WO2023086903A1 - Cannabidiol nanoparticle compositions - Google Patents

Abstract

Provided herein is a cannabidiol nanoparticle composition comprising a microparticle of a pharmaceutically acceptable excipient and nanoparticles of cannabidiol, wherein the surface of the microparticle is coated with the nanoparticles of cannabidiol.

Description

CANNABIDIOL NANOPARTICLE COMPOSITIONS

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of the priority of U.S. Provisional Application No. 63/263,877, filed November 10, 2021; the disclosure of which is incorporated herein by reference in its entirety.

FIELD

[0002] Provided herein is a cannabidiol nanoparticle composition comprising a microparticle of a pharmaceutically acceptable excipient and nanoparticles of cannabidiol, wherein the surface of the microparticle is coated with the nanoparticles of cannabidiol.

BACKGROUND

[0003] Cannabidiol (CBD) is one of the key cannabinoid constituents in Cannabis plants, which is not psychoactive and well-tolerated, and exhibits broad spectrum therapeutic properties. Bergamaschi et a!.. Curr. Drug Saf. 2011, 6, 237-49; Noreen et a!.. Crit. Rev. Eukaryot. Gene Expr. 2018, 28, 73-86. CBD has been studied clinically for treating different central nervous system (CNS) and peripheral disorders. Fernandez -Ruiz et al., Br. J. Clin. Pharmacol. 2013, 75, 323-33; Maroon and Bost, Surg. Neurol. Int. 2018, 9, 91; Navarrete et al., Int. J. Mol. Sci. 2021, 22, 2992. For example, CBD has been shown to reverse and prevent cognitive deficits in AD rodent models. Esposito et al., Br. J. Pharmacol. 2007, 151, 1272-9; Cheng at al., J. Alzheimers. Dis. 2014, 42, 1383-96.

[0004] However, CBD is practically insoluble in water, undergoes extensive first pass metabolism, and is mostly excreted vzri the kidneys. Huestis, Chem. Biodivers. 2007, 4, 1770- 804; Miller et al, Front. Pharmacol. 2018, 9, 1365. As a result, the oral bioavailability of CBD is very low (6-13%). Mechoulam et al., J. Clin. Pharmacol. 2002, 42, 11S-9S; Paudel et al., Drug Dev. Ind. Pharm. 2010, 36, 1088-97. Therefore, there is a need for a pharmaceutical composition for effective cannabidiol administration. SUMMARY OF THE DISCLOSURE

[0005] Provided herein is a coated particle comprising: (i) a microparticle that comprises a pharmaceutically acceptable excipient, and (ii) nanoparticles of cannabidiol; wherein the surface of the microparticle is coated with the nanoparticles of cannabidiol.

[0006] Also provided herein is a pharmaceutical composition comprising coated particles, each particle comprising: (i) a microparticle that comprises a pharmaceutically acceptable excipient, and (ii) nanoparticles of cannabidiol; wherein the surface of the microparticle is coated with the nanoparticles of cannabidiol.

[0007] Additionally, provided herein is a method of preparing coated particles, each particle comprising: (i) a microparticle that comprises a pharmaceutically acceptable excipient, and (ii) nanoparticles of cannabidiol, comprising the steps of: a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a cannabidiol vapor; and b. depositing the cannabidiol vapor on the surfaces of the microparticles at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surfaces of the microparticles, thus forming the coated particles.

[0008] Furthermore, provided herein is a method of preparing nanoparticles of cannabidiol, comprising the steps of: a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a cannabidiol vapor; and b. depositing the cannabidiol vapor on the surface of a microparticle comprising a pharmaceutically acceptable excipient at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surface of the microparticle.

[0009] Provided herein are coated particles, each particle comprising: (i) a microparticle that comprises a pharmaceutically acceptable excipient, and (ii) nanoparticles of cannabidiol; wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a cannabidiol vapor; and b. depositing the cannabidiol vapor on the surfaces of the microparticles at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surfaces of the microparticles, thus forming the coated particles.

[0010] Provided herein are nanoparticles of cannabidiol, which are prepared by a method comprising the steps of a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a cannabidiol vapor; and b. depositing the cannabidiol vapor on the surface of a microparticle comprising a pharmaceutically acceptable excipient at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surface of the microparticle.

[0011] Provided herein is a pharmaceutical composition comprising coated particles, each particle comprising: (i) a microparticle that comprises a pharmaceutically acceptable excipient, and (ii) nanoparticles of cannabidiol; wherein the coated particles are prepared by a method comprising the steps of a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a cannabidiol vapor; and b. depositing the cannabidiol vapor on the surfaces of the microparticles at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surfaces of the microparticles, thus forming the coated particles.

[0012] Provided herein is a pharmaceutical composition comprising nanoparticles of cannabidiol, which are prepared by a method comprising the steps of a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a cannabidiol vapor; and b. depositing the cannabidiol vapor on the surface of a microparticle comprising a pharmaceutically acceptable excipient at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surface of the microparticle.

[0013] Provided herein is a batch of coated particles, each particle comprising: (i) a microparticle that comprises a pharmaceutically acceptable excipient, and (ii) nanoparticles of cannabidiol; wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a cannabidiol vapor; and b. depositing the cannabidiol vapor on the surfaces of the microparticles at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surfaces of the microparticles, thus forming the coated particles.

[0014] Provided herein is a batch of nanoparticles of cannabidiol, which are prepared by a method comprising the steps of: a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a cannabidiol vapor; and b. depositing the cannabidiol vapor on the surface of a microparticle comprising a pharmaceutically acceptable excipient at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surface of the microparticle.

[0015] Provided herein is a batch of a pharmaceutical composition comprising coated particles, each particle comprising: (i) a microparticle that comprises a pharmaceutically acceptable excipient, and (ii) nanoparticles of cannabidiol; wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a cannabidiol vapor; and b. depositing the cannabidiol vapor on the surfaces of the microparticles at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surfaces of the microparticles, thus forming the coated particles.

[0016] Provided herein is a batch of a pharmaceutical composition comprising nanoparticles of cannabidiol and a pharmaceutical acceptable excipient, wherein the nanoparticles are prepared by a method comprising the steps of: a. vaporizing cannabidiol at a predetermined temperature under a first predetermined vacuum pressure to form a cannabidiol vapor; and b. depositing the cannabidiol vapor on the surface of a microparticle comprising the pharmaceutically acceptable excipient at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surface of the microparticle.

[0017] Provided herein is a device for administering cannabidiol by intranasal spray, comprising coated particles, nanoparticles, or a pharmaceutical composition provided herein, and a spray device.

[0018] Provided herein is a device for administering cannabidiol by inhalation, comprising coated particles, nanoparticles, or a pharmaceutical composition provided herein, and an inhaler.

[0019] Provided herein is a kit administering cannabidiol by intranasal spray, comprising coated particles, nanoparticles, or a pharmaceutical composition provided herein, and a spray device.

[0020] Provided herein is a kit for administering cannabidiol by inhalation, comprising coated particles, nanoparticles, or a pharmaceutical composition provided herein, and an inhaler.

BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIG. 1 illustrates the formation of nanoparticles of cannabidiol on the surfaces of microparticles of an excipient by contacting the microparticles with a vapor of cannabidiol.

DETAILED DESCRIPTION

[0022] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0023] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0024] The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.

[0025] The terms “treat,” “treating,” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.

[0026] The terms “prevent,” “preventing,” and “prevention” are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.

[0027] The terms “alleviate” and “alleviating” refer to easing or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. The terms can also refer to reducing adverse effects associated with an active ingredient. Sometimes, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.

[0028] The term “therapeutically effective amount” or “effective amount” is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term “therapeutically effective amount” or “effective amount” also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0029] The term “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of a subject (e.g., a human or an animal) without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 23rd ed.;

Adejare et al., Eds.; Academic Press: London, 2020; Handbook of Pharmaceutical Excipients, 9th ed.; Sheskey et al., Eds.; Pharmaceutical Press: London, 2020; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Synapse Information Resources: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; Drugs and the Pharmaceutical Sciences 199; Informa Healthcare: New York, NY, 2009.

[0030] The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations. In certain embodiments, the term “about” or “approximately” means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0031] The term “batch” refers to a defined quantity of a compound, material, or drug product processed in a process or series of processes so that it is homogeneous within specified limits. To complete certain stages of manufacture, it may be necessary to divide a batch into a number of sub-batches, which are later brought together to form a final homogeneous batch. In the case of continuous manufacture, the batch corresponds to a defined fraction of the production, characterized by its intended homogeneity. In manufacturing a drug product, synthetic intermediates and the drug product are each identified by a batch number. [0032] In certain embodiments, “optically active” and ’’enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. In certain embodiments, an optically active compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 98% or more of one enantiomer and about 2% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 99% or more of one enantiomer and about 1% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question.

[0033] In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the compound about its chiral center(s). The (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, (+) and (-), is not related to the absolute configuration of the compound, R and S.

[0034] The terms “substantially pure” and “substantially homogeneous” mean, when referred to a substance, sufficiently homogeneous to appear free of readily detectable impurities as determined by a standard analytical method used by one of ordinary skill in the art, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure such that further purification would not detectably alter the physical, chemical, biological, and/or pharmacological properties, such as enzymatic and biological activities, of the substance. In certain embodiments, “substantially pure” or “substantially homogeneous” refers to a collection of molecules, wherein at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by standard analytical methods. As used herein, when an atom at a particular position in an isotopically enriched molecule is designated as a particular less prevalent isotope, a molecule that contains other than the designated isotope at the specified position is an impurity with respect to the isotopically enriched compound. Thus, for a deuterated compound that has an atom at a particular position designated as deuterium, a compound that contains a protium at the same position is an impurity.

Coated Particles and Nanoparticles

[0035] In one embodiment, provided herein is a coated particle comprising: (i) a microparticle that comprises a pharmaceutically acceptable excipient, and (ii) nanoparticles of cannabidiol; wherein the surface of the microparticle is coated with the nanoparticles of cannabidiol.

[0036] In certain embodiments, the surface of the microparticle is coated with a layer of the nanoparticles. In certain embodiments, the surface of the microparticle is substantially coated with a layer of the nanoparticles. In certain embodiments, the surface of the microparticle is coated with a thin layer of the nanoparticles. In certain embodiments, the surface of the microparticle is substantially coated with a thin layer of the nanoparticles. In certain embodiments, the surface of the microparticle is coated with a single layer of the nanoparticles. In certain embodiments, the surface of the microparticle is substantially coated with a single layer of the nanoparticles.

[0037] In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is hydrophilic. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is water-soluble. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is inhalation-grade.

[0038] In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is a sugar. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is dextrose, fructose, glucose, lactose, maltose, starch, sucrose, trehalose, or a mixture thereof. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is dextrose, glucose, lactose, sucralose, sucrose, or a mixture thereof. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is dextrose. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is fructose. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is glucose. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is lactose. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is lactose monohydrate. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is anhydrous lactose. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is inhalation-grade lactose. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is inhalation-grade lactose monohydrate. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is inhalation-grade anhydrous lactose. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is starch. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is sucrose. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is trehalose.

[0039] In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is a sugar alcohol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is arabitol, erythritol, fucitol, galactitol, iditol, inositol, isomalt, lactitol, maltitol, maltotritol, mannitol, ribitol, sorbitol, threitol, volemitol, xylitol, or a mixture thereof. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is erythritol, lactitol, maltitol, mannitol, sorbitol, xylitol, or a mixture thereof. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is arabitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is erythritol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is fucitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is galactitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is iditol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is inositol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is isomalt. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is lactitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is maltitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is maltotritol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is mannitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is D-mannitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is inhalation-grade mannitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is inhalation-grade D-mannitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is ribitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is sorbitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is threitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is volemitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is xylitol.

[0040] In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is a cellulose. In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is microcrystalline cellulose (MCC). In certain embodiments, the pharmaceutically acceptable excipient in the coated particle provided herein is methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethyl cellulose (CMC), cellulose acetate, or cellulose acetate phthalate (CAP).

[0041] In certain embodiments, the microparticle in the coated particle provided herein has various shapes, including, but not limited to, a sphere, spheroid, platelet, fibril, or fiber. In certain embodiments, the microparticle in the coated particle provided herein is substantially spherical. In certain embodiments, the microparticle in the coated particle provided herein is spherical. In certain embodiments, the microparticle in the coated particle provided herein is spheroidal.

[0042] In certain embodiments, the microparticle in the coated particle provided herein has an average particle size (Dso) ranging from about 1 to about 5,000 pm, from about 10 to about 5,000 pm, from about 50 to about 3,000 pm, from about 100 to about 3,000 pm, from about 100 to about 800 pm, from about 100 to about 700 pm, from about 200 to about 600 pm, from about 400 to about 500 pm, from about 100 to about 400 pm, or from about 10 to about 150 pm. In certain embodiments, the microparticle in the coated particle provided herein has an average particle size ranging from about 1 to about 5,000 pm. In certain embodiments, the microparticle in the coated particle provided herein has an average particle size ranging from about 10 to about 5,000 pm. In certain embodiments, the microparticle in the coated particle provided herein has an average particle size ranging from about 50 to about 3,000 pm. In certain embodiments, the microparticle in the coated particle provided herein has an average particle size ranging from about 100 to about 3,000 pm. In certain embodiments, the microparticle in the coated particle provided herein has an average particle size ranging from about 100 to about 800 pm. In certain embodiments, the microparticle in the coated particle provided herein has an average particle size ranging from about 100 to about 700 pm. In certain embodiments, the microparticle in the coated particle provided herein has an average particle size ranging from about 200 to about 600 pm. In certain embodiments, the microparticle in the coated particle provided herein has an average particle size ranging from about 400 to about 500 pm. In certain embodiments, the microparticle in the coated particle provided herein has an average particle size ranging from about 100 to about 400 pm. In certain embodiments, the microparticle in the coated particle provided herein has an average particle size ranging from about 10 to about 150 pm. In certain embodiments, the microparticle in the coated particle provided herein has an average particle size of about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 800, about 1,000, about 2,000, or about 2,500 pm.

[0043] In one embodiment, provided herein is a coated particle comprising: (i) a microparticle that comprises mannitol and (ii) nanoparticles of cannabidiol; wherein the surface of the mannitol microparticle is coated with the nanoparticles of cannabidiol. [0044] In another embodiment, provided herein is a coated particle consisting of: (i) a microparticle of mannitol and (ii) nanoparticles of cannabidiol; wherein the surface of the mannitol microparticle is coated with the nanoparticles of cannabidiol.

[0045] In one embodiment, the microparticle comprises mannitol. In another embodiment, the microparticle comprises inhalation-grade mannitol.

[0046] In certain embodiments, the surface of the mannitol microparticle is coated with a layer of the nanoparticles. In certain embodiments, the surface of the mannitol microparticle is substantially coated with a layer of the nanoparticles. In certain embodiments, the surface of the mannitol microparticle is coated with a single layer of the nanoparticles. In certain embodiments, the surface of the mannitol microparticle is substantially coated with a single layer of the nanoparticles.

[0047] In certain embodiments, the mannitol microparticle in the coated particle provided herein has various shapes, including, but not limited to, a sphere, spheroid, platelet, fibril, or fiber. In certain embodiments, the mannitol microparticle in the coated particle provided herein is substantially spherical. In certain embodiments, the mannitol microparticle in the coated particle provided herein is spherical. In certain embodiments, the mannitol microparticle in the coated particle provided herein is spheroidal.

[0048] In certain embodiments, the mannitol microparticle in the coated particle provided herein has an average particle size ranging from about 1 to about 5,000 pm, from about 10 to about 5,000 pm, from about 50 to about 3,000 pm, from about 100 to about 3,000 pm, from about 100 to about 800 pm, from about 100 to about 700 pm, from about 200 to about 600 pm, from about 400 to about 500 pm, from about 100 to about 400 pm, or from about 10 to about 150 pm. In certain embodiments, the mannitol microparticle in the coated particle provided herein has an average particle size ranging from about 1 to about 5,000 pm. In certain embodiments, the mannitol microparticle in the coated particle provided herein has an average particle size ranging from about 10 to about 5,000 pm. In certain embodiments, the mannitol microparticle in the coated particle provided herein has an average particle size ranging from about 50 to about 3,000 pm. In certain embodiments, the mannitol microparticle in the coated particle provided herein has an average particle size ranging from about 100 to about 3,000 pm. In certain embodiments, the mannitol microparticle in the coated particle provided herein has an average particle size ranging from about 100 to about 800 pm. In certain embodiments, the mannitol microparticle in the coated particle provided herein has an average particle size ranging from about 100 to about 700 pm. In certain embodiments, the mannitol microparticle in the coated particle provided herein has an average particle size ranging from about 200 to about 600 pm. In certain embodiments, the mannitol microparticle in the coated particle provided herein has an average particle size ranging from about 400 to about 500 pm. In certain embodiments, the mannitol microparticle in the coated particle provided herein has an average particle size ranging from about 100 to about 400 pm. In certain embodiments, the mannitol microparticle in the coated particle provided herein has an average particle size ranging from about 10 to about 150 pm. In certain embodiments, the mannitol microparticle in the coated particle provided herein has an average particle size of about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 800, about 1,000, about 2,000, or about 2,500 pm.

[0049] In one embodiment, provided herein is a coated particle comprising: (i) a microparticle that comprises microcrystalline cellulose (MCC) and (ii) nanoparticles of cannabidiol; wherein the surface of the MCC microparticle is coated with the nanoparticles of cannabidiol.

[0050] In another embodiment, provided herein is a coated particle consisting of: (i) a microparticle of MCC and (ii) nanoparticles of cannabidiol; wherein the surface of the MCC microparticle is coated with the nanoparticles of cannabidiol.

[0051] In one embodiment, the microparticle comprises MCC.

[0052] In certain embodiments, the surface of the MCC microparticle is coated with a layer of the nanoparticles. In certain embodiments, the surface of the MCC microparticle is substantially coated with a layer of the nanoparticles. In certain embodiments, the surface of the MCC microparticle is coated with a single layer of the nanoparticles. In certain embodiments, the surface of the MCC microparticle is substantially coated with a single layer of the nanoparticles. [0053] In certain embodiments, the MCC microparticle in the coated particle provided herein has various shapes, including, but not limited to, a sphere, spheroid, platelet, fibril, or fiber. In certain embodiments, the MCC microparticle in the coated particle provided herein is substantially spherical. In certain embodiments, the MCC microparticle in the coated particle provided herein is spherical. In certain embodiments, the MCC microparticle in the coated particle provided herein is spheroidal.

[0054] In certain embodiments, the MCC microparticle in the coated particle provided herein has an average particle size ranging from about 1 to about 5,000 pm, from about 10 to about 5,000 pm, from about 50 to about 3,000 pm, from about 100 to about 3,000 pm, from about 100 to about 800 pm, from about 100 to about 700 pm, from about 200 to about 600 pm, from about 400 to about 500 pm, from about 100 to about 400 pm, or from about 10 to about 150 pm. In certain embodiments, the MCC microparticle in the coated particle provided herein has an average particle size ranging from about 1 to about 5,000 pm. In certain embodiments, the MCC microparticle in the coated particle provided herein has an average particle size ranging from about 10 to about 5,000 pm. In certain embodiments, the MCC microparticle in the coated particle provided herein has an average particle size ranging from about 50 to about 3,000 pm. In certain embodiments, the MCC microparticle in the coated particle provided herein has an average particle size ranging from about 100 to about 3,000 pm. In certain embodiments, the MCC microparticle in the coated particle provided herein has an average particle size ranging from about 100 to about 800 pm. In certain embodiments, the MCC microparticle in the coated particle provided herein has an average particle size ranging from about 100 to about 700 pm. In certain embodiments, the MCC microparticle in the coated particle provided herein has an average particle size ranging from about 200 to about 600 pm. In certain embodiments, the MCC microparticle in the coated particle provided herein has an average particle size ranging from about 400 to about 500 pm. In certain embodiments, the MCC microparticle in the coated particle provided herein has an average particle size ranging from about 100 to about 400 pm. In certain embodiments, the MCC microparticle in the coated particle provided herein has an average particle size ranging from about 10 to about 150 pm. In certain embodiments, the MCC microparticle in the coated particle provided herein has an average particle size of about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 800, about 1,000, about 2,000, or about 2,500 pm. [0055] In one embodiment, cannabidiol in the coated particle provided herein is (1 ?,2 ?)-5'-methyl-4-pentyl-2'-(prop-l-en-2-yl)-r,2',3',4'-tetrahydro-[l,r-biphenyl]-2,6-diol, the structure of which is shown below; or an isotopic variant thereof. In certain embodiments, cannabidiol in the coated particle provided herein is amorphous.

[0056] In certain embodiments, the nanoparticles in the coated particle provided herein have an average particle size ranging from about 1 to about 5,000 nm, from about 10 to about 4,000 nm, from about 20 to about 3,000 nm, from about 50 to about 2,000 nm, from about 200 to about 1,000 nm, or from about 100 to about 700 nm. In certain embodiments, the nanoparticles in the coated particle provided herein have an average particle size ranging from about 1 to about 5,000 nm. In certain embodiments, the nanoparticles in the coated particle provided herein have an average particle size ranging from about 10 to about 4,000 nm. In certain embodiments, the nanoparticles in the coated particle provided herein have an average particle size ranging from about 20 to about 3,000 nm. In certain embodiments the nanoparticles in the coated particle provided herein have an average particle size ranging from about 50 to about 2,000 nm. In certain embodiments the nanoparticles in the coated particle provided herein have an average particle size ranging from about 200 to about 1,000 nm. In certain embodiments, the nanoparticles in the coated particle provided herein have an average particle size ranging from about 100 to about 700 nm. In certain embodiments, the nanoparticles in the coated particle provided herein have an average particle size of about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 800, about 900, about 100, about 1,500, or about 2,000 nm.

[0057] In certain embodiments, the nanoparticles in the coated particle provided herein are formed on the surface of the microparticle. In certain embodiments, the nanoparticles in the coated particle provided herein are formed on the surface of the microparticle by physical vapor deposition. See, e.g., Baldo et al., Adv. Mater. 1998, 10, 1505-14; WO 2021/168043 Al; the disclosure of each of which is incorporated herein by reference in its entirety.

[0058] In certain embodiments, the percentage of the nanoparticles in the coated particle is ranging from about 0.1 to about 50% by weight, from about 1 to about 50% by weight, from about 2 to about 50% by weight, from about 5 to about 50% by weight, about 10 to about 40% by weight, about 20 to about 40% by weight, or about 30 to about 40% by weight. In certain embodiments, the percentage of the nanoparticles in the coated particle is ranging from about 0.1 to about 50% by weight. In certain embodiments, the percentage of the nanoparticles in the coated particle is ranging from about 1 to about 50% by weight. In certain embodiments, the percentage of the nanoparticles in the coated particle is ranging from about 2 to about 50% by weight. In certain embodiments, the percentage of the nanoparticles in the coated particle is ranging from about 5 to about 50% by weight. In certain embodiments, the percentage of the nanoparticles in the coated particle is ranging from about 10 to about 40% by weight. In certain embodiments, the percentage of the nanoparticles in the coated particle is ranging from about 20 to about 40% by weight. In certain embodiments, the percentage of the nanoparticles in the coated particle is ranging from about 30 to about 40% by weight. In certain embodiments, the percentage of the nanoparticles in the coated particle is about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50% by weight.

[0059] In certain embodiments, the coated particle provided herein has an average particle size ranging from about 1 to about 5,000 pm, from about 10 to about 5,000 pm, from about 20 to about 5,000 pm, from about 50 to about 5,000 pm, from about 100 to about 3,000 pm, from about 100 to about 3,000 pm, from about 200 to about 3,000 pm, from about 500 to about 3,000 pm, or from about 10 to about 1,500 pm. In certain embodiments, the coated particle provided herein has an average particle size ranging from about 1 to about 5,000 pm. In certain embodiments, the coated particle provided herein has an average particle size ranging from about 10 to about 5,000 pm. In certain embodiments, the coated particle provided herein has an average particle size ranging from about 20 to about 5,000 pm. In certain embodiments, the coated particle provided herein has an average particle size ranging from about 100 to about 5,000 pm. In certain embodiments, the coated particle provided herein has an average particle size ranging from about 100 to about 3,000 pm. In certain embodiments, the coated particle provided herein has an average particle size ranging from about 200 to about 3,000 pm. In certain embodiments, the coated particle provided herein has an average particle size ranging from about 500 to about 3,000 pm. In certain embodiments, the coated particle provided herein has an average particle size ranging from about 10 to about 1,500 pm. In certain embodiments, the coated particle provided herein has an average particle size of about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1,000, about 1,500, about 2,000, about 2,500, or about 3,000 pm.

[0060] In certain embodiments, the coated particle provided herein is for intranasal administration. In certain embodiments, the coated particle provided herein is for administration by inhalation.

Method of Preparation

[0061] In one embodiment, provided herein is a method of preparing coated particles, each particle comprising: (i) a microparticle that comprises a pharmaceutically acceptable excipient and (ii) nanoparticles of cannabidiol, comprising the steps of: a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surface of the microparticle at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles of cannabidiol on the surfaces of the microparticles, thus forming the coated particles.

[0062] In another embodiment, provided herein is a method of preparing nanoparticles of cannabidiol, comprising the steps of: a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surface of a microparticle comprising a pharmaceutically acceptable excipient at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles of cannabidiol on the surface of the microparticle. [0063] In certain embodiments, the first predetermined temperature is ranging from about 20 to about 500 °C, 20 to about 300 °C, 30 to about 300 °C, from about 30 to about 200 °C, from about 40 to about 150 °C, from about 40 to about 120 °C, from about 50 to about 100 °C, or from about 55 to about 80 °C. In certain embodiments, the first predetermined temperature is ranging from about 20 to about 500 °C. In certain embodiments, the first predetermined temperature is ranging from about 20 to about 300 °C. In certain embodiments, the first predetermined temperature is ranging from about 30 to about 300 °C. In certain embodiments, the first predetermined temperature is ranging from about 30 to about 200 °C. In certain embodiments, the first predetermined temperature is ranging from about 40 to about 150 °C. In certain embodiments, the first predetermined temperature is ranging from about 40 to about 120 °C. In certain embodiments, the first predetermined temperature is ranging from about 50 to about 100 °C. In certain embodiments, the first predetermined temperature is ranging from about 55 to about 80 °C. In certain embodiments, the first predetermined temperature is ranging from about 40 to about 60 °C. In certain embodiments, the first predetermined temperature is about 50, about 55, about 60, about 65, about 70, about 75, or about 80 °C.

[0064] In certain embodiments, the predetermined vacuum pressure is no greater than about 10'³ torr, no greater than about 10'⁴ torr, no greater than about 10'⁵ torr, no greater than about 10'⁶ torr, no greater than about 10'⁷ torr, no greater than about 10'⁸ torr, or no greater than about 10'⁹ torr. In certain embodiments, the predetermined vacuum pressure is no greater than about 10'³ torr. In certain embodiments, the first predetermined vacuum pressure is no greater than about 10'⁴ torr. In certain embodiments, the predetermined vacuum pressure is no greater than about 10'⁵ torr. In certain embodiments, the predetermined vacuum pressure is no greater than about 10'⁶ torr. In certain embodiments, the first predetermined vacuum pressure is no greater than about 10'⁷ torr. In certain embodiments, the predetermined vacuum pressure is no greater than about 10'⁸ torr. In certain embodiments, the predetermined vacuum pressure is no greater than about 10'⁹ torr. In certain embodiments, the predetermined vacuum pressure is about 10'⁴, about 10'⁵, about 10'⁶, about 10'⁷, or about 10'⁸ torr.

[0065] In certain embodiments, the predetermined vacuum pressure is ranging from about 10'³ to about 10'⁸ torr. In certain embodiments, the predetermined vacuum pressure is ranging from about 10'⁴ to about 10'⁸ torr. In certain embodiments, the predetermined vacuum pressure is ranging from about 10'⁵ to about 10'⁷ torr. In certain embodiments, the predetermined vacuum pressure is ranging from about 10'⁵ to about 10'⁶ torr. In certain embodiments, the predetermined vacuum pressure is ranging from about 10'⁵ to about 10'⁸ torr. In certain embodiments, the predetermined vacuum pressure is ranging from about 10'⁷ to about 10'⁸ torr.

[0066] In certain embodiments, the predetermined agitation speed is ranging from about 10 to about 500 revolutions per minute (rpm), from about 10 to about 250 rpm, from about 20 to about 200 rpm, from about 100 to about 150 rpm, from about 20 to about 120 rpm, from about 20 to about 100 rpm, from about 50 to about 100 rpm, or from about 80 to about 100 rpm. In certain embodiments, the predetermined agitation speed is ranging from about 10 to about 500 rpm. In certain embodiments, the predetermined agitation speed is ranging from about 10 to about 250 rpm. In certain embodiments, the predetermined agitation speed is ranging from about 20 to about 200 rpm. In certain embodiments, the predetermined agitation speed is ranging from about 100 to about 150 rpm. In certain embodiments, the predetermined agitation speed is ranging from about 20 to about 120 rpm. In certain embodiments, the predetermined agitation speed is ranging from about 20 to about 100 rpm. In certain embodiments, the predetermined agitation speed is ranging from about 50 to about 100 rpm. In certain embodiments, the predetermined agitation speed is ranging from about 80 to about 100 rpm. In certain embodiments, the predetermined agitation speed is about 80, about 85, about 90, about 95, or about 100 rpm.

[0067] To efficiently deposit the vapor of cannabidiol onto the surface of a microparticle of a pharmaceutically acceptable excipient, the second predetermined temperature is set to be lower than the first predetermined temperature. Thus, in certain embodiments, the second predetermined temperature is no less than about 10, about no less than about 20, no less than about 50, or no less than about 100 °C lower than the first predetermined temperature.

[0068] In certain embodiments, the second predetermined temperature is no greater than about 200 °C, no greater than about 100 °C, no greater than about 50 °C, no greater than about 40 °C, no greater than about 35 °C, no greater than about 30 °C, or no greater than about 25 °C. In certain embodiments, the second predetermined temperature is no greater than about 200 °C. In certain embodiments, the second predetermined temperature is no greater than about 100 °C. In certain embodiments, the second predetermined temperature is no greater than about 50 °C. In certain embodiments, the second predetermined temperature is no greater than about 40 °C. In certain embodiments, the second predetermined temperature is no greater than about 35 °C. In certain embodiments, the second predetermined temperature is no greater than about 30 °C. In certain embodiments, the second predetermined temperature is no greater than about 25 °C.

[0069] In certain embodiments, the second predetermined temperature is ranging from about 10 to about 200 °C, from about 20 to about 150 °C, from about 20 to about 120 °C, from about 20 to about 90 °C, from about 20 to about 60 °C, from about 15 to about 50 °C, or from about 20 to about 40 °C. In certain embodiments, the second predetermined temperature is ranging from about 10 to about 200 °C. In certain embodiments, the second predetermined temperature is ranging from about 20 to about 150 °C. In certain embodiments, the second predetermined temperature is ranging from about 20 to about 120 °C. In certain embodiments, the second predetermined temperature is ranging from about 20 to about 90 °C. In certain embodiments, the second predetermined temperature is ranging from about 20 to about 60 °C. In certain embodiments, the second predetermined temperature is ranging from about 15 to about 50 °C. In certain embodiments, the second predetermined temperature is ranging from about 20 to about 40 °C. In certain embodiments, the second predetermined temperature is about 20, about 25, about 30, about 35, or about 40 °C. In certain embodiments, the second predetermined temperature is ambient temperature.

[0070] Thus, in one embodiment, provided herein are coated particles, each particle comprising: (i) a microparticle that comprises a pharmaceutically acceptable excipient and (ii) nanoparticles of cannabidiol; wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing cannabidiol at the first predetermined temperature under the predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surface of the microparticle at the predetermined agitation speed and the second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surfaces of the microparticles, thus forming the coated particles. [0071] In another embodiment, provided herein are nanoparticles of cannabidiol, which are prepared by a method comprising the steps of: a. vaporizing cannabidiol at the first predetermined temperature under the predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surface of a microparticle comprising a pharmaceutically acceptable excipient at the predetermined agitation speed and the second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surface of the microparticle.

[0072] In yet another embodiment, provided herein is a batch of coated particles, each particle comprising: (i) a microparticle that comprises a pharmaceutically acceptable excipient and (ii) nanoparticles of cannabidiol; wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing cannabidiol at the first predetermined temperature under the predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surface of the microparticle at the predetermined agitation speed and the second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surfaces of the microparticles, thus forming the coated particles.

[0073] In still another embodiment, provided herein is a batch of nanoparticles of cannabidiol, which are prepared by a method comprising the steps of: a. vaporizing cannabidiol at the first predetermined temperature under the predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surface of a microparticle comprising a pharmaceutically acceptable excipient at the predetermined agitation speed and the second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surface of the microparticle.

[0074] In one embodiment, provided herein are coated particles, each particle comprising: (i) a mannitol microparticle and (ii) nanoparticles of cannabidiol; wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing cannabidiol at the first predetermined temperature under the predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surfaces of the mannitol microparticles at the predetermined agitation speed and the second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surfaces of the mannitol microparticles, thus forming the coated particles.

[0075] In another embodiment, provided herein are nanoparticles of cannabidiol, which are prepared by a method comprising the steps of a. vaporizing cannabidiol at the first predetermined temperature under the predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surface of a mannitol microparticle at the predetermined agitation speed and the second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surface of the mannitol microparticle.

[0076] In yet another embodiment, provided herein is a batch of coated particles, each particle comprising: (i) a mannitol microparticle and (ii) nanoparticles of cannabidiol; wherein the coated particles are prepared by a method comprising the steps of a. vaporizing cannabidiol at the first predetermined temperature under the predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surfaces of the mannitol microparticles at the predetermined agitation speed and the second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surfaces of the mannitol microparticles, thus forming the coated particles.

[0077] In still another embodiment, provided herein is a batch of nanoparticles of cannabidiol, which are prepared by a method comprising the steps of a. vaporizing cannabidiol at the first predetermined temperature under the predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surface of a mannitol microparticle at the predetermined agitation speed and the second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surface of the mannitol microparticle. [0078] In one embodiment, provided herein are coated particles, each particle comprising: (i) an MCC microparticle and (ii) nanoparticles of cannabidiol; wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing cannabidiol at the first predetermined temperature under the predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surfaces of the MCC microparticles at the predetermined agitation speed and the second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surfaces of the MCC microparticles, thus forming the coated particles.

[0079] In another embodiment, provided herein are nanoparticles of cannabidiol, which are prepared by a method comprising the steps of: a. vaporizing cannabidiol at the first predetermined temperature under the predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surface of an MCC microparticle at the predetermined agitation speed and the second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surface of the MCC microparticle.

[0080] In yet another embodiment, provided herein is a batch of coated particles, each particle comprising: (i) an MCC microparticle and (ii) nanoparticles of cannabidiol; wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing cannabidiol at the first predetermined temperature under the predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surfaces of the MCC microparticles at the predetermined agitation speed and the second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surfaces of the MCC microparticles, thus forming the coated particles.

[0081] In still another embodiment, provided herein is a batch of nanoparticles of cannabidiol, which are prepared by a method comprising the steps of: a. vaporizing cannabidiol at the first predetermined temperature under the predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surface of an MCC microparticle at the predetermined agitation speed and the second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surface of the MCC microparticle.

Pharmaceutical Compositions

[0082] In one embodiment, provided herein is a pharmaceutical composition comprising coated particles, each particle comprising: (i) a microparticle that comprises a pharmaceutically acceptable excipient and (ii) nanoparticles of cannabidiol, wherein the surface of the microparticle is coated with the nanoparticles of cannabidiol.

[0083] In another embodiment, provided herein is a pharmaceutical composition comprising coated particles, each particle comprising: (i) a microparticle that comprises a pharmaceutically acceptable excipient and (ii) nanoparticles of cannabidiol; wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surfaces of the microparticles at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surfaces of the microparticles, thus forming the coated particles.

[0084] In yet another embodiment, provided herein is a pharmaceutical composition comprising nanoparticles of cannabidiol, which are prepared by a method comprising the steps of: a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surface of a microparticle comprising a pharmaceutically acceptable excipient at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surface of the microparticle.

[0085] In yet another embodiment, provided herein is a batch of a pharmaceutical composition comprising coated particles, each particle comprising: (i) a microparticle that comprises a pharmaceutically acceptable excipient and (ii) nanoparticles of cannabidiol; wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surfaces of the microparticles at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surfaces of the microparticles, thus forming the coated particles.

[0086] In still another embodiment, provided herein is a batch of a pharmaceutical composition comprising a pharmaceutical acceptable excipient and nanoparticles of cannabidiol, wherein the nanoparticles are prepared by a method comprising the steps of: a. vaporizing cannabidiol at a predetermined temperature under a first predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surface of a microparticle comprising the pharmaceutically acceptable excipient at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surface of the microparticle.

[0087] In one embodiment, provided herein is a pharmaceutical composition comprising coated particles, each particle comprising: (i) a mannitol microparticle and (ii) nanoparticles of cannabidiol, wherein the surface of the mannitol microparticle is coated with the nanoparticles of cannabidiol.

[0088] In another embodiment, provided herein is a pharmaceutical composition comprising coated particles, each particle comprising: (i) a mannitol microparticle and (ii) nanoparticles of cannabidiol; wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surfaces of the mannitol microparticles at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surfaces of the mannitol microparticles, thus forming the coated particles.

[0089] In yet another embodiment, provided herein is a pharmaceutical composition comprising nanoparticles of cannabidiol, which are prepared by a method comprising the steps of: a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surface of a mannitol microparticle comprising a pharmaceutically acceptable excipient at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surface of the mannitol microparticle.

[0090] In yet another embodiment, provided herein is a batch of a pharmaceutical composition comprising coated particles, each particle comprising: (i) a mannitol microparticle and (ii) nanoparticles of cannabidiol; wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surfaces of the mannitol microparticles at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surfaces of the mannitol microparticles, thus forming the coated particles.

[0091] In still another embodiment, provided herein is a batch of a pharmaceutical composition comprising mannitol and nanoparticles of cannabidiol, wherein the nanoparticles are prepared by a method comprising the steps of: a. vaporizing cannabidiol at a predetermined temperature under a first predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surface of a mannitol microparticle at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surface of the mannitol microparticle.

[0092] In one embodiment, provided herein is a pharmaceutical composition comprising coated particles, each particle comprising: (i) an MCC microparticle and (ii) nanoparticles of cannabidiol, wherein the surface of the MCC microparticle is coated with the nanoparticles of cannabidiol.

[0093] In another embodiment, provided herein is a pharmaceutical composition comprising coated particles, each particle comprising: (i) an MCC microparticle and (ii) nanoparticles of cannabidiol; wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surfaces of the MCC microparticles at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surfaces of the MCC microparticles, thus forming the coated particles.

[0094] In yet another embodiment, provided herein is a pharmaceutical composition comprising nanoparticles of cannabidiol, which are prepared by a method comprising the steps of: a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surface of an MCC microparticle comprising a pharmaceutically acceptable excipient at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surface of the MCC microparticle.

[0095] In yet another embodiment, provided herein is a batch of a pharmaceutical composition comprising coated particles, each particle comprising: (i) an MCC microparticle and (ii) nanoparticles of cannabidiol; wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surfaces of the MCC microparticles at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surfaces of the MCC microparticles, thus forming the coated particles.

[0096] In still another embodiment, provided herein is a batch of a pharmaceutical composition comprising MCC and nanoparticles of cannabidiol, wherein the nanoparticles are prepared by a method comprising the steps of: a. vaporizing cannabidiol at a predetermined temperature under a first predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surface of an MCC microparticle at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles on the surface of the MCC microparticle.

[0097] In certain embodiments, a pharmaceutical composition provided herein is formulated for intranasal administration.

[0098] In certain embodiments, a pharmaceutical composition provided herein is formulated as a dry powder. In certain embodiments, a pharmaceutical composition provided herein is formulated as a dry powder for administration by inhalation.

[0099] The pharmaceutical compositions provided herein can each independently be provided in a unit-dosage form or multiple-dosage form. A unit-dosage form, as used herein, refers to physically discrete a unit suitable for administration to a subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical excipient(s). Examples of a unit-dosage form include, but are not limited to, a capsule or blister. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in a segregated unit-dosage form. Examples of a multiple-dosage form include, are not limited to, a blister pack, blister disk, blister strip, cartridge, or reservoir. [00100] In one embodiment, a pharmaceutical composition provided herein is formulated as a capsule for intranasal administration. In another embodiment, a pharmaceutical composition provided herein is formulated as a blister for intranasal administration.

[00101] In one embodiment, a pharmaceutical composition provided herein is formulated as a capsule for administration by inhalation. In another embodiment, a pharmaceutical composition provided herein is formulated as a blister for administration by inhalation.

[00102] In one embodiment, a pharmaceutical composition provided herein is formulated as a multi-dose blister pack for intranasal administration. In another embodiment, a pharmaceutical composition provided herein is formulated as a multi-dose blister disk for intranasal administration. In yet another embodiment, a pharmaceutical composition provided herein is formulated as a multi-dose blister strip for intranasal administration. In yet another embodiment, a pharmaceutical composition provided herein is formulated as a multi-dose cartridge for intranasal administration. In still another embodiment, a pharmaceutical composition provided herein is formulated as a multi-dose reservoir for intranasal administration.

[00103] In one embodiment, a pharmaceutical composition provided herein is formulated as a multi-dose blister pack for administration by inhalation. In another embodiment, a pharmaceutical composition provided herein is formulated as a multi-dose blister disk for administration by inhalation. In yet another embodiment, a pharmaceutical composition provided herein is formulated as a multi-dose blister strip for administration by inhalation. In yet another embodiment, a pharmaceutical composition provided herein is formulated as a multidose cartridge for administration by inhalation. In still another embodiment, a pharmaceutical composition provided herein is formulated as a multi-dose reservoir for administration by inhalation.

[00104] In one embodiment, a pharmaceutical composition provided herein is formulated for administration by a dry powder inhaler. In one embodiment, the dry powder inhaler is a passive dry powder inhaler. In another embodiment, the dry powder inhaler is an active dry powder inhaler.

[00105] The pharmaceutical compositions provided herein can each independently be administered at once or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the subject being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the subject’s need and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition.

[00106] In one embodiment, provided herein is a device for intranasal administration of cannabidiol, comprising coated particles provided herein and a nasal spray. In another embodiment, provided herein is a device for intranasal administration of cannabidiol, comprising nanoparticles provided herein and a nasal spray. In yet another embodiment, provided herein is a device for administration of intranasal cannabidiol, comprising a pharmaceutical composition provided herein and a nasal spray.

[00107] In one embodiment, provided herein is a device for administration of cannabidiol by inhalation, comprising coated particles provided herein and an inhaler. In another embodiment, provided herein is a device for administration of cannabidiol by inhalation, comprising nanoparticles provided herein and an inhaler. In yet another embodiment, provided herein is a device for administration of cannabidiol by inhalation, comprising a pharmaceutical composition provided herein and an inhaler.

[00108] In one embodiment, provided herein is a kit for intranasal administration of cannabidiol, comprising coated particles provided herein and a nasal spray. In another embodiment, provided herein is a kit for intranasal administration of cannabidiol, comprising nanoparticles provided herein and a nasal spray. In yet another embodiment, provided herein is a kit for intranasal administration of cannabidiol, comprising a pharmaceutical composition provided herein and a nasal spray.

[00109] In one embodiment, provided herein is a kit for administration of cannabidiol by inhalation, comprising coated particles provided herein and an inhaler. In another embodiment, provided herein is a kit for administration of cannabidiol by inhalation, comprising nanoparticles provided herein and an inhaler. In yet another embodiment, provided herein is a kit for administration of cannabidiol by inhalation, comprising a pharmaceutical composition provided herein and an inhaler.

[00110] In certain embodiments, the nasal spray is an actuator. In certain embodiments, the nasal spray is a metered-dose actuator. In certain embodiments, the inhaler is a metered-dose inhaler. In certain embodiments, the inhaler is a dry powder inhaler.

[00111] In certain embodiments, the kit further comprises instructions for administration of cannabidiol.

[00112] The disclosure will be further understood by the following non-limiting examples.

EXAMPLES

[00113] As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society, the Journal of Medicinal Chemistry, or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); L (microliters); pm (micrometer); nm (nanometer); h (hour or hours); min (minutes); rpm (revolutions per minute); and HPLC (high performance liquid chromatography).

[00114] Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade). All procedures are conducted at room temperature unless otherwise specified. Methodologies illustrated herein are intended to exemplify the applicable technologies through the use of specific examples and are not indicative of the scope of the disclosure.

Example 1 Preparation of mannitol microparticles surface-coated with cannabidiol nanoparticles (4% drug loading)

[00115] Mannitol microparticles surface-coated with cannabidiol nanoparticles were prepared using organic vapor phase deposition (OVPD) technology. See, e.g., Baldo et al., Adv. Mater. 1998, 10, 1505-14; KR 100644219 Bl; and WO 2021/168043 Al, the disclosure of each of which is incorporated herein by reference in its entirety. Cannabidiol (2.5 g) was nanosized at about 135 to 150 °C under 2 x 10'⁵ torr as described in WO 2021/168043 Al, the disclosure of which is incorporated herein by reference in its entirety. The vaporized cannabidiol was in-situ coated on mannitol (50 g). HPLC assay showed that the coated microparticles had a drug loading of 4% with no impurities over 0.15% by area detected.

[00116] A cannabidiol nanoparticle sample for a particle sizer VIEWSIZER™ 3000 was prepared by adding the cannabidiol nanoparticles (0.03 gram) in XZERO nanopure water (10 mL) and sonicated for 3 min. The sample was centrifuged at 10,000 rpm for 3 min and then analyzed by the particle sizer. The cannabidiol nanoparticles were determined to have a Dso of 85 nm.

Example 2

Preparation of mannitol microparticles surface-coated with cannabidiol nanoparticles (12.2% drug loading)

[00117] Cannabidiol (16 g) was nanosized at about 140 °C under 1 x 10'⁵ torr as described in WO 2021/168043 Al, the disclosure of which is incorporated herein by reference in its entirety. The vaporized cannabidiol was in-situ coated on mannitol (130 g) with an average particle size (Dso) of 550 nm as determined by a SALD-2300 (Shimadzu) particle sizer. HPLC assay showed that the coated microparticles had a drug loading of 12.2% with no impurities over 0.15% by area detected.

[00118] The cannabidiol nanoparticles were analyzed using a scattering electron microscope (SEM) at 20 kV with a 3.5 spot size. Sample preparation was achieved by mounting 250 mg of the loaded carrier powder (i.e., the mannitol microparticles) onto spectra grade carbon adhesive tabs fixed to pin stub specimen mounts. Excess powder was removed with compressed air to retain the adhered powder only. Mounts with adhered samples were then coated in a 6 nm platinum layer using an EMS 150 Sputter Coater. The cannabidiol nanoparticles were analyzed by SEM to have an average particle size of about 450 nm.

[00119] A cannabidiol nanoparticle sample for a particle sizer SALD-2300 (Shimazu) was prepared in a 1% solution (v/v) of TWEEN 80 in water. The coated microparticles containing about 5 mg of cannabidiol were added to a solution containing 2 mL of the 1% TWEEN 80 solution and 20 mL of water in a flask. The mixture was sonicated for 8 min to ensure mannitol fully dissolved. Triplicate measurements of triplicate sample aliquots (total 9 measurements) were performed on the particle sizer SALD-2300 by adding 5 mL of water to a batch cell with agitation set to slow for a blank measurement. A 2.5 mL of the cannabidiol nanoparticle sample was added into a batch cell and agitated to disperse for 10 sec. After the agitation, 3 consecutive measurements were taken. The cannabidiol nanoparticles were analyzed by the Shimazu particle sizer to have a Dso of about 338 nm.

Example 3 Preparation of lactose microparticles surface-coated with cannabidiol nanoparticles (23.7% drug loading)

[00120] Cannabidiol (30 g) was nanosized at 130-145 under 5 x 10 "⁶ torr as described in WO 2021/168043 Al, the disclosure of which is incorporated herein by reference in its entirety. The vaporized cannabidiol was in-situ coated on lactose (125 g) with an average particle size (Dso) of 150 nm as determined by static laser scattering. HPLC assay showed that the coated microparticles had a drug loading of 23.7% with no impurities over 0.15% by area detected.

[00121] A cannabidiol nanoparticle sample for a particle sizer SALD-2300 (Shimazu) was prepared in a 1% solution (v/v) of TWEEN 80 in water. The coated microparticles containing about 10 mg of cannabidiol were added to a solution containing 2 mL of the 1% TWEEN 80 solution and 20 mL of water in a flask. The mixture was sonicated for 8 min to ensure lactose fully dissolved. Triplicate measurements of triplicate sample aliquots (total 9 measurements) were performed on the particle sizer SALD-2300 by adding 5 mL of water to a batch cell with agitation set to slow for a blank measurement. A 2.5 mL of the cannabidiol nanoparticle sample was added into a batch cell and agitated to disperse for 10 sec. After the agitation, 3 consecutive measurements were taken. The cannabidiol nanoparticles were analyzed by the Shimazu particle sizer to have a D50 of 150 nm. Example 4 Pharmacokinetic studies of cannabidiol nanoparticle in rats

[00122] Male rats (Sprague Dawley, < 15 weeks) with a body weight ranging from 250 to 275 g were visually inspected, weighed, and determined to be free of abnormalities and illness upon receipt and on the day of dosing. The rats were single housed (due to catheters) in solid bottom cages.

[00123] As a control, a suspension of crystalline CBD without nanosizing in 5% CMC was prepared at a crystalline CBD concentration of 12 mg/mL. A suspension of the mannitol microparticles surface-coated with CBD nanoparticles with 12.2% CBD loading was prepared at a mannitol microparticle concentration of 98.4 mg/mL, equivalent to a CBD concentration of 12 mg/mL. The crystalline CBD and CBD nanoparticles were administered via oral gavage to four groups of rats, each group having four rats, the rats each at 120 mg/kg of active CBD. Two groups were administered with the crystalline CBD formulation, whereas the remaining two groups were administered with the CBD nanoparticle formulation.

[00124] For the pharmacokinetics in rat plasma, blood samples (0.6 mL per time point) were collected at 0 (z.e., before administration), 0.5, 1, 2, 4, 6, 8, 12, and 24 h after administration via a jugular vein cannula. Each collected sample was centrifuged at 4 °C, and plasma was collected and frozen at -80 °C within 1 h of collection. Following the final blood collection at 24 h, all rats were euthanized via CCb asphyxiation and death confirmed by bilateral pneumothorax. The plasma samples were analyzed by HPLC with a Phenom enex Luna Cl 8 column (5 pm, 50 x 2 mm) or a Shimadzu Nexcol C18 column (1.8 pm, 50 x 2.1 mm). The PK results are summarized in Table 1.

Table 1. Pharmacokinetics of Crystalline CBD and CBD Nanoparticles in Rat Plasma

[00125] For the pharmacokinetics in rat brain, the rats were sacrificed and brain tissues were collected at 1, 6, and 12 h after administration. The tissue samples were rinsed with 0.9% sodium chloride solution, blotted dry, and frozen at -80 °C for analysis. The tissue samples were analyzed by HPLC with a Restek Ultra AQ Cl 8 column (3 pm, 100 x 2.1 mm). The PK results are summarized in Table 2.

Table 2. Pharmacokinetics of Crystalline CBD and CBD Nanoparticles in Rat Brain

[00126] The examples set forth above are provided to give those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments and are not intended to limit the scope of what is disclosed herein. Modifications that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.

Claims

What is claimed is:

1. A coated particle comprising: (i) a microparticle that comprises a pharmaceutically acceptable excipient and (ii) nanoparticles of cannabidiol; wherein the surface of the microparticle is coated with the nanoparticles of cannabidiol.

2. The coated particle of claim 1, wherein the surface of the microparticle is coated with a layer of the nanoparticles.

3. The coated particle of claim 1 or 2, wherein the surface of the microparticle is coated with a single layer of the nanoparticles.

4. The coated particle of any one of claims 1 to 3, wherein the coated particle is prepared by a method comprising the steps of: a. vaporizing cannabidiol at a first predetermined temperature under a predetermined vacuum pressure to form a vapor; and b. depositing the vapor on the surface of the microparticle at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the nanoparticles of cannabidiol on the surfaces of the microparticles, thus forming the coated particle.

5. The coated particle of claim 4, wherein the first predetermined temperature is ranging from about 20 to about 300 °C.

6. The coated particle of claim 4 or 5, wherein the predetermined vacuum pressure is no greater than about 10'³ torr.

7. The coated particle of any one of claims 4 to 6, wherein the predetermined agitation speed is ranging from about 10 to about 250 rpm.

8. The coated particle of any one of claims 4 to 7, wherein the second predetermined temperature is no greater than about 200 °C.

9. The coated particle of any one of claims 4 to 8, wherein the second predetermined temperature is ranging from about 20 to about 150 °C.

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10. The coated particle of any one of claims 1 to 9, wherein the pharmaceutically acceptable excipient is a hydrophilic excipient.

11. The coated particle of any one of claims 1 to 10, wherein the pharmaceutically acceptable excipient is a sugar alcohol.

12. The coated particle of any one of claims 1 to 11, wherein the pharmaceutically acceptable excipient is arabitol, erythritol, fucitol, galactitol, iditol, inositol, isomalt, lactitol, maltitol, maltotritol, mannitol, ribitol, sorbitol, threitol, volemitol, xylitol, or a mixture thereof.

13. The coated particle of any one of claims 1 to 12, wherein the pharmaceutically acceptable excipient is mannitol, sorbitol, xylitol, or a mixture thereof.

14. The coated particle of any one of claims 1 to 13, wherein the pharmaceutically acceptable excipient is mannitol.

15. The coated particle of any one of claims 1 to 14, wherein the pharmaceutically acceptable excipient is inhalation-grade mannitol.

16. The coated particle of any one of claims 1 to 10, wherein the pharmaceutically acceptable excipient is a cellulose.

17. The coated particle of any one of claims 1 to 10 and 16, wherein the pharmaceutically acceptable excipient is microcrystalline cellulose.

18. The coated particle of any one of claims 1 to 17, wherein the microparticle has an average particle size ranging from about 1 to about 5,000 pm.

19. The coated particle of any one of claims 1 to 18, wherein the nanoparticles have an average particle size ranging from about 100 to about 3,000 nm.

20. The coated particle of any one of claims 1 to 19, wherein the coated particle contains the nanoparticles in an amount ranging from about 0.1 to about 50% by weight.

21. The coated particle of any one of claims 1 to 20, wherein the coated particle has an average particle size ranging from about 1 to about 5,000 pm.

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22. A pharmaceutical composition comprising a coated particle of any one of claims 1 to 21.

23. The pharmaceutical composition of claim 22, wherein the pharmaceutical composition is formulated for intranasal administration.

24. The pharmaceutical composition of claim 22 or 23, wherein the pharmaceutical composition is formulated as nasal spray.

25. The pharmaceutical composition of claim 22, wherein the pharmaceutical composition is for administration by inhalation.

26. The pharmaceutical composition of claim 22 or 25, wherein the pharmaceutical composition is formulated as a dry powder.

27. The pharmaceutical composition of any one of claims 22 to 26, wherein the pharmaceutical composition is formulated as a single dosage form.

28. The pharmaceutical composition of claim 27, wherein the single dosage form is a capsule, blister, or nasal spray.

29. The pharmaceutical composition of any one of claims 22 to 26, wherein the pharmaceutical composition is formulated as a multi-dosage form.

30. The pharmaceutical composition of any one of claims 29, wherein the multidosage form is a cartridge or reservoir.