Compositions containing ultrafine compounds and preparation thereof

Abstract

To provide a stable, non-degradable composition comprising a pharmaceutical grade, inhalable, soluble, and highly bioavailable API.SOLUTION: A composition comprising a pharmaceutical grade cyclodextrin encapsulated active pharmaceutical ingredient (API) having a purity of 99.9% and an increased bioavailability of 200% compared to a formulation of a non-cyclodextrin encapsulated active pharmaceutical ingredient, and a pharmaceutically acceptable carrier, excipient, emulsifier, and / or binder, A water-soluble, stable, non-degradable, edible, inhalable, soluble or drinkable composition in which the active pharmaceutical ingredient is a cannabinoid and the cannabinoid is one or more of cannabidiol (CBD) or (-) - trans - δ 9-tetrahydrocannabinol (δ 9-THC).SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 923,726, filed October 21, 2019, and U.S. Provisional Application No. 62 / 929,455, filed November 1, 2019, the contents of which are incorporated by reference in their entireties.

[0002] This application relates to pharmaceutical-grade, highly bioavailable, ultrafine cyclodextrin-encapsulated active pharmaceutical ingredients, stable, non-degradable, edible, inhalable, soluble, and drinkable compositions comprising the disclosed cyclodextrin-encapsulated active pharmaceutical ingredients, and methods for making the ultrafine cyclodextrin-encapsulated active pharmaceutical ingredients. [Background technology]

[0003] Lipophilic active pharmaceutical ingredients (APIs) are poorly water-soluble, and their extraction and purification are time-consuming processes requiring extraction, distillation, and purification. These processes involve the use of hazardous solvents and often result in products that suffer from low stability and lack of efficacy. Additionally, the resulting API products lack pharmaceutical-grade purity and have poor bioavailability.

[0004] Cannabinoids are lipophilic APIs naturally occurring in the annual plants Cannabis sativa, Cannabis indica, Cannabis ruderalis, and their hybrids. Tetrahydrocannabinol (THC), the most active naturally occurring cannabinoid, is beneficial for the treatment of a wide range of medical conditions, including glaucoma, AIDS wasting, neuropathic pain, treatment of spasticity associated with multiple sclerosis, fibromyalgia, vomiting, and chemotherapy-induced nausea. Cannabidiol (CBD) has no psychotropic effects and is FDA-approved for the treatment of epilepsy. Cannabinol (CBN) is an effective sedative and anti-inflammatory agent. There is growing demand for recreational use of cannabinoids in general, and THC, CBD, and CBN in particular. Psychoactive drugs, such as psychedelics, are also in demand for their effects on states of consciousness. However, the solubility of these APIs in water is limited. For example, currently available cannabidiol (CBD) isolates have a water solubility of only 0.0126 mg / ml.

[0005] Cannabinoids are derived from the precursor cannabigerolic acid (CBGA) or its analog cannabigerovaric acid (CBGVA). Enzymatic conversion of CBGA produces a wide variety of cannabinoids, including (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), (-)-trans-Δ9-tetrahydrocannabiphorolol (Δ9-THCP), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabidiol (CBD), cannabinodiol (CBND), and cannabinol (CBN). Enzymatic conversion of CBGVA produces Δ9-tetrahydrocannabivarin (Δ9-THCV), cannabivarin (CBV), cannabidivarin (CBDV), and cannabichromevarin (CBCV).

[0006] There is a need in the art for the efficient and safe production of stable, non-degradable compositions containing pharmaceutical-grade, inhalable, soluble, and highly bioavailable APIs. Summary of the Invention

[0007] This application presents a solution to the aforementioned problems by providing stable, non-degradable, edible, inhalable, soluble, or drinkable compositions containing pharmaceutical-grade, highly bioavailable, ultrafine cyclodextrin-encapsulated active pharmaceutical ingredients, and a rapid, cost-effective, and easily scalable process for producing pharmaceutical-grade, highly bioavailable, ultrafine cyclodextrin-encapsulated active pharmaceutical ingredients. The disclosed process does not require the use of organic solvents and therefore meets the most restrictive health guideline requirements. The resulting ultrafine pharmaceutical active ingredients can be used for pulmonary and oral delivery, food, and pharmaceutical and medical applications.

[0008] Provided herein are stable, non-degradable, edible, inhalable, soluble, or drinkable compositions comprising a pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredient (API) having 99.9% purity and a 200% increased bioavailability compared to formulations of the non-cyclodextrin-encapsulated active pharmaceutical ingredient, and a pharmaceutically acceptable carrier, excipient, and / or binder.

[0009] Suitable active pharmaceutical ingredients include, but are not limited to, cannabinoids, psychedelics, analgesics, anesthetics, anti-inflammatory agents, antibacterial agents, antiviral agents, anticoagulants, anticonvulsants, antidepressants, and muscle relaxants.

[0010] In some embodiments, the pharmaceutical grade cyclodextrin-encapsulated active pharmaceutical ingredient is in the form of nanoparticles having an average particle size of 100 nm to 40 μm and a size distribution within 1% to 50% of the average particle size.

[0011] In some embodiments, the pharmaceutical grade cyclodextrin-encapsulated active pharmaceutical ingredient is in the form of an ultra-fine dry powder having an average particle size of 100 nm to 5 μm.

[0012] In some embodiments, the pharmaceutical grade cyclodextrin-encapsulated active pharmaceutical ingredient is in the form of a soluble or drinkable solution or suspension.

[0013] In some embodiments, the API is encapsulated in one or more acetylated cyclodextrins. Suitable acetylated cyclodextrins include, but are not limited to, acetylated α-cyclodextrin, acetylated β-cyclodextrin, acetylated γ-cyclodextrin, or any mixture thereof.

[0014] In some embodiments, API is encapsulated in one or more acetylated cyclodextrins and one or more hydrophilic cyclodextrins.Suitable acetylated cyclodextrins include but are not limited to acetylated α-cyclodextrin, acetylated β-cyclodextrin, acetylated γ-cyclodextrin, or any mixture thereof.Suitable hydrophilic cyclodextrins include but are not limited to hydrophilic α-cyclodextrin, hydrophilic β-cyclodextrin, hydrophilic γ-cyclodextrin, or any mixture thereof.

[0015] In some embodiments, the API and one or more acetylated cyclodextrins are in a molar ratio of API:acetylated cyclodextrin ranging from 1:0.5 to 1:10. In some embodiments, the molar ratio of API:acetylated cyclodextrin is 1:0.5, 1:0.75, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, or 1:10.

[0016] In some embodiments, the API is encapsulated in one or more hydrophilic cyclodextrins. Suitable hydrophilic cyclodextrins include, but are not limited to, hydrophilic α-cyclodextrin, hydrophilic β-cyclodextrin, hydrophilic γ-cyclodextrin, or any mixture thereof.

[0017] In some embodiments, the pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredient is a psychedelic such as psilocin or psilocybin.

[0018] In some embodiments, the pharmaceutical grade cyclodextrin-encapsulated active pharmaceutical ingredient is one or more cannabinoids, such as cannabigerolic acid (CBGA), cannabigerovaric acid (CBGVA), tetrahydrocannabinolic acid (THCA), cannabichromenic acid (CBCA), cannabidiolic acid (CBDA), tetrahydrocannabivaric acid (THCVA), cannabichromevaric acid (CBCVA), cannabidivaric acid (CBDVA), (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), trans-Δ9-tetrahydrocannabiphorol (Δ9-THCP), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabidiol (CBD), cannabinodiol (CBND), and cannabinol (CBN).

[0019] In some embodiments, the cannabinoid is cannabidiol (CBD). In some embodiments, the cannabinoid is tetrahydrocannabinol (THC). In some embodiments, one or more cannabinoids are cannabidiol (CBD) and tetrahydrocannabinol (THC). In some embodiments, the cannabinoid is cannabinol (CBN). In some embodiments, the cannabinoid is tetrahydrocannabipherol (THCP).

[0020] Suitable pharmaceutically acceptable carriers, excipients, and binders that can be used in the disclosed compositions include, but are not limited to, sodium citrate, dicalcium phosphate, starch, lactose, sucrose, glucose, mannitol, silicic acid, carboxymethylcellulose, alginate, gelatin, lecithin, polyvinylpyrrolidone, sucrose, acacia, humectants, solubilizers, emulsifiers, disintegrating agents, solution retarding agents, absorption accelerators, wetting agents, absorbents, lubricants, oils, adjuvants, sweeteners, flavoring agents, perfumes, buffers, and any mixtures thereof.

[0021] In some embodiments, the disclosed compositions are in the form of an inhaler, capsule, tablet, pill, powder, beads, lozenges, dragees, granules, dietary composition, food, beverage, emulsion, solution, suspension, cream, gel, sunscreen, shampoo, toothpaste, transdermal patch, plaster, implant, syrup, elixir, injection, or infusion.

[0022] In some embodiments, the disclosed compositions are formulated in immediate release, sustained release, or controlled release forms.

[0023] In some embodiments, the disclosed compositions further comprise a coating. Suitable coatings include, but are not limited to, enteric coatings, extended-release coatings, sustained-release coatings, delayed-release coatings, and immediate-release coatings.

[0024] The disclosed compositions can be formulated for oral, mucosal, pulmonary, topical, parenteral, transdermal, or submucosal administration.

[0025] In some embodiments, the disclosed compositions are in the form of a food product. Suitable food products include, but are not limited to, bread, cookies, soup, cereal, salad, sandwiches, sprouts, vegetables, or candy.

[0026] In some embodiments, the disclosed compositions are in the form of a beverage. Suitable beverages include, but are not limited to, tea, juice, syrup, soda, fermented drinks, alcoholic drinks, non-alcoholic drinks, distilled drinks, and brewed drinks.

[0027] The foregoing and other features of the present disclosure will become more apparent from the following detailed description, which proceeds with reference to the accompanying drawings. [Brief explanation of the drawings]

[0028] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate one or more examples of embodiments and, together with the description of the exemplary embodiments, serve to explain the principles and implementation of the embodiments.

[0029] [Figure 1A] 1 shows CBD isolate before processing. The CBD isolate has a crystalline morphology and a large amount of aggregation between large particles. [Figure 1B] Figure 1 shows the CBD distillate after treatment at a pressure of 3500 psi and a temperature of 40°C. The resulting distillate particles exhibited a spherical amorphous morphology and particle sizes ranging from 100 nm to 40 μm. [Figure 2A] Figure 1 shows a 32x magnification of purified CBD nanoparticles complexed with α-cyclodextrin at a cannabinoid:cyclodextrin molar ratio of 1:2.5 w / w (250 mg CBD complexed with 100 mg α-cyclodextrin) produced by the disclosed method. The CBD nanoparticles have a spherical morphology and particle sizes ranging from 100 nm to 40 μm. [Figure 2B] Figure 1 shows a 200x magnification of purified CBD nanoparticles complexed with α-cyclodextrin at a cannabinoid:cyclodextrin molar ratio of 1:2.5 w / w (250 mg CBD complexed with 100 mg α-cyclodextrin) produced by the disclosed method. The CBD nanoparticles have a spherical morphology and particle sizes ranging from 100 nm to 40 μm. [Figure 3]This shows CBD isolate crystals before processing. The crystals are insoluble in both acid and water. [Figure 4] Figure 1 shows purified CBD nanoparticles in water after processing, showing that the CBD nanoparticles are completely dissolved in the water. [Figure 5] Figure 1 shows purified CBD nanoparticles in an acidic medium that mimics stomach conditions after processing. The CBD nanoparticles are completely dissolved in the acidic solution, and the solution is clear. [Figure 6] This diagram shows the equipment used for rapid expansion of supercritical solutions. Canister 1 contains a solvent fluid, such as CO2 (99.0%). Inlet valve 2 opens and controls the flow to the inlet of HPLC pump 3. Outlet valve 4 opens and controls the flow of high-pressure solvent to extraction vessel 8. Pressure gauge 5 indicates the pressure of the solvent in the inlet line and extraction vessel 8. Thermometer 6 indicates the internal temperature of extraction vessel 8. Heating band 7 regulates the internal heat of extraction vessel 8. Extraction vessel 8 contains a solute to be mixed and dissolved in the supercritical fluid. Spray valve 9 dispenses the supercritical solution in the extraction vessel via spray nozzle 11 into precipitation / collection chamber 10, where the process takes place and the final product is collected. Pressure-responsive valve or vent 12 reduces the pressure in precipitation / collection chamber 10. [Figure 7] 1 shows a simplified apparatus for some embodiments of the processes provided herein. An API and one or more acetylated cyclodextrins are inserted into heated and pressurized vessel 1 via a supply valve. Supercritical, subcritical, propellant, or liquid carbon dioxide is then released from a CO tank via supply valve 5, cooled in cooling chamber 3, and pumped by pump 4 through inlet valve 6 into heated and pressurized vessel 1, dissolving the API and acetylated cyclodextrin into a cyclodextrin-encapsulated API solution. This solution then passes through transfer valve 8, is depressurized using a short burst through nozzle 9, and is collected in powder collection vessel 2 and sorted by particle size via final product outlet 10. [Figure 8]1 shows a simplified apparatus for an additional embodiment of the process provided herein. One or more hydrophilic cyclodextrins are fed into heated and pressurized vessel 12 via supply valve 22 and dissolved in a hydrophilic liquid at controlled pressure and temperature via pressure control valve 21 to form an aqueous hydrophilic cyclodextrin solution. The API is inserted into heated and pressurized vessel 11 via supply valve 17. Supercritical, subcritical, propellant, or liquid carbon dioxide is then released from a CO2 tank via supply valve 15, cooled in cooling chamber 13, and pumped by pump 14 through inlet valve 16 into heated and pressurized vessel 11 to dissolve the API. This API solution then passes through transfer valve 18 and is depressurized using short bursts through nozzle 19 into heated and pressurized vessel 12, dispersing droplets of the API solution into the aqueous cyclodextrin solution. The water-soluble hydrophilic API concentrate thus formed is collected via final product outlet 20. [Figure 9] 1 shows the dissolution profiles of cyclodextrin-encapsulated API samples compared to unprocessed API containing equivalent amounts of API. DETAILED DESCRIPTION OF THE INVENTION

[0030] The following explanations of terms are provided to better explain the present disclosure and to guide those skilled in the art in practicing the present disclosure. As used herein, "comprising" means "including" and does not mean that the compositions and methods exclude unrecited elements. When used to define compositions and methods, "consisting essentially of" shall mean excluding other elements of any essential importance to the combination. For example, a composition consisting essentially of the elements defined herein does not exclude other elements that do not materially affect the basic and novel characteristics of the claimed invention. "Consisting of" shall mean excluding more than trace amounts of other recited components and substantial method steps. The singular forms "a," "an," or "the" include plural references unless the context clearly dictates otherwise. The term "or" refers to a single element of stated alternative elements or a combination of two or more elements unless the context clearly dictates otherwise. All numerical designations, including ranges, such as pH, temperature, time, concentration, amount, and molecular weight, are approximations that vary by (+) or (-) 10%, 1%, or 0.1%, as appropriate. It should also be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such reagents are known in the art. Unless otherwise explained, 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 disclosure belongs. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0031] In order to facilitate review of the various embodiments of the disclosure, the following explanations of specific terms are provided:

[0032] About: A term used to indicate a change in value by + / - 10% of the value, or optionally + / - 5% of the value, or in some embodiments, + / - 1% of the value.

[0033] Administer: To provide or give a composition, such as a supplement composition, to a subject by an effective route. Application is local. Exemplary application routes include, but are not limited to, oral and topical routes.

[0034] Agitate or Stir: A mechanical action that can include, but is not limited to, rotating, vibrating, vortexing, whirling, shaking, sonicating, stirring, or any action that causes mixing. Mechanical actions include actions performed by hand or with a rotating device.

[0035] Active Pharmaceutical Ingredient: A biologically active ingredient in a finished product that has a direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or in the restoration, correction, or modification of one or more physiological functions in a subject, such as a human or animal subject.

[0036] Alcohol: an organic compound containing a hydroxyl functional group -OH attached to a carbon.

[0037] Analog: A compound that has a similar structure to another compound, but differs from it, for example, in one or more atoms, functional groups, or substructures. API analogs include compounds that are structurally related to naturally occurring APIs but whose chemical and biological properties may differ from those of the naturally occurring API, as well as compounds derived from naturally occurring APIs by chemical, biological, or semisynthetic transformation of the naturally occurring API.

[0038] Cannabinoid: A diverse class of chemical compounds that activate cannabinoid receptors. Cannabinoids produced by plants are called phytocannabinoids. Typical cannabinoids isolated from cannabis plants include, but are not limited to, tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), and cannabigerol monomethyl ether (CBGM).

[0039] Cell: A living biological cell, which may or may not be identical to the parent cell, its progeny, or potential progeny.

[0040] Bring into contact: To bring into direct physical association.

[0041] Co-solvent: A solvent added to a fluid in an amount less than 50% of the total volume.

[0042] Cyclodextrin: A family of cyclic oligosaccharides produced from starch by enzymatic conversion and whose structure includes a macrocyclic ring of α-D-glucopyranoside units linked by α-1,4 glycosidic bonds. Typical cyclodextrins contain six to eight glucose subunits within the ring, forming a cone shape. α-Cyclodextrin contains six glucose subunits, β-Cyclodextrin contains seven glucose subunits, and γ-Cyclodextrin contains eight glucose subunits. Cyclodextrins have a hydrophobic inner core and a hydrophilic exterior, allowing them to form complexes with hydrophobic compounds.

[0043] Effective amount: An amount of an active agent (alone or together with one or more other active agents) sufficient to induce a desired response, e.g., an amount sufficient to prevent, treat, reduce, and / or ameliorate a condition.

[0044] Emulsifier: A surfactant that reduces the interfacial tension between oil and water, minimizing the surface energy resulting from the formation of small droplets. Emulsifiers include gums, fatty acid conjugates, and cationic, anionic, and amphiphilic surfactants, which can stabilize emulsions by suspending the oil phase, coating the oil droplets, and preventing the separation of the internal oil phase. The membrane coating produced by the emulsifier is a barrier between the immiscible phases, which also prevents the association, solidification, and coalescence of the droplets. Examples of emulsifiers include lecithin, glyceryl monostearate, methylcellulose, sodium lauryl sulfate, sodium oleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristrearate, tragacanth, triethanolamine oleate, polyethylene sorbitan monolaurate, poloxamer, detergents, Tween 80 (polyoxyethylene sorbitan monooleate), Tween 20 (polyoxyethylene sorbitan monolaurate), cetearyl glucoside, polyglucosides, sorbitan monooleate (Span 80), sorbitan monolaurate (Span 20), polyoxyethylene monostearate (Myrj 45), polyoxyethylene vegetable oil (Emulphor), cetylpyridinium chloride, polysaccharide gums, xanthan gum, tragacanth, gum arabica, acacia, or proteins and conjugated proteins that can form and protect stable oils in glycerin emulsions.

[0045] Hydrophilic: A polymer, substance, or compound capable of absorbing more than 10% water at 100% relative humidity (RH).

[0046] Hydrophobic: A polymer, substance, or compound that can absorb less than 1% water at 100% relative humidity (RH).

[0047] Lipophilic: A substance or compound that has an affinity for non-polar environments compared to polar or aqueous environments.

[0048] Nanoparticle: a particle of matter measurable on the nanometer scale. Nanoparticles can be in solid or semi-solid form.

[0049] Oil: Any fatty substance in the form of a viscous liquid at room temperature (25°C) and atmospheric pressure (760 mmHg). Oils are hydrophobic and lipophilic, have a high carbon and hydrogen content, and are usually flammable and surface active. Oils can be of animal, vegetable, or petrochemical origin and can be volatile or non-volatile. Oils can be used for food, fuel, medical purposes, and to make paints and plastics.

[0050] Organic solvent: a hydrocarbon-based solvent, optionally containing one or more polar groups, capable of dissolving substances that have low solubility in water.

[0051] Permeation enhancer: A natural or synthetic molecule that facilitates the transport of a co-administered active agent across a biological membrane.

[0052] pH adjuster or pH modifier: A molecule or buffer used to achieve the desired pH control in a formulation. Exemplary pH modifiers include acids (e.g., acetic acid, adipic acid, carbonic acid, citric acid, fumaric acid, phosphoric acid, sorbic acid, succinic acid, tartaric acid), basic pH modifiers (e.g., magnesium oxide, tribasic potassium phosphate), and pharmaceutically acceptable salts thereof.

[0053] Psychedelic drugs: hallucinogens that induce abnormal states of consciousness and psychedelic experiences via serotonin 2A receptor agonism.

[0054] Purify or purify: Any technique or method that increases the degree of purity of a substance of interest, such as an enzyme, protein, or compound from a sample containing the substance of interest. Non-limiting examples of purification methods include silica gel column chromatography, size exclusion chromatography, hydrophobic interaction chromatography, ion exchange chromatography, including but not limited to cation and anion exchange chromatography, free-flow electrophoresis, high performance liquid chromatography (HPLC), and differential precipitation.

[0055] Purity: The quality of an unadulterated, uncontaminated, and safe product obtained by the disclosed method and meeting pharmaceutical standards.

[0056] Recovery: A process involving the isolation and collection of a product from a reaction mixture. Recovery methods can include, but are not limited to, chromatography, e.g., silica gel chromatography and HPLC, activated carbon treatment, filtration, distillation, precipitation, drying, chemical derivatization, and any combination thereof.

[0057] Supercritical fluid: Any substance at a temperature and pressure above its critical point where there are no distinct liquid and gas phases. The solubility of a material in a fluid increases as the density of the fluid increases. Fluid density increases with pressure, and at a constant density, the solubility of a material in a fluid increases as temperature increases. Exemplary supercritical fluids include, but are not limited to, carbon dioxide, water, methane, propane, ethane, ethylene, propylene, methanol, ethanol, acetone, and nitrogen oxides.

[0058] Viscosity: A measure of a fluid's resistance to gradual deformation due to shear or tensile stress.

[0059] Water-immiscible: any non-aqueous or hydrophobic fluid, liquid, or solvent that separates from solution into two distinct phases when mixed with water.

[0060] Water-insoluble: A compound or composition that has a solubility in water of less than 5%, less than 3%, or less than 1%, as measured in water at 20°C.

[0061] Methods for producing highly bioavailable edible, inhalable, soluble, or drinkable pharmaceutical-grade pure active pharmaceutical ingredients The development of efficient processes for the production of pure lipophilic API compounds with high bioavailability has been hindered to date by the API's low solubility in aqueous and acidic conditions. As a result, the preparation and purification of traditional lipophilic APIs is a time-consuming process that often requires the use of toxic organic solvents. In addition, APIs produced by currently available methods suffer from a lack of purity and have low bioavailability.

[0062] Disclosed herein is a rapid and efficient method that overcomes these challenges by using supercritical, subcritical, propellant, or liquid carbon dioxide and acetylated and / or hydrophilic cyclodextrins to create high-purity, ultrafine API-cyclodextrin inclusion complexes suitable for pulmonary and oral delivery. The method provided herein significantly reduces API particle size, does not involve the use of toxic organic solvents, and produces pure active pharmaceutical compounds that meet the most stringent health requirements. Because cyclodextrin encapsulation protects the API from degradation after production, pure active pharmaceutical compounds produced according to the disclosed method are highly stable for extended periods, such as 16 months or more at room temperature, and do not degrade over time. In addition, because carbon dioxide is a gas at atmospheric pressure, CO removal is much faster and safer than organic solvent removal, and no residual solvent remains in the final product.

[0063] Thus, in some embodiments, a method is provided that includes: (i) dissolving an API and one or more acetylated cyclodextrins in supercritical, subcritical, propellant, or liquid carbon dioxide in a reaction chamber; (ii) pumping the carbon dioxide at a set pressure and a set temperature for a predetermined period of time to obtain an acetylated cyclodextrin-encapsulated API solution; (iii) decompressing the acetylated cyclodextrin-encapsulated API solution; (iv) spraying the acetylated cyclodextrin-encapsulated API solution through a nozzle into a heated precipitator to obtain ultrafine inhalable nanoparticles of the acetylated cyclodextrin-encapsulated active pharmaceutical ingredient; and (v) collecting and sorting the ultrafine inhalable nanoparticles of the acetylated cyclodextrin-encapsulated active pharmaceutical ingredient by particle size.

[0064] The disclosed method produces inhalable, pharmaceutical-grade, highly bioavailable ultrafine nanoparticles of cyclodextrin-encapsulated active pharmaceutical ingredients. The inhalable ultrafine nanoparticles have an average particle size of 100 nm to 40 μm and a size distribution within about 1% to about 50% of the average particle size. The ultrafine nanoparticles can also be added to foods such as solid foods, beverages, seasonings, and dietary supplements, and can be used in medical and pharmaceutical applications in immediate-release, sustained-release, and controlled-release formulations for long-term and sustained effects.

[0065] In some embodiments, the method includes (i) milling a hydrophilic cyclodextrin into particles having an average particle size of 100 nm to 5 μm; (ii) dissolving an API and one or more acetylated cyclodextrins in supercritical, subcritical, propellant, or liquid carbon dioxide in a reaction chamber; (iii) pumping carbon dioxide at a set pressure and a set temperature for a predetermined period of time to obtain an acetylated cyclodextrin-encapsulated API solution; and (iv) decompressing the acetylated cyclodextrin-encapsulated API solution. (v) adding hydrophilic cyclodextrin particles to the acetylated cyclodextrin-encapsulated API solution to form a hydrophilic cyclodextrin suspension-acetylated cyclodextrin-encapsulated API solution mixture; (vi) spraying the mixture through a nozzle into a heated precipitator to obtain an ultra-fine inhalable dry powder of cyclodextrin-encapsulated active pharmaceutical ingredient; and (vii) collecting and sorting the ultra-fine inhalable dry powder of cyclodextrin-encapsulated active pharmaceutical ingredient by particle size.

[0066] The disclosed method produces pharmaceutical-grade, highly bioavailable, ultrafine, inhalable dry powders of cyclodextrin-encapsulated active pharmaceutical ingredients. The particle size of the dry powder can be varied by determining the particle size of the hydrophilic cyclodextrin, rather than by dissolving the powder in carbon dioxide to form a suspension. The hydrophobicity of the inhalable dry powder is controlled by adjusting the ratio between acetylated cyclodextrin and hydrophilic cyclodextrin. The dry powder produced in this manner is readily soluble in water, hydrophilic liquids, brewed or fermented alcoholic and non-alcoholic beverages, and juices. It can be added to foods such as solid foods, beverages, seasonings, and dietary supplements, and can be used in medical and pharmaceutical applications in immediate-release, sustained-release, and controlled-release formulations for long-term and sustained effects.

[0067] In additional embodiments, a method is provided that includes: (i) dissolving a hydrophilic cyclodextrin in a hydrophilic liquid at controlled pressure and temperature to form an aqueous hydrophilic cyclodextrin solution; (ii) dissolving an API in supercritical, subcritical, propellant, or liquid carbon dioxide in a reaction chamber; (iii) pumping the carbon dioxide at a set pressure and a set temperature for a predetermined period of time to obtain an API solution; (iv) decompressing the API solution; and (v) spraying the API solution through a nozzle into the aqueous hydrophilic cyclodextrin solution to obtain a drinkable solution or suspension of the hydrophilic cyclodextrin-encapsulated active pharmaceutical ingredient. The hydrophilic liquid may include, but is not limited to, water, juice, syrup, milk, or an alcoholic beverage, optionally containing excipients. In some embodiments, the controlled pressure is 50-100 bars, and the controlled temperature is 30-70°C. The API solution is sprayed into an aqueous cyclodextrin solution to form API droplets that disperse in the aqueous cyclodextrin solution, producing a water-soluble cyclodextrin-encapsulated API concentrate. The aqueous cyclodextrin solution may contain stabilizers, thickeners, and surfactants to improve the stability of the API compound in solution.

[0068] The disclosed method produces pharmaceutical-grade, highly bioavailable, soluble or drinkable solutions or suspensions containing ultrafine cyclodextrin-encapsulated active pharmaceutical ingredients. The cyclodextrin-encapsulated API solutions and suspensions are ready for consumption without any further preparation and can be diluted in water, hydrophilic liquids, brewed or fermented alcoholic and non-alcoholic beverages, juice, or any other drinkable liquid.

[0069] Suitable active pharmaceutical ingredients that can be treated according to the disclosed methods can include, but are not limited to, any form of cannabinoid, psychedelic, analgesic, anesthetic, anti-inflammatory, antibacterial, antiviral, anticoagulant, anticonvulsant, antidepressant, and muscle relaxant.

[0070] The API may be in the form of a crude plant extract, distillate, purified distillate, twice purified distillate, triple purified distillate, or isolate. The plant extract may contain plant materials such as lipids and waxes, chlorophyll, and terpenes such as myrcene, geraniol, limonene, terpineol, pinene, menthol, thymol, carvacrol, camphor, and sesquiterpenes. The distillate can be prepared by mixing the extract with alcohol, filtering the mixture to remove the plant material, and then heating to remove the alcohol. For further purification, the distillate can be heated to perform short-path distillation, and this process can be repeated several times to obtain twice purified distillate, triple purified distillate, or isolate with higher purity. In an alternative embodiment, the API may be in a crystalline form.

[0071] Suitable cannabinoids and cannabinoid precursors include, but are not limited to, cannabigerolic acid (CBGA), cannabigerovaric acid (CBGVA), tetrahydrocannabinolic acid (THCA), cannabichromenic acid (CBCA), cannabidiolic acid (CBDA), tetrahydrocannabivaric acid (THCVA), cannabichromevaric acid (CBCVA), cannabidivaric acid (CBDVA), (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), (-)-trans-Δ9-tetrahydrocannabiferol (Δ9-THCP), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabidiol (CBD), cannabinodiol (CBND), cannabinol (CBN), analogs thereof, or any mixtures thereof.

[0072] Suitable psychedelics include, but are not limited to, psilocin and psilocybin.

[0073] In some embodiments, the methods disclosed herein provide for the acetylation of cyclodextrins to increase the Lewis acid:Lewis base interaction between the cyclodextrins and carbon dioxide, significantly increasing their solubility. In other embodiments, the methods disclosed herein provide for the use of acetylated cyclodextrins to increase the solubility of APIs in carbon dioxide, and hydrophilic cyclodextrins to form inhalable powders of ultrafine cyclodextrin-encapsulated APIs. In other embodiments, the methods disclosed herein provide for the use of hydrophilic cyclodextrins to disperse API droplets and produce water-soluble API concentrates.

[0074] Suitable cyclodextrins include, but are not limited to, α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. Acetylated forms of cyclodextrin include, but are not limited to, α-cyclodextrin exadeacetate (AACD), β-cyclodextrin heneicosaacetate (ABCD), and γ-cyclodextrin octadeacetate (AGCD). Suitable hydrophilic cyclodextrins include, but are not limited to, hydrophilic α-cyclodextrin, hydrophilic β-cyclodextrin, hydrophilic γ-cyclodextrin, and any mixture thereof.

[0075] For processing, API extracts, distillates, purified distillates, twice purified distillates, triple purified distillates, or high quality isolates can be combined with acetylated and / or hydrophilic cyclodextrins at molar ratios of API:cyclodextrin ranging from 1:0.5 to 1:10. In some examples, the molar ratio of API:cyclodextrin is 1:0.5, 1:0.75, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, or 1:10.

[0076] The API and cyclodextrin can be mixed for a period of time defined by the type and form of API used, the type of cyclodextrin used, the temperature and pressure conditions, and the force used for mixing. In some embodiments, the preset pressure is in the range of 2,500 psi to 6,500 psi, and the preset temperature is in the range of 37°C to 55°C. After pressurization, the API solution is decompressed at supersonic speeds to induce particle formation by expelling the API solution through a nozzle for short bursts. The nozzle diameter is in the range of 1 μm to 10 μm. In some embodiments, the nozzle diameter is 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, or 7 μm. Decompression is best achieved by expelling the supercritical solution through the nozzle in short bursts, such as 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 second bursts.

[0077] The supercritical, subcritical, propellant, or liquid carbon dioxide may include an excipient or dispersant. In some embodiments, the disclosed method may further include (vi) converting the carbon dioxide to a gas, (vii) filtering and pressurizing the carbon dioxide gas to achieve a supercritical, subcritical, propellant, or liquid state, and (viii) recycling the carbon dioxide within the reaction chamber for subsequent batch processing.

[0078] The finely divided cannabinoid nanoparticles produced by the methods provided herein have an average particle size of about 100 nm to about 40 μm, and a size distribution within about 1% to about 50% of the average particle size.

[0079] The methods provided herein offer many advantages. In particular, the disclosed methods significantly reduce API particle size, do not require the use of toxic organic solvents, and rapidly and efficiently produce highly pure, ultrafine API-cyclodextrin inclusion complexes in the form of nanoparticles, dry powders, solutions, and suspensions suitable for pulmonary and / or oral delivery. The cyclodextrin-encapsulated APIs produced by the disclosed methods are 99.9% pure, have a 200% increased bioavailability compared to formulations of non-cyclodextrin-encapsulated active pharmaceutical ingredients, and have excellent stability at room temperature for extended periods of time, such as 16 months, 24 months, 3 years, 4 years, and 5 years.

[0080] Equipment for producing pharmaceutical-grade pure ultrafine cyclodextrin encapsulated API Diagrams of exemplary devices for carrying out the disclosed methods are shown in Figures 6, 7, and 8. However, any device, system, or equipment known in the art can be used to carry out the methods provided herein.

[0081] In the diagram shown in Figure 6, canister 1 contains a 99% pure fluid, such as CO2. Inlet valve 2 opens and controls the flow of solvent fluid to an inlet that accesses HPLC pump 3. Outlet valve 4 opens and controls the flow of high-pressure solvent to extraction vessel 8. Pressure gauge 5, integrated as part of the HPLC pump, indicates the pressure of the solvent in the inlet line and extraction vessel 8. Thermometer 6 indicates the internal temperature of extraction vessel 8. Heating band 7 regulates the internal level of heat in extraction vessel 8. Extraction vessel 8 contains an API, with or without acetylated cyclodextrin, that is dissolved in CO2. Once the API solution is formed, spray valve 9 depressurizes the API solution in the extraction vessel by releasing the solution through spray nozzle 11 into precipitation chamber 10, where the final product is collected. Pressure-responsive valve or vent 12 reduces the pressure in precipitation chamber 10, resulting in the spontaneous formation of ultrafine API nanoparticles or dry powder, which can then be collected and sorted according to their size.

[0082] In the diagram shown in Figure 7, the API and one or more acetylated cyclodextrins are inserted into heated and pressurized vessel 1 via supply valve. Supercritical, subcritical, propellant, or liquid carbon dioxide is then released from a CO2 tank via supply valve 5, cooled in cooling chamber 3, and pumped by pump 4 through inlet valve 6 into heated and pressurized vessel 1 to dissolve the API and acetylated cyclodextrin into a cyclodextrin-encapsulated API solution. This solution then passes through transfer valve 8, is depressurized using short bursts through nozzle 9, and is collected in powder collection vessel 2 and sorted by particle size via final product outlet 10.

[0083] In the diagram shown in Figure 8, one or more hydrophilic cyclodextrins are fed into heated and pressurized vessel 12 via supply valve 22 and dissolved in a hydrophilic liquid at controlled pressure and temperature via pressure control valve 21 to form an aqueous hydrophilic cyclodextrin solution. The API is inserted into heated and pressurized vessel 11 via supply valve 17. Supercritical, subcritical, propellant, or liquid carbon dioxide is then released from a CO2 tank via supply valve 15, cooled in cooling chamber 13, and pumped by pump 14 through inlet valve 16 into heated and pressurized vessel 11 to dissolve the API. This API solution then passes through transfer valve 18 and is depressurized using short bursts through nozzle 19 into heated and pressurized vessel 12, dispersing droplets of the API solution into the aqueous cyclodextrin solution. The water-soluble hydrophilic API concentrate thus formed is collected via final product outlet 20.

[0084] Pharmaceutical Grade Ultrafine Cyclodextrin Encapsulated API Additionally, provided herein are stable, edible, inhalable, soluble, or drinkable pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredients produced by the disclosed methods. The stable, edible, inhalable, soluble, or drinkable pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredients have a purity of 99.9% and a 200% increased bioavailability compared to formulations of non-cyclodextrin-encapsulated active pharmaceutical ingredients. The active pharmaceutical ingredient may be a cannabinoid, psychedelic, analgesic, anesthetic, anti-inflammatory, antibacterial, antiviral, anticoagulant, anticonvulsant, antidepressant, or muscle relaxant.

[0085] In some embodiments, the pharmaceutical grade cyclodextrin-encapsulated active pharmaceutical ingredient is in the form of inhalable nanoparticles having an average particle size of 100 nm to 40 μm and a size distribution within 1% to 50% of the average particle size.

[0086] In some embodiments, the pharmaceutical grade cyclodextrin-encapsulated active pharmaceutical ingredient is in the form of an inhalable ultra-fine dry powder having an average particle size of 100 nm to 5 μm.

[0087] In some embodiments, the pharmaceutical grade cyclodextrin-encapsulated active pharmaceutical ingredient is in the form of a drinkable or soluble solution or suspension.

[0088] Due to their stability, the disclosed edible, inhalable, soluble, or drinkable pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredients can be easily manufactured, mixed with other edible ingredients or preparations, and consumed or distributed without risk of resuspension or separation. In particular, the disclosed edible, inhalable, soluble, or drinkable pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredients are completely soluble in water, have an average bioavailability increased by 200% (+ / - 10%) compared to non-cyclodextrin-encapsulated active pharmaceutical ingredients, and can be maintained indefinitely after production.

[0089] Compositions Comprising Pharmaceutical Grade Ultrafine Cyclodextrin-Encapsulated API The disclosed edible, inhalable, soluble, or drinkable pharmaceutical grade cyclodextrin-encapsulated active pharmaceutical ingredients can be formulated as compositions for oral, pulmonary, enteral, parenteral, intravenous, topical, mucosal, and submucosal administration, such as in prescription, non-prescription, and retail offerings of medical and pharmaceutical products, for the treatment, prevention, and relief of diseases, disorders, illnesses, and complaints including, but not limited to, Alzheimer's disease, epilepsy, mild and chronic pain, chemotherapy-induced peripheral neuropathy, insomnia, opioid and drug addiction, addiction prevention, inflammatory lung diseases, anxiety disorders, PTSD, panic attacks, phobias, allergies, coronaviruses, respiratory distress disorders and diseases including asthma and COPD, and Meniere's disease.

[0090] The disclosed compositions can be formulated in immediate release, sustained release, or controlled release form, and can be coated with compounds that accelerate or reduce API release.Therefore, the disclosed compositions can include enteric coating, extended release coating, sustained release coating, delayed release coating, and immediate release coating.The methods used to coat compositions and the materials used to prepare such coatings are well known in the field of pharmaceutical formulation.Coating materials can include, but are not limited to, glyceryl monostearate, glyceryl distearate, polymeric substances, and waxes.

[0091] Solid dosage forms suitable for oral administration can include, but are not limited to, capsules, tablets, pills, powders, beads, lozenges, dragees, granules, aerogels, crumbles, snaps, and the like. Such solid dosage forms may include at least one pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate; fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, silicates, and sodium carbonate; solution retardants, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as acetyl alcohol and glycerol monostearate; absorbents, such as kaolin and bentonite clay; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and buffers.

[0092] Solid oral dosage forms can also be formulated as edible compositions and include any ingestible preparation containing the disclosed cannabinoid nanoparticles mixed with food. The food can be dried, cooked, boiled, freeze-dried or baked, and can be in the form of bread, cookies, tea, juice, soup, cereal, salad, sandwich, sprouts, vegetables, candy, pills, tablets, etc.

[0093] Liquid dosage forms for oral administration can include, but are not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs, which may contain inert diluents commonly used in the art. For example, liquid formulations may contain water, polyethylene glycol ether, or any other pharmaceutically acceptable solvent; solubilizing agents and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, and dimethylformamide; oils, such as cottonseed, peanut, corn, germ, olive, castor, and sesame oil; glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan; adjuvants, such as wetting agents; emulsifying and suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, and mixtures thereof; sweetening agents, flavoring agents, fragrances, and any mixtures thereof.

[0094] Liquid oral dosage forms can also be formulated as edible compositions and can include any ingestible preparation containing the disclosed cannabinoid nanoparticles mixed with a drink product, including, but not limited to, tea, juice, syrup, soup, soda, brewed drinks, fermented drinks, distilled drinks, and the like.

[0095] Parenteral administration can include subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques. Suspensions for parenteral administration can be encapsulated using various polymers, sugars, and chelating agents to obtain stable preparations or granules. Polymers for encapsulation can include cross-linked polymers, non-cross-linked polymers, or polymers dispersed within the crystalline structure of sugar starch or protein molecules. Granules can be further processed to obtain sublingual membranes, suppositories, dispersible powders, tablets, gel capsules, etc.

[0096] Compositions for parenteral injection may include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include, but are not limited to, water, ethanol, polyols such as glycerol, propylene glycol, polyethylene glycol, carboxymethylcellulose, and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants. The disclosed compositions for parenteral administration may also contain auxiliary agents, such as, but not limited to, preservatives, wetting agents, emulsifying agents, and dispersing agents, isotonic agents such as sugars, sodium chloride, and agents that delay absorption, such as aluminum monostearate and gelatin.

[0097] Injectable depot forms can be made by forming matrices of the API in biodegradable polymers, such as, but not limited to, polylactide-polyglycolide, poly(orthoesters), and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the disclosed API in liposomes that are compatible with body tissues. Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use.

[0098] The disclosed compositions can be prepared in the form of inhalation preparations for pulmonary delivery.Suitable preparations include but are not limited to aerosols, inhalers, breath-activated inhalers, dry powder inhalers, capsules and blister inhalers, multi-dose inhalers, metered-dose inhalers, vaporizers, sprays, nasal sprays, etc., and can contain various carriers or excipients known in the formulation field.

[0099] The topical composition may be in the form of a powder, liquid solution, emulsion, liquid suspension, cream, ointment, gel, gum gel, mouthwash, sunscreen, toothpaste, shampoo, conditioner, liquid soap, and may be applied to the face, eyes, lips, teeth, hair, forehead, nails, hands, feet, shoulders, arms, back, or legs of a subject. Suitable subjects include mammals, e.g., animal or human subjects.

[0100] The disclosed compositions may be in the form of a patch, wound dressing, bandage, plaster, stent, implant, aerogel, crumble, snap, or hydrogel for transdermal application, and may be formulated for immediate release, extended release, or sustained release.Various additives known to those skilled in the art may be included in transdermal formulations.Examples of additives include, but are not limited to, solubilizers, skin permeation enhancers, preservatives (e.g., antioxidants), humectants, gelling agents, buffers, surfactants, emulsifiers, emollients, thickeners, stabilizers, moisturizers, dispersants, and pharmaceutical carriers.Examples of humectants include, but are not limited to, jojoba oil and evening primrose oil. Suitable skin permeation enhancers include, but are not limited to, lower alkanols such as methanol, ethanol, and 2-propanol; alkyl methyl sulfoxides such as dimethyl sulfoxide (DMSO), decyl methyl sulfoxide (C10 MSO), and tetradecyl methyl sulfoxide; pyrrolidone, urea; N,N-diethyl-m-toluamide; C2-C6 alkanediols, dimethylformamide (DMF), N,N-dimethylacetamide (DMA), and tetrahydrofurfuryl alcohol. Examples of solubilizers include, but are not limited to, hydrophilic ethers such as diethylene glycol monoethyl ether and diethylene glycol monoethyl ether oleate; polyoxy 35 castor oil, polyoxy 40 hydrogenated castor oil, polyethylene glycol (PEG), and polyethylene glycol derivatives such as PEG-8 caprylic / capric glyceride; alkyl methyl sulfoxides such as DMSO; pyrrolidone, DMA, and mixtures thereof.

[0101] Prevention and / or treatment of infection can be achieved by including antibiotics and various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, and the like, in the disclosed compositions.

[0102] The disclosed compositions may also be administered by a variety of other routes, including mucosal, subcutaneous, and intramuscular administration, and may contain a variety of carriers or excipients known in the formulation art, such as non-toxic solid, semi-solid, or liquid fillers, diluents, encapsulating materials, and pharmaceutically acceptable formulation aids.

[0103] The disclosed compositions may include various carriers or excipients known in the formulation art, such as non-toxic solid, semi-solid or liquid fillers, diluents, encapsulating materials, and pharmaceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants, buffers, flavoring agents, bacteriostats, fungicides, emollients, plasticizers, permeation enhancers, antioxidants, pigments, lubricants, preservatives, humectants, salts, and any mixtures thereof. [Example]

[0104] Example 1: Cannabinoid Extracts, Distillates, and Isolates The cannabinoid precursors cannabigerolic acid (CBGA) and cannabigerovaric acid (CBGVA) were obtained by extraction from the cannabis plant or purchased commercially. The cannabinoids tetrahydrocannabinolic acid (THCA), cannabinolic acid (CBDA), cannabichromenic acid (CBCA), (-)-trans-Δ9-tetrahydrocannabinolic acid (Δ9-THCA), tetrahydrocannabivaric acid (THCVA), cannabichromevaric acid (CBCVA), and cannabidivaric acid (CBDVA) were extracted from the Cannabis sativa plant by organic solvent extraction, steam, or supercritical fluid extraction. The neutral forms of cannabinoids, tetrahydrocannabinol (THC), cannabidiol (CBD), (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabidiol (CBD), cannabinodiol (CBND), and cannabinol (CBN), were obtained by decarboxylation of their corresponding acidic forms by heating, drying, or burning. For thermal decarboxylation, the cannabinoid extract was heated to 95°C for approximately 20 minutes until melted, then cooled in a freezer for approximately 15 minutes.

[0105] The cannabinoid extract was subjected to molecular distillation and the distillate was purified by removing terpenes, organic material and chlorophyll by thin layer chromatography (THLC), high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry and / or gas chromatography-flame ionization detector (GC-FID) analysis.

[0106] The cannabinoid liquid oil distillate obtained as described above was used as is. Alternatively, the purified cannabinoid liquid oil distillate was purified again to obtain double-distilled cannabinoids. The double-distilled cannabinoids were purified a third time to obtain a triple-distilled cannabinoid isolate having a high purity.

[0107] Example 2: Pilot study Finely divided nanoparticles were produced as disclosed herein. The system was optimized to minimize the effects of humidity by flushing with CO2 prior to cannabinoid addition, and the pressure release process was optimized for 0.5 seconds with a 25 second repressurization cycle to prevent nozzle freezing and ensure uniformity and reproducibility.

[0108] Cannabinoids in the form of extract, distillate, or isolate were added to a 10 ml high-pressure reactor chamber, and liquid CO2 was pumped into the reactor chamber at 1000 psi. The reactor was heated to 40°C, and the pressure was increased to a range of approximately 1500 psi to approximately 1700 psi. The temperature was either held at 40°C or increased to 50°C. The pressure was then increased in 1000 psi increments from approximately 2500 psi to approximately 6500 psi using a syringe pump. In preliminary experiments, a temperature of 40°C and a pressure of 3500 psi were selected. The resulting solution was released in 0.5-second bursts through a 5 μm nozzle. Figure 1A shows the CBD isolate before processing. The CBD isolate has a crystalline morphology and a large amount of agglomeration between large particles. Figure 1B shows the CBD distillate after processing at 3500 psi and 40°C. The resulting distillate particles exhibited a more spherical amorphous morphology and had particle sizes ranging from 100 nm to 40 μm.

[0109] Example 3: Complexation with cyclodextrin To increase the solubility of cannabinoids in water, cannabinoid extracts, distillates, and isolates produced as described in Example 1 were combined with α-cyclodextrin or β-cyclodextrin at molar ratios of cannabinoid:cyclodextrin ranging from 1:0.5 to 1:10 and added to a 10 ml reactor chamber. Supercritical CO2 was pumped into the reactor chamber at 1,000 psi, the reactor chamber was heated to 40 °C, and the pressure was increased to 3,500 psi. The resulting solution was released in 0.5-second bursts through a 5 μm nozzle. Cyclodextrin was found to be insoluble under the process conditions.

[0110] To increase their solubility in supercritical fluids, α-cyclodextrin and β-cyclodextrin were acetylated by replacing one or more hydroxyl groups with one or more acetyl groups, thereby increasing Lewis acid:Lewis base interactions in the supercritical fluid. 2.0 g of α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin was acetylated in 10 ml of acetic anhydride in a 100 ml round-bottom flask. 0.05 g of iodine was added to the mixture, and the flask was stirred in the dark for 2 hours. The reaction was quenched with 50 ml of water, and 1% (w / w) aqueous sodium thiosulfate solution was added dropwise until the solution became clear. The reaction was stirred for 1 hour, and the resulting solution was extracted four times with 40 ml of dichloromethane (DCM). The organic fractions were combined, washed twice with 50 ml of water, and dried over sodium sulfate before solvent removal. The final products were dried under vacuum to obtain α-cyclodextrin heneicosaacetate (AACD), β-cyclodextrin heneicosaacetate (ABCD), or γ-cyclodextrin octadeacetate (AGCD), respectively.

[0111] Acetylated cyclodextrin was then combined with cannabinoid extracts, distillates, and isolates at molar ratios of cannabinoid:cyclodextrin ranging from 1:0.5 to 1:10 and added to a 10 ml reactor chamber. Supercritical CO2 was pumped into the reactor chamber at 1,000 psi, the reactor chamber was heated to 40 °C, and the pressure was increased to 3,500 psi. The resulting solution was expelled in 0.5 second bursts through a 5 μm nozzle.

[0112] The results showed that under the experimental conditions, the solubility of AACD, ABCD, and AGCD in supercritical CO2 increased to 1.1 wt% and 1.3 wt%, respectively. Furthermore, cannabinoid complexation with acetylated cyclodextrin prevented the resuspension of cannabinoids and their impurities, such as terpenes and waxes, during processing.

[0113] Example 4: Preparation of cannabinoid ultrafine nanoparticles Cannabinoid complexes with acetylated cyclodextrin were prepared as described in Example 3 at cannabinoid:cyclodextrin molar ratios ranging from 1:0.5 to 1:10 and each was added to a 10 ml reactor chamber. The cannabinoid-cyclodextrin complexes were dissolved in supercritical fluid at 3500 psi and 40°C. The solution was depressurized through a 5 micron nozzle into a 19 liter expansion chamber with tubular exhaust to ensure maximum recovery of microparticles. Figures 2A and 2B show 32x and 200x magnifications, respectively, of particles of CBD distillate complexed with α-cyclodextrin at a cannabinoid:cyclodextrin molar ratio of 1:2.5 w / w (250 mg CBD complexed with 100 mg α-cyclodextrin). The resulting CBD nanoparticles exhibited a spherical morphology with particle sizes ranging from 100 nm to 40 µm. The addition of acetylated cyclodextrin produced a fine powder that did not resuspend after processing, as shown in Figure 2A and Figure 2B, suggesting the integration of the CBD compound within the AACD rings.

[0114] Example 5: Bioavailability of cannabinoid ultrafine nanoparticles The bioavailability of the cannabinoid ultrafine nanoparticles obtained as described in Example 4 was investigated by visually assessing the solubility of the finely divided nanoparticles in simulated gastric conditions. 0.5 g of NaCl was added to 0.155 M aqueous HCl to mimic gastric acid conditions. 10 mg of the finely divided nanoparticles, 10 mg of the crystalline isolate, and 10 mg of the distillate were each placed in a vial containing 10 ml of acidic solution and incubated at 37°C for 10 hours. At the end of the 10-hour period, only minimal solubility of the preparation was observed. An additional 10 ml of acidic solution was added, and the mixture was incubated at 37°C for 10 more hours. At the end of the 20-hour period, the cannabinoid nanoparticles dissolved in the acidic solution. In contrast, the crystalline isolate and distillate showed complete insolubility (Figures 3-5).

[0115] Example 6: Relative bioavailability testing of cannabinoid ultrafine nanoparticles A high-performance liquid chromatography (HPLC) separator equipped with a UV detector was used to conduct a comparative bioavailability test of the cannabinoid ultrafine nanoparticles obtained as described in Example 4 (test samples) compared to a cannabinoid isolate in water (control sample) to determine the concentration of CBD in each sample. Control samples were prepared by filtering 1 ml of each sample through a 0.45 μm filter into a 2 ml HPLC vial, and 1 ml of methanol (MeOH) was added to each sample vial. The HPLC mobile phase consisted of 65% acetonitrile and 35% water. A flow rate of 1 ml per minute resulted in the elution of CBD after approximately 4.5 minutes.

[0116] The percentage area was measured after 32 hours, which represents the amount of CBD in each sample compared to the background signal created by MeOH in each sample. The percentage area of ​​the test sample was found to be 4.1163% of the total sample, compared to 0.7706% of the total sample for the control sample.

[0117] These results demonstrate that the disclosed purified cannabinoid micronized nanoparticles improve the solubility of CBD when compared to a control cannabinoid isolate in water. The significant increase in solubility (up to six-fold in this case) indicates the potential for dramatic improvements in the bioavailability of the disclosed formulations. This significant increase in bioavailability can dramatically improve therapeutic efficacy.

[0118] Example 7: Preparation of water-soluble cyclodextrin-encapsulated API nanoparticles To increase the aqueous solubility of the API, cannabinoid distillate as described in Example 1 was combined with various cyclodextrins, and the resulting mixture was placed in a high-pressure reactor. Liquefied CO2 was pumped into the reactor until the reactor pressure reached 5,000 psi. The mixture was stirred in the reactor for 30 minutes to produce the cyclodextrin-encapsulated cannabinoid. The mixture was then sprayed into a cycloclone to evaporate the CO2, resulting in a cyclodextrin-encapsulated cannabinoid dry powder. The collected CO2 was stored in a buffer tank for future use. Table 1 below shows the percentage of cannabinoid content in each sample. Table 1 also shows that the average percentage of cannabinoid content in the cyclodextrin-encapsulated cannabinoid nanoparticles was 10-fold higher than the average cannabinoid content in standard non-cyclodextrin-encapsulated cannabinoid nanoparticles. [Table 1]

[0119] Example 8: Dissolution Profile of Cyclodextrin-Encapsulated API Powder Dissolution profiles were determined by dissolving the samples obtained from Example 7. A commercial THC oil (Reign Drops, THC 30 mg / ml) was used as a standard control. Each sample containing an equal amount of cannabinoid (40 mg) was dissolved in 200 ml of distilled water. The temperature was kept constant at 50°C.

[0120] At time intervals of 0.5, 1, 2, 3, 5, 10, 20, and 30 minutes, 2 ml of each sample solution was removed from the medium and immediately filtered through a 0.45 μm syringe filter. The filtered solutions were then analyzed by HPLC at 220 nm using 0.085% phosphoric acid in methanol and 0.085% phosphoric acid in water as the mobile phase. The results, summarized in Table 2 below and illustrated in Figure 9, show that over 90% of the cyclodextrin-encapsulated API dry powder was dissolved in water. In contrast, only 26% of the standard control non-cyclodextrin-encapsulated cannabinoid dry powder was dissolved in water. These results confirmed that the cyclodextrin-encapsulated API had superior bioavailability and efficacy compared to the non-cyclodextrin-encapsulated API. [Table 2]

[0121] Example 9: In vivo absorption studies of cyclodextrin-encapsulated cannabinoids Baker's yeast (Saccharomyces cerevisiae) was used to measure transport rates across membranes and assess the in vivo uptake of cyclodextrin-encapsulated cannabinoids compared to unencapsulated THC absorption over a 2-hour period.

[0122] The yeast was inoculated into the sugar solution and allowed to acclimate at 35°C for 15 minutes. Half the yeast culture was then treated with a solution containing unencapsulated THC as a control, and half the yeast culture was treated with an equal volume of a solution containing an equal amount of THC in the form of cyclodextrin-encapsulated THC. Treatment was carried out for 2 hours at 35°C with gentle agitation to facilitate gas exchange. At the end of treatment, the solution was removed by centrifugation, and the yeast cells were washed with saline solution, lysed, and subjected to organic extraction. The organic cannabinoid solution was analyzed by HPLC. The results, shown in Table 3 below, demonstrate that cyclodextrin microencapsulation improves THC transport and absorption across the yeast membrane by 200% compared to the transport of unencapsulated THC. Overall, these results demonstrate that cyclodextrin microencapsulation can improve cannabinoid absorption in eukaryotic systems, such as humans, providing users with an enhanced recreational or medicinal experience. [Table 3]

[0123] It is to be understood that the illustrated embodiments are merely examples of the disclosed methods and should not be considered as limiting the scope of the invention, which is rather defined by the claims that follow.

Claims

1. A stable, non-degradable, edible, inhalable, soluble, or drinkable composition comprising a pharmaceutical grade cyclodextrin-encapsulated active pharmaceutical ingredient (API) having a purity of 99.9% and an increased bioavailability of 200% compared to formulations of non-cyclodextrin-encapsulated active pharmaceutical ingredient, and a pharmaceutically acceptable carrier, excipient, and / or binder, wherein the active pharmaceutical ingredient is a cannabinoid, psychedelic, analgesic, anesthetic, anti-inflammatory, antibacterial, antiviral, anticoagulant, anticonvulsant, antidepressant, or muscle relaxant.

2. 10. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 1, wherein the pharmaceutical grade cyclodextrin-encapsulated active pharmaceutical ingredient is in the form of nanoparticles having an average particle size of 100 nm to 40 μm and a size distribution within 1% to 50% of the average particle size.

3. 10. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 1, wherein the pharmaceutical grade cyclodextrin-encapsulated active pharmaceutical ingredient is in the form of an ultra-fine dry powder having an average particle size of 100 nm to 5 μm.

4. 10. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 1, wherein the pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredient is in the form of a drinkable solution or suspension.

5. The psychedelic is psilocin or psilocybin, and the cannabinoid is cannabigerolic acid (CBGA), cannabigerovaric acid (CBGVA), tetrahydrocannabinolic acid (THCA), cannabichromenic acid (CBCA), cannabidiolic acid (CBDA), tetrahydrocannabivaric acid (THCVA), cannabichromevaric acid (CBCVA), cannabidivaric acid (CBDVA), (-)-trans-Δ9- 10. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 1, wherein the compound is one or more of tetrahydrocannabinol (Δ9-THC), trans-Δ9-tetrahydrocannabiphorol (Δ9-THCP), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabidiol (CBD), cannabinodiol (CBND), or cannabinol (CBN).

6. 3. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 2, wherein the API is encapsulated in one or more acetylated cyclodextrins, and the one or more acetylated cyclodextrins comprise acetylated α-cyclodextrin, acetylated β-cyclodextrin, acetylated γ-cyclodextrin, or any mixture thereof.

7. 4. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 3, wherein the API is encapsulated in one or more acetylated cyclodextrins and one or more hydrophilic cyclodextrins.

8. 8. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 7, wherein the one or more acetylated cyclodextrins comprise acetylated α-cyclodextrin, acetylated β-cyclodextrin, acetylated γ-cyclodextrin, or any mixture thereof, and the one or more hydrophilic cyclodextrins comprise hydrophilic α-cyclodextrin, hydrophilic β-cyclodextrin, hydrophilic γ-cyclodextrin, or any mixture thereof.

9. 8. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 6 or 7, wherein the API and the one or more acetylated cyclodextrins are in a molar ratio of API:acetylated cyclodextrin ranging from 1:0.5 to 1:10, or the molar ratio of API:acetylated cyclodextrin is 1:0.5, 1:0.75, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, or 1:

10.

10. 5. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 4, wherein the API is encapsulated in one or more hydrophilic cyclodextrins, and the one or more hydrophilic cyclodextrins comprise hydrophilic α-cyclodextrin, hydrophilic β-cyclodextrin, hydrophilic γ-cyclodextrin, or any mixture thereof.

11. 11. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 6, 7, or 10, wherein the API is one or more cannabinoids or one or more psychedelics.

12. 12. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 11, wherein the one or more cannabinoids is cannabidiol (CBD).

13. 12. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 11, wherein the one or more cannabinoids is tetrahydrocannabinol (THC).

14. 12. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 11, wherein the one or more cannabinoids are cannabidiol (CBD) and tetrahydrocannabinol (THC).

15. 12. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 11, wherein the one or more cannabinoids is cannabinol (CBN).

16. 12. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 11, wherein the one or more psychedelics include psilocin or psilocybin.

17. 10. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 1, wherein the pharmaceutically acceptable carrier, excipient, or binder comprises one or more of sodium citrate, dicalcium phosphate, starch, lactose, sucrose, glucose, mannitol, silicic acid, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, acacia, humectants, solubilizers, emulsifiers, disintegrants, solution retarders, absorption accelerators, wetting agents, absorbents, lubricants, oils, adjuvants, sweeteners, flavoring agents, fragrances, or buffers.

18. 18. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 17, wherein the composition is in the form of an inhaler, capsule, tablet, pill, powder, beads, lozenge, dragee, granule, edible composition, food, beverage, emulsion, solution, suspension, cream, gel, sunscreen, shampoo, toothpaste, transdermal patch, plaster, implant, syrup, elixir, injection, or infusion.

19. 20. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 18, wherein the composition is formulated in an immediate release, sustained release, or controlled release form.

20. 20. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 19, wherein the composition further comprises a coating, wherein the coating is an enteric coating, an extended-release coating, a sustained-release coating, a delayed-release coating, or an immediate-release coating.

21. 20. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 19, wherein the composition is formulated for oral, mucosal, pulmonary, topical, parenteral, transdermal, or submucosal administration.

22. 20. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 18, wherein the food product is bread, a cookie, soup, cereal, salad, a sandwich, sprouts, vegetables, or candy.

23. 19. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition of claim 18, wherein the beverage is tea, juice, syrup, soda, fermented drink, alcoholic drink, non-alcoholic drink, distilled drink, or brewed drink.

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