Apomorphine compositions and therapeutic applications

Abstract

Provided herein are apomorphine compositions comprising an excipient particle and apomorphine nanoparticles, wherein the surface of the excipient particle is coated by Vapor-phase-deposition with the apomorphine nanoparticles. Also provided herein are methods of their preparation and use for treating, preventing, or ameliorating one or more symptoms of a neurological disorder.

Description

APOMORPHINE COMPOSITIONS AND THERAPEUTIC APPLICATIONSCROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of the priority of U.S. Provisional Application No. 63 / 658,786, filed June 11, 2024; the disclosure of which is incorporated herein by reference in its entirety.FIELD

[0002] Provided herein are apomorphine compositions comprising an excipient particle and apomorphine nanoparticles, wherein the surface of the excipient particle is coated with the apomorphine nanoparticles. Also provided herein are methods of their preparation and use for treating, preventing, or ameliorating one or more symptoms of a neurological disorder.BACKGROUND

[0003] Parkinson’s disease (PD), one of the world’s fastest growing neurological disorders, is a chronic debilitating disease affecting approximately 1% of the population over the age of 60. Connolly and Lang, JAMA 2014, 311, 1670-83; Carbone etal., CNS Drugs 2019, 33, 905-18; Yang et al., NPJ Parkinsons Dis. 2020, 6, 15. Apomorphine with a similar chemical structure as the neurotransmitter dopamine has been used for treating late stage PD. Carbone et al., CNS Drugs 2019, 33, 905-18. Apomorphine is administered as a hydrochloride salt in the abdomen region via a subcutaneous injection or infusion. Id. However, subcutaneous apomorphine therapy may give rise to problems with patient compliance associated with needle phobia or local pain due to irritation and inflammation followed by a formation of subcutaneous nodules. Pietz et al. , J. Neurol. Neurosurg. Psychiatry 1998, 65, 709- 16; Borkar et al. , Asian J. Pharm. Sci. 2018, 13, 507-17.

[0004] The inherent instability of apomorphine poses another complication in clinical practice. Udvardy etal., J. Mol. Struct. 2011, 1002, 37-44; Ang etal., Drug Des. Devel. Ther. 2016, 10, 3253-65; Tan et al., Nanomedicine 2019, 17, 236-45. Apomorphine spontaneously undergoes oxidative decomposition in an aqueous solution to yield a greenish colored solution, making it difficult to formulate as a stable pharmaceutical solution. Garrido et al, J. Chem. Soc.Perkin Trans II 2002, 10, 1713-17; Udvardy et al., J. Mol. Struct. 2011, 1002, 37-44; Ang et al., Drug Des. Devel. Ther. 2016, 10, 3253-65; Tan et al., Nanomedicine 2019, 17, 236-45. Therefore, there is a pressing unmet need for a stable and effective apomorphine therapy for treating PD noninvasively. Borkar et al., Asian J. Pharm. Sci. 2018, 13, 507-17; Tan et al., Nanomedicine 2019, 17, 236-45.SUMMARY OF THE DISCLOSURE

[0005] Provided herein is a coated particle comprising (i) an excipient particle i.e., a particle comprising a pharmaceutically acceptable excipient) and (ii) apomorphine nanoparticles (i.e., “nanoparticles of apomorphine”); wherein the surface of the excipient particle is coated with the apomorphine nanoparticles.

[0006] Also provided herein is a coated particle comprising (i) an excipient particle and (ii) vapor-phase-deposited apomorphine nanoparticles; wherein the surface of the excipient particle is coated with the vapor-phase-deposited apomorphine nanoparticles.

[0007] Additionally provided herein is a pharmaceutical composition comprising coated particles, each coated particle comprising (i) an excipient particle and (ii) apomorphine nanoparticles, wherein the surface of the excipient particle is coated with the apomorphine nanoparticles.

[0008] Furthermore, provided herein is a pharmaceutical composition comprising coated particles, each coated particle comprising (i) an excipient particle and (ii) vapor-phase-deposited apomorphine nanoparticles, wherein the surface of the excipient particle is coated with the vapor-phase-deposited apomorphine nanoparticles.

[0009] Provided herein is a method of preparing coated particles, each coated particle comprising (i) an excipient particle and (ii) apomorphine nanoparticles, comprising the steps of: a. vaporizing apomorphine at a first predetermined temperature under a predetermined vacuum pressure to form an apomorphine vapor; and b. depositing the apomorphine vapor on the surfaces of the excipient particles at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the apomorphine nanoparticles on the surfaces ofthe excipient particles, thus forming the coated particles.

[0010] Provided herein are coated particles, each coated particle comprising (i) an excipient particle and (ii) apomorphine nanoparticles, wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing apomorphine at a first predetermined temperature under a predetermined vacuum pressure to form an apomorphine vapor; and b. depositing the apomorphine vapor on the surfaces of the excipient particles at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the apomorphine nanoparticles on the surfaces of the excipient particles, thus forming the coated particles.

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

[0012] Provided herein is a batch of coated particles, each coated particle comprising (i) an excipient particle and (ii) apomorphine nanoparticles, wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing apomorphine at a first predetermined temperature under a predetermined vacuum pressure to form an apomorphine vapor; and b. depositing the apomorphine vapor on the surfaces of the excipient particles at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the apomorphine nanoparticles on the surfaces of the excipient particles, thus forming the coated particles.

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

[0014] Provided herein is a device for administering apomorphine intranasally, comprising coated particles or a pharmaceutical composition provided herein and a spray device.

[0015] Provided herein is a kit administering apomorphine intranasally, comprising coated particles or a pharmaceutical composition provided herein, and a spray device.

[0016] Provided herein is a method of treating, preventing, or alleviating one or more symptoms of a neurological disorder in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of coated particles or a pharmaceutical composition provided herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 illustrates the formation of apomorphine nanoparticles on the surfaces of excipient particles by contacting the excipient particles with an apomorphine vapor.

[0018] FIG. 2 shows the pharmacokinetic profiles of dry powder apomorphine nanoparticle formulations Fl (Group 2, 1.5 mg / dose) and F2 (Group 3, 0.5 mg / dose) administered intranasally, in comparison with apomorphine HC1 (Group 3) administered subcutaneously.DETAILED DESCRIPTION

[0019] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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, orhuman, which is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] In certain embodiments, “optically active” and ’’enantiomerically active” refer toa 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.

[0030] 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.

[0031] 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, aracemic 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

[0032] In one embodiment, provided herein is a coated particle comprising (i) an excipient particle (z.e., a particle comprising a pharmaceutically acceptable excipient) and (ii) apomorphine nanoparticles (z.c., “nanoparticles of apomorphine”), wherein the surface of the excipient particle is coated with the apomorphine nanoparticles.

[0033] In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is hydrophilic. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is water-soluble. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is inhalation-grade.

[0034] In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is a sugar. In certain embodiments, the pharmaceutically acceptable excipient in a 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 a coated particle provided herein is dextrose, glucose, lactose, sucralose, sucrose, or a mixture thereof. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is dextrose. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is fructose. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is glucose. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is lactose. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is lactose monohydrate. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is anhydrous lactose. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein isinhalation-grade lactose. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is inhalation-grade lactose monohydrate. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is inhalation-grade anhydrous lactose. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is starch. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is sucrose. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is trehalose.

[0035] In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is a sugar alcohol. In certain embodiments, the pharmaceutically acceptable excipient in a 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 a coated particle provided herein is erythritol, lactitol, maltitol, mannitol, sorbitol, xylitol, or a mixture thereof. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is arabitol. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is erythritol. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is fucitol. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is galactitol. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is iditol. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is inositol. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is isomalt. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is lactitol. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is maltitol. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is maltotritol. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is mannitol. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is D-mannitol. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is inhalation-grade mannitol, i certain embodiments, the pharmaceutically acceptableexcipient in a coated particle provided herein is inhalation-grade D-mannitol. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is ribitol. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is sorbitol. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is threitol. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is volemitol. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is xylitol.

[0036] In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is a cellulose. In certain embodiments, the pharmaceutically acceptable excipient in a coated particle provided herein is microcrystalline cellulose (MCC). In certain embodiments, the pharmaceutically acceptable excipient in a 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).

[0037] In certain embodiments, the excipient particle in a coated particle provided herein has various shapes, including, but not limited to, a sphere, spheroid, platelet, fibril, or fiber. In certain embodiments, the excipient particle in a coated particle provided herein is substantially spherical. In certain embodiments, the excipient particle in a coated particle provided herein is spherical. In certain embodiments, the excipient particle in a coated particle provided herein is spheroidal.

[0038] In certain embodiments, the excipient particle in a coated particle provided herein has an average particle size (Dso) ranging from about 1 to about 5,000 nm, from about 10 to about 2,500 nm, from about 50 to about 1,000 nm, from about 100 to about 1,000 nm, from about 100 to about 900 nm, from about 100 to about 750 nm, or from about 100 to about 500 nm. In certain embodiments, the excipient particle in a coated particle provided herein has an average particle size ranging from about 1 to about 5,000 nm. In certain embodiments, the excipient particle in a coated particle provided herein has an average particle size ranging from about 10 to about 2,500 nm. In certain embodiments, the excipient particle in a coated particle provided herein has an average particle size ranging from about 50 to about 1,000 nm. In certainembodiments, the excipient particle in a coated particle provided herein has an average particle size ranging from about 100 to about 1,000 nm. In certain embodiments, the excipient particle in a coated particle provided herein has an average particle size ranging from about 100 to about 750 nm. In certain embodiments, the excipient particle in a coated particle provided herein has an average particle size ranging from about 100 to about 500 nm. In certain embodiments, the excipient particle in a 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, or about 500 nm. In certain embodiments, the excipient particle in a coated particle provided herein has an average particle size of about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, or about 900 nm.

[0039] In certain embodiments, the excipient particle in a coated particle provided herein has an average particle size suitable for intranasal administration.

[0040] In certain embodiments, the excipient particle in a coated particle provided herein is a microparticle. In certain embodiments, the excipient particle in a coated particle provided herein is a nanoparticle.

[0041] In one embodiment, provided herein is a coated particle comprising (i) a mannitol particle a particle comprising mannitol) and (ii) apomorphine nanoparticles, wherein the surface of the mannitol particle is coated with the apomorphine nanoparticles.

[0042] In another embodiment, provided herein is a coated particle consisting of (i) a mannitol particle and (ii) apomorphine nanoparticles, wherein the surface of the mannitol particle is coated with the apomorphine nanoparticles.

[0043] In one embodiment, the mannitol particle comprises mannitol. In another embodiment, the mannitol particle comprises inhalation-grade mannitol.

[0044] In certain embodiments, the mannitol particle in a coated particle provided herein has various shapes, including, but not limited to, a sphere, spheroid, platelet, fibril, or fiber. In certain embodiments, the mannitol particle in a coated particle provided herein is substantially spherical. In certain embodiments, the mannitol particle in a coated particle provided herein is spherical. In certain embodiments, the mannitol particle in a coated particle provided herein isspheroidal.

[0045] In certain embodiments, the mannitol particle in a coated particle provided herein has an average particle size ranging from about 1 to about 5,000 nm, from about 10 to about 2,500 nm, from about 50 to about 1,000 nm, from about 100 to about 1,000 nm, from about 100 to about 900 nm, from about 100 to about 750 nm, or from about 100 to about 500 nm. In certain embodiments, the mannitol particle in a coated particle provided herein has an average particle size ranging from about 1 to about 5,000 nm. In certain embodiments, the mannitol particle in a coated particle provided herein has an average particle size ranging from about 10 to about 2,500 nm. In certain embodiments, the mannitol particle in a coated particle provided herein has an average particle size ranging from about 50 to about 1,000 nm. In certain embodiments, the mannitol particle in a coated particle provided herein has an average particle size ranging from about 100 to about 1,000 nm. In certain embodiments, the mannitol particle in a coated particle provided herein has an average particle size ranging from about 100 to about 900 nm. In certain embodiments, the mannitol particle in a coated particle provided herein has an average particle size ranging from about 100 to about 750 nm. In certain embodiments, the mannitol particle in a coated particle provided herein has an average particle size ranging from about 100 to about 500 nm. In certain embodiments, the mannitol particle in a 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, or about 500 nm. In certain embodiments, the mannitol particle in a coated particle provided herein has an average particle size of about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, or about 900 nm.

[0046] In certain embodiments, the mannitol particle in a coated particle provided herein has an average particle size suitable for intranasal administration.

[0047] In certain embodiments, the mannitol particle in a coated particle provided herein is a microparticle. In certain embodiments, the mannitol particle in a coated particle provided herein is a nanoparticle.

[0048] In certain embodiments, the apomorphine in a coated particle provided herein is (6o ?)-6-methyl-5,6,6a,7-tetrahydro-4 -dibenzo[de,g]quinoline-10,l l-diol, which has the structure shown below. In certain embodiments, the apomorphine in a coated particle providedherein is a free base.

[0049] In certain embodiments, the apomorphine nanoparticles in a coated particle provided herein have an average particle size ranging from about 1 to about 1,000 nm, from about 1 to about 900 nm, from about 1 to about 500 nm, from about 2 to about 400 nm, from about 5 to about 300 nm, or from about 10 to about 200 nm. In certain embodiments, the apomorphine nanoparticles in a coated particle provided herein have an average particle size ranging from about 1 to about 1,000 nm. In certain embodiments, the apomorphine nanoparticles in a coated particle provided herein have an average particle size ranging from about 1 to about 900 nm. In certain embodiments, the apomorphine nanoparticles in a coated particle provided herein have an average particle size ranging from about 1 to about 500 nm. In certain embodiments, the apomorphine nanoparticles in a coated particle provided herein have an average particle size ranging from about 2 to about 400 nm. In certain embodiments, the apomorphine nanoparticles in a coated particle provided herein have an average particle size ranging from about 5 to about 300 nm. In certain embodiments, the apomorphine nanoparticles in a coated particle provided herein have an average particle size ranging from about 10 to about 200 nm.

[0050] In certain embodiments, the apomorphine nanoparticles in a coated particle provided herein are formed on the surface of the excipient particle. In certain embodiments, the apomorphine nanoparticles in a coated particle provided herein are formed on the surface of the excipient particle by physical vapor deposition. See, e.g., Baldo etal., Adv. Mater. 1998, 10, 1505-14; WO 2021 / 168043 Al; the disclosure of each of which is incorporated herein by reference in its entirety. In certain embodiments, the apomorphine nanoparticles in a coated particle provided herein are vapor-phase-deposited nanoparticles.

[0051] In certain embodiments, the percentage of the apomorphine nanoparticles in a coated particle is ranging from about 0.1 to about 50% by weight, from about 1 to about 50% byweight, about 1 to about 40% by weight, about 1 to about 30% by weight, or about 1 to about 20% by weight. In certain embodiments, the percentage of the apomorphine nanoparticles in a coated particle is ranging from about 0.1 to about 50% by weight. In certain embodiments, the percentage of the apomorphine nanoparticles in a coated particle is ranging from about 1 to about 50% by weight. In certain embodiments, the percentage of the apomorphine nanoparticles in a coated particle is ranging from about 1 to about 40% by weight. In certain embodiments, the percentage of the apomorphine nanoparticles in a coated particle is ranging from about 1 to about 30% by weight. In certain embodiments, the percentage of the apomorphine nanoparticles in a coated particle is ranging from about 1 to about 20% by weight. In certain embodiments, the percentage of the apomorphine nanoparticles in a coated particle is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10% by weight. In certain embodiments, the percentage of the apomorphine nanoparticles in a coated particle is about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20% by weight. In certain embodiments, the percentage of the apomorphine nanoparticles in a coated particle is about 3, about 7, or about 13% by weight.

[0052] In certain embodiments, a coated particle provided herein has an average particle size ranging from about 1 to about 5,000 nm, from about 10 to about 2,500 nm, from about 50 to about 1,000 nm, from about 100 to about 1,000 nm, from about 100 to about 900 nm, from about 100 to about 750 nm, or from about 100 to about 500 nm. In certain embodiments, a coated particle provided herein has an average particle size ranging from about 1 to about 5,000 nm. In certain embodiments, a coated particle provided herein has an average particle size ranging from about 10 to about 2,500 nm. In certain embodiments, a coated particle provided herein has an average particle size ranging from about 50 to about 1,000 nm. In certain embodiments, a coated particle provided herein has an average particle size ranging from about 100 to about 1,000 nm. In certain embodiments, a coated particle provided herein has an average particle size ranging from about 100 to about 900 nm. In certain embodiments, a coated particle provided herein has an average particle size ranging from about 100 to about 750 nm. In certain embodiments, a coated particle provided herein has an average particle size ranging from about 100 to about 500 nm. In certain embodiments, a 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, or about 500 nm. In certain embodiments, a coated particle provided herein has an average particlesize of about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, or about 900 nm.

[0053] In certain embodiments, a coated particle provided herein has an average particle size suitable for intranasal administration.

[0054] In certain embodiments, a coated particle provided herein is a microparticle. In certain embodiments, a coated particle provided herein is a nanoparticle.Method of Preparation

[0055] In one embodiment, provided herein is a method of preparing coated particles, each coated particle comprising (i) an excipient particle and (ii) apomorphine nanoparticles, comprising the steps of: a. vaporizing apomorphine at a first predetermined temperature under a predetermined vacuum pressure to form an apomorphine vapor; and b. depositing the apomorphine vapor on the surface of the excipient particle at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the apomorphine nanoparticles on the surfaces of the excipient particles, thus forming the coated particles.

[0056] In another embodiment, provided herein is a method of preparing nanoparticles of apomorphine, comprising the steps of: a. vaporizing apomorphine at a first predetermined temperature under a predetermined vacuum pressure to form an apomorphine vapor; and b. depositing the apomorphine vapor on the surface of an excipient particle at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the apomorphine nanoparticles on the surface of the excipient particle.

[0057] In yet another embodiment, provided herein is a batch of coated particles, each coated particle comprising (i) an excipient particle and (ii) apomorphine nanoparticles, wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing apomorphine at the first predetermined temperature under the predeterminedvacuum pressure to form an apomorphine vapor; and b. depositing the apomorphine vapor on the surface of the excipient particle at the predetermined agitation speed and the second predetermined temperature under the predetermined vacuum pressure to form the apomorphine nanoparticles on the surfaces of the excipient particles, thus forming the coated particles.

[0058] In still another embodiment, provided herein is a batch of apomorphine nanoparticles, which are prepared by a method comprising the steps of: a. vaporizing apomorphine at the first predetermined temperature under the predetermined vacuum pressure to form an apomorphine vapor; and b. depositing the apomorphine vapor on the surface of an excipient particle at the predetermined agitation speed and the second predetermined temperature under the predetermined vacuum pressure to form the apomorphine nanoparticles on the surface of the excipient particle.

[0059] In certain embodiments, the first predetermined temperature is ranging from about 20 to about 500 °C, 25 to about 300 °C, 50 to about 250 °C, from about 50 to about 200 °C, from about 50 to about 150 °C, or from about 100 to about 150 °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 25 to about 300 °C. In certain embodiments, the first predetermined temperature is ranging from about 50 to about 250 °C. In certain embodiments, the first predetermined temperature is ranging from about 50 to about 200 °C. In certain embodiments, the first predetermined temperature is ranging from about 100 to about 200 °C. In certain embodiments, the first predetermined temperature is ranging from about 150 to about 200 °C. In certain embodiments, the first predetermined temperature is ranging from about 50 to about 150 °C. In certain embodiments, the first predetermined temperature is ranging from about 100 to about 150 °C. In certain embodiments, the first predetermined temperature is about 100, about 110, about 120, about 130, about 140, or about 150 °C.

[0060] In certain embodiments, the predetermined vacuum pressure is no greater than about 10'3torr, no greater than about 10'4torr, no greater than about 10'5torr, no greater thanabout 10'6torr, no greater than about 10'7torr, no greater than about 10'8torr, or no greater than about 10'9torr. In certain embodiments, the predetermined vacuum pressure is no greater than about 10'3torr. In certain embodiments, the first predetermined vacuum pressure is no greater than about 10'4torr. In certain embodiments, the predetermined vacuum pressure is no greater than about 10'5torr. In certain embodiments, the predetermined vacuum pressure is no greater than about 10'6torr. In certain embodiments, the first predetermined vacuum pressure is no greater than about 10'7torr. In certain embodiments, the predetermined vacuum pressure is no greater than about 10'8torr. In certain embodiments, the predetermined vacuum pressure is no greater than about 10'9torr. In certain embodiments, the predetermined vacuum pressure is about 1 O’4, about 10'5, about 10'6, about 10'7, or about 10'8torr.

[0061] In certain embodiments, the predetermined vacuum pressure is ranging from about 10'3to about 10'8torr. In certain embodiments, the predetermined vacuum pressure is ranging from about 10'4to about 10'8torr. In certain embodiments, the predetermined vacuum pressure is ranging from about 10'5to about 10'7torr. In certain embodiments, the predetermined vacuum pressure is ranging from about 10'5to about 10'7torr.

[0062] 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, or from about 50 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 about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100 rpm.

[0063] To efficiently deposit the vapor of apomorphine onto the surface of an excipient particle, 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, no less than about 20, no less than about 50, or no less than about 100 °C lower than the first predetermined temperature.

[0064] 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.

[0065] 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 25 to about 120 °C, from about 25 to about 100 °C, or from about 25 to about 50 °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 25 to about 120 °C. In certain embodiments, the second predetermined temperature is ranging from about 25 to about 100 °C. In certain embodiments, the second predetermined temperature is ranging from about 25 to about 50 °C. In certain embodiments, the second predetermined temperature is about 25, about 30, about 35, about 40, about 45, or about 50 °C. In certain embodiments, the second predetermined temperature is ambient temperature.

[0066] In one embodiment, provided herein are coated particles, each coated particle comprising (i) a mannitol particle and (ii) apomorphine nanoparticles; wherein the coated particles are prepared by a method comprising the steps of:a. vaporizing apomorphine at the first predetermined temperature under the predetermined vacuum pressure to form an apomorphine vapor; and b. depositing the apomorphine vapor on the surfaces of the mannitol particles at the predetermined agitation speed and the second predetermined temperature under the predetermined vacuum pressure to form the apomorphine nanoparticles on the surfaces of the mannitol particles, thus forming the coated particles.

[0067] In another embodiment, provided herein are apomorphine nanoparticles, which are prepared by a method comprising the steps of: a. vaporizing apomorphine at the first predetermined temperature under the predetermined vacuum pressure to form an apomorphine vapor; and b. depositing the apomorphine vapor on the surface of a mannitol particle at the predetermined agitation speed and the second predetermined temperature under the predetermined vacuum pressure to form the apomorphine nanoparticles on the surface of the mannitol particle.

[0068] In yet another embodiment, provided herein is a batch of coated particles, each coated particle comprising (i) a mannitol particle and (ii) apomorphine nanoparticles; wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing apomorphine at the first predetermined temperature under the predetermined vacuum pressure to form an apomorphine vapor; and b. depositing the apomorphine vapor on the surfaces of the mannitol particles at the predetermined agitation speed and the second predetermined temperature under the predetermined vacuum pressure to form the apomorphine nanoparticles on the surfaces of the mannitol particles, thus forming the coated particles.

[0069] In still another embodiment, provided herein is a batch of apomorphine nanoparticles, which are prepared by a method comprising the steps of: a. vaporizing apomorphine at the first predetermined temperature under the predetermined vacuum pressure to form an apomorphine vapor; and b. depositing the apomorphine vapor on the surface of a mannitol particle at the predetermined agitation speed and the second predetermined temperature under thepredetermined vacuum pressure to form the apomorphine nanoparticles on the surface of the mannitol particle.

[0070] In certain embodiments, the apomorphine in the vaporizing step is a free base. In certain embodiments, the apomorphine in the vaporizing step is an apomorphine solvate. In certain embodiments, the apomorphine in the vaporizing step is an apomorphine solvate of acetone, acetonitrile, 1,4-di oxane, ethanol, ethylene glycol, formamide, methyl acetate, methyl tert-butyl ether (TBME), nitromethane, 2-propanol, pyridine, TBME, THF, or water. In certain embodiments, the apomorphine in the vaporizing step is an apomorphine solvate of ethanol. In certain embodiments, the apomorphine in the vaporizing step is an apomorphine solvate of 2- propanol. In certain embodiments, the apomorphine in the vaporizing step is a crystalline solid of apomorphine free base, or a hydrate or solvate thereof described in US 2017 / 0368052 Al, the disclosure of which is incorporated herein by reference in its entirety.

[0071] In certain embodiments, the apomorphine in the vaporizing step is a crystalline free base. In certain embodiments, the apomorphine in the vaporizing step is a crystalline apomorphine solvate. In certain embodiments, the apomorphine in the vaporizing step is a crystalline apomorphine solvate of acetone, acetonitrile, 1,4-di oxane, ethanol, ethylene glycol, formamide, methyl acetate, methyl tert-butyl ether (TBME), nitromethane, 2-propanol, pyridine, TBME, THF, or water. In certain embodiments, the apomorphine in the vaporizing step is a crystalline apomorphine solvate of ethanol. In certain embodiments, the apomorphine in the vaporizing step is a crystalline apomorphine hemiethanol solvate. In certain embodiments, the apomorphine in the vaporizing step is a crystalline apomorphine solvate of 2-propanol.Pharmaceutical Compositions

[0072] In one embodiment, provided herein is a pharmaceutical composition comprising coated particles, each coated particle comprising (i) an excipient particle and (ii) apomorphine nanoparticles, wherein the surface of the excipient particle is coated with the apomorphine nanoparticles.

[0073] In another embodiment, provided herein is a pharmaceutical composition comprising coated particles, each coated particle comprising (i) an excipient particle and (ii)vapor-phase-deposited apomorphine nanoparticles, wherein the surface of the excipient particle is coated with the vapor-phase-deposited apomorphine nanoparticles.

[0074] In yet another embodiment, provided herein is a pharmaceutical composition comprising coated particles, each coated particle comprising (i) an excipient particle and (ii) apomorphine nanoparticles; wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing apomorphine at a first predetermined temperature under a predetermined vacuum pressure to form an apomorphine vapor; and b. depositing the apomorphine vapor on the surfaces of the excipient particles at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the apomorphine nanoparticles on the surfaces of the excipient particles, thus forming the coated particles.

[0075] In yet another embodiment, provided herein is a pharmaceutical composition comprising nanoparticles of apomorphine, which are prepared by a method comprising the steps of a. vaporizing apomorphine at a first predetermined temperature under a predetermined vacuum pressure to form an apomorphine vapor; and b. depositing the apomorphine vapor on the surface of an excipient particle at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the apomorphine nanoparticles on the surface of the excipient particle.

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

[0077] In still another embodiment, provided herein is a batch of a pharmaceutical composition comprising apomorphine nanoparticles, wherein the apomorphine nanoparticles are prepared by a method comprising the steps of: a. vaporizing apomorphine at a predetermined temperature under a first predetermined vacuum pressure to form an apomorphine vapor; and b. depositing the apomorphine vapor on the surface of an excipient particle at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the apomorphine nanoparticles on the surface of the excipient particle.

[0078] In one embodiment, provided herein is a pharmaceutical composition comprising coated particles, each coated particle comprising (i) a mannitol particle and (ii) apomorphine nanoparticles, wherein the surface of the mannitol microparticle is coated with the apomorphine nanoparticles.

[0079] In another embodiment, provided herein is a pharmaceutical composition comprising coated particles, each coated particle comprising (i) a mannitol particle and (ii) vapor-phase-deposited apomorphine nanoparticles, wherein the surface of the mannitol microparticle is coated with the vapor-phase-deposited apomorphine nanoparticles.

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

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

[0082] In yet another embodiment, provided herein is a batch of a pharmaceutical composition comprising coated particles, each coated particle comprising (i) a mannitol particle and (ii) apomorphine nanoparticles; wherein the coated particles are prepared by a method comprising the steps of: a. vaporizing apomorphine at a first predetermined temperature under a predetermined vacuum pressure to form an apomorphine vapor; and b. depositing the apomorphine vapor on the surfaces of the mannitol particles at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the apomorphine nanoparticles on the surfaces of the mannitol particles, thus forming the coated particles.

[0083] In still another embodiment, provided herein is a batch of a pharmaceutical composition comprising apomorphine nanoparticles, wherein the apomorphine nanoparticles are prepared by a method comprising the steps of: a. vaporizing apomorphine at a predetermined temperature under a first predetermined vacuum pressure to form an apomorphine vapor; and b. depositing the apomorphine vapor on the surface of a mannitol particle at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the apomorphine nanoparticles on the surface of the mannitol particle.

[0084] In certain embodiments, a pharmaceutical composition provided herein further comprises an additional pharmaceutically acceptable excipient.

[0085] Thus, in one embodiment, provided herein is a pharmaceutical composition comprising coated particles, each coated particle comprising (i) an excipient particle and (ii) apomorphine nanoparticles, wherein the surface of the excipient particle is coated with the apomorphine nanoparticles; and an additional pharmaceutically acceptable excipient.

[0086] In another embodiment, provided herein is a pharmaceutical composition comprising coated particles, each coated particle comprising (i) an excipient particle and (ii) vapor-phase-deposited apomorphine nanoparticles, wherein the surface of the excipient particle is coated with the vapor-phase-deposited apomorphine nanoparticles; and an additional pharmaceutically acceptable excipient.

[0087] In certain embodiments, the additional pharmaceutically acceptable excipient in a pharmaceutical composition provided herein is an antioxidant, a binder, a diluent, a disintegrant, a fdler, a glidant, a lubricant, a preservative, a sweetening agent, a thickener, or a combination thereof. In certain embodiments, the additional pharmaceutically acceptable excipient in a pharmaceutical composition provided herein is an antioxidant, a disintegrant, a diluent, a filler, a lubricant, a sweetening agent, a thickener, or a combination thereof.

[0088] In one embodiment, a pharmaceutical composition provided herein comprises coated particles provided herein, a lubricant, and a mucoadhesive agent.

[0089] In another embodiment, a pharmaceutical composition provided herein comprises coated particles provided herein, an antioxidant, a lubricant, and a mucoadhesive agent.

[0090] In yet another embodiment, a pharmaceutical composition provided herein comprises coated particles provided herein, a filler, a lubricant, and a mucoadhesive agent.

[0091] In still another embodiment, a pharmaceutical composition provided herein comprises coated particles provided herein, an antioxidant, a disintegrant, a lubricant, and a mucoadhesive agent.

[0092] In certain embodiments, the coated particles in a pharmaceutical composition provided herein is ranging from about 50% to about 99%, from about 60% to about 98% by weight, or from about 70% to about 98% weight. In certain embodiments, the coated particles ina pharmaceutical composition provided herein is ranging from about 50% to about 99%. In certain embodiments, the coated particles in a pharmaceutical composition provided herein is ranging from about 60% to about 98% by weight. In certain embodiments, the coated particles in a pharmaceutical composition provided herein is ranging from about 70% to about 98% weight. In certain embodiments, the coated particles in a pharmaceutical composition provided herein is about 70, about 75, about 80, about 85, about 90, about 92, about 95, about 96, about 97, or about 98% weight.

[0093] In certain embodiments, a pharmaceutical composition provided herein comprises from about 0.01 to about 5% by weight, from about 0.05 to about 2% by weight, from about 0.1 to about 1% by weight, or from about 0.1 to about 0.5% by weight of an antioxidant. In certain embodiments, a pharmaceutical composition provided herein comprises from about 0.01 to about 5% by weight of an antioxidant. In certain embodiments, a pharmaceutical composition provided herein comprises from about 0.05 to about 2% by weight of an antioxidant. In certain embodiments, a pharmaceutical composition provided herein comprises from about 0.1 to about 1% by weight of an antioxidant. In certain embodiments, a pharmaceutical composition provided herein comprises from about 0.1 to about 0.5% by weight of an antioxidant. In certain embodiments, a pharmaceutical composition provided herein comprises about 0.1, about 0.2, about 0.3, about 0.4, or about 0.5% by weight of an antioxidant. In certain embodiments, a pharmaceutical composition provided herein comprises about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, or about 5% by weight of an antioxidant.

[0094] In certain embodiments, the antioxidant in a pharmaceutical composition provided herein is ascorbic acid, ascorbyl palmitate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), or tocopheryl polyethylene glycol succinate%vitamin E TPGS). In certain embodiments, the antioxidant in a pharmaceutical composition provided herein is ascorbic acid. In certain embodiments, the antioxidant in a pharmaceutical composition provided herein is ascorbyl palmitate. In certain embodiments, the antioxidant in a pharmaceutical composition provided herein is butylated hydroxytoluene. In certain embodiments, the antioxidant in a pharmaceutical composition provided herein is butylated hydroxyanisole. In certain embodiments, the antioxidant in a pharmaceutical composition provided herein is vitamin E TPGS.

[0095] In certain embodiments, a pharmaceutical composition provided herein comprises from about 0.1 to about 50% by weight, from about 0.5 to about 40% by weight, from about 1 to about 25% by weight, or from about 2 to about 25% by weight of a fdler. In certain embodiments, a pharmaceutical composition provided herein comprises from about 0.1 to about 50% by weight of a filler. In certain embodiments, a pharmaceutical composition provided herein comprises from about 0.5 to about 40% by weight of a filler. In certain embodiments, a pharmaceutical composition provided herein comprises from about 1 to about 25% by weight of a filler. In certain embodiments, a pharmaceutical composition provided herein comprises from about 2 to about 25% by weight of a filler. In certain embodiments, a pharmaceutical composition provided herein comprises about 5, about 10, about 15, about 20, or about 25% by weight of a filler.

[0096] In certain embodiments, the filler in a pharmaceutical composition provided herein is calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, or pre-gelatinized starch. In certain embodiments, the filler in a pharmaceutical composition provided herein is mannitol.

[0097] In certain embodiments, a pharmaceutical composition provided herein comprises from about 0.01 to about 5% by weight, from about 0.05 to about 2% by weight, from about 0.1 to about 1% by weight, or from about 0.1 to about 0.5% by weight of a lubricant. In certain embodiments, a pharmaceutical composition provided herein comprises from about 0.01 to about 5% by weight of a lubricant. In certain embodiments, a pharmaceutical composition provided herein comprises from about 0.05 to about 2% by weight of a lubricant. In certain embodiments, a pharmaceutical composition provided herein comprises from about 0.1 to about 1% by weight of a lubricant. In certain embodiments, a pharmaceutical composition provided herein comprises from about 0.1 to about 0.5% by weight of a lubricant. In certain embodiments, a pharmaceutical composition provided herein comprises about 0.1, about 0.2, about 0.3, about 0.4, or about 0.5% by weight of a lubricant.

[0098] In certain embodiments, the lubricant in a pharmaceutical composition provided herein calcium stearate, magnesium stearate, mannitol, silica, starch, talc, or zinc stearate. In certain embodiments, the lubricant in a pharmaceutical composition provided herein isAEROSIL® 200, CAB-O-SIL®, colloidal silicon dioxide, or asbestos-free talc. In certain embodiments, the lubricant in a pharmaceutical composition provided herein is colloidal silicon dioxide.

[0099] In certain embodiments, a pharmaceutical composition provided herein comprises from about 0.1 to about 10% by weight, from about 0.2 to about 5% by weight, or from about 0.5 to about 2% by weight of a mucoadhesive agent. In certain embodiments, a pharmaceutical composition provided herein comprises from about 0.1 to about 10% by weight of a mucoadhesive agent. In certain embodiments, a pharmaceutical composition provided herein comprises from about 0.2 to about 5% by weight of a thickener. In certain embodiments, a pharmaceutical composition provided herein comprises from about 0.5 to about 2% by weight of a mucoadhesive agent. In certain embodiments, a pharmaceutical composition provided herein comprises about 0.5, about 1, about 1.5, or about 2% by weight of a mucoadhesive agent.

[0100] In certain embodiments, the mucoadhesive agent in a pharmaceutical composition provided herein is hydroxypropyl methylcellulose (HPMC).

[0101] In one embodiment, provided herein is a pharmaceutical composition comprising the coated particles provided herein, an antioxidant, and a mucoadhesive agent.

[0102] In another embodiment, provided herein is a pharmaceutical composition comprising about 97% by weight of the coated particles provided herein, about 1% by weight of an antioxidant, and about 2% by weight of a mucoadhesive agent.

[0103] In yet another embodiment, provided herein is a pharmaceutical composition comprising about 96% by weight of the coated particles provided herein, about 2% by weight of an antioxidant, and about 2% by weight of a mucoadhesive agent.

[0104] In one embodiment, provided herein is a pharmaceutical composition comprising the coated particles provided herein, an antioxidant, a lubricant, and a mucoadhesive agent.

[0105] In another embodiment, provided herein is a pharmaceutical composition comprising about 97% by weight of the coated particles provided herein, about 1% by weight of an antioxidant, about 0.5% by weight of a lubricant, and about 2% by weight of a mucoadhesiveagent.

[0106] In yet another embodiment, provided herein is a pharmaceutical composition comprising about 96% by weight of the coated particles provided herein, about 2% by weight of an antioxidant, about 0.5% by weight of a lubricant, and about 2% by weight of a mucoadhesive agent.

[0107] In certain embodiments, the antioxidant in a pharmaceutical composition provided herein is ascorbic acid. In certain embodiments, the antioxidant in a pharmaceutical composition provided herein is ascorbyl palmitate. In certain embodiments, the lubricant in a pharmaceutical composition provided herein is colloidal silicon dioxide. In certain embodiments, the mucoadhesive agent in a pharmaceutical composition provided herein is hydroxypropyl methylcellulose (HPMC).

[0108] In one embodiment, provided herein is a pharmaceutical composition comprising the coated particles provided herein, ascorbic acid, and HPMC.

[0109] In another embodiment, provided herein is a pharmaceutical composition comprising about 97% by weight of the coated particles provided herein, about 1% by weight of ascorbic acid, and about 2% by weight of HPMC.

[0110] In yet another embodiment, provided herein is a pharmaceutical composition comprising about 96% by weight of the coated particles provided herein, about 2% by weight of ascorbic acid, and about 2% by weight of HPMC.

[0111] In one embodiment, provided herein is a pharmaceutical composition comprising the coated particles provided herein, ascorbyl palmitate, and HPMC.

[0112] In another embodiment, provided herein is a pharmaceutical composition comprising about 97% by weight of the coated particles provided herein, about 1% by weight of ascorbyl palmitate, and about 2% by weight of HPMC.

[0113] In yet another embodiment, provided herein is a pharmaceutical composition comprising about 96% by weight of the coated particles provided herein, about 2% by weight of ascorbyl palmitate, and about 2% by weight of HPMC.

[0114] In one embodiment, provided herein is a pharmaceutical composition comprising the coated particles provided herein, ascorbic acid, colloidal silicon dioxide, and HPMC.

[0115] In another embodiment, provided herein is a pharmaceutical composition comprising about 97% by weight of the coated particles provided herein, about 1% by weight of ascorbic acid, about 0.5% by weight of colloidal silicon dioxide, and about 2% by weight of HPMC.

[0116] In yet another embodiment, provided herein is a pharmaceutical composition comprising about 96% by weight of the coated particles provided herein, about 2% by weight of ascorbic acid, about 0.5% by weight of colloidal silicon dioxide, and about 2% by weight of HPMC.

[0117] In one embodiment, provided herein is a pharmaceutical composition comprising the coated particles provided herein, ascorbyl palmitate, colloidal silicon dioxide, and HPMC.

[0118] In another embodiment, provided herein is a pharmaceutical composition comprising about 97% by weight of the coated particles provided herein, about 1% by weight of ascorbyl palmitate, about 0.5% by weight of colloidal silicon dioxide, and about 2% by weight of HPMC.

[0119] In yet another embodiment, provided herein is a pharmaceutical composition comprising about 96% by weight of the coated particles provided herein, about 2% by weight of ascorbyl palmitate, about 0.5% by weight of colloidal silicon dioxide, and about 2% by weight of HPMC.

[0120] In certain embodiments, the coated particles provided herein have a drug loading ranging from about 1 to about 50% by weight, from about 1 to about 25% by weight, from about 2 to about 20% by weight, or from about 5 to about 15% by weight. In certain embodiments, the coated particles provided herein have a drug loading ranging from about 1 to about 50% by weight. In certain embodiments, the coated particles provided herein have a drug loading ranging from about 1 to about 25% by weight. In certain embodiments, the coated particles provided herein have a drug loading ranging from about 2 to about 20% by weight. In certain embodiments, the coated particles provided herein have a drug loading ranging from about 5 toabout 15% by weight. In certain embodiments, the coated particles provided herein have a drug loading of about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, or about 15% by weight.

[0121] In certain embodiments, a pharmaceutical composition provided herein is formulated for intranasal administration. 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 intranasal administration.

[0122] 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 nasal spray pump. In one embodiment, a pharmaceutical composition provided herein is formulated as a multi-dose cartridge for intranasal administration. In another embodiment, a pharmaceutical composition provided herein is formulated as a multi-dose reservoir for intranasal administration.

[0123] 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.

[0124] In one embodiment, provided herein is a device for intranasal administration of apomorphine, comprising coated particles provided herein and a nasal spray pump. In another embodiment, provided herein is a device for intranasal administration of apomorphine,comprising apomorphine nanoparticles provided herein and a nasal spray pump. In yet another embodiment, provided herein is a device for intranasal administration of apomorphine, comprising vapor-phase-deposited apomorphine nanoparticles provided herein and a nasal spray pump. In still another embodiment, provided herein is a device for intranasal administration of apomorphine, comprising a pharmaceutical composition provided herein and a nasal spray pump.

[0125] In one embodiment, provided herein is a kit for intranasal administration of apomorphine, comprising coated particles provided herein and a nasal spray pump. In another embodiment, provided herein is a kit for intranasal administration of apomorphine, comprising apomorphine nanoparticles provided herein and a nasal spray pump. In yet another embodiment, provided herein is a kit for intranasal administration of apomorphine, comprising vapor-phase- deposited apomorphine nanoparticles provided herein and a nasal spray pump. In still another embodiment, provided herein is a kit for intranasal administration of apomorphine, comprising a pharmaceutical composition provided herein and a nasal spray pump.

[0126] In certain embodiments, the kit further comprises instructions for administration of apomorphine.Methods of Use

[0127] In one embodiment, provided herein is a method of treating, preventing, or alleviating one or more symptoms of a neurological disorder in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of apomorphine.

[0128] In certain embodiments, the neurological disorder is Parkinson’s disease. In certain embodiments, the neurological disorder is Stage I, II, III, IV, or V Parkinson’s disease. In certain embodiments, the neurological disorder is Stage I Parkinson’s disease. In certain embodiments, the neurological disorder is Stage II Parkinson’s disease. In certain embodiments, the neurological disorder is Stage III Parkinson’s disease. In certain embodiments, the neurological disorder is Stage IV Parkinson’s disease. In certain embodiments, the neurological disorder is Stage V Parkinson’s disease.

[0129] In certain embodiments, a method provided herein comprises alleviating an OFF episode associated with Parkinson’s disease.

[0130] In certain embodiments, the neurological disorder is early, moderate, or advanced Parkinson’s disease. In certain embodiments, the neurological disorder is early Parkinson’s disease. In certain embodiments, the neurological disorder is moderate Parkinson’s disease. In certain embodiments, the neurological disorder is advanced Parkinson’s disease.

[0131] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0132] In certain embodiments, the therapeutically effective amount of apomorphine in a pharmaceutical composition provided herein is ranging from about 0.5 to about 100 mg per day, from about 0.5 to about 50 mg per day, from about 1 to about 40 mg per day, from about 2 to about 30 mg per day, or from about 2 to about 10 mg per day. In certain embodiments, the therapeutically effective amount of apomorphine in a pharmaceutical composition provided herein is ranging from about 0.5 to about 100 mg per day. In certain embodiments, the therapeutically effective amount of apomorphine in a pharmaceutical composition provided herein is ranging from about 0.5 to about 50 mg per day. In certain embodiments, the therapeutically effective amount of apomorphine in a pharmaceutical composition provided herein is ranging from about 1 to about 40 mg per day. In certain embodiments, the therapeutically effective amount of apomorphine in a pharmaceutical composition provided herein is ranging from about 2 to about 30 mg per day. In certain embodiments, the therapeutically effective amount of apomorphine in a pharmaceutical composition provided herein is ranging from about 2 to about 10 mg per day.

[0133] In certain embodiments, a pharmaceutical composition provided herein is administered intranasally.

[0134] In certain embodiments, a pharmaceutical composition provided herein is administered once daily (QD), twice daily (BID), three times daily (TID), four times daily (QID), five times daily, six times daily, seven times daily, eight times daily, nine times daily, or ten times daily. In certain embodiments, a pharmaceutical composition provided herein is administered once daily (QD). In certain embodiments, a pharmaceutical composition provided herein is administered twice daily (BID). In certain embodiments, a pharmaceutical composition provided herein is administered three times daily (TID). In certain embodiments, apharmaceutical composition provided herein is administered four times daily (QID). In certain embodiments, a pharmaceutical composition provided herein is administered five times daily. In certain embodiments, a pharmaceutical composition provided herein is administered six times daily. In certain embodiments, a pharmaceutical composition provided herein is administered seven times daily. In certain embodiments, a pharmaceutical composition provided herein is administered eight times daily. In certain embodiments, a pharmaceutical composition provided herein is administered nine times daily. In certain embodiments, a pharmaceutical composition provided herein is administered ten times daily.

[0135] The disclosure will be further understood by the following non-limiting examples.EXAMPLES

[0136] 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).

[0137] 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 apomorphine hemiethanol solvate

[0138] To a mixture of apomorphine HC1 hemihydrate (30.53 g, 97.6 mmol) and ascorbic acid 6-palmitate (1.97 g, 4.76 mmol) in ethanol (150 mL) under N2 was added 3-amino- propan-l-ol (8.8 g, 9.0 mL, 0.12 mol) to form a golden-brown solution. The mixture was stirred at 75 °C for 30 min and then cooled to 50 °C. After the mixture was stirred for approximately 30min, thick precipitates were formed. The mixture was cooled to 25 °C for 2 h, followed by addition of heptane (150 mL). The mixture was stirred at 25 °C for 18 h to form a thick greybrown slurry. The mixture was cooled to 0 °C and stirred for 1 h. The resulting precipitates were collected by filtration under nitrogen and washed with a mixture of EtOH (45 mL) and heptane (45 mL). The filter cake was dried under a flow of nitrogen to afford apomorphine ’AEtOH as a beige / off-white solid (23.88 g, HPLC purity: 99.85%) in 81% yield. The solid was confirmed by1HNMR and TGA to be apomorphine hemiethanol solvate.Example 2Preparation of apomorphine nanoparticles-coated mannitol particles (3% drug loading)

[0139] Apomorphine nanoparticles-coated mannitol particles were prepared using organic vapor phase deposition (OVPD) technology. See, e.g, WO 2021 / 168043 Al, the disclosure of which is incorporated herein by reference in its entirety. An apomorphine solvate (e.g., apomorphine hemiethanol) (4.5 g) was nanosized at about 130 to 150 °C under about 3 x 10'6torr as described in WO 2021 / 168043 Al, the disclosure of which is incorporated herein by reference in its entirety. The vaporized apomorphine was in-situ coated at about 50 °C on mannitol particles (50 g) with an agitation speed of 65 rpm to yield 48.5 g of apomorphine nanoparticles-coated coated mannitol particles as a free-flowing white powder. The apomorphine nanoparticles-coated coated mannitol particles were analyzed by HPLC to have a drug loading of 3% and by a Shimazu particle sizer SALD-2300 to have a Dio, Dso, and D$>o of 213, 310, and 516 nm, respectively.Example 3Preparation of apomorphine nanoparticles-coated mannitol particles (7% drug loading)

[0140] Apomorphine nanoparticles-coated mannitol particles were prepared using organic vapor phase deposition (OVPD) technology. See, e.g., WO 2021 / 168043 Al, the disclosure of which is incorporated herein by reference in its entirety. Apomorphine freebase ethanol solvate (API) is evaporated under 1 ~70 x 10'7torr pressure with 185-195 °C heating inside a vacuum chamber designed to produce drug nano-coating on micron-sized excipient, and deposited on 420 gram mannitol, which was agitated at 75 rpm. Ethanol solvate is first dissociated from the API, leaving apomorphine freebase is nano-coated on mannitol at 7% drugloading by weight ratio.Example 4Preparation of apomorphine nanoparticles-coated mannitol particles (7.6% drug loading)

[0141] An apomorphine solvate (e.g., apomorphine hemiethanol) (7.5 g) was nanosized at about 170 to 190 °C under about 5 x 10'6torr as described in WO 2021 / 168043 Al, the disclosure of which is incorporated herein by reference in its entirety. The vaporized apomorphine was in-situ coated at about 70 °C on mannitol particles (45 g) with an agitation speed of 65 rpm to yield 52 g of apomorphine nanoparticles-coated coated mannitol particles as a free-flowing white powder. The apomorphine nanoparticles-coated coated mannitol particles were analyzed by HPLC to have a drug loading of 7.6% and by a Shimazu particle sizer SALD- 2300 to have a Dio, Dso, and D90 of 213, 310, and 516 nm, respectively.Example 5Preparation of apomorphine nanoparticles-coated mannitol particles (13% drug loading)

[0142] An apomorphine solvate (e.g, apomorphine isopropanol) (10 g) was nanosized at about 170 to 190 °C under about 5 x 10'6torr as described in WO 2021 / 168043 Al, the disclosure of which is incorporated herein by reference in its entirety. The vaporized apomorphine was in-situ coated at about 78 °C on mannitol particles (43 g) with an agitation speed of 65 rpm to yield 53.5 g of apomorphine nanoparticles-coated coated mannitol particles as a free-flowing white powder. The apomorphine nanoparticles-coated coated mannitol particles were analyzed by HPLC to have a drug loading of 9.7% and by a Shimazu particle sizer SALD-2300 to have a Dio, D50, and Ds>o of 213, 310, and 516 nm, respectively.Example 6 Dry powder apomorphine nanoparticle formulations

[0143] Dry powder apomorphine nanoparticle formulations were prepared by mixing the ingredients shown in Table 1. Dry powder apomorphine nanoparticle formulation Fl was analyzed by a Shimazu particle sizer SALD-2300 to have a Dio, D50, and D90 of 292, 403, and 602 nm, respectively. Dry powder apomorphine nanoparticle formulation F3 was analyzed by a Shimazu particle sizer SALD-2300 to have a Dio, D50, and D90 of 279, 379, and 563 nm,Table 1. Dry Powder Apomorphine Nanoparticle FormulationsExample 7Dry powder apomorphine nanoparticle formulations

[0144] Dry powder apomorphine nanoparticle formulations F6 and F7 were prepared by mixing the ingredients shown in Table 2.Table 2. Dry Powder Apomorphine Nanoparticle FormulationsExample 8Dry powder nasal spray

[0145] For 1.5 mg / dose, a dry powder nasal spray device was prepared by filling aunidose dosing tube of an APT AR unidose powder nasal spray device with dry powder apomorphine nanoparticle formulation Fl (57.5-58.5 mg). For 0.5 mg / dose, a dry powder nasal spray device was prepared by filling a unidose dosing tube of an APTAR unidose powder nasal spray device with dry powder aapomorphine nanoparticle formulation F2 (27.5-28.5 mg).Example 9Pharmacokinetic studies of dry powder apomorphine nanoparticle formulations in dogs

[0146] Ten 1-2 year old beagle male dogs with a body weight ranging from 5 to 10 kg were randomized into four groups: Group 1 (1 dog), Group 2 (3 dogs), Group 3 (3 dogs), and Group 4 (3 dogs). Group 1 was a control group receiving a placebo with no aapomorphine once on Day 1 by intranasal installation using an intranasal delivery device. Dry powder apomorphine nanoparticle formulations Fl (1.5 mg / dose) and F2 (0.5 mg / dose) were each administered once on Day 1 to the dogs in Groups 3 and 2, respectively, by intranasal installation using an intranasal delivery device. During intranasal installation, the head of each dog was positioned horizontally and the tip of the delivery device was inserted minimally into the right nares. Once inserted, the pump of the device was actuated to deliver the dose of the test material; and the muzzle of the dog was titled upward for approximately 60-90 seconds to limit drainage of the test material from the nose. A sterile solution (2.5 mg / mL) of apomorphine hydrochloride hemihydrate USP was administered in the amount of 0.51 mg once on Day 1 to each dog in Group 4 by subcutaneous (SC) injection into the interscapular area. Blood samples (0.6 mL per time point) were obtained at 0 (i.e., before administration), 0.083, 0.167, 0.33, 0.5, 0.75, 1, 1.5, and 3 h after administration. Each blood sample was centrifuged at 2-8 °C and plasma was collected and frozen at -70 °C or lower. The plasma samples were analyzed by LC-MS / MS. The PK results are summarized in Table 3 and their pharmacokinetic profiles are shown in FIG. 2.Table 3. Pharmacokinetics of dry powder apomorphine nanoparticle formulations Fl and F2Example 10Slug Mucosal Irritation Assay

[0147] A slug mucosal irritation (SMI) assay was performed as described in Lenoir et al., Toxicol. In Vitro 2013, 27, 1954-61, the disclosure of which is incorporated herein by reference in its entirety.

[0148] 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) an excipient particle and (ii) vapor-phase- deposited apomorphine nanoparticles, wherein the surface of the excipient particle is coated with the vapor-phase-deposited apomorphine nanoparticles.

2. The coated particle of claim 1, wherein the coated particle is prepared by a method comprising the steps of: a. vaporizing apomorphine or a solvate thereof at a first predetermined temperature under a predetermined vacuum pressure to form an apomorphine vapor; and b. depositing the apomorphine vapor on the surface of the excipient particle at a predetermined agitation speed and a second predetermined temperature under the predetermined vacuum pressure to form the vapor-phase-deposited apomorphine nanoparticles on the surface of the excipient particle, thus forming the coated particle.

3. The coated particle of claim 2, wherein the apomorphine in the vaporizing step is a free base.

4. The coated particle of claim 2 or 3, wherein the apomorphine in the vaporizing step is an apomorphine solvate.

5. The coated particle of any one of claims 2 to 4, wherein the apomorphine in the vaporizing step is an apomorphine solvate of acetone, acetonitrile, 1,4-dioxane, ethanol, ethylene glycol, formamide, methyl acetate, methyl tert-butyl ether (TBME), nitromethane, 2-propanol, pyridine, TBME, THF, or water.

6. The coated particle of any one of claims 2 to 5, wherein the apomorphine in the vaporizing step is apomorphine hemiethanol solvate.

7. The coated particle of any one of claims 2 to 6, wherein the apomorphine in the vaporizing step is crystalline.

8. The coated particle of any one of claims 2 to 7, wherein the first predetermined temperature is ranging from about 50 to about 300 °C.

9. The coated particle of any one of claims 2 to 8, wherein the predetermined vacuum pressure is no greater than about 10'5torr.

10. The coated particle of any one of claims 2 to 9, wherein the predetermined vacuum pressure is no greater than about 10'6torr.

11. The coated particle of any one of claims 2 to 10, wherein the predetermined vacuum pressure is no greater than about 10'7torr.

12. The coated particle of any one of claims 2 to 11, wherein the predetermined agitation speed is ranging from about 10 to about 250 rpm.

13. The coated particle of any one of claims 2 to 12, wherein the second predetermined temperature is ranging from about 20 to about 150 °C.

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

15. The coated particle of any one of claims 1 to 14, wherein the pharmaceutically acceptable excipient is a sugar alcohol.

16. The coated particle of any one of claims 1 to 15, 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.

17. The coated particle of any one of claims 1 to 16, wherein the pharmaceutically acceptable excipient is mannitol, sorbitol, xylitol, or a mixture thereof.

18. The coated particle of any one of claims 1 to 17, wherein the pharmaceutically acceptable excipient is mannitol.

19. The coated particle of any one of claims 1 to 18, wherein the vapor-phase- deposited apomorphine nanoparticles have an average particle size ranging from about 1 to about 900 nm.

20. The coated particle of any one of claims 1 to 19, wherein the coated particlecomprises the vapor-phase-deposited apomorphine nanoparticles in an amount ranging from about 1 to about 20% by weight.

21. The coated particle of any one of claims 1 to 20, wherein the coated particle comprises the vapor-phase-deposited apomorphine nanoparticles in an amount of about 3, about 7, about 10, about 11, about 12, or about 13% by weight.

22. The coated particle of any one of claims 1 to 21, wherein the coated particle is a nanoparticle.

23. The coated particle of any one of claims 1 to 22, wherein the coated particle has an average particle size ranging from about 100 to about 900 nm.

24. A pharmaceutical composition comprising a coated particle of any one of claims 1 to 23.

25. The pharmaceutical composition of claim 24, further comprising an additional pharmaceutically acceptable excipient.

26. The pharmaceutical composition of claim 25, wherein the additional pharmaceutically acceptable excipient is an antioxidant, a binder, a diluent, a disintegrant, a filler, a glidant, a lubricant, a mucoadhesive agent, a sweetening agent, or a combination thereof.

27. The pharmaceutical composition of claim 25 or 26, wherein the additional pharmaceutically acceptable excipient is an antioxidant, a disintegrant, a diluent, a filler, a lubricant, a mucoadhesive agent, a sweetening agent, or a combination thereof.

28. The pharmaceutical composition of any one of claims 24 to 27, comprising the coated particle, an antioxidant, and a mucoadhesive agent.

29. The pharmaceutical composition of claim 28, comprising about 97% of the coated particle, about 1% by weight of the antioxidant, and about 2% by weight of the mucoadhesive agent.

30. The pharmaceutical composition of claim 28, comprising about 96% of the coatedparticle, about 2% by weight of the antioxidant, and about 2% by weight of the mucoadhesive agent.

31. The pharmaceutical composition of any one of claims 24 to 27, comprising the coated particle, an antioxidant, a lubricant, and a mucoadhesive agent.

32. The pharmaceutical composition of claim 31, comprising about 97% of the coated particle, about 1% by weight of the antioxidant, about 0.5% by weight of the lubricant, and about 2% by weight of the mucoadhesive agent.

33. The pharmaceutical composition of claim 31, comprising about 96% of the coated particle, about 2% by weight of the antioxidant, about 0.5% by weight of the lubricant, and about 2% by weight of the mucoadhesive agent.

34. The pharmaceutical composition of any one of claims 26 to 33, wherein the antioxidant is ascorbic acid.

35. The pharmaceutical composition of any one of claims 26 to 33, wherein the antioxidant is ascorbyl palmitate.

36. The pharmaceutical composition of any one of claims 26, 27, and 31 to 35, wherein the lubricant is colloidal silicon dioxide.

37. The pharmaceutical composition of any one of claims 26 to 36, wherein the mucoadhesive agent is hydroxypropyl methylcellulose.

38. The pharmaceutical composition of any one of claims 24 to 37, wherein the coated particle has a drug loading ranging from about 5 to about 15% by weight.

39. The pharmaceutical composition of any one of claims 24 to 38, wherein the coated particle has a drug loading of about 7% by weight.

40. The pharmaceutical composition of any one of claims 24 to 39, wherein the pharmaceutical composition is formulated as a dry powder.

41. The pharmaceutical composition of any one of claims 24 to 40, wherein thepharmaceutical composition is formulated for intranasal administration.

42. The pharmaceutical composition of any one of claims 24 to 41, wherein the pharmaceutical composition is formulated as nasal spray.

43. The pharmaceutical composition of any one of claims 24 to 42, wherein the pharmaceutical composition is formulated as a single dosage form.

44. The pharmaceutical composition of claim 43, wherein the single dosage form is actuated by a nasal spray device.

45. The pharmaceutical composition of any one of claims 24 to 44, wherein the pharmaceutical composition is formulated as a multi-dosage form.

46. A method of treating, preventing, or alleviating one or more symptoms of a neurological disorder in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a coated particle of any one of claims 1 to 23 or a pharmaceutical composition of any one of claims 24 to 45.

47. The method of claim 46, wherein the neurological disorder is Parkinson’s disease.

48. The method of claim 47, comprising alleviating an OFF episode associated with Parkinson’s disease.

49. The method of any one of claims 46 to 48, wherein the neurological disorder is advanced Parkinson’s disease.

50. The method of any one of claims 46 to 49, wherein the therapeutically effective amount of apomorphine is ranging from about 0.5 to about 100 mg per day.

51. The method of any one of claims 46 to 50, wherein the subj ect is a human.

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