WO2024031152A1 - Process for improving powder flow characteristics of a crystalline compound - Google Patents

Abstract

A process for improving powder flow characteristics of a compound having acicular crystalline morphology, such as psilocybin trihydrate, is disclosed. The process includes the steps of a) preparing a feed solution comprising psilocybin trihydrate, a stabilizing polymer such as polyvinyl pyrrolidone and an oligosaccharide such as lactose, and, b) spray-drying the feed solution to produce composite particles comprising a solid dispersion of amorphous psilocybin, the stabilizing polymer and the oligosaccharide. The resulting composite particles may be readily formulated as solid oral dosages, such as tablets and capsules, and demonstrate improved dissolution in aqueous media in comparison with psilocybin trihydrate.

Description

"Process for improving powder flow characteristics of a crystalline compound"

Technical Field

[0001 ] The disclosure relates to a process for improving powder flow characteristics of a crystalline compound, in particular an acicular crystalline compound such as psilocybin. The disclosure also relates to a powder composition, a pharmaceutical composition, and a feed solution for a spray-dryer to prepare said powder composition.

[0002] The disclosure further relates to a process for improving the dissolution of psilocybin in an aqueous media.

Background

[0003] The discussion of the background to the disclosure is intended to facilitate an understanding of the disclosure. However, it should be appreciated that the discussion is not an acknowledgement or admission that any of the material referred to was published, known or part of the common general knowledge as at the priority date of the application.

[0004] There is increasing interest in the use of psychedelics for psycho-assisted therapies for mental disorders such as depression, anxiety and addiction. In particular, micro-dosing of psychedelic compounds are reported to show favourable therapeutic outcomes. One potential psychedelic for micro-dosing (1 mg) is the mushroom derived prodrug psilocybin. Various studies have also shown the effectiveness of higher doses (i.e. 25 mg) of psilocybin with psychotherapy for patients who are suffering major depressive disorder and other mental disorders.

[0005] Dried mushroom powder containing psilocybin is available in relatively large size 00 capsules. The dose used recreationally ranges between 1 -5 g of dried mushroom material which is thought to contain from 4-10 mg psilocybin as well as other potentially psychoactive ingredients, producing varying or undesirably psychoactive outcomes. Currently, there is no known commercially available oral solid dosage form containing synthetic psilocybin. [0006] A scalable synthetic route for the production of synthetic psilocybin has been recently released. Synthetic psilocybin is prepared as white needle-like crystals with a melting point of 190-198 °C. However, synthetic psilocybin has been reported to be hygroscopic.

[0007] Powder blends intended for automated capsule filling generally require fewer processing steps and excipient requirements than tabletted formulations. For most automated capsule powder fillers, the powder’s ability to flow, retain homogeneity, and compress is critical to achieving successful filling outcomes. Other critical material properties include material hydrophobicity, powder density, powder cohesion/adhesion and tensile strength.

[0008] Good powder flow characteristics of a powder blend are set out in Table 1 .

[0009] The powder flow behaviour of synthetic psilocybin is problematic due to its needle-like crystal morphology and hygroscopicity.

[0010] The requirements for a powder blend that is intended to be made into a tablet are homogeneity, good flow properties, and good compactability for tablet compression. The resultant tablet should be homogeneous, resistant to breakage and chipping (friability), disintegrates and dissolves well. Different excipients compositions are required for the tablet formulation to meet these requirements. Although the active pharmaceutical ingredient (API) is blended with these excipients (diluents, disintegrants, flavours, flow aids, binders and so forth) to overcome potential processing challenges in handling the API alone, the poor powder flow behaviour of synthetic psilocybin mean that it is difficult to produce a homogeneous blend with the excipients. [0011] The process as described herein seeks to overcome at least some of the disadvantages and problems described above.

Summary

[0012] Crystalline compounds, in particular crystalline compounds with acicular morphology, such as psilocybin trihydrate, have poor powder flow characteristics and slow dissolution kinetics.

[0013] The inventors have discovered a process to convert crystalline psilocybin tryihydrate into amorphous particles having improved powder flow characteristics and improved dissolution kinetics in aqueous media in comparison to crystalline psilocybin trihydrate.

[0014] In one aspect there is provided a process for improving powder flow characteristics of a compound having crystalline morphology, the process comprising the steps of: a) preparing a feed solution comprising said compound, a stabilizing polymer and an oligosaccharide; and, b) spray-drying the feed solution to produce composite particles comprising a solid dispersion of the compound, the stabilizing polymer and the oligosaccharide, wherein the compound has amorphous morphology.

[0015] In one embodiment, the compound comprises psilocybin trihydrate or paracetamol. In one form, the crystalline morphology may be acicular.

[0016] In one embodiment, the stabilizing polymer comprises polyvinyl pyrrolidone (PVP).

[0017] In one embodiment, the oligosaccharide comprises lactose.

[0018] In one embodiment, the feed solution further comprises leucine.

[0019] In one embodiment, the feed solution is an aqueous solution, optionally with a co-solvents. [0020] In another aspect of the disclosure there is provided a process for improving dissolution of psilocybin in an aqueous media, the process comprising the steps of: a) preparing a feed solution comprising psilocybin trihydrate, PVP and lactose; and, b) spray-drying the feed solution to produce composite particles comprising a solid dispersion of amorphous psilocybin, PVP and lactose.

[0021] In one embodiment, the ratio of the amount by weight of psilocybin, PVP, and lactose in the feed solution may be 1 :4:2.

[0022] In one embodiment, the feed solution further comprises leucine. In this particular embodiment, the ratio of the amount by weight of psilocybin, PVP, and lactose in the feed solution may be 1 :2:1 .

[0023] In one embodiment, the solution comprises an aqueous solution, optionally with a co-solvent. Suitable co-solvents may include, but are not limited to, an alcohol such as methanol and ethanol; ketones such as acetone, methyl ethyl ketone and methyl iso-butyl ketone; and various other solvents such as acetonitrile, dimethyl acetamide or dimethyl sulfoxide.

[0024] In one embodiment, the ratio of the amount by weight of psilocybin to solvent in the solution is about 1 :40.

[0025] In one embodiment, the step of spray-drying the solution comprises atomizing the feed solution and introducing the atomized solution into a spray-drying chamber having an inlet temperature less than the glass transition temperature (t_g) of the crystalline compound. It will be appreciated that the inlet temperature will vary depending on the crystalline compound. For example, the inlet temperature may be in a range of 80 °C to 120 °C when the crystalline compound is paracetamol.

Alternatively, the inlet temperature may be in a range of from 110 °C to 140 °C when the compound is psilocybin.

[0026] In one embodiment, the composite particles produced in step b) have a particle size distribution of D90 < 20 pm, in particular D90 < 15 pm. [0027] In one embodiment, the ratio of the amount by weight of psilocybin, PVP, and lactose in the solid dispersion may be in a range of from 1 :4:2 to 1 :2:1 .

[0028] In one embodiment, the process further comprises blending the composite particles of the solid dispersion with a pharmaceutically acceptable diluent to produce a powder blend.

[0029] In one embodiment, the ratio of the amount by weight of the composite particles and the pharmaceutically acceptable diluent in the powder blend is about 1 :10.

[0030] In one embodiment, the pharmaceutically acceptable diluent comprises lactose monohydrate having a particle size distribution D50 < 130 pm.

[0031 ] In another aspect there is provided a powder composition comprising composite particles comprising a solid dispersion of amorphous psilocybin, PVP and lactose having a particle size distribution of D90 < 20 pm.

[0032] In a further aspect there is provided a pharmaceutical composition comprising composite particles comprising a solid dispersion of amorphous psilocybin, PVP and lactose, and one or more pharmaceutically acceptable excipients and/or adjuvants.

[0033] In one embodiment, the one or more pharmaceutically acceptable excipients and/or adjuvants comprises a pharmaceutically acceptable diluent. In one form the pharmaceutically acceptable diluent comprises lactose having a particle size distribution D50 < 130 pm. The ratio of the amount by weight of the composite particles and the one or more pharmaceutically acceptable diluent may be about 1 :10 to about 1 :3.

[0034] In one embodiment, the pharmaceutical composition has a Carr's compressibility index of 31 % and Hausner ratio of 1 .31 .

[0035] In one embodiment the composite particles of the powder composition and the pharmaceutical composition have a particle size distribution of D90 < 20 pm. [0036] In one embodiment, the ratio of the amount by weight of psilocybin, PVP, and lactose in the solid dispersion is about 1 :4:2 in the powder composition and the pharmaceutical composition.

[0037] In a still further aspect there is provided a feed solution for a spray-dryer comprising psilocybin, a PVP, lactose and, optionally, leucine.

[0038] In one embodiment, the feed solution is an aqueous solution.

[0039] In one embodiment, the ratio of the amount by weight of psilocybin, PVP, and lactose in the feed solution may be in a range of from 1 :4:2 to 1 :2:1 .

[0040] In one embodiment, the ratio of the amount by weight of psilocybin to water in the aqueous feed solution is about 1 :40.

Brief Description of Drawings

[0041 ] Notwithstanding any other forms which may fall within the scope of the process as set forth in the Summary, specific embodiments will now be described with reference to the accompanying figures below:

[0042] Figure 1 is a scanning electron micrograph (SEM) of psilocybin trihydrate at 450x magnification;

[0043] Figure 2 is a SEM at 3000x magnification of psilocybin trihydrate;

[0044] Figure 3 is a SEM at 3000x magnification of a spray-dried powder prepared in accordance with one embodiment;

[0045] Figure 4 is a SEM at 3000x magnification of a powder blend prepared in accordance with another embodiment;

[0046] Figure 5 is a mean particle size distribution of the spray-dried powder, the powder blend and psilocybin trihydrate; [0047] Figure 6 is a differential thermogram of psilocybin trihydrate;

[0048] Figure 7 is a differential thermogram of the spray-dried powder prepared in accordance with one embodiment;

[0049] Figure 8 is a thermogram of psilocybin trihydrate;

[0050] Figure 9 is a thermogram of the spray-dried powder prepared in accordance with one embodiment of the disclosure as described in Example 1 ;

[0051 ] Figure 10 is a DVS isotherm plot of psilocybin trihydrate;

[0052] Figure 11 is a DVS isotherm plot of the spray-dried powder prepared in accordance with one embodiment of the disclosure as described in Example 1 ;

[0053] Figure 12 is an XRD of psilocybin trihydrate and the spray-dried powder prepared in accordance with one embodiment of the disclosure as described in Example 1 ;

[0054] Figure 13 is a dissolution release profile of psilocybin trihydrate and the powder blend prepared in accordance with another embodiment of the disclosure as described in Example 1 ;

[0055] Figure 14 is a thermogram of psilocybin trihydrate;

[0056] Figure 15 is a thermogram of the spray-dried powder prepared in accordance with another embodiment of the disclosure as described in Example 12;

[0057] Figure 16 is an XRD of psilocybin trihydrate and the spray-dried powder prepared in accordance with another embodiment of the disclosure as described in Example 12; and

[0058] Figure 17 is a dissolution release profile of psilocybin trihydrate and the tablets prepared in accordance with the disclosure as described in Example 14. Description of Embodiments

The disclosure relates to a process for improving powder flow characteristics of a crystalline compound, in particular an acicular crystalline compound such as psilocybin. The disclosure also relates to a powder composition, a pharmaceutical composition, and a feed solution for a spray-dryer to prepare said powder composition.

[0059] The disclosure further relates to a process for improving the dissolution of psilocybin in an aqueous media.

GENERAL TERMS

[0060] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or groups of compositions of matter. Thus, as used herein, the singular forms "a", "an" and "the" include plural aspects unless the context clearly dictates otherwise. For example, reference to "a" includes a single as well as two or more; reference to "an" includes a single as well as two or more; reference to "the" includes a single as well as two or more and so forth.

[0061 ] Each example of the present disclosure described herein is to be applied mutatis mutandis to each and every other example unless specifically stated otherwise. The present disclosure is not to be limited in scope by the specific examples described herein, which are intended for the purpose of exemplification only. Functionally-equivalent products, compositions and processes are clearly within the scope of the disclosure as described herein.

[0062] The term "and/or", e.g., "X and/or Y" shall be understood to mean either "X and Y" or "X or Y" and shall be taken to provide explicit support for both meanings or for either meaning.

[0063] Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0064] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although processes and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable processes and materials are described below. In case of conflict, the present specification, including definitions, will control. In addition, the materials, processes, and examples are illustrative only and not intended to be limiting.

[0065] The term “about” as used herein means within 5%, and more preferably within 1%, of a given value or range. For example, “about 3.7%” means from 3.5 to 3.9%, preferably from 3.66 to 3.74%. When the term “about” is associated with a range of values, e.g., “about X% to Y%”, the term “about” is intended to modify both the lower (X) and upper (Y) values of the recited range. For example, “about 20% to 40%” is equivalent to “about 20% to about 40%”.

SPECIFIC TERMS

[0066] The term ‘acicular’ as used herein refers to crystals that have a needle-like form or morphology.

[0067] The term ‘amorphous’ as used herein refers to a substance having a disordered arrangement of atoms or molecules in the solid state. An amorphous substance does not display any distinct peaks in an X-ray diffraction pattern, thereby indicating an absence of crystallinity (or ordered arrangement of atoms or molecules) in the substance.

[0068] The term ‘crystalline” as used herein refers to a substance having an ordered arrangement of atoms or molecules in the solid state. In particular the ordered arrangement takes the form of a three-dimensional arrangement within a single repeating unit called a unit cell. A crystalline material may display one or more morphologies governed by the unit cell and the conditions (e.g., temperature, solution saturation, nucleation and so forth) under which the crystal is grown. The morphology of a crystal describes the set of crystallographic planes that show on the crystal surface. The crystal shape is given by the relative length to width of the crystal faces.

[0069] The term ‘oligosaccharide’ as used herein refers to a saccharide polymer containing two or more sugar molecules (monomers), for example 2 to 200 sugar molecules, 30 to 100 sugar molecules, or 3 to 10 sugar molecules.

[0070] The term “pharmaceutically acceptable” as used herein refers to pharmaceutically active agents or inert ingredients which are suitable for use in contact with internal organs, live tissue or the skin of human beings without undue toxicity, incompatibility, instability, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.

[0071] The term “solid dispersion” as used herein refers to a solid composition comprising two or more components wherein the minor component(s) is/are homogeneously distributed throughout a single solid phase of the major component(s).

[0072] The term “spray-drying” as used herein refers to a well-known process of breaking up a liquid solution or liquid dispersion into small droplets (also known as atomization) and rapidly evaporating solvent from the small droplets to produce solid particles of the solute(s).

PROCESS

[0073] Embodiments described herein generally relate to a process for improving powder flow characteristics of a crystalline compound, in particular an acicular crystalline compound such as psilocybin or paracetamol. Advantageously, the process produces an amorphous composite particle of the compound having improved dissolution kinetics in aqueous media. The amorphous composite particles have suitable powder flow characteristics for formulation as solid dosages, such as capsules and tablets.

Preparing the feed solution [0074] The process as disclosed herein comprises preparing a feed solution for a spray-dryer comprising the crystalline compound, a stabilizing polymer and an oligosaccharide

[0075] The crystalline compound may be psilocybin trihydrate or paracetamol. Both psilocybin trihydrate and paracetamol have acicular morphology. Unprocessed (i.e. non-milled) particles thereof may frequently present as highly agglomerated particles having a particle size diameter > 500 pm.

[0076] The stabilizing polymer may be polyvinyl pyrrolidone (PVP). PVP is a water- soluble polymer obtained by polymerization of monomer /V-vinylpyrrolidone. PVP is an inert, non-toxic, temperature-resistant, pH-stable, biocompatible, biodegradable polymer. It is a common excipient in pharmaceutical formulations and has multiple uses as a binder for tablets and capsules, a film former for ophthalmic solutions, to aid in flavouring liquids and chewable tablets, and as an adhesive for transdermal systems.

[0077] The oligosaccharide may be lactose monohydrate. The lactose monohydrate may be finely milled (e.g., particle size diameter D50 < 20 pm) to assist solubilisation of the oligosaccharide when preparing the feed solution for spray-drying.

[0078] . In some embodiments, the feed solution may further comprise leucine. The ratio by weight of leucine to PVP in the feed solution may be 1 :50.

[0079] The crystalline compound, the stabilizing polymer, the oligosaccharide and, optionally, leucine may be mixed in any order with a solvent such as water to prepare the feed solution for the spray-dryer. An optional co-solvent that is miscible with water may be used to enhance the solubility of the crystalline compound in the feed solution. The ratio of the amount by weight of the crystalline compound to volume of solvent (or solvent + co-solvent) in the feed solution is about 1 :40.

[0080] Suitable co-solvents may include, but are not limited to, an alcohol such as methanol and ethanol; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; and various other solvents such as acetonitrile, dimethyl acetamide or dimethyl sulfoxide. [0081 ] The mixture may be agitated and heated to a mild elevated temperature up to 60 °C to facilitate dissolution of the crystalline compound, the stabilizing polymer the oligosaccharide, and leucine (if used) in the solvent. The feed solution may be maintained above 30 °C to prevent precipitation of the crystalline compound therefrom.

[0082] The ratio of the amount by weight of the crystalline compound, PVP and lactose in the feed solution may be in a range of about 1 :4:2 to about 1 :2:1 . When spray-dried as will be described below, the feed solutions prepared as described above produce powder yields greater than 70%, even powder yields greater than 80%.

[0083] The inventors have discovered that although it is possible to prepare spray- dried particles of the crystalline compound from an alternative feed solution comprising the crystalline compound and PVP in a ratio of 1 :4 in the absence of the oliogosaccharide, the powder yields arising from the alternative feed solution are less than 70% under the same or similar spray-drying conditions.

Spray-drying

[0084] The process further comprises the step of spray-drying the feed solution to produce composite particles comprising a solid dispersion of the compound, the stabilizing polymer and the oligosaccharide. The compound in the solid dispersion has amorphous morphology.

[0085] Spray-drying processes and spray-drying equipment are described generally in Perry's Chemical Engineers' Handbook, pages 20-54 to 20-57 (Sixth Edition 1984). More details on spray-drying processes and equipment are reviewed by Marshall, “Atomization and Spray-Drying. 50 Chem. Eng. Prog. Monogr: Series 2 (1954), and Masters, Spray Drying Handbook (Fourth Edition 1985).

[0086] Evaporation of solvent from the droplets is achieved by maintaining the partial pressure of solvent in the spray-drying chamber well below the vapor pressure of the solvent at the temperature of the drying droplets. This is accomplished by (1 ) maintaining the pressure in the spray-drying apparatus at a partial vacuum (e.g., 0.01 to 0.50 atm); or (2) mixing the liquid droplets with a warm drying gas; or (3) both (1) and (2). In addition, at least a portion of the heat required for evaporation of the solvent may be provided by heating the feed solution.

[0087] The feed solution comprising the compound, stabilising polymer and oligosaccharide (and optionally leucine) can be spray-dried under a wide variety of conditions and yet still yield solid dispersions with acceptable properties and yields. For example, various types of nozzles can be used to atomize the feed solution and introduce the feed solution into the spray-dry chamber as a dispersion of small droplets. Any type of nozzle may be used to spray the feed solution as long as the droplets that are formed are sufficiently small that they dry during the residence time of the droplets in the spray-drying chamber and they do not stick to or coat the spraydrying chamber wall.

[0088] Although the maximum droplet size varies widely as a function of the size, shape and flow pattern within the spray dryer chamber, generally droplets should be less than about 500 pm in diameter when they exit the nozzle. Examples of types of nozzles that may be used to form the solid amorphous dispersions include, but are not limited to, a two-fluid nozzle, a fountain-type nozzle, a flat fan-type nozzle, a pressure nozzle or a rotary atomizer.

[0089] The feed solution can be delivered to the spray nozzle or nozzles at a wide range of flow rates. The feed solution flow rates to the spray nozzle can vary over a wide range depending on the type of nozzle, spray-dryer chamber size and spray-dry conditions such as the inlet temperature and flow rate of the drying gas. Generally, the energy for evaporation of solvent from the spray solution in a spray-drying process comes primarily from the drying gas. Generally, the feed solution may be delivered to the spray nozzle or nozzles at a feed rate of 2.5 ml/minute to 5 ml/minute.

[0090] The drying gas can, in principle, be essentially any gas, but for safety reasons and to minimize undesirable oxidation of the drug or other materials in the solid dispersion, an inert gas such as nitrogen, nitrogen-enriched air or argon is utilized. The drying gas is typically introduced into the drying chamber at a flow rate of about 400 L/hour. [0091 ] The inlet temperature of the spray-drying chamber may vary but should be less than the glass transition temperature (t_g) of the compound. Inlet temperatures above the glass transition temperature of the compound lead to low powder yields. Generally, the inlet temperature of the spray-drying chamber may be in a range of from 110 °C to 140 °C.

[0092] The large surface-to-volume ratio of the droplets and the large driving force for evaporation of solvent leads to rapid solidification times for the droplets.

Solidification times may be less than about 20 seconds, less than about 10 seconds, or less than 1 second. This rapid solidification facilitates the particles to maintain a uniform, homogeneous dispersion instead of separating into drug-rich and polymer- rich phases. The solidification times may be varied by tuning various operating parameters such as the inlet temperature, the outlet temperature, the feed solution flow rate, the drying gas feed flow rate, and so forth.

[0093] Following solidification, the solid powder typically may reside in the spraydrying chamber for about 5 to 60 seconds, further evaporating solvent from the solid powder. The final solvent content of the solid dispersion as it exits the spray-drying chamber is less than 10 wt% since this reduces the mobility of the drug molecules in the solid amorphous dispersion, thereby improving its stability. Following solidification, the resulting powder particles can be dried to remove residual solvent using suitable drying processes such as tray drying, fluid bed drying, microwave drying, belt drying, rotary drying, vacuum drying, and other drying processes known in the art.

Powder composition

[0094] The spray-drying process as described above produces small solid particles of the amorphous compound homogeneously dispersed in a matrix of the stabilising polymer and the oligosaccharide. The resulting composite particles are uniform, generally spherical and have a particle size distribution of D90 < 20 pm.

[0095] The ratio of the amount by weight of the amorphous compound, the stabilising polymer and the oligosaccharide in the composite particle produced by spray-drying is effectively retained from the composition of the feed solution. For example, the ratio of the amount by weight of psilocybin, PVP, and lactose in the solid dispersion is in a range of from 1 :4:2 to 1 :2:1 .

[0096] In view of the uniformity and size of the composite particles, no further processing such as granulation and milling is required.

Pharmaceutical compositions

[0097] The composite particles prepared by spray-drying the feed solution as described above may be mixed with one or more pharmaceutically acceptable excipients and/or adjuvants to prepare a pharmaceutical composition, in particular an oral solid dosage formulation. Suitable examples of oral solid dosage formulations include, but are not limited to a hard gelatine capsule, a soft gelatine capsule, hydroxypropyl methylcellulose (HPMC) capsule, pullulan capsule, a tablet, an effervescent tablet, a strip, a caplet, a sachet, a lozenge, a suspension, a sub-lingual or buccal delivered from for local absorption, an effervescent powder, or a powder for a suspension.

[0098] Generally the oral dosage formulation may further comprise at least one pharmaceutical excipient selected from a group comprising fillers, binders, anti-caking agents, disintegrants, lubricants, glidants, preservatives, antioxidants, surfactants, effervescent excipients, colouring agents, coating agents, sweetening agents, sustained release agents and so forth for their customary properties and in typical amounts with adversely affecting the properties of the powder composition.

[0099] Suitable examples of fillers and binders include, but are not limited to, lactose, mannitol, xylitol, microcrystalline cellulose, methyl cellulose, dibasic calcium phosphate (anhydrous and dihydrate), starch, and any combinations thereof.

[0100] An anti-caking agent may be included to prevent the formation of lumps (caking) and to assist flowability properties of the oral solid dosage formulation. Suitable examples of anti-caking agents include, but are not limited to, silicon dioxide (silica), lactose, tricalcium phosphate, and any combination thereof. [0101 ] Disinteg rants may be added to oral solid dosage formulations to aid in their de-aggregation and to cause rapid break-up of the solids when they come into contact with moisture. Suitable examples of disintegrants include, but are not limited to, corn starch, potato starch, sodium starch glycolate, sodium alginate, sodium carboxy methyl cellulose, methyl cellulose, and croscarmellose sodium crospovidone, and crosslinked forms of polyvinyl pyrrolidone, and any combinations thereof.

[0102] Lubricants and glidants may be added to oral solid dosage formulations to enhance powder flow by reducing inter-particle friction. Suitable examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc and any combination thereof.

[0103] Suitable examples of glidants include, but are not limited to, metal silicates, silicon dioxides such as colloidal anhydrous silica, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, metal hydroxides, and any combination thereof.

[0104] Preservatives may be added to oral solid dosage formulations to prolong storage life of said formulation by reducing degradation and alteration of the active ingredient over time. Suitable examples of preservatives include, but are not limited to, sulphites, benzalkonium chloride, methyl paraben, propyl paraben, benzyl alcohol, sodium benzoate, and any combination thereof.

[0105] Antioxidants are a class of preservatives which inhibit the oxidation of other molecules. Suitable examples of antioxidants include, but are not limited to, phenolic- based antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butyl-hydroquinone (TBHQ), 4-hydroxymethyl-2,6-di-tert-butylphenol (HMBP), 2,4,5-trihydroxy-butyrophenone (THBP), propyl gallate (PG), triamyl gallate, gallic acid (GA), tocopherol acetate, reducing agents such as L-ascorbic acid (vitamin C), L-ascorbyl palmitate, L-ascorbyl stearate, thioglycolic acid (TGA) ascorbyl palmitate (ASP), sulphite-based antioxidants such as sodium sulphite, sodium metabisulphite, sodium bisulphite and thioglycerol and other agents such as disodium ethylenediamine tetraacetate (EDTA), sodium pyrophosphate, sodium metaphosphate, methionine, erythorbic acid and lecithin and any combination thereof. [0106] Effervescent excipients may be used in powders and tablets in combination with acidic agents to cause a reaction that produces carbon dioxide. Suitable examples of effervescent excipients include sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, ammonium bicarbonate. The effervescent excipients may be combined with acidic agents, typically weak organic acids such as citric acid and/or ascorbic acid.

[0107] The oral solid dosage formulations may additionally include inorganic salts such as sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, sodium bicarbonate and organic salts such as sodium citrate, potassium citrate, sodium acetate and so forth.

[0108] In some particular embodiments, the oral solid dosage formulation may comprise psilocybin in an amount from about 1 mg to about 25 mg.

[0109] In particular, the composite particles as described herein may be blended with one or more pharmaceutically acceptable excipients and/or adjuvants to produce a powder blend having suitable powder flow characteristics for automated capsule filling such as with conventional gelatine capsules.

[0110] For example, composite particles comprising a solid dispersion of amorphous psilocybin, PVP and lactose may be blended with lactose monohydrate having a particle size distribution of D50 < 130 pm. The ratio by weight of composite particles to lactose monohydrate may be about 1 :10. This particular powder blend demonstrates suitable powder flow characteristics with a Carr's compressibility index of 31% and Hausner ratio of 1 .31 .

[0111] The gelatine capsules filled with the above powder blend comprising amorphous psilocybin, PVP and lactose show improved drug dissolution rates in comparison with similar studies of gelatine capsules filed with psilocybin trihydrate.

[0112] In other embodiments, the composite particles as described herein may be blended with one or more pharmaceutically acceptable excipients and/or adjuvants to produce a powder blend having suitable characteristics for forming tablets. [0113] For example, composite particles comprising a solid dispersion of amorphous psilocybin, PVP, lactose and leucine may be blended with lactose, microcrystalline cellulose, sodium croscarmellose, silica and magnesium stearate by suitable blending means. The resulting powder blend may be tableted by conventional means.

[0114] Pharmaceutical compositions may be generally provided herein which comprise about 0.1 to about 1000 mg, about 1 to about 200 mg, about 2 to about 100 mg, about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg of amorphous psilocybin as active pharmaceutical ingredient (API).

[0115] Various embodiments may be illustrated by the following examples. The examples are provided for illustrative purposes only and are not to be construed as limiting the scope or content of the disclosure in any way.

Examples

Example 1. Preparation of spray-dried powder from acicular psilocybin

[0116] A feed solution suitable for spray-drying was prepared by mixing (in no particular order) psilocybin trihydrate (2.975 g, equivalent to 2.50 g psilocybin), finely milled lactose monohydrate (5 g) and PVP (10 g) in water (Milli-Q, 100 mL) and heating the solution to 60 °C on a magnetic stirrer plate to promote dissolution of psilocybin trihydrate. The solution was maintained above 30 °C to prevent precipitation of psilocybin during spray drying and holding time. The solution had a measured pH of 3.39.

[0117] The heated solution was subsequently spray-dried using a BUCHI 290 mini spray-dryer with 0.7 mm two-fluid nozzle, 150 mm cap size, inlet temperature 130 +/- 1 °C, outlet temperature range monitored at 81 -84 °C, aspirator setting of 90%, air flow rate of 400 L/h and feed rate of 2.5 mL/minute. The prepared solution was spray-dried within 1 h of preparing the feed solution, yielding a fine white powder with powder yields of >70% Example 2. Preparation of powder blend with spray-dried amorphous psilocybin powder.

[0118] The fine white powder prepared in Example 1 (10 g) was diluted with direct compression spray-dried lactose (SuperTab 11 SD, 90g) by blending the mixture in a small-scale impellor driven high-shear wet granulator (4M8T, ProcCeptT, Zelzate, Belgium) at 250 revolutions per minute for 5 minutes.

Example 3. Psilocybin assay and content uniformity

[0119] The content and uniformity of psilocybin in the spray-dried powder and powder blend were quantified by liquid chromatography coupled with mass spectrometry, using a Shamadzu UHPLC Nexera X2 system coupled with a triple quadrupole mass spectrometer LCMS-8050 (Shamadzu Corporation).

Chromatographic separation was performed using a Phenomenex Kinetex 2.6 urn C18 100A (100 x 2.1 mm) LC column used with an elution flow rate of 0.6 mL per minute and a gradient method outlined in Table 2.

[0120] The MS was operated with an electrospray ionisation (ESI) source in negative mode. Nebulising gas (nitrogen) had a flow rate of 3.0 L/Min. Flow rates of the drying and heating gas, air and nitrogen, respectively, were maintained at 10.0 L/Min. The interface voltage was set at 3.5 kV, while the interface temperature was set at 300 °C. The heat block temperature and desolvation line were set at 400 °C and 250 °C, respectively. A summary of optimised parameters for the MS is outlined in Table 3.

Table 2

Table 3

[0121 ] Psilocybin content in the spray-dried powder was assessed by sampling 10 +/-0.2 mg of powder from 10 spots in the powder storage jar (three spots from the top and the bottom of the jar and four from the middle) and transferred to a 10 mL glass volumetric flask. These samples were then dissolved and made to volume using a solution of 0.1% formic acid in LCMS grade water.

[0122] Psilocybin content in the powder blend was assessed by sampling ten samples of 20 +/-0.2 mg powder. These samples were then dissolved and made to volume using a solution of 0.1% formic acid in LCMS grade water.

[0123] Psilocybin content uniformity was deemed acceptable if there was less than 5% relative standard deviation (RSD) across the samples. The assay was validated based on replicates at seven concentrations and was considered valid when precision and accuracy were within +/- 10%.

[0124] Psilocybin content recovery in the spray-dried powder and powder blend was assayed to be >95% indicating that psilocybin was preserved post spray-drying and blending process. The mass of powder blend required for 1 mg of psilocybin was determined to be 71 .88 mg.

[0125] Content homogeneity of the powder blend was <4%, thus satisfying the <5% RSD requirement.

Example 4. Powder flow and compressibility behaviour via Carr’s index and Hausner ratio

[0126] Bulk and tapped density measurements were performed to characterise powder flow and powder compressibility via Carr's compressibility index (Equation 1 ) and Hausner ratio (Equation 2), respectively. Powder poured density (pp) was measured using a 25 mL measuring cylinder and funnel placed at a fixed height above the cylinder. A volume of 10 mL of powder sample was used, and the mass of the powder was noted to calculate the ratio of mass and powder and the ratio to derive bulk density. Tapped density (pT) was determined using an automatic tapper (Auto tapped density analyser, Quantachrome Instruments, Boynton Beach, FL) which was operated at 1250 taps using a 3.18 mm vertical travel at a tapping speed of 260 tap/min. Measurements were performed in triplicate.

Carr’s compressibility index (C) = 100 (Equation 1)

Hausner ratio (H) = — (Equafat 21 ' PP

[0127] The blended powder prepared according to Example 2 had a Carr's compressibility index of 31 % and Hausner ratio of 1 .31 suggesting that this blend was within ideal powder flow specifications and suitable for automated capsule filling applications (as per Table 1 ). The Carr’s compressibility index and Hausner ratio for psilocybin trihydrate, on the other hand, was measured as 19% and 1.19, respectively, which is outside ideal powder flow behaviour.

Example 5. Particle morphology via SEM

[0128] As received psilocybin trihydrate appeared as an off-white, relative large highly agglomerated particles > 500 pm (Figure 1). Under SEM, the agglomerated particles appear to comprise needle-shaped finer particles < 20 pm that are highly compacted (Figure 2).

[0129] The spray-dried powder prepared as described herein appeared as relatively uniform crumpled spheres < 20 pm (Figure 3). The morphology of the spray-dried powder particles may indicate that there was relatively early surface film formation in the spray drying process followed by a deflation event that produced the crumpled rough surfaces.

[0130] The particle surface roughness may be advantageous in powder blending by providing additional inter-particulate contact points. As shown in Figure 4, the spray- dried powder particles occupy crevices of the lactose diluent in the powder blend prepared according to Example 2. Example 6. Particle size distribution via laser diffraction

[0131 ] The particle size distribution of the powders was determined by laser diffraction via the Malvern Mastersizer 2000 (Malvern Instruments Ltd, Worcestershire, UK) equipped with a Scrirocco 2000 dry powder dispersion unit. The powders were dispersed with 3.5 bar dispersing air pressure. Triplicate measurements were undertaken and the following parameters were derived: Spann, Dv10, Dv50 and Dv90.

[0132] Figure 5 shows the mean particle size distribution of the spray-dried powder prepared in Example 1 , the powder blend prepared in Example 2 and as-received psilocybin trihydrate. The average particles size distributions are set out in Table 4.

Table 4

[0133] The respective measured particle size distributions of the spray-dried powder and the powder blend were unimodal, whereas the measured particle size distribution of psilocybin trihydrate was found to be bimodal and even exceeded the limitation of the master sizer instrument, demonstrating the highly agglomerated nature of the psilocybin trihydrate particles. The spray-dried powder has a relatively uniform fine particle size distribution. The influence of blending the spray-dried powder with the lactose diluent was to increase overall particle size and reduce particle size uniformity.

Example 7. Solid state thermal analysis via Differential Scanning Calorimetry (DSC) [0134] DSC was performed using a DSC 850 (Perkin Elmer Inc., Massachusetts, USA). Powder samples containing 4 mg of powder were sealed in vented aluminium pans with a 3-bar rating and scanned from 35 to 270 °C at 20 °C/minute.

[0135] Solid state thermal analysis via DSC suggests that the as-received psilocybin trihydrate was present in the crystalline hydrate form (Figure 6), evidenced by a prominent endothermic peak at 60-100 °C and proceeded by another peak at 120 °C, suggesting dehydration, followed by a molecular rearrangement. This was followed by a melting event of anhydrous psilocybin at 217 °C.

[0136] In contrast, the differential thermogram for the spray-dried powder (Figure 7) suggests an amorphous material due to the lack of distinct endothermic peaks relative to psilocybin trihydrate. Transition events were identified at 120 °C and 240 °C, probably coinciding with a change in the physical properties of lactose and PVP. The first thermal event appears to be a combination of a dehydration and glass transition, whereas the latter resembles a glass transition. The glass transition at these two points occurs at higher temperatures than the spray drying outlet temperature (81 -84 °C) and is not expected to have a material effect on the spray drying method used to produce the spray-dried powder as described herein.

Example 8. Solid state thermal analysis via thermogravimetric analysis (TGA)

[0137] Thermogravimetric analysis of psilocybin trihydrate and the spray-dried powder were obtained using a Perkin-Elmer Pyris 1 TGA. Samples (~4.5 mg) were loaded onto open platinum sample pans, suspended from the TGA microbalance and scanned from 35 to 270 °C at 10 °C /min.

[0138] Thermogravimetric analysis of psilocybin trihydrate (Figure 8) demonstrated a mass loss of 15% between 50-100 °C corresponding to a dehydration event to produce anhydrous psilocybin. A further thermal event was detected at 220-270 °C, which may coincide with melting and degradation of anhydrous psilocybin.

[0139] Thermogravimetric analysis of the spray-dried powder prepared in Example 1 showed an initial loss of residual moisture from the spray-dried particles. The latter thermal event at 220 °C appears to correspond with lactose degradation. Example 9. Moisture sorption via Dynamic Vapour Sorption (DVS)

[0140] Water sorption isotherms were measured on 20.0 mg samples using a DVS apparatus (DVS Intrinsic 1 , Surface Measurements Systems Ltd, London, UK) operated under a continuous flow (200 mL/minute) of high purity nitrogen gas from 0- 90% relative humidity (RH), at 10% RH increments at 25 °C on the condition of dm/dt <0.002.

[0141 ] The moisture isotherm for psilocybin trihydrate indicated relatively rapid and reversible moisture sorption kinetics (~6 hours). A maximum mass gain of 18.03% was attained upon subjecting the sample to 90% RH (Figure 10). The isotherm resembled a Type IV DVS isotherm, typically associated with mesoporous materials (35). Moisture sorption appeared to be restricted to surface interactions until a critical moisture activity of 70% RH was attained, followed by an open hysteresis pattern during the de-sorption cycle. A mass gain of 0.48% remained at 0% RH. Potential moisture-induced morphological changes and/or moisture-pore interactions may have led to the open hysteresis pattern.

[0142] In contrast, the isotherm for the spray dried powder prepared in Example 1 exhibited relatively slow moisture sorption kinetic uptake, as evidenced by the >7 day run time (Figure 11 ). Relatively large moisture uptake was detected when compared to psilocybin trihydrate. For example, a maximum moisture mass gain of 70.08% was attained at 90% RH, suggesting that the spray-dried powder was predominately in the amorphous state, where moisture-surface adsorption and bulk absorption may have occurred. Furthermore, at 60% RH, a phase transition, possibly attributed to moisture- induced glass transition, may have led to re-crystallisation.

Example 10. Crystallinity via X-ray Diffraction (XRD)

[0143] Powder samples were packed onto a steel sample tray and then analysed by a Shimadzu XRD 7000 (Shimadzu Corporation, Kyoto, Japan). Samples were scanned from 10 to 35°, with an angular increment of 27min. The crystalline status of the powders was qualitatively assessed from the diffraction patterns. [0144] Two different diffraction patterns (Figure 12) were measured for psilocybin trihydrate and the spray-dried powder prepared in Example 1 . The presence of one or several prominent peaks at 13° 20, 19° 20 and 23 ° 20 in the Psilocybin trihydrate diffractogram pattern suggests a crystalline material, whereas the absence of the same peaks for the spray-dried powder suggests a largely or completely amorphous material.

Example 11. Dissolution

[0145] The powder blend as prepared in Example 2 was manually filled into size 3, clear gelatine capsules (Capsuleguy, Adelaide, Australia) at a target fill weight of 71 ,88±0.02 mg (equivalent to 1 mg psilocybin). Psilocybin trihydrate was also manually filled into gelatine capsules at a target fill weight of 1 .19±0.02 mg. The powder fill weight of both capsules was determined in order to achieve the target psilocybin fill weight of 1 .00 mg.

[0146] The drug dissolution rate was determined using a USP II paddle apparatus VK7000 (Vankel Technology Group Inc. Cary, NC, USA) at 37 ± 0.5 °C and a paddle rotating speed of 50 rpm in 500 mL of Milli Q water. One capsule per dissolution vessel was used with the capsule inserted into a stainless steel 25 X 9.5mm wire sinker (ProSense B.V, Oosterhout, Netherlands). A total of 6 vessels were used per formulation. One millilitre of the sample was withdrawn from the dissolution medium at 0,2,5, 10, 15, 20, 30 and 45 minutes. Samples were filtered through a regenerated cellulose syringe microfilter of 0.45 pm pore size directly into 2mL HPLC glass screw cap vials.

[0147] When filled and released from size 3 gelatine capsules, the powder blend as prepared in Example 2 produced a more rapid dissolution profile when compared to psilocybin trihydrate (Figure 13). The powder blend attained >90% psilocybin release by 10 minutes in all six dissolution vessels (RSD<10%). In contrast, psilocybin trihydrate attained >90% release by 30 minutes across six dissolution vessels (RSD<10%). The relatively large variation associated with the release and dissolution of crystalline Psilocybin trihydrate may be a function of the agglomerated and varied particle size and its inherent crystallinity. Example 12. Preparation of spray-dried powder from acicular psilocybin

[0148] A feed solution suitable for spray-drying was prepared by mixing (in no particular order) psilocybin trihydrate (7.74 g, equivalent to 6.50 g psilocybin), finely milled lactose monohydrate (8.2 g), leucine (0.30 g) and PVP (15 g) in water (Milli-Q, 200 mL) and heating the solution to 50-60 °C on a magnetic stirrer plate to promote dissolution of psilocybin trihydrate. The solution was maintained above 30 °C to prevent precipitation of psilocybin during spray drying and holding time.

[0149] The heated solution was subsequently spray-dried using a BUCHI 290 mini spray-dryer with 0.7 mm two-fluid nozzle, 150 mm cap size, inlet temperature 130 +/- 1 °C, outlet temperature range monitored at 82-86 °C, aspirator setting of 90%, air flow rate of 400 L/h and feed rate of 2.5 mL/minute. The prepared solution was spray-dried within 1 h of preparing the feed solution, yielding a fine white powder with powder yields of >70%

Example 13. Preparation of powder blend with spray-dried amorphous psilocybin powder.

[0150] The fine white powder prepared in Example 12 (23.1 g) was blended with direct compression spray-dried lactose (SuperTab 11SD, 62g), microcrystalline cellulose (Avicel PH102, 10g), sodium croscarmellose (Primellose, 2g) and silica (1 g) in a small-scale impellor driven high-shear wet granulator (4M8T, ProcCeptT, Zelzate, Belgium) at 200 revolutions per minute (rpm) for 15 minutes. Magnesium stearate (1.9 g) was then added to the mixture and blended for 4 minutes at 70 rpm.

Example 14. Tableting

[0151 ] The powder blend prepared according to Example 13 was tableted using an eccentric single-punch table press (minipress M II, Riva S.A., Buenos Aires, Argentina). The tablet die and punch used was a standard convex tablet with a 05- inch diameter. The powder was filled in a hopper and set at a punch rate of 40 tablets/min. Said tablets contained 25 mg psilocybin.

Example 15. Psilocybin assay via liquid chromatography [0152] The content of psilocybin in the spray-dried powder of Example 13 and powder blend of Example 14 were quantified by liquid chromatography using a Shamadzu UHPLC Nexera X2 system (Shamadzu Corporation, Kyoto, Japan). Chromatographic separation was performed using a Phenomenex Kinetex 1.6 pm C18 100A (30 x 2.1 mm) LC column used with an elution flow rate of 0.5 mL per minute and a gradient method outlined in Table 5.

Table 5

Example 16. Solid state thermal analysis via Differential Scanning Calorimetry (DSC)

[0153] DSC was performed using a DSC 850 (Perkin Elmer Inc., Massachusetts, USA). Powder samples containing 4 mg of powder were sealed in vented aluminium pans with a 3-bar rating and scanned from 35 to 270 °C at 20 °C/minute.

[0154] Solid state thermal analysis via DSC suggests that the as-received psilocybin trihydrate was present in the crystalline hydrate form (Figure 14), evidenced by a prominent endothermic peak at 60-100 °C and proceeded by another peak at 120 °C, suggesting dehydration, followed by a molecular rearrangement. This was followed by a melting event of anhydrous psilocybin at 217 °C.

[0155] In contrast, the differential thermogram for the spray-dried powder (Figure 15) indicates an amorphous material due to the lack of distinct endothermic peaks relative to psilocybin trihydrate. Transition events were identified at 110 °C and 230 °C, probably coinciding with a change in the physical properties of lactose, leucine and PVP. The first thermal event appears to be a combination of a dehydration and glass transition, whereas the latter resembles a glass transition. The glass transition at these two points occurs at higher temperatures than the spray drying outlet temperature (81-84 °C) and is not expected to have a material effect on the spray drying method used to produce the spray-dried powder as described herein.

Example 17. Crystallinity via X-ray Diffraction (XRD)

[0156] Powder samples were packed onto a steel sample tray and then analysed by a Shimadzu XRD 7000 (Shimadzu Corporation, Kyoto, Japan). Samples were scanned from 10 to 40°, with an angular increment of 27min. The crystalline status of the powders was qualitatively assessed from the diffraction patterns.

[0157] Two different diffraction patterns (Figure 16) were measured for psilocybin trihydrate and the spray-dried powder prepared in Example 12. The presence of one or several prominent peaks at 13° 20, 19° 20 and 23 ° 20 in the Psilocybin trihydrate diffractogram pattern suggests a crystalline material, whereas the absence of the same peaks for the spray-dried powder suggests a largely or completely amorphous material.

Example 18. Tablet mass uniformity

[0158] Tablets (n=20) prepared according to Example 14 were randomly selected and weighed. The mean standard deviation and RSD% were then calculated. Following the European Pharmacopoeial guidelines (EU 2.9.40), no more than two tablet weights could deviate from the average mass by ± 5%, and none can deviate from the average mass by ± 10%. [0159] The mean tablet mass and RSD were 494.19 mg (RSD 1 .61%). None of the tablets deviated from the average mass by ± 5% and the RSD% values were below 2%, indicating high precision.

Example 19. Tablet thickness

[0160] The thickness (height) for ten tablets was measured with a Kincrome 150 mm digital vernier calliper (Kincrome, Victoria, Australia). The mean standard deviation and RSD% were then calculated.

[0161 ] The mean tablet thickness (height) results were 4.22 mm (RSD 0.65%).

Example 20. Tablet hardness

[0162] The force required to break ten individual tablets were tested based on USP 1217 requirements. Tablet hardness was measured using a tablet harness tester (Erweker TBH-210D, ERWEKA GmbH, 63225 Langen (Hessen), Germany). The mean standard deviation and RSD% were then calculated.

[0163] The mean tablet hardness results were 127.5 N (RSD 3.92%).

Example 21. Friability

[0164] At least 6.5 grams of tablets were weighed and placed in a friability drum and run for 100 cycles (25 rpm) using an industry-standard friability tester (Erwka TA 100, ERWEKA GmbH, 63225 Langen (Hessen), Germany). The tablets were then collected and weighed again to measure total mass loss. The percentage loss should be <1.0% to pass the friability frequirements. This test follows the guidelines as per United States Pharmacopoeia (USP) <1216> Tablet Friability monograph.

[0165] The friability percentage losses are 0.14%, meeting the friability requirement of <1%.

Example 21. Disintegration [0166] An industry-standard disintegration unit (ED2L, ElectroLab, Mumbai-400063, India) was used to measure the time for 6 tablets to disintegrate whilst continually immersing in water vessels heated to 37 °C. Six tablets were placed in a six-tube basket rack (with wire mesh on the base) and weighted to prevent the tablets from floating. Prior to the disintegration test, 700 mL of water was added to a 1000 mL vessel and heated to 37 ± 2 °C. The water level was maintained at least 15 mm from the top and 25 mm from the bottom of the wire basket with an immersion (up/down) frequency rate of 29-32 cycles/min. After test commencement, disintegration was observed and timed until all tablet contents had escaped from the bottom of the wire mesh. To meet the disintegration requirements of the United States Pharmacopoeia (USP) <701> Disintegration monograph, the disintegration time should be within 15 minutes.

[0167] The disintegration time for the tablets was 9 minutes and 44 seconds, below the 15 minute maximum requirement.

Example 22. Tablet Dissolution

[0168] Dissolution tests followed the guidelines as per the United States Pharmacopoeia (USP) <711> Dissolution monograph, The drug dissolution rate was determined using a USP II paddle apparatus VK7000 and VK750D bath heater circulator (Vankel Technology Group Inc. Cary, NC, USA) at 37 ± 0.5 °C and a paddle rotating speed of 50 rpm in 900 mL of phosphate buffer pH 5.8. After securing the stirring paddles, the distance between the bottom of the paddle and the bottom of the vessel was set at 2.5 cm.

[0169] One tablet per dissolution vessel was placed into the vessel at the start of the dissolution test. A total of 6 vessels were used. Post each sample collection, 1 mL of phosphate buffer solution was added to the vessel. After commencing the test, a 1 mL sample was withdrawn from the dissolution medium at 0.5, 10, 15, 20, 30 and 45 minutes. Samples were filtered through a 0.45 pm cellulose syringe microfilter and analysed via HPLC.

[0170] The dissolution results for Batch 1 and Batch 2 of the tablets are shown in Figure 17 together with the dissolution profile of 25 mg psilocybin trihydrate in a hydroxymethylpropyl cellulose (HPMC) capsule. The average dissolution concentration at 30 minutes for Batch 1 was 81 .29% and for Batch 2 was 86.58%. The dissolution profiles of the tablets from Batch 1 and Batch 2 produced similar dissolution profiles to the 25 mg psylocybin trihydrate HPMC capsules. All three dissolution profiles attained a mean of > 80% psilocybin by 30 minutes (RSD < 10%). For the first five minutes, the psilocybin trihydrate in the capsule dissolution profile indicated a delay in capsule rupture and release and dissolution of the contents.

[0171 ] It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the above-described embodiments, without departing from the broad general scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

[0172] In the claims which follow and in the preceding description except where the context requires otherwise due to express language or necessary implication, the word “comprise” or variations such as “comprises” or “comprising” is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

Claims

CLAIMS:

1 . A process for improving powder flow characteristics of a compound having crystalline morphology, the process comprising the steps of: a) preparing a feed solution comprising said compound, a stabilizing polymer and an oligosaccharide; and, b) spray-drying the feed solution to produce composite particles comprising a solid dispersion of the compound, the stabilizing polymer and the oligosaccharide, wherein the compound has amorphous morphology.

2. The process according to claim 1 , wherein the compound comprises psilocybin trihydrate.

3. The process according to claim 1 or claim 2, wherein the crystalline morphology is acicular.

4. The process according to any one of the preceding claims, wherein the stabilizing polymer comprises polyvinyl pyrrolidone (PVP).

5. The process according to any one of the preceding claims, wherein the oligosaccharide comprises lactose.

6. A process for improving dissolution of psilocybin trihydrate in an aqueous media, the process comprising the steps of: a) preparing a feed solution comprising psilocybin trihydrate, PVP and lactose; and, b) spray-drying the feed solution to produce composite particles comprising a solid dispersion of amorphous psilocybin, PVP and lactose.

7. The process according to claim 5 or claim 6, wherein the ratio of the amount by weight of psilocybin, PVP, and lactose in the feed solution is about 1 :4:2.

8. The process, according to any one of claims 1 to 7, wherein the feed solution comprises an aqueous solution, optionally with a co-solvent.

9. The process according to any one of claims 5 to 8, wherein the ratio of the amount by weight of psilocybin to solvent in the solution is about 1 :40.

10. The process according to any one of claims 5 to 9, wherein the step of spraydrying the feed solution comprises atomizing the feed solution and introducing the atomized feed solution into a spray-drying chamber having an inlet temperature less than the glass transition temperature (t_g) of said compound.

11 . The process according to claim 10, wherein the inlet temperature is in a range of from 110 °C to 140 °C.

12. The process according to any one of claims 5 to 11 , wherein the composite particles produced in step b) have a particle size distribution of D90 < 20 pm.

13. The process according to any one of claims 5 to 12, wherein the ratio of the amount by weight of psilocybin, PVP, and lactose in the solid dispersion is about 1 :4:2.

14. The process according to any one of the preceding claims further comprising blending the composite particles with a pharmaceutically acceptable diluent to produce a powder blend.

15. The process according to claim 14, wherein the ratio of the amount by weight of the composite particles and the pharmaceutically acceptable diluent in the powder blend is about 1 :10.

16. The process according to claim 14 or claim 15, wherein the pharmaceutically acceptable diluent comprises lactose monohydrate having a particle size distribution D50 < 130 pm.

17. The process according to any one of claims 14 to 16, wherein the powder blend has a Carr's compressibility index of 31% and Hausner ratio of 1 .31 .

18. A powder composition comprising composite particles comprising a solid dispersion of amorphous psilocybin, PVP and lactose.

19. The powder composition according to claim 18 having a particle size distribution of D90 < 20 pm.

20. A pharmaceutical composition comprising composite particles comprising a solid dispersion of amorphous psilocybin, PVP and lactose, and one or more pharmaceutically acceptable excipients and/or adjuvants.

21 . The pharmaceutical composition according to claim 20, wherein the one or more pharmaceutically acceptable excipients and/or adjuvants comprises a pharmaceutically acceptable diluent.

22. The pharmaceutical composition according to claim 21 , wherein the pharmaceutically acceptable diluent comprises lactose having a particle size distribution D50 < 130 pm.

23. The pharmaceutical composition according to claim 21 or claim 22, wherein the ratio of the amount by weight of the composite particles and the one or more pharmaceutically acceptable diluent is about 1 :10.

24. The pharmaceutical composition according to any one of claims 21 to 23, wherein the pharmaceutical composition has a Carr's compressibility index of 31% and Hausner ratio of 1.31.

25. The powder composition according to claim 18 and the pharmaceutical composition according to any one of claims 20 to 24, wherein the composite particles have a particle size distribution of D90 < 20 pm.

26. The powder composition according to claim 18, 19 or claim 25 and the pharmaceutical composition according to any one of claims 20 to 25, wherein the ratio of the amount by weight of psilocybin, PVP, and lactose in the solid dispersion is about 1 :4:2.

27. The powder composition according to claim 18, 19 or claim 25 and the pharmaceutical composition according to any one of claims 20 to 25, further comprising leucine.

28. The powder composition according to claim 27 and the pharmaceutical composition according to claim 27, wherein the ratio of the amount by weight of psilocybin, PVP, and lactose in the solid dispersion is about 1 :1 :1.

29. A feed solution for a spray-dryer comprising psilocybin, PVP and lactose.

30. The feed solution according to claim 29, wherein the feed solution is an aqueous solution.

31 . The feed solution according to claim 29 or claim 30, wherein the ratio of the amount by weight of psilocybin, PVP, and lactose in the feed solution is about 1 :4:2.

32. The feed solution according to claim 30 or claim 31 , wherein the ratio of the amount by weight of psilocybin to water in the aqueous feed solution is about 1 :40.

33. The feed solution according to claim 29 or claim 30, further comprising leucine.

34. The feed solution according to claim 33, wherein the ratio of the amount by weight of psilocybin, PVP, and lactose in the feed solution is about 1 :2:1 .