalation route. The method comprises: a) exposing a thin layer of 5-MeO-DMT, configured on a solid support, to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT; wherein said aerosol has one or more of the following characteristics: 1) contains aerosol particles that are characterized by a mass-mean aerodynamic diameter of less than 3 microns, 2) contains aerosol particles that are characterized by less than 1% by weight of impurities and less than 0.5% by weight of 5-MeO-DMT degradation products, 3) can be administered to a patient via a single inhalation.

[0047] In terms of the composition, method and kit of the present invention, the generation of aerosol particles characterized by a mass-average aerodynamic diameter of less than 3 microns, with less than 1% by weight of impurities and less than 0.5% by weight of 5-MeO-DMT drug degradation products, in an aerosol volume that can be administered to a patient via a single inhalation, is achieved by definition a) a dosage amount of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT, b) the thickness of the thin layer of 5-MeO-DMT, c) the thermal energy to which the thin layer of 5-MeO-DMT is exposed (defined by temperature and duration of exposure), and d) the total amount of air passing over the thin layer of 5-MeO-DMT (defined by airflow rate and duration of airflow).

[0048] Preferably, in terms of the composition, method and kit of the present invention, the thin layer of 5-MeO-DMT is exposed to thermal energy via the passage of air over the thin layer, in which case the air is heated. The heated air passing over the thin layer may have a temperature in the range of about 180°C to about 260°C. The air passing over the thin layer may in particular have a temperature of about 210°C.

[0049] Alternatively, in the composition, method and kit aspects of the present invention, the thin layer of 5-MeO-DMT is exposed to thermal energy via the solid support, in which case the air passing over the thin layer is not heated, but the solid support is heated. The heated solid support may have a temperature in the range of about 180 °C to about 420 °C.

[0050] Preferably, in terms of the composition, method and kit of the present invention, the 5-MeO-DMT used for forming the thin layer on the solid support is highly pure, with a purity of at least 99%, preferably at least 99.5%.

[0051] Preferably, in terms of the composition, method and kit of the present invention, a dosage amount of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT, configured on the solid support, is from about 1 mg to about 25 mg, preferably from about 2 mg to about 20 mg, more preferably from about 4 mg to about 20 mg. Useful specific amounts are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Preferred specific amounts are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0052] Solid supports, in which 5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided, may have a variety of shapes. Examples of such shapes include, without limitation, cylinders less than 1.0 mm in diameter, boxes less than 1.0 mm thick, and virtually any shape permeated by small pores (e.g., less than 1.0 mm in size). Preferably, solid supports provide a large surface area to volume ratio (e.g., greater than 100 per meter) and a surface area to mass ratio (e.g., greater than 1 cm2 per gram).

[0053] A solid support of one shape can also be transformed into another shape with different properties. For example, a flat sheet 0.25 mm thick has a surface area to volume ratio of about 8,000 per meter. Rolling the sheet into a hollow cylinder 1 cm in diameter produces a support that retains the high surface area to mass ratio of the original sheet, but has a lower surface area to volume ratio (about 400 per meter).

[0054] A range of different materials is used to construct the solid supports. Classes of such materials include, without limitation, metals, inorganic materials, carbonaceous materials, and polymers. The following are examples of classes of materials: aluminum, silver, gold, stainless steel, copper, and tungsten; silica, glass, silicon, and alumina; graphite, porous carbons, carbon wires, and carbon felts; polytetrafluoroethylene and polyethylene glycol. Combinations of materials and coated variants of materials are also used.

[0055] Where aluminum is used as a solid support, aluminum foil is a suitable material. Examples of silica, alumina, and silicon-based materials include amorphous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (an alumina with a defined surface area greater than 2 m²/g from Aldrich, St. Louis, Mo.), and a silicon wafer as used in the semiconductor industry. Carbon felts and wires are available from American Kynol, Inc., New York, N.Y.

[0056] Preferably, the thickness of the thin layer of 5-MeO-DMT, configured on the solid support, is less than about 10 μm, in particular less than about 7.5 μm. It can have a thickness in the range of about 0.1 μm to about 10 μm, in particular in the range of 0.3 μm to 7.5 μm.

[0057] Preferably, in the aspects of composition, method and kit of the present invention, the total amount of air passing over the thin layer of 5-MeO-DMT is defined by a flow rate of between about 6 liters per minute and about 80 liters per minute, such as between about 6 liters per minute and about 40 liters per minute, preferably between about 8 liters per minute and about 16 liters per minute, and the duration of airflow is chosen so that the total aerosol volume does not exceed about 3 liters, preferably between about 2 liters and 3 liters. For example, at an airflow rate of about 6 liters per minute, the duration of airflow would be less than about 30 seconds. A useful specific duration and airflow rate is about 12 liters per minute and about 15 seconds, leading to an aerosol volume of about 3 liters. Another useful duration and specific airflow rate is 10 liters per minute and approximately 15 seconds, leading to an aerosol volume of approximately 2.5 liters. Another useful duration and specific airflow rate is 8 liters per minute and approximately 15 seconds, leading to an aerosol volume of approximately 2 liters. Another useful duration and specific airflow rate is 10 liters per minute and approximately 12 seconds, leading to an aerosol volume of approximately 2 liters.

[0058] The aerosol formation rate is greater than 0.1 mg/sec.

[0059] In terms of the composition, method and kit of the present invention, the aerosol has a particle mass density of about 0.5 mg/l to about 12.5 mg/l, preferably about 1.3 mg/l to about 10 mg/l, in particular about 2 mg/l to about 9 mg/l.

[0060] In terms of the composition, method and kit of the present invention, the 5-MeO-DMT aerosol particles are characterized by a mass-average aerodynamic diameter of less than 3 microns and greater than 0.1 microns, preferably less than 2.5 microns and greater than 0.1 microns, more preferably less than 2 microns and greater than 0.1 microns.

[0061] In terms of the composition, method and kit of the present invention, the 5-MeO-DMT aerosol particles are characterized by less than 1% by weight of impurities, preferably less than 0.5% by weight of impurities. In terms of the composition, method and kit of the present invention, the 5-MeO-DMT aerosol particles are characterized by less than 0.5% by weight of 5-MeO-DMT degradation products, preferably less than 0.2% by weight of 5-MeO-DMT degradation products.

[0062] In a specific aspect of the composition of the present invention, a composition for delivering a therapeutically effective amount of 5-MeO-DMT comprises an aerosol, wherein the aerosol is formed by a) exposing a dosage amount of 12 mg of 5-MeO-DMT, configured as a thin layer less than 5 microns thick on a solid support, to a temperature of 210°C via passage of heated air over the thin layer for a duration of 15 seconds; wherein said aerosol has one or more of the following characteristics: 1) contains aerosol particles that are characterized by a mass-average aerodynamic diameter of less than 3 microns, 2) contains aerosol particles that are characterized by less than 1% impurities and less than 0.5% by weight of 5-MeO-DMT degradation products, 3) can be administered to a patient via a single inhalation.

[0063] A person skilled in the art, being familiar with the aerosol characteristics and aerosolization conditions defined in the present invention, can identify suitable vaporization systems or devices that lead to the required aerosol characteristics. Examples of such suitable vaporization systems or devices include, for example, the Volcano medical vaporization system with dosed capsules associated with a drip pad (Storz &Bickel; as described, for example, in EP 0 933 093 B1, and Germany EP 1 884 254 B1 and Registered Community Design 003387299-0001) and the Staccato device (Alexza Pharmaceuticals, Mountain View, USA; as described, for example, in US 7,458,374 B2, US 9,370,629 B2 and US 9,687,487 B2).

[0064] The generated aerosol can be collected in a balloon and inhaled by the patient from the balloon.

Examples Example 1. Administration and aerosol generation of 5-MeO-DMT Volcano medical vaporization system

[0065] A 5-MeO-DMT aerosol was generated by volatilizing the drug using the Volcano medical vaporization system (Storz & Bickel, Germany). The device consists of a hot air generator and a detachable valve balloon from which the aerosol is inhaled by the patient. The hot air generator can generate adjustable temperatures between approximately 40°C and approximately 210°C, with an airflow rate of approximately 12 liters per minute. The central part of the device is the dosing capsule to which relevant doses of 5-MeO-DMT in an ethanol solution are applied and which is then placed in the filling chamber of the device where it is heated via hot air. The dosing capsules contain a small disc made of tightly packed stainless steel wire mesh (called the drip pad or liquid pad). The bottom and lid of the dosing capsules have holes, allowing flow through the dosing capsules. Dosing capsules and drip pads have the following characteristics, based on measurements of 10 sample capsules: Example 1, Table 1. Characteristics of dosing capsules and drip pads.

[0067] All measurements showed the mean and standard deviation for measurements of 10 capsules, except for the diameter of holes in the cap and base, which is based on 40 measurements across two capsules, and for the diameter of the stainless steel wire in the drip pad, which is based on 40 measurements at different locations on the stainless steel wire.

Generation and administration of 5-MeO-DMT in aerosol form.

[0068] Step 1: A freebase solution of 5-MeO-DMT in 100% ethanol is prepared in a volumetric flask so that the target dosage of freebase 5-MeO-DMT to be administered via inhalation to the patient is contained in a solution volume of 200 μl. Typical target dosages are from 1 mg to 25 mg 5-MeO-DMT. For example, for a target dosage of 18 mg 5-MeO-DMT, 90 mg of 5-MeO-DMT will be dissolved in 100% ethanol to a final solution volume of 1 ml. Aliquots of the stock solution can then be stored in vials until further use.

[0069] Step 2: 200 μl of the solution are transferred to a dosing capsule containing the dropper pad (Storz & Bickel, Germany), and then the dosing capsule is closed with its cap.

[0070] Step 3: The dosed capsule filled with the 5-MeO-DMT ethanol solution is transferred to the filling chamber of a Volcano medical vaporizer, which has been preheated to a temperature of 55°C. Then, the vaporizer's airflow is switched on for 60 seconds at a pre-set rate of approximately 12 l/min. The heated air will flow through the dosed capsule, allowing the ethanol to evaporate, with the target dosage of 5-MeO-DMT being left in the capsule as a thin layer covering the stainless steel wire mesh. Accurate preparation of the dosed capsule can be confirmed by demonstrating that the increase in the final weight of the capsule compared to the weight of the empty capsule corresponds to the target dosage of 5-MeO-DMT.

[0071] Step 4: The dosed capsule is removed from the filling chamber. It is then transferred to the filling chamber of a second Volcano medical vaporizer, which has been preheated to 210°C and the airflow has been set for at least 5 minutes and then switched off immediately before the transfer. An inhalation balloon with a valve (Storz & Bickel, Germany) is fitted to the mouthpiece of the filling chamber, the filling chamber is firmly closed, and immediately afterwards the airflow is switched on for exactly 15 seconds at the pre-set flow rate of approximately 12 l/min, and then switched off. This will allow the full dose of 5-MeO-DMT to aerosolize and be distributed in approximately 3 liters of air in the inhalation balloon. Accurate aerosolization of the 5-MeO-DMT can be confirmed by demonstrating that the weight of the capsule has returned to approximately its initial weight.

[0072] Step 5: The balloon is detached from the pre-filling chamber, which automatically closes the valve. After the nozzle is attached to the balloon, the aerosol is ready for immediate administration to the patient, or for immediate analytical procedures.

[0073] Step 6: To prepare for administration, the patient is initially asked to perform 1-2 deep inhalations with full exhalations, ending this sequence with a deep exhalation. Then, with the mouthpiece firmly held against the lips, the entire volume of the inhalation balloon is inhaled in one breath, holding the breath for 10 (±2.5) seconds, followed by a normal exhalation. After completing the inhalation procedure, the patient will be instructed to lie down.

Example 2. Loading of capsules dosed with 5-MeO-DMT, and determination of aerosolized dose.

[0074] Triplicates of capsules dosed with a target dosage of 5-MeO-DMT of 2 mg and 18 mg were prepared as described in Example 1, Steps 1 to 3, using a stock solution of 5-MeO-DMT stored as 200 μl aliquots in single-use vials. To confirm accurate loading of the capsules dosed with the target dosage of 5-MeO-DMT, the baseline weight of the empty capsules was subtracted from the weight of the capsules after Step 3, confirming that approximately 94% of the target dose of 5-MeO-DMT was loaded into the capsules, with only minimal variability (Example 2, Table 1). The fact that not 100% of the target dose was achieved can be explained by the loss of material in the vials used for storing the 5-MeO-DMT stock solution (which had approximately 2 μl of residual volume) and by additional loss at the ends of the pipette used to transfer the solution from the vials to the capsules. Such loss, however, can be avoided by pipetting a larger volume of the stock solution and by optimizing the pipetting technique.

[0075] 5-MeO-DMT was then aerosolized from the dosed capsules as described in Example 1, Steps 4 and 5. To confirm accurate aerosolization of 5-MeO-DMT from the dosed capsules, the weight after Step 4 was subtracted from the weight after Step 3, confirming that between 96% and 100% of the loaded dose was aerosolized (Example 2, Table 1). Example 2, Table 1. Loading of dosed capsules with 5-MeO-DMT and subsequent aerosolization.

[0076] Weights are shown in mg for triplicates of capsules dosed with a target dosage of 5-MeO-DMT of 2 mg and 18 mg. 1 loaded dose = Empty weight - Weight after Step 3. 2 aerosolized dose = Weight after Step 3 - Weight after Step 4.

[0077] Instead of determining the loading of 5-MeO-DMT target dose capsules by weighing the 5-MeO-DMT-dosed capsules before and after the formation of the 5-MeO-DMT layer, alternatively the loading can also be determined by extracting the drug from the dosed capsule and measuring the analytical amount.

[0078] Instead of determining the extent of aerosolization of the target dose of 5-MeO-DMT from the capsules by weighing the capsules before and after the formation of the 5-MeO-DMT layer and again after aerosolization, alternatively the emitted dose of 5-MeO-DMT can be determined by supplying the aerosol containing 5-MeO-DMT into a confined chamber and measuring the amount of 5-MeO-DMT collected in the chamber analytically.

Example 3. 5-MeO-DMT layer thickness

[0079] The thickness of the 5-MeO-DMT layer covering the stainless steel wire mesh after evaporation of the ethanol solvent can be calculated as follows: 5-MeO-DMT layer thickness (μm) = 5-MeO-DMT loaded dose (mg)/[5-MeO-DMT density (mg/cm3) x wire surface area (cm2)]*10000. The wire surface area can be calculated based on the wire (which can be measured, or calculated from the wire mesh) and wire diameter (which can be measured).

[0080] For the capsules dosed as prepared in Example 2, the following layer thickness was determined: Example 3. Table 1. Layer thickness of 5-MeO-DMT for capsules dosed as prepared in Example 2. 1. Loaded dose from Example 2; For the calculations, a 5-MeO-DMT density of 1100 mg/cm3 was assumed.

[0081] For a target loaded dose of 2 mg, the thickness of the 5-MeO-DMT layer based on an average wire surface area of 37.78 cm2 can be calculated as 0.48 μm; and for a target loaded dose of 20 mg, the thickness of the 5-MeO-DMT layer can be calculated as 4.8 μm.

Example 4. Determination of aerosol particle formation rate and aerosol density of 5-MeO-DMT

[0082] The aerosol particle formation rate can be calculated as follows: aerosol particle formation rate = aerosolized dose/aerosolization time. For the aerosolized dose data and the aerosolization time of 15 seconds from Example 2, the following aerosol particle formation rate was determined: Example 4, Table 1. aerosol particle formation rate for capsules dosed as prepared in Example 2. 1. Aerosolized dose of Example 2

[0083] For a target aerosolized dose of 2 mg and an aerosolization time of 15 seconds, the aerosol particle formation rate can be calculated as 0.13 mg/s; and for a target aerosolized dose of 20 mg and an aerosolization time of 15 seconds, the particle formation rate can be calculated as 1.33 mg/s.

[0084] The density of 5-MeO-DMT in aerosol can be calculated as follows: Mass density of 5-MeO-DMT in aerosol = aerosolized dose/Aerosol volume. For the aerosolized dose data and the aerosol volume of approximately 3 liters from Example 2, the following density of 5-MeO-DMT in aerosol was determined: Example 4, Table 2. Mass density of 5-MeO-DMT in aerosol for capsules dosed as prepared in Example 2. 1Aerosolized dose of Example 2.

[0085] For a target aerosolized dose of 2 mg in 3 liters, the density of 5-MeO-DMT in aerosol can be calculated as 0.66 mg/l; for a target aerosolized dose of 20 mg in 3 liters, the density of 5-MeO-DMT in aerosol can be calculated as 6.66 mg/l. For a target aerosolized dose of 2 mg in 2 liters, the density of 5-MeO-DMT in aerosol can be calculated as 1 mg/l; for a target aerosolized dose of 20 mg in 2 liters, the density of 5-MeO-DMT in aerosol can be calculated as 10 mg/l.

Example 5. HPLC assay for the determination of the purity of 5-MeO-DMT

[0086] An HPLC assay was developed to allow determination of the purity of 5-MeO-DMT. The assay was tested for linearity and accuracy. Based on the results, the method was considered suitable for the purpose.

[0087] The following method parameters were used: Example 5, Table 1. Gradient

[0088] Typical retention time of 5-MeO-DMT: 5.5 min

Testing the HPLC method for linearity:

[0089] A 5-MeO-DMT solution was prepared in methanol. A nominal concentration of 0.15 mg/ml was taken. Example 5, Table 2. HPLC method testing for linearity.

[0090] All duplicate injections were within ±2%

[0091] Linearity of the HPLC method

[0092] % interception Y the nominal concentration was determined to be 0.8%. The method is considered linear, as shown in Figure 1.

Testing the HPLC method for accuracy:

[0093] Six sample solutions were prepared at nominal concentration (12-18 mg in 100 ml of methanol). The purity results were as follows: Example 5, Table 3. HPLC method test for accuracy.

[0095] Acceptance criteria for purity values across six samples would be 1% RSD, the actual reading was 0.07%. Therefore, the analytical method is considered to exhibit adequate precision.

Example 6. Evaluation of purity and aerosol degradation products of 5-MeO-DMT

[0096] Duplicates of capsules dosed with a target dosage of 5-MeO-DMT of 18 mg were prepared as described in Example 1, Steps 1 to 3, using a solution of 180.7 mg of freebase 5-MeO-DMT in 2 ml of ethanol (90.4 mg/ml), of which 200 μl were pipetted onto the dropper pad in the capsules. The purity of the 5-MeO-DMT starting material, as determined by HPLC, was 99.605%, with three minor fractions of impurities (Example 6, Table 1). Example 6, Table 1. Purity of 5-MeO-DMT starting material.

[0098] 5-MeO-DMT was then aerosolized from the capsules as described in Example 1, Steps 4 and 5, except that only one Volcano Medical Vaporizer was used (i.e., the vaporizer in Step 3 and Step 4 was the same, with preheating between capsule preparation and aerosol generation performed according to the instructions).

[0099] For aerosol purity analysis, each replicated valve flask containing the aerosol was connected to a Solid Phase Extraction (SPE) cartridge (Discovery® DSC-18). A vacuum was then applied until the flask was completely emptied. Four 5 ml aliquots of methanol were added to the cartridge and the pure extracts were analyzed by HPLC. Extract 1 was subsequently diluted (from 1 ml to 10 ml) to obtain a response in the linear range.

[00100] For replication 1, Extract 1 (Example 6, Table 1), the purity of the aerosol was found to be even higher than the purity of the starting material (99.710% versus 99.605%), that pre-existing impurities 2 and 3 were undetectable while pre-existing Impurity 1 only minimally increased (0.206% versus 0.099%), and that only a minimal amount of new 5-MeO-DMT degradation products occurred (Degradation product 1: 0.039%, Degradation product 2: 0.044%), with a total percentage of 5-MeO-DMT degradation products in the aerosol of 0.19% (including the additional amount of Impurity 1). The results for the other replicates were very similar and the results for the other extracts did not change the conclusions. Example 6, Table 2. Aerosol purity of 5-MeO-DMT, Replicate 1, Extract 1. The amount of Impurity 1 increased after aerosolization, and the additional amount of Impurity 1 is also considered a degradation product.

[00101] Finally, a highly pure aerosol with only a minimal amount of degradation products can be generated based on the methods and compositions described herein.

Example 7. Clinical evidence for inhalation of the target dose of 5-MeO-DMT in a single inhalation and for rapid systemic absorption.

[00102] A clinical trial was conducted in which free-base 5-MeO-DMT (purity not less than 99%) was administered to patients with treatment-resistant major depressive disorder (TRD). Patients recruited for the trial had to meet the DSM-5 diagnostic criteria for single-episode or recurrent major depressive disorder and had to be treatment-resistant, both aspects as assessed by a registered psychiatrist or psychologist. On the day of administration, a single 12 mg dose of 5-MeO-DMT was administered to patients via a single inhalation as described in Example 1. Patients were closely monitored for 3.5 hours after administration, with additional follow-up visits 1 day and 7 days after dosing.

[00103] Two patients with major depressive disorder were re-created for the study. The inhalation procedure was adequately performed with a single inhalation by both patients and was well tolerated with no adverse events related to inhalation, especially no coughing. The first psychedelic symptoms as assessed by an observer occurred immediately after inhalation. The psychedelic experience was highly intense, with both patients achieving a peak psychedelic experience as assessed by the revised 30-item Mystic Experience Questionnaire (MEQ30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90). The duration of the psychedelic experience as judged by an external observer was 16 minutes for patient 1 and 40 minutes for patient 2.

[00104] Notably, both patients reported a formal remission of their depressive symptoms, as assessed by a score of 10 or less on the Montgomery-Asberg Depression Rating Scale (MADRS), as early as the first assessment time two hours after drug administration, with the further effect deepening at the follow-up visits on day 1 and day 7.

[00105] These data demonstrate that inhalation of an aerosol containing 5-MeO-DMT aerosol particles generated as described in Example 1 (i.e., aerosolization of a thin layer of 5-MeO-DMT via airflow heated to 210°C at a flow rate of 12 liters/minute for 15 seconds over a thin layer) is well tolerated and can be inhaled within a single inhalation. This also demonstrates that 5-MeO-DMT from such aerosol particles is rapidly absorbed systemically, as evidenced by the rapid onset of psychedelic effects within seconds of inhalation initiation. Such rapid systemic absorption is considered to occur via the pulmonary alveoli.

Example 8. Evaluation of the mass-mean-aerodynamic diameter of 5-MeO-DMT aerosols.

[00106] The particle size distribution of 5-MeO-DMT aerosol particles as generated according to the compositions and methods of the present invention are determined according to United States Pharmacopeia (USP) methods using the Next Generation Impactor (NGI) (United States Pharmacopeia (USP) <601> Apparatus 6) as shown in Figure 2.

[00107] This device fractionates the delivered large aerosol pellet into a discrete series of size ranges based on the inertia of droplets or particles and provides a measure of the aerodynamic diameter of the aerosol droplets produced. The droplet size range captured by each stage in the NGI may be dependent on the measured airflow used. For the present analysis, experiments were conducted using an airflow of 30 liters/minute (Experiments 1 and 3) and 15 liters/minute (Experiments 2 and 4).

[00108] Based on a log-normal particle size distribution, an aerodynamic size distribution is characterized by the mass-mean-aerodynamic diameter (MMAD) and geometric standard deviation (GSD). In addition, the fine particle fraction (FPF) is determined as the percentage by weight of droplets having an aerodynamic diameter less than or equal to 5 μm, relative to the total droplets in the impactor.

Example 8 - Experiment 1

[00109] A first experiment is performed using a Volcano medical vaporization system as described in Example 1 with dosed capsules having a nominal drug load of 6 mg of 5-MeO-DMT free base/capsule. The aerosol recovered in the balloon is measured using the NGI operated using a flow rate of 30 liters/min.

[00110] The experiment is performed in triplicate.

[00111] The results are shown in the table below.

Example 8 - Experiment 2

[00112] A second experiment is also performed using a Volcano medical vaporization system as described in Example 1 with dosed capsules having a nominal drug load of 6 mg of 5-MeO-DMT free base/capsule. The aerosol recovered in the balloon is measured using the NGI operated using a flow rate of 15 liters/min.

[00113] In this experiment, NGI cups were coated with glycerol to prevent possible re-entrainment of droplets. In addition, approximately 8 drops of 30% glycerol in water were added to each filter paper located below the corresponding NGI Stage Jets.

[00114] The experiment is performed in triplicate.

[00115] The results are shown in the table below.

[00116] Data may not be reliable due to experimental problems with the cup coating.

Example 8 - Experiment 3

[00117] Experiment 1 is repeated using capsules with a nominal drug loading of 18 mg/capsule. The results are shown in the table below.

Example 8 - Experiment 4

[00118] Experiment 2 is repeated using capsules with a nominal drug load of 18 mg/capsule. The results are shown in the table below.

[00119] The data above show that the MMAD is less than 3 μm and greater than 0.1 μm, in particular less than 2.5 μm and greater than 0.1 μm, especially less than 2 μm and greater than 0.1 μm. At least 80% by weight of, in particular at least 85% by weight of, and especially at least 90% by weight of the aerosol particles (droplets) have an aerodynamic diameter less than or equal to 5 μm.

Example 9. Determining the Delivered Dose - A Prophetic Example

[00120] The amount of 5-MeO-DMT delivered to the patient by the compositions and methods according to the invention is confirmed according to United States Pharmacopeia (USP) methods by collecting the aerosol in a suitable aerosol sampling apparatus such as Apparatus A United States USP <601> shown in Figure 3. The aerosol is typically sampled at a flow rate of 28.3 Liters/minute. Once aerosol sampling is complete, both ends of the dosing tube are capped and the drug is extracted from the filter using a suitable recovery solvent and assayed using a suitably validated analytical technique.

Example 10. Preparation of Starting Material

[00121] 5-MeO-DMT (2.0 g) was dissolved in MTBE (4 mL, 2.0 volumes) at 35 to 40°C before being cooled to room temperature for 30 minutes. After stirring at room temperature for 50 minutes, no crystallization was observed; therefore, the temperature of the charge was decreased to 7 to 12°C for 30 minutes. After stirring at 7 to 12°C for 10 minutes, crystallization occurred. The charge was subsequently filtered after one hour of stirring at 7 to 12°C. After washing with MTBE (1 mL, 0.5 volumes) at 7 to 12°C, the charge was taken dry under vacuum for 3.5 hours to provide a pale orange solid weighing 1.02 g (50% recovery). The isolated solid was analyzed for purity by HPLC. The purity found was 99.74% area.

[00122] The table below shows the impurity profile of isolated material. Example 10, Table 1. Impurity profile of isolated material.

[00123] The analysis results indicated that the overall purity of the material was increased and the impurities at RRT 1.18 and RRT 1.24 were purged to below 0.10%. The impurity at RRT 2.38 was also reduced to below the NMT target of 0.10%.

[00124] Solvent analysis of sample indicated an MTBE level of 17 ppm against an expected NMT limit of 5000 ppm.

Claims (22)

1. Aerosol, characterized in that it comprises (a) a pharmaceutically acceptable gas; (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has a particle mass density of about 0.5 mg/l to about 12.5 mg/l. 2. Aerosol, according to claim 1, characterized in that the particle mass density in aerosol is between about 1.3 mg/l and about 10 mg/l, in particular between about 2 mg/l and about 9 mg/l. 3. Aerosol, according to claim 1 or 2, characterized in that the pharmaceutically acceptable gas is air. 4. Aerosol, according to any one of claims 1 to 3, characterized in that the fine particle fraction (FPF), determined as the percentage by weight of aerosol particles having an aerodynamic diameter of less than or equal to 5 μm, relative to the total mass of aerosol particles, is at least 90% by weight. 5. Aerosol, according to any one of claims 1 to 4, characterized in that the aerosol particles contain less than 1% by weight of impurities, in particular less than 0.5% by weight of impurities. 6. Aerosol, according to any one of claims 1 to 5, characterized in that it contains less than 0.5% by weight of 5-MeO-DMT degradation products, in particular less than 0.2% by weight of 5-MeO-DMT degradation products resulting from a chemical modification of 5-MeO-DMT as a result of a chemical reaction during aerosol formation. 7. Aerosol, according to any one of claims 1 to 6, characterized in that it essentially consists of (a) air; (b) aerosolized particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. 8. Aerosol, according to any one of claims 1 to 7, characterized in that the aerosol particles contain 5-MeO-DMT in the form of the free base. 9. Aerosol, according to any one of claims 1 to 8, characterized in that it has a mass-average aerodynamic diameter of less than 3 microns and greater than 0.1 microns, in particular a mass-average aerodynamic diameter of less than 2 microns and greater than 0.1 microns. 10. Aerosol, according to any of the preceding claims, characterized in that it is formed by a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, configured on a solid support, to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT to produce aerosol particles. 11. Aerosol, according to claim 10, characterized in that the thin layer has a thickness of less than about 10 μm, in particular less than about 7.5 μm, wherein the thickness is calculated based on the amount of 5-MeO-DMT or its pharmaceutically acceptable salt and the surface area of the carrier. 12. Aerosol, according to claim 11, characterized in that the thin layer has a thickness in the range of 0.1 μm to 10 μm, in particular in the range of 0.3 μm to 7.5 μm. 13. Aerosol, according to any of claims 10 to 12, characterized in that the thin layer of 5-MeO-DMT, configured on a solid support, is exposed to thermal energy via the passage of air over the thin layer. 14. Aerosol, according to any one of claims 10 to 12, characterized in that the thin layer of 5-MeO-DMT, configured on a solid support, is exposed to thermal energy via the solid support. 15. Aerosol, according to claim 14, characterized in that the air passing over the thin layer has a temperature in the range of about 180°C to about 240°C. 16. Aerosol, according to claim 15, characterized in that the air passing over the thin layer has a temperature of about 210°C and passes over the thin layer at a rate of about 12 l/min for a duration of about 15 seconds. 17. Aerosol, according to any of the preceding claims, characterized in that said aerosol particles are contained in a volume equal to or less than about 3 liters, in particular in a volume of about 2 to about 3 liters. 18. Aerosol, according to any of the preceding claims, characterized in that it is for use in therapy. 19. Aerosol, according to claim 18, characterized in that it is administered to a patient via a single inhalation. 20. A method for forming an aerosol, characterized in that the method involves generating aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof. 21. Kit, characterized in that it comprises a solid support and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof. 22. Invention, characterized by - in any of its embodiments or in any applicable category of claim, for example, product or process or use, or any other type of claim encompassed by the matter initially described, disclosed or illustrated in the patent application; and/or Composition comprising an aerosol comprising 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and/or Use of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, for the preparation of an aerosol, composition, product, medicament or kit to prevent, improve or treat a disorder, disease or health condition.