Therapeutic nanoparticles and methods of making same

Abstract

The present invention provides a coated particle comprising (i) a microparticle comprising a pharmaceutically acceptable excipient and (ii) a nanoparticle of a therapeutic agent wherein the surface of the microparticle is coated with the nanoparticle. The invention also provides a pharmaceutical composition containing the coated particle. In addition, the invention provides a preparation method thereof.

Description

Related Applications

[0001] This application is a divisional application filed on October 18, 2022, with application number 202180029355.1 and invention name “Therapeutic agent nanoparticles and preparation methods thereof”. Technical Field

[0002] The present application provides a coated particle, which comprises: (i) microparticles containing a pharmaceutically acceptable excipient, and (ii) therapeutic agent nanoparticles, wherein the surface of the microparticles is coated with the nanoparticles. The present application also provides a pharmaceutical composition comprising the coated particles. In addition, the present invention provides a preparation method thereof. Background Art

[0003] One of the main challenges in current drug formulations is poor water solubility. Savjani et al., ISRNPharm.2012, 2012, 195727. More than 70% of small molecule new chemical entities (NCEs) and about 40% of currently marketed drugs have poor water solubility. Kolliparaand Gandhi, ActaPharm.Sin.B 2014, 4, 333-349. Various technologies have been developed to improve the solubility of poorly soluble drugs, including particle size reduction, crystal engineering, salt formation, solid dispersions, use of surfactants and complexation. See, for example, Id.; Challaet al., AAPS PharmSciTech 2005, 6, E329-E357; Salama, Drug Deliv. Transl. Res. 2020, 10, 1-12. Despite advances in formulation technology, poor water solubility remains a major obstacle to the development of small molecule drugs. Therefore, there is a need for an efficient and robust technology for the formulation of poorly soluble small molecules for therapeutic use. Summary of the invention

[0004] The present invention provides a coated particle, which comprises: (i) microparticles containing a pharmaceutically acceptable excipient, and (ii) nanoparticles, wherein each nanoparticle contains a therapeutic agent, wherein the surface of the microparticle is coated with the nanoparticles.

[0005] The present invention also provides a pharmaceutical composition comprising coated particles, wherein each coated particle comprises: (i) microparticles comprising a pharmaceutically acceptable excipient and (ii) therapeutic agent nanoparticles, wherein the surface of the microparticles is coated with nanoparticles.

[0006] The present invention also provides a method for preparing coated particles, wherein each coated particle comprises: (i) microparticles containing a pharmaceutically acceptable excipient, and (ii) nanoparticles of a therapeutic agent, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form nanoparticles on the surface of the microparticles, thereby forming coated particles.

[0007] The present invention also provides a method for preparing therapeutic agent nanoparticles, comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the microparticles, wherein the microparticles contain a pharmaceutically acceptable excipient.

[0008] The present invention also provides a coated particle, wherein each coated particle comprises: (i) microparticles containing a pharmaceutically acceptable excipient and (ii) nanoparticles of a therapeutic agent; and the coated particle is prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form nanoparticles on the surface of the microparticles, thereby forming coated particles.

[0009] The present invention also provides a therapeutic agent nanoparticle, wherein the therapeutic agent nanoparticle is prepared by the following method, which comprises: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the microparticles, wherein the microparticles contain a pharmaceutically acceptable excipient.

[0010] The present invention also provides a pharmaceutical composition comprising coated particles, wherein each coated particle comprises: (i) microparticles containing a pharmaceutically acceptable excipient and (ii) nanoparticles of a therapeutic agent; and the coated particles are prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form nanoparticles on the surface of the microparticles, thereby forming coated particles.

[0011] The present invention also provides a pharmaceutical composition comprising therapeutic agent nanoparticles, wherein the therapeutic agent nanoparticles are prepared by the following method, which comprises: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the microparticles, wherein the microparticles contain a pharmaceutically acceptable excipient.

[0012] The present invention also provides a batch of coated particles, wherein each coated particle comprises: (i) microparticles comprising a pharmaceutically acceptable excipient and (ii) nanoparticles of a therapeutic agent; and the coated particles are prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form nanoparticles on the surface of the microparticles, thereby forming coated particles.

[0013] The present invention also provides a batch of therapeutic agent nanoparticles, wherein the therapeutic agent nanoparticles are prepared by the following method, which comprises: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the microparticles, wherein the microparticles contain a pharmaceutically acceptable excipient.

[0014] The present invention also provides a batch of pharmaceutical compositions comprising coated particles, wherein each coated particle comprises: (i) microparticles comprising a pharmaceutically acceptable excipient and (ii) nanoparticles of a therapeutic agent; and the coated particles are prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form nanoparticles on the surface of the microparticles, thereby forming coated particles.

[0015] The present invention also provides a batch of pharmaceutical compositions, which include therapeutic agent nanoparticles and a pharmaceutically acceptable excipient, wherein the therapeutic agent nanoparticles are prepared by the following method, which includes: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the microparticles, wherein the microparticles contain the pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 It is shown that nanoparticles of a therapeutic agent are formed on the surface of microparticles of a hydrophilic excipient by contacting the microparticles with the therapeutic agent in a gaseous state. DETAILED DESCRIPTION

[0017] In order to fully understand the content of the present disclosure, the following term explanation is provided.

[0018] Generally speaking, what is used in the present invention is the nomenclature known and commonly used in the art, and some experimental procedures in organic chemistry, medicinal chemistry and pharmacology.Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as those of ordinary skill in the art are generally understood.

[0019] 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" and is compatible with the other ingredients of the pharmaceutical formulation and is suitable for contact with the tissues or organs of a subject (e.g., a human or animal) without excessive toxicity, irritation, allergic reaction, immunogenicity and other problems or complications, and has an appropriate benefit / risk ratio. See, for example, Remington: The Science and Practice of Pharmacy, 22nd ed.; Allen Ed.; Pharmaceutical Press: London, 2012; Handbook of Pharmaceutical Excipients, 8th ed.; Sheskey et al., Eds.; Pharmaceutical Press: London, 2017; 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.

[0020] The term "about" or "approximately" refers to the acceptable error of a particular value determined by one of ordinary skill in the art, which depends in part on how the particular value is measured or determined. In certain embodiments, the term "about" or "approximately" refers to a standard deviation within 1, 2, or 3. In certain embodiments, the term "about" or "approximately" refers to an error 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.

[0021] The term "batch" refers to a defined quantity of a compound, material, or drug product that is processed in a process or series of processes so that it is homogeneous within specified limits. To accomplish certain stages of manufacturing, it may be necessary to divide a batch into multiple sub-batches, which are then combined together to form the final homogeneous batch. In continuous manufacturing, batches correspond to defined segments of production characterized by the expected homogeneity within each segment. In the manufacture of drug products, both synthetic intermediates and drug products are identified by batch numbers. Coated particles and nanoparticles

[0022] In one embodiment, the present invention provides a coated particle comprising: (i) microparticles comprising a pharmaceutically acceptable excipient, and (ii) nanoparticles, each nanoparticle comprising a therapeutic agent; wherein the surface of the microparticles is coated with the nanoparticles.

[0023] In certain embodiments, the surface of the microparticles is coated with a layer of nanoparticles. In certain embodiments, the surface of the microparticles is substantially coated with a layer of nanoparticles. In certain embodiments, the surface of the microparticles is coated with a thin layer of nanoparticles. In certain embodiments, the surface of the microparticles is substantially coated with a thin layer of nanoparticles. In certain embodiments, the surface of the microparticles is coated with a monolayer of nanoparticles. In certain embodiments, the surface of the microparticles is substantially coated with a monolayer of nanoparticles.

[0024] In certain embodiments, the pharmaceutically acceptable excipients in the coated particles provided by the present invention are hydrophilic. In certain embodiments, the pharmaceutically acceptable excipients in the coated particles provided by the present invention are water-soluble.

[0025] In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is sugar. In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is glucose (dextrose), fructose, glucose (glucose), lactose, maltose, molasses, sucrose, trehalose or a mixture thereof. In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is glucose (dextrose), glucose (glucose), lactose, sucralose, sucrose or a mixture thereof. In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is glucose (dextrose). In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is D-glucose (D-dextrose). In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is fructose. In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is glucose (glucose). In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is lactose. In certain embodiments, the pharmaceutically acceptable excipient in the coated granules provided by the present invention is maltose. In certain embodiments, the pharmaceutically acceptable excipient in the coated granules provided by the present invention is molasses. In certain embodiments, the pharmaceutically acceptable excipient in the coated granules provided by the present invention is sucrose. In certain embodiments, the pharmaceutically acceptable excipient in the coated granules provided by the present invention is trehalose.

[0026] In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is a sugar alcohol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is arabitol, erythritol, fucitol, galactitol, iditol, inositol, isomalt, lactitol, maltitol, maltotriose, mannitol, ribitol, sorbitol, threitol, heptyl alcohol, xylitol or a mixture thereof. In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is erythritol, lactitol, maltitol, mannitol, sorbitol, xylitol or a mixture thereof. In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is arabitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is erythritol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is fucitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated granules provided by the present invention is galactitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated granules provided by the present invention is iditol. In certain embodiments, the pharmaceutically acceptable excipient in the coated granules provided by the present invention is inositol. In certain embodiments, the pharmaceutically acceptable excipient in the coated granules provided by the present invention is isomalt. In certain embodiments, the pharmaceutically acceptable excipient in the coated granules provided by the present invention is lactitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated granules provided by the present invention is maltitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated granules provided by the present invention is maltotriitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated granules provided by the present invention is mannitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated granules provided by the present invention is ribitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated granules provided by the present invention is sorbitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is threitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is heptyl alcohol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is xylitol.

[0027] In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is glucose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), lactose, mannitol or polyvinyl pyrrolidone (PVP). In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is glucose or mannitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is glucose. In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is HPC. In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is HPMC. In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is lactose. In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is mannitol. In certain embodiments, the pharmaceutically acceptable excipient in the coated particles provided by the present invention is PVP.

[0028] In certain embodiments, the microparticles in the coated particles provided by the present invention can have various shapes, including but not limited to spheres, ellipsoids, flakes, fibrils or fibers. In certain embodiments, the microparticles in the coated particles provided by the present invention are substantially spherical. In certain embodiments, the microparticles in the coated particles provided by the present invention are spherical. In certain embodiments, the microparticles in the coated particles provided by the present invention are ellipsoids.

[0029] In certain embodiments, the microparticles in the coated particles provided by the present invention have an average particle size (D50) in the range of about 1 to about 1,000 μm, about 10 to about 500 μm, about 20 to about 500 μm, about 50 to about 300 μm, or about 100 to about 300 μm. In certain embodiments, the microparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 1,000 μm. In certain embodiments, the microparticles in the coated particles provided by the present invention have an average particle size in the range of about 10 to about 500 μm. In certain embodiments, the microparticles in the coated particles provided by the present invention have an average particle size in the range of about 20 to about 500 μm. In certain embodiments, the microparticles in the coated particles provided by the present invention have an average particle size in the range of about 50 to about 300 μm. In certain embodiments, the microparticles in the coated particles provided by the present invention have an average particle size in the range of about 100 to about 300 μm. In certain embodiments, the microparticles in the coated particles provided herein have an average particle size of about 50 μm, about 100 μm, about 150 μm, about 200 μm, about 250 μm, about 300 μm, about 350 μm, about 400 μm, about 450 μm, or about 500 μm.

[0030] In certain embodiments, the microparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 100 μm, about 1 to about 50 μm, or about 1 to about 25 μm. In certain embodiments, the microparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 100 μm. In certain embodiments, the microparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 50 μm. In certain embodiments, the microparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 25 μm. In certain embodiments, the microparticles in the coated particles provided by the present invention have an average particle size in the range of about 5 μm, about 10 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, about 35 μm, about 40 μm, about 45 μm or about 50 μm.

[0031] In another embodiment, the present invention provides a coated particle comprising: (i) microparticles comprising mannitol, and (ii) nanoparticles, each nanoparticle comprising a therapeutic agent; wherein the surface of the mannitol microparticles is coated with the nanoparticles.

[0032] In certain embodiments, the surface of the mannitol microparticles is coated with a layer of nanoparticles. In certain embodiments, the surface of the mannitol microparticles is substantially coated with a layer of nanoparticles. In certain embodiments, the surface of the mannitol microparticles is coated with a monolayer of nanoparticles. In certain embodiments, the surface of the mannitol microparticles is substantially coated with a monolayer of nanoparticles.

[0033] In certain embodiments, the mannitol microparticles in the coated particles provided by the present invention can have various shapes, including but not limited to spheres, ellipsoids, flakes, fibrils or fibers. In certain embodiments, the mannitol microparticles in the coated particles provided by the present invention are substantially spherical. In certain embodiments, the mannitol microparticles in the coated particles provided by the present invention are spherical. In certain embodiments, the mannitol microparticles in the coated particles provided by the present invention are ellipsoids.

[0034] In certain embodiments, the mannitol microparticles in the coated particles provided by the present invention have an average particle size (D50) in the range of about 1 to about 1,000 μm, about 10 to about 500 μm, about 20 to about 500 μm, about 50 to about 300 μm, or about 100 to about 300 μm. In certain embodiments, the mannitol microparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 1,000 μm. In certain embodiments, the mannitol microparticles in the coated particles provided by the present invention have an average particle size in the range of about 10 to about 500 μm. In certain embodiments, the mannitol microparticles in the coated particles provided by the present invention have an average particle size in the range of about 20 to about 500 μm. In certain embodiments, the mannitol microparticles in the coated particles provided by the present invention have an average particle size in the range of about 50 to about 300 μm. In certain embodiments, the mannitol microparticles in the coated particles provided by the present invention have an average particle size in the range of about 100 to about 300 μm. In certain embodiments, the mannitol microparticles in the coated particles provided herein have an average particle size of about 50 μm, about 100 μm, about 150 μm, about 200 μm, about 250 μm, about 300 μm, about 350 μm, about 400 μm, about 450 μm, or about 500 μm.

[0035] In certain embodiments, the mannitol microparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 100 μm, about 1 to about 50 μm, or about 1 to about 25 μm. In certain embodiments, the mannitol microparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 100 μm. In certain embodiments, the mannitol microparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 50 μm. In certain embodiments, the mannitol microparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 25 μm. In certain embodiments, the mannitol microparticles in the coated particles provided by the present invention have an average particle size in the range of about 5 μm, about 10 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, about 35 μm, about 40 μm, about 45 μm or about 50 μm.

[0036] In another embodiment, the present invention provides a coated particle comprising: (i) microparticles comprising D-glucose (D-dextrose), and (ii) nanoparticles, each nanoparticle comprising a therapeutic agent; wherein the surface of the D-glucose microparticles is coated with the nanoparticles.

[0037] In certain embodiments, the surface of the D-glucose microparticles is coated with a layer of nanoparticles. In certain embodiments, the surface of the D-glucose microparticles is substantially coated with a layer of nanoparticles. In certain embodiments, the surface of the D-glucose microparticles is coated with a monolayer of nanoparticles. In certain embodiments, the surface of the D-glucose microparticles is substantially coated with a monolayer of nanoparticles.

[0038] In certain embodiments, the D-glucose microparticles in the coated particles provided by the present invention can have various shapes, including but not limited to sphere, ellipsoid, thin slice, fibril or fiber. In certain embodiments, the D-glucose microparticles in the coated particles provided by the present invention are substantially spherical. In certain embodiments, the D-glucose microparticles in the coated particles provided by the present invention are spherical. In certain embodiments, the D-glucose microparticles in the coated particles provided by the present invention are ellipsoid.

[0039] In certain embodiments, the D-glucose microparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 1,000 μm, about 10 to about 500 μm, about 20 to about 500 μm, about 50 to about 300 μm, or about 100 to about 300 μm. In certain embodiments, the D-glucose microparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 1,000 μm. In certain embodiments, the D-glucose microparticles in the coated particles provided by the present invention have an average particle size in the range of about 10 to about 500 μm. In certain embodiments, the D-glucose microparticles in the coated particles provided by the present invention have an average particle size in the range of about 20 to about 500 μm. In certain embodiments, the D-glucose microparticles in the coated particles provided by the present invention have an average particle size in the range of about 50 to about 300 μm. In certain embodiments, the D-glucose microparticles in the coated particles provided by the present invention have an average particle size in the range of about 100 to about 300 μm. In certain embodiments, the D-glucose microparticles in the coated particles provided herein have an average particle size of about 50 μm, about 100 μm, about 150 μm, about 200 μm, about 250 μm, about 300 μm, about 350 μm, about 400 μm, about 450 μm, or about 500 μm.

[0040] In certain embodiments, the D-glucose microparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 100 μm, about 1 to about 50 μm, or about 1 to about 25 μm. In certain embodiments, the D-glucose microparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 100 μm. In certain embodiments, the D-glucose microparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 50 μm. In certain embodiments, the D-glucose microparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 25 μm. In certain embodiments, the D-glucose microparticles in the coated particles provided by the present invention have an average particle size in the range of about 5 μm, about 10 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, about 35 μm, about 40 μm, about 45 μm or about 50 μm.

[0041] In certain embodiments, coated particles containing D-glucose are formulated as sterile solids for reconstitution.

[0042] In certain embodiments, the therapeutic agent in the coated particles provided herein is a Class II compound according to the Biopharmaceutics Classification System (BCS), i.e., a BCS Class II compound. In certain embodiments, the therapeutic agent in the coated particles provided herein is a BCS Class III compound. In certain embodiments, the therapeutic agent in the coated particles provided herein is a BCS Class IV compound.

[0043] In certain embodiments, the therapeutic agent in the coated particles provided herein has low solubility relative to the biopharmaceutics classification system. In certain embodiments, the therapeutic agent in the coated particles provided herein has low permeability relative to the biopharmaceutics classification system.

[0044] In certain embodiments, the therapeutic agent in the coated particles provided by the present invention is a solid. In certain embodiments, the therapeutic agent in the coated particles provided by the present invention has a melting point in the range of about 50 to about 500°C, about 100 to about 400°C, about 100 to about 300°C, or about 150 to about 300°C. In certain embodiments, the therapeutic agent in the coated particles provided by the present invention has a melting point in the range of about 50 to about 500°C. In certain embodiments, the therapeutic agent in the coated particles provided by the present invention has a melting point in the range of about 100 to about 400°C. In certain embodiments, the therapeutic agent in the coated particles provided by the present invention has a melting point in the range of about 100 to about 300°C. In certain embodiments, the therapeutic agent in the coated particles provided by the present invention has a melting point in the range of about 150 to about 300°C.

[0045] In certain embodiments, the therapeutic agent in the coated particles provided by the present invention is amiodarone, atorvastatin, azithromycin, carbamazepine, carvedilol, chlorpromazine, cisapride, ciprofloxacin, cloxacillin, cyclosporin, danazol, dapsone, diclofenac, diflunisal, digoxin, erythromycin, fenofibrate, flurbiprofen, glipizide, glyburide, griseofulvin, hydroxyzine, ibuprofen, indina vir, indomethacin, itraconazole, ifveramycin, ketoconazole, ketoprofen, lansoprazole, lovastatin, mebendazole, midazolam, naproxen, nelfinavir, niclosamide, ofloxacin, oxaprozin, phenazopyridine, phenytoin, piroxicam, praziquantel, raloxifene, ritonavir, saquinavir, sirolimus, spironolactone, tacrolimus, talinolol, tamoxifen, terfenadine, or warfarin.

[0046] In certain embodiments, the therapeutic agent in the coated particles provided herein is amlodipine, amoxicillin, cimetidine, ciprofloxacin, ethosuximide, metronidazole, acetaminophen, phenoxymethylpenicillin, or procainamide.

[0047] In certain embodiments, the therapeutic agent in the coated particles provided herein is amoxicillin, amphotericin B, cephalexin, chloramphenicol, chlorthalidone, chlorothiazide, ciprofloxacin, clindamycin, colistin, furosemide, hydrochlorothiazide, mebendazole, meloxicam, methotrexate, neomycin, furazolidone, oxamidine, phenobarbital, prednisolone, sulfamethoxazole or trimethoprim.

[0048] In certain embodiments, the therapeutic agent in the coated particles provided herein is arformoterol, asenapine, dabigatran, desonide, dexlansoprazole, diclofenac, efavirenz, emtricitabine, erlotinib, fesoterodine fumarate, formoterol, isotretinoin, lacosamide, lenalidomide, lubiprostone, maraviroc, mesalazine, nebivolol, posaconazole, roflumilast, sitagliptin, sunitinib, tenofovir, ticagrelor, varenicline or vilazodone.

[0049] In certain embodiments, the therapeutic agent in the coated particles provided by the present invention is carbamazepine, ibuprofen, nifedipine, piroxicam, plumbagin, verapamil or zileuton. In certain embodiments, the therapeutic agent in the coated particles provided by the present invention is ibuprofen or nifedipine. In certain embodiments, the therapeutic agent in the coated particles provided by the present invention is carbamazepine. In certain embodiments, the therapeutic agent in the coated particles provided by the present invention is ibuprofen. In certain embodiments, the therapeutic agent in the coated particles provided by the present invention is nifedipine. In certain embodiments, the therapeutic agent in the coated particles provided by the present invention is piroxicam. In certain embodiments, the therapeutic agent in the coated particles provided by the present invention is plumbagin. In certain embodiments, the therapeutic agent in the coated particles provided by the present invention is verapamil. In certain embodiments, the therapeutic agent in the coated particles provided by the present invention is zileuton.

[0050] In certain embodiments, the nanoparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 500nm, about 1 to about 200nm, about 2 to about 200nm, about 5 to about 200nm, about 10 to about 200nm, or about 10 to about 100nm. In certain embodiments, the nanoparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 500nm. In certain embodiments, the nanoparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 200nm. In certain embodiments, the nanoparticles in the coated particles provided by the present invention have an average particle size in the range of about 1 to about 50nm. In certain embodiments, the nanoparticles in the coated particles provided by the present invention have an average particle size in the range of about 2 to about 200nm. In certain embodiments, the nanoparticles in the coated particles provided by the present invention have an average particle size in the range of about 5 to about 200nm. In certain embodiments, the nanoparticles in the coated particles provided by the present invention have an average particle size in the range of about 10 to about 200nm. In certain embodiments, the nanoparticles in the coated particles provided by the present invention have an average particle size in the range of about 10 to about 100nm.

[0051] In certain embodiments, the nanoparticles in the coated particles provided by the present invention have an average particle size in the range of about 10 to about 500nm, about 10 to about 200nm, or about 20 to about 200nm. In certain embodiments, the nanoparticles in the coated particles provided by the present invention have an average particle size in the range of about 10 to about 500nm. In certain embodiments, the nanoparticles in the coated particles provided by the present invention have an average particle size in the range of about 10 to about 200nm. In certain embodiments, the nanoparticles in the coated particles provided by the present invention have an average particle size in the range of about 20 to about 200nm. In certain embodiments, the nanoparticles in the coated particles provided by the present invention have an average particle size in the range of about 10nm, about 20nm, about 30nm, about 40nm or about 50nm. In certain embodiments, the nanoparticles in the coated particles provided by the present invention have an average particle size of about 100nm, about 150nm, about 200nm, about 250nm, about 300nm, about 350nm, about 400nm, about 450nm or about 500nm.

[0052] In certain embodiments, the nanoparticles in the coated particles provided by the present invention are formed on the surface of the microparticles. In certain embodiments, the nanoparticles in the coated particles provided by the present invention are formed on the surface of the microparticles by organic vapor deposition. See, for example, Baldo et al., Adv. Mater. 1998, 10, 1505-1514.

[0053] In certain embodiments, the weight ratio of nanoparticles in coated particles is about 0.1% to about 25%, about 0.2% to about 20%, about 0.5% to about 10%, or about 1% to about 10%. In certain embodiments, the weight ratio of nanoparticles in coated particles is about 0.1% to about 25%. In certain embodiments, the weight ratio of nanoparticles in coated particles is about 0.2% to about 20%. In certain embodiments, the weight ratio of nanoparticles in coated particles is about 0.5% to about 10%. In certain embodiments, the weight ratio of nanoparticles in coated particles is about 1% to about 10%. In certain embodiments, the weight ratio of nanoparticles in coated particles is about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10%.

[0054] In certain embodiments, the coated particles provided by the present invention have an average particle size in the range of about 1 to about 1,000 μm, about 10 to about 500 μm, about 20 to about 500 μm, about 50 to about 300 μm, or about 100 to about 300 μm. In certain embodiments, the coated particles provided by the present invention have an average particle size in the range of about 1 to about 1,000 μm. In certain embodiments, the coated particles provided by the present invention have an average particle size in the range of about 10 to about 500 μm. In certain embodiments, the coated particles provided by the present invention have an average particle size in the range of about 20 to about 500 μm. In certain embodiments, the coated particles provided by the present invention have an average particle size in the range of about 50 to about 300 μm. In certain embodiments, the coated particles provided by the present invention have an average particle size in the range of about 100 to about 300 μm. In certain embodiments, the coated particles provided herein have an average particle size of about 50 μm, about 100 μm, about 150 μm, about 200 μm, about 250 μm, about 300 μm, about 350 μm, about 400 μm, about 450 μm, or about 500 μm.

[0055] In certain embodiments, the coated particles provided by the present invention have an average particle size in the range of about 1 to about 100 μm, about 1 to about 50 μm, or about 1 to about 25 μm. In certain embodiments, the coated particles provided by the present invention have an average particle size in the range of about 1 to about 100 μm. In certain embodiments, the coated particles provided by the present invention have an average particle size in the range of about 1 to about 50 μm. In certain embodiments, the coated particles provided by the present invention have an average particle size in the range of about 1 to about 25 μm. In certain embodiments, the coated particles provided by the present invention have an average particle size in the range of about 5 μm, about 10 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, about 35 μm, about 40 μm, about 45 μm, or about 50 μm. Preparation method

[0056] In one embodiment, the present invention provides a method for preparing coated particles, wherein each coated particle comprises: (i) microparticles comprising a pharmaceutically acceptable excipient and (ii) nanoparticles of a therapeutic agent, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form nanoparticles on the surface of the microparticles, thereby forming coated particles.

[0057] In another embodiment, the present invention provides a method for preparing nanoparticles of a therapeutic agent, comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the microparticles, wherein the microparticles contain a pharmaceutically acceptable excipient.

[0058] In certain embodiments, the first predetermined temperature is about 50 to about 500°C, about 100 to about 400°C, about 50 to about 300°C, about 100 to about 300°C, about 100 to about 250°C, about 150 to about 300°C, or about 200 to about 300°C. In certain embodiments, the first predetermined temperature is about 50 to about 500°C. In certain embodiments, the first predetermined temperature is about 100 to about 400°C. In certain embodiments, the first predetermined temperature is about 50 to about 300°C. In certain embodiments, the first predetermined temperature is about 100 to about 300°C. In certain embodiments, the first predetermined temperature is about 100 to about 300°C. In certain embodiments, the first predetermined temperature is about 100 to about 250°C. In certain embodiments, the first predetermined temperature is about 150 to about 300°C. In certain embodiments, the first predetermined temperature is about 200 to about 300°C. In certain embodiments, the first predetermined temperature is about 150°C, about 175°C, about 200°C, about 250°C, about 250°C, about 275°C, or about 300°C.

[0059] In certain embodiments, the first predetermined temperature is about 50 to about 250°C, about 80 to about 250°C, or about 100 to about 250°C. In certain embodiments, the first predetermined temperature is about 50 to about 250°C. In certain embodiments, the first predetermined temperature is about 80 to about 250°C. In certain embodiments, the first predetermined temperature is about 100 to about 250°C. In certain embodiments, the first predetermined temperature is about 80°C, about 90°C, about 100°C, about 125°C, about 150°C, about 175°C, about 200°C, about 225°C, or about 250°C.

[0060] In certain embodiments, the predetermined vacuum pressure is no greater than about 10 -1 torr, not more than about 10 -2 torr, not more than about 10 -3 torr, not more than about 10 -4 torr, not more than about 10 -5 torr, not more than about 10 -6 torr, not more than about 10 - 7 torr, not more than about 10 -8 torr or not more than about 10 -9In certain embodiments, the predetermined vacuum pressure is no greater than about 10 -1 In certain embodiments, the predetermined vacuum pressure is no greater than about 10 -2 In certain embodiments, the predetermined vacuum pressure is no greater than about 10 -3 In certain embodiments, the predetermined vacuum pressure is no greater than about 10 -4 In certain embodiments, the predetermined vacuum pressure is no greater than about 10 -5 In certain embodiments, the predetermined vacuum pressure is no greater than about 10 -6 In certain embodiments, the predetermined vacuum pressure is no greater than about 10 -7 In certain embodiments, the predetermined vacuum pressure is no greater than about 10 -8 In certain embodiments, the predetermined vacuum pressure is no greater than about 10 -9 In some embodiments, the predetermined vacuum pressure is about 10 -3 , about 10 -4 , about 10 -5 , about 10 -6 , about 10 -7 , about 10 -8 or about 10 -9 torr.

[0061] In some embodiments, the predetermined vacuum pressure is about 10 -3 To about 10 -9 In some embodiments, the predetermined vacuum pressure is about 10 -3 To about 10 -6 In certain embodiments, the predetermined vacuum pressure is about 10 -3 To about 10 - 4 In some embodiments, the predetermined vacuum pressure is about 10 -4 To about 10 -8 In some embodiments, the predetermined vacuum pressure is about 10 -4 To about 10 -7 In some embodiments, the predetermined vacuum pressure is about 10 -4 To about 10 - 6 torr.

[0062] In certain embodiments, the predetermined stirring speed is about 10 to about 200 revolutions per minute (rpm), about 20 to about 150rpm, about 20 to about 120rpm, about 20 to about 100rpm, about 50 to about 100rpm, or about 80 to about 100rpm. In certain embodiments, the predetermined stirring speed is about 10 to about 200rpm. In certain embodiments, the predetermined stirring speed is about 20 to about 150rpm. In certain embodiments, the predetermined stirring speed is about 20 to about 120rpm. In certain embodiments, the predetermined stirring speed is about 20 to about 100rpm. In certain embodiments, the predetermined stirring speed is about 50 to about 100rpm. In certain embodiments, the predetermined stirring speed is about 80 to about 100rpm. In certain embodiments, the predetermined stirring speed is about 80, about 85, about 90, about 95 or about 100rpm.

[0063] In order to effectively solidify the vapor of the therapeutic agent onto the surface of the particles of the pharmaceutically acceptable excipient, the second predetermined temperature is set to be lower than the first predetermined temperature. The second predetermined temperature is not less than about 10°C, not less than about 20°C, not less than about 50°C, or not less than about 100°C lower than the first predetermined temperature.

[0064] In certain embodiments, the second predetermined temperature is 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 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 about 10 to about 100°C, about 15 to about 50°C, or about 20 to about 40°C. In certain embodiments, the second predetermined temperature is about 10 to about 100°C. In certain embodiments, the second predetermined temperature is about 15 to about 50°C. In certain embodiments, the second predetermined temperature is about 20 to about 40°C. In certain embodiments, the second predetermined temperature is about 20°C, about 25°C, about 30°C, about 35°C, or about 40°C. In certain embodiments, the second predetermined temperature is ambient temperature.

[0066] In one embodiment, the present invention provides a coated particle, wherein each coated particle comprises: (i) microparticles comprising a pharmaceutically acceptable excipient and (ii) nanoparticles of a therapeutic agent; and the coated particle is prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form nanoparticles on the surface of the microparticles, thereby forming coated particles.

[0067] In another embodiment, the present invention provides a therapeutic agent nanoparticle prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the microparticles, wherein the microparticles contain a pharmaceutically acceptable excipient.

[0068] In another embodiment, the present invention provides a batch of coated particles, wherein each coated particle comprises: (i) microparticles comprising a pharmaceutically acceptable excipient and (ii) nanoparticles of a therapeutic agent; and the coated particles are prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form nanoparticles on the surface of the microparticles, thereby forming coated particles.

[0069] In another embodiment, the present invention provides a batch of therapeutic agent nanoparticles prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the microparticles, wherein the microparticles contain a pharmaceutically acceptable excipient.

[0070] In one embodiment, the present invention provides a coated particle, wherein each coated particle comprises: (i) mannitol microparticles and (ii) therapeutic agent nanoparticles; and the coated particle is prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the mannitol microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form nanoparticles on the surface of the mannitol microparticles, thereby forming coated particles.

[0071] In another embodiment, the present invention provides a therapeutic agent nanoparticle prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the mannitol microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the mannitol microparticles.

[0072] In another embodiment, the present invention provides a batch of coated particles, wherein each coated particle comprises: (i) mannitol microparticles and (ii) therapeutic agent nanoparticles; and the coated particles are prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the mannitol microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form nanoparticles on the surface of the mannitol microparticles, thereby forming coated particles.

[0073] In another embodiment, the present invention provides a batch of therapeutic agent nanoparticles prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the mannitol microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the mannitol microparticles.

[0074] In one embodiment, the present invention provides a coated particle, wherein each coated particle comprises: (i) D-glucose microparticles and (ii) therapeutic agent nanoparticles; and the coated particle is prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the D-glucose microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form nanoparticles on the surface of the D-glucose microparticles, thereby forming coated particles.

[0075] In another embodiment, the present invention provides a therapeutic agent nanoparticle prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the D-glucose microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the mannitol microparticles.

[0076] In another embodiment, the present invention provides a batch of coated particles, wherein each coated particle comprises: (i) D-glucose microparticles and (ii) therapeutic agent nanoparticles; and the coated particles are prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the D-glucose microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form nanoparticles on the surface of the D-glucose microparticles, thereby forming coated particles.

[0077] In another embodiment, the present invention provides a batch of therapeutic agent nanoparticles prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the D-glucose microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the D-glucose microparticles. Pharmaceutical composition

[0078] In one embodiment, the present invention provides a pharmaceutical composition comprising coated particles, wherein each coated particle comprises: (i) microparticles comprising a pharmaceutically acceptable excipient and (ii) therapeutic agent nanoparticles; and the surface of the microparticles is coated with the nanoparticles.

[0079] In another embodiment, the present invention provides a pharmaceutical composition comprising coated particles, wherein each coated particle comprises: (i) microparticles comprising a pharmaceutically acceptable excipient and (ii) nanoparticles of a therapeutic agent; and the coated particles are prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form nanoparticles on the surface of the microparticles, thereby forming coated particles.

[0080] In another embodiment, the present invention provides a pharmaceutical composition comprising therapeutic agent nanoparticles, wherein the therapeutic agent nanoparticles are prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the microparticles, wherein the microparticles contain a pharmaceutically acceptable excipient.

[0081] In another embodiment, the present invention provides a batch of pharmaceutical compositions comprising coated particles, wherein each coated particle comprises: (i) microparticles comprising a pharmaceutically acceptable excipient and (ii) nanoparticles of a therapeutic agent; and the coated particles are prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form nanoparticles on the surface of the microparticles, thereby forming coated particles.

[0082] In another embodiment, the present invention provides a batch of pharmaceutical compositions comprising therapeutic agent nanoparticles and a pharmaceutically acceptable excipient, wherein the nanoparticles are prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the microparticles, wherein the microparticles contain the pharmaceutically acceptable excipient.

[0083] In one embodiment, the present invention provides a pharmaceutical composition comprising coated particles, wherein each coated particle comprises: (i) mannitol microparticles and (ii) therapeutic agent nanoparticles; and the surface of the mannitol microparticles is coated with the nanoparticles.

[0084] In another embodiment, the present invention provides a pharmaceutical composition comprising coated particles, wherein each coated particle comprises: (i) mannitol microparticles and (ii) therapeutic agent nanoparticles; and the coated particles are prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the mannitol microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form nanoparticles on the surface of the mannitol microparticles, thereby forming coated particles.

[0085] In another embodiment, the present invention provides a pharmaceutical composition comprising therapeutic agent nanoparticles, wherein the therapeutic agent nanoparticles are prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the mannitol microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the mannitol microparticles, wherein the mannitol microparticles contain a pharmaceutically acceptable excipient.

[0086] In another embodiment, the present invention provides a batch of pharmaceutical compositions comprising coated particles, wherein each coated particle comprises: (i) mannitol microparticles and (ii) therapeutic agent nanoparticles; and the coated particles are prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the mannitol microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form nanoparticles on the surface of the mannitol microparticles, thereby forming coated particles.

[0087] In another embodiment, the present invention provides a batch of pharmaceutical compositions comprising therapeutic agent nanoparticles and a pharmaceutically acceptable excipient, wherein the nanoparticles are prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the mannitol microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the mannitol microparticles, wherein the mannitol microparticles contain the pharmaceutically acceptable excipient.

[0088] In one embodiment, the present invention provides a pharmaceutical composition comprising coated particles, wherein each coated particle comprises: (i) D-glucose microparticles and (ii) therapeutic agent nanoparticles; and the surface of the D-glucose microparticles is coated with the nanoparticles.

[0089] In another embodiment, the present invention provides a pharmaceutical composition comprising coated particles, wherein each coated particle comprises: (i) D-glucose microparticles and (ii) therapeutic agent nanoparticles; and the coated particles are prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the D-glucose microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form nanoparticles on the surface of the D-glucose microparticles, thereby forming coated particles.

[0090] In another embodiment, the present invention provides a pharmaceutical composition comprising therapeutic agent nanoparticles, wherein the therapeutic agent nanoparticles are prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the D-glucose microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the D-glucose microparticles, wherein the D-glucose microparticles contain a pharmaceutically acceptable excipient.

[0091] In another embodiment, the present invention provides a batch of pharmaceutical compositions comprising coated particles, wherein each coated particle comprises: (i) D-glucose microparticles and (ii) therapeutic agent nanoparticles; and the coated particles are prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the D-glucose microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form nanoparticles on the surface of the D-glucose microparticles, thereby forming coated particles.

[0092] In another embodiment, the present invention provides a batch of pharmaceutical compositions comprising therapeutic agent nanoparticles and a pharmaceutically acceptable excipient, wherein the nanoparticles are prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the D-glucose microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the D-glucose microparticles, wherein the D-glucose microparticles contain the pharmaceutically acceptable excipient.

[0093] The pharmaceutical compositions provided by the present invention can be independently formulated into various dosage forms, including but not limited to dosage forms for oral, parenteral and topical administration. The pharmaceutical compositions can also be independently formulated into modified release dosage forms, including delayed release, extended release, prolonged release, sustained release, pulsed release, controlled release, accelerated release, rapid release, targeted release, programmed release and gastric retention dosage forms. The dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al., Eds.; Drugs and the Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008.

[0094] In one embodiment, the pharmaceutical composition provided by the present invention is formulated into a dosage form for oral administration. In another embodiment, the pharmaceutical composition provided by the present invention is formulated into a dosage form for parenteral administration. In yet another embodiment, the pharmaceutical composition provided by the present invention is formulated into a dosage form for topical administration.

[0095] In one embodiment, the pharmaceutical composition provided by the present invention is formulated into a sterile solid dosage form for reconstitution for parenteral administration. In another embodiment, the pharmaceutical composition provided by the present invention is formulated into a solid dosage form for reconstitution for intravenous administration. In another embodiment, the pharmaceutical composition provided by the present invention is formulated into a solid dosage form for reconstitution for intramuscular administration. In another embodiment, the pharmaceutical composition provided by the present invention is formulated into a solid dosage form for reconstitution for subcutaneous administration.

[0096] In certain embodiments, the pharmaceutical compositions provided by the present invention are formulated into non-sterile solid dosage forms. In certain embodiments, the pharmaceutical compositions provided by the present invention are formulated into non-sterile solid dosage forms for ear, skin, gums, nose, eye, oral, oral mucosa, rectum, transdermal or vaginal administration or administration by inhalation. In certain embodiments, the pharmaceutical compositions provided by the present invention are formulated into non-sterile solid dosage forms for eye or oral administration or administration by inhalation.

[0097] The pharmaceutical composition provided by the present invention can be independently in unit dosage form or multiple dosage form. As used in the present invention, unit dosage form refers to physically discrete units suitable for application to subjects, and is packaged separately as known in the art. Each unit dose contains a predetermined amount of active ingredients (e.g., compound provided by the present invention) sufficient to produce the desired therapeutic effect, and required pharmaceutical excipients. The example of unit dosage form includes but is not limited to ampoules, syringes and individually packaged tablets and capsules. Unit dosage form can be administered in divided or multiple doses. Multiple dosage forms are multiple identical unit dosage forms packaged in a single container, administered in separate unit dosage forms. The example of multiple dosage forms includes but is not limited to vials, tablet or capsule bottles, or pint or gallon bottles.

[0098] Pharmaceutical composition provided by the invention can be used once or repeatedly at time intervals independently of each other. It should be understood that the precise dosage and duration for the treatment can change with the age, body weight and individual condition of the treated object, and can be determined by using known test schemes or by in vivo or in vitro tests or diagnostic data extrapolation based on experience. It should also be understood that for any particular individual, specific dosage regimens should be adjusted over time according to the needs of the experimenter and the professional judgment of the people who use or supervise the use of the pharmaceutical composition. A. Oral administration

[0099] The pharmaceutical composition for oral administration provided by the present invention is solid, semisolid or liquid dosage form.As used in the present invention, oral administration also includes buccal, tongue and sublingual administration.Suitable oral dosage forms include but are not limited to tablets, instant dissolves, chewable tablets, capsules, pills, strips, tablets, lozenges, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral sprays, solutions, emulsions, suspensions, wafers, sprinkles, elixirs and syrups.Except for active ingredient, pharmaceutical composition can comprise one or more pharmaceutically acceptable carriers or excipients, include but are not limited to adhesives, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweeteners, flavoring agents, emulsifiers, suspensions and dispersants, preservatives, solvents, non-aqueous liquids, organic acids and carbon dioxide sources.

[0100] The tablet may be made cohesive by a binder or granulator to ensure that the tablet remains intact after compression. Suitable binders or granulators include, but are not limited to, starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH ); gelatin; sugars such as sucrose, glucose, dextrose, molasses and lactose; natural and synthetic gums such as gum arabic, alginic acid, alginates, Irish moss extract, panwar gum, ghatti gum, isabgol shell mucilage, carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone (PVP), larch arabinogalactan, powdered tragacanth gum, and guar gum; celluloses, such as ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC); and microcrystalline cellulose, such as PH-101, PH-103, PH-105 and RC-581. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextran, kaolin, mannitol, silicic acid, sorbitol, starch, and pregelatinized starch. The amount of binder or filler in the pharmaceutical composition provided by the present invention varies with the type of formulation and is readily determined by one of ordinary skill in the art. In the pharmaceutical composition provided by the present invention, the amount of binder or filler may be about 50% to about 99% by weight.

[0101] Suitable diluents include but are not limited to calcium hydrogen phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch and icing sugar. Some diluents, such as mannitol, lactose, sorbitol, sucrose and inositol, when present in sufficient amounts, can make some compressed tablets disintegrate in the mouth by chewing. This compressed tablet can be used as chewable tablets. The amount of diluent in the pharmaceutical composition provided by the invention varies with the type of preparation, and is easily determined for those of ordinary skill in the art.

[0102] Suitable disintegrators include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and HV; citrus pulp; cross-linked cellulose, such as cross-linked carboxymethyl cellulose; cross-linked polymers, such as cross-linked povidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clay; and algae. The amount of disintegrant in the pharmaceutical composition provided by the present invention varies with the type of formulation and is readily determined by a person of ordinary skill in the art. The pharmaceutical composition provided by the present invention may contain about 0.5% to about 15% or about 1% to about 5% by weight of a disintegrant.

[0103] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium; and silicon dioxide or silica gel, such as 200 and The amount of lubricant in the pharmaceutical composition provided herein varies with the type of formulation and is readily determined by one of ordinary skill in the art. The pharmaceutical composition provided herein may contain from about 0.1% to about 5% lubricant by weight.

[0104] Suitable glidants include, but are not limited to, colloidal silicon dioxide, and asbestos-free talc. Suitable colorants include, but are not limited to, any approved, certified water-soluble FD&C dyes, water-insoluble FD&C dyes suspended in alumina hydrates, and lakes. Lakes are combinations of insoluble forms of dyes formed by adsorbing water-soluble dyes onto hydrated oxides of heavy metals. Suitable flavor enhancers include, but are not limited to, natural flavors extracted from plants such as fruits, and synthetic mixtures of compounds that produce pleasant flavors, such as mint and methyl salicylate. Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifiers include, but are not limited to, gelatin, gum arabic, gum tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate ( 20), polyoxyethylene sorbitan monooleate 80 ( 80) and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Gum arabic, sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinyl pyrrolidone. Suitable preservatives include, but are not limited to, glycerol, methyl and propyl parabens, benzoic acid, sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerol, sorbitol, ethanol and syrup. Suitable non-aqueous liquids for emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric acid and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

[0105] It will be appreciated that various carriers and excipients may serve multiple functions, even within the same formulation.

[0106] The pharmaceutical composition for oral administration provided by the present invention can be in the form of compressed tablets, ground tablets, chewable lozenges, quick-dissolving tablets, multiple compressed tablets or enteric-coated tablets, sugar-coated tablets or film-coated tablets. Enteric-coated tablets are compressed tablets coated with substances that resist gastric acid but dissolve or decompose in the intestine, thereby protecting the active ingredients from the acidic environment of the stomach. Enteric coatings include but are not limited to fatty acids, fats, phenyl salicylate, wax, shellac, ammoniated shellac and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets wrapped in sugar coatings, thereby helping to cover up unpleasant tastes or odors and protecting tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include but are not limited to hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. Film coatings have the same general characteristics as sugar coatings. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, press-coated tablets or dry-coated tablets.

[0107] Tablet dosage forms can be prepared from powdered, crystalline or granular active ingredients alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and / or colorants. Flavor enhancers and sweeteners are particularly useful in the formation of chewable tablets and lozenges.

[0108] The pharmaceutical composition for oral administration provided by the present invention is a soft capsule or a hard capsule, which can be made of gelatin, methylcellulose, starch or calcium alginate. Hard gelatin capsules, also known as dry filled capsules (DFC), consist of two parts, one part slides over the other part, thereby completely encapsulating the active ingredient. Soft elastic capsules (SEC) are a soft spherical shell, such as a gelatin shell, which is plasticized by adding glycerol, sorbitol or similar polyols. The soft gelatin shell can contain a preservative to prevent microbial growth. Suitable preservatives, as described in the present invention, include methylparaben and propylparaben, and sorbic acid. Liquid, semisolid and solid dosage forms provided by the present invention can be encapsulated in capsules. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing this solution can be prepared by methods described in U.S. Patent Nos. 4,328,245, 4,409,239 and 4,410,545. Capsules may also be coated as known to those skilled in the art to modify or sustain dissolution of the active ingredient.

[0109] The pharmaceutical composition for oral administration provided by the present invention can be a liquid and semisolid dosage form, including emulsions, solutions, suspensions, elixirs and syrups. An emulsion is a two-phase system in which one liquid is dispersed in another liquid in the form of globules, and the form can be oil-in-water or water-in-oil. An emulsion can include a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier and a preservative. A suspension can include a pharmaceutically acceptable suspending agent and a preservative. An alcohol aqueous solution can include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, such as acetaldehyde diethyl acetal; and a water-soluble solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. An elixir is a transparent, sugared alcohol aqueous solution. A syrup is a concentrated aqueous solution of sugar (e.g., sucrose) and may also contain a preservative. For liquid dosage forms, for example, a solution in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, to facilitate measurement during administration.

[0110] Other useful liquid and semisolid dosage forms include, but are not limited to, materials containing the active ingredient and dialkylated mono- or poly-alkylene glycols, including 1,2-dimethoxymethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol. These dosage forms may further contain one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[0111] The pharmaceutical composition for oral administration provided by the present invention can also be in the form of liposomes, micelles, microspheres or nanosystems. Micellar dosage forms can be prepared as described in US Pat. No. 6,350,458.

[0112] The pharmaceutical composition for oral administration provided by the present invention can be in the form of non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients for non-effervescent granules or powders can include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients for effervescent granules or powders can include organic acids and carbon dioxide sources.

[0113] Coloring agents and flavoring agents can be used in all dosage forms described herein.

[0114] The pharmaceutical composition for oral administration provided by the present invention can be formulated into immediate release or modified release dosage forms, including delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release forms. B. Parenteral Administration

[0115] The pharmaceutical composition provided by the present invention can be administered parenterally by injection, infusion or implantation for local or systemic administration. In the present invention, parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, intravesical and subcutaneous administration.

[0116] The pharmaceutical composition for parenteral administration provided by the present invention can be formulated into any dosage form suitable for parenteral administration, including but not limited to solution, suspension, emulsion, micelle, liposome, microsphere, nanosystem and suitable solid form for solution or suspension before injection. Such dosage form can be prepared according to conventional methods known to those skilled in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, the same.

[0117] The pharmaceutical compositions for parenteral administration provided by the present invention may include one or more pharmaceutically acceptable carriers and excipients, including but not limited to aqueous media, water-miscible media, non-aqueous media, antimicrobial agents or preservatives for antimicrobial growth, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting agents or emulsifiers, complexing agents, isolating agents or chelating agents, cryoprotectants, lyoprotectants, thickeners, pH adjusters and inert gases.

[0118] Suitable aqueous media include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic glucose injection, sterile water injection, glucose and lactated Ringer's injection. Suitable non-aqueous media include, but are not limited to, fixed oils of plant origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, coconut oil medium chain triglycerides and palm seed oil. Suitable water miscible media include, but are not limited to, ethanol, 1,3-butylene glycol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N,N-dimethylacetamide and dimethyl sulfoxide.

[0119] Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol, and glucose. Suitable buffers include, but are not limited to, phosphates and citrates. Suitable antioxidants include, but are not limited to, those described above in the present invention, such as bisulfites and sodium pyrosulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending agents and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinyl pyrrolidone, such as those described above in the present invention. Suitable emulsifiers include, but are not limited to, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate, such as those described above in the present invention. Suitable isolating agents or chelating agents include, but are not limited to, EDTA. Suitable pH regulators include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether 7-β-cyclodextrin.

[0120] When the pharmaceutical compositions provided by the present invention are formulated for multiple dose administration, the multiple dose parenteral preparations must contain antimicrobial agents at bacteriostatic or bacteriostatic concentrations. As known and practiced in the art, all parenteral preparations must be sterile.

[0121] In one embodiment, the pharmaceutical composition for parenteral administration can be in the form of a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is in the form of a sterile dry soluble product, including lyophilized powders and subcutaneous tablets, which are reconstituted by a vehicle before use. In another embodiment, the pharmaceutical composition is in the form of a ready-to-use sterile suspension. In another embodiment, the pharmaceutical composition is in the form of a sterile dry insoluble product, which is reconstituted by a vehicle before use. In another embodiment, the pharmaceutical composition is in the form of a ready-to-use sterile emulsion.

[0122] The pharmaceutical compositions for parenteral administration provided by the present invention can be formulated into immediate release or modified release dosage forms, including delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release forms.

[0123] The pharmaceutical composition for parenteral administration provided by the present invention can be formulated into a suspension, solid, semisolid or thixotropic liquid for administration as an implanted reservoir. In one embodiment, the pharmaceutical composition provided by the present invention is dispersed in a solid inner matrix, which is surrounded by an outer polymer film that is insoluble in body fluids but allows the active ingredient in the pharmaceutical composition to diffuse through.

[0124] Suitable inner matrices include, but are not limited to, polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, organosilicone carbonate copolymers, hydrophilic polymers (such as hydrogels of acrylic acid and methacrylate), collagen, cross-linked polyvinyl alcohol, and partially cross-linked hydrolyzed polyvinyl acetate.

[0125] Suitable outer polymer films include, but are not limited to, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers. C. Topical administration

[0126] The pharmaceutical compositions provided by the present invention can be topically applied to the skin, orifices or mucous membranes. As used herein, topical administration includes (endo)dermal, conjunctival, intracorneal, intraocular, ocular, otic, transdermal, nasal, vaginal, urethral, ​​respiratory and rectal administration.

[0127] The pharmaceutical composition provided by the invention can be formulated into any dosage form suitable for topical administration for local or systemic action, including but not limited to emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, powders, powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, rinses, sprays, suppositories, bandages and skin patches. The topical preparations of the pharmaceutical composition provided by the invention can also include liposomes, micelles, microspheres and nano systems.

[0128] In the pharmaceutical compositions provided by the present invention, pharmaceutically acceptable carriers and excipients suitable for topical preparations include, but are not limited to, aqueous media, water-miscible media, non-aqueous media, antimicrobial agents or preservatives for antimicrobial growth, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting agents or emulsifiers, complexing agents, isolating agents or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickeners and inert gases.

[0129] The pharmaceutical composition can also be delivered by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECT TM and BIOJECT TM For topical administration.

[0130] The pharmaceutical composition provided by the present invention can be in the form of ointment, cream and gel. Suitable ointment media include oily or hydrocarbon media, including lard, benzoated lard, olive oil, cottonseed oil and other oils; white vaseline; emulsifiable or absorbent media, such as hydrophilic vaseline, hydroxy stearyl sulfate and anhydrous lanolin; dehydrated media, such as hydrophilic ointment; water-soluble ointment media, including polyethylene glycols of different molecular weights; emulsion media, whether water-in-oil (W / O) emulsion or oil-in-water (O / W) emulsion, including cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. See, for example, Remington: The Science and Practice of Pharmacy, supra, the same. These media can be used as emollients, but usually require the addition of antioxidants and preservatives.

[0131] Suitable cream bases can be oil-in-water or water-in-oil. Suitable cream media can be washable and include an oil phase, an emulsifier and an aqueous phase. The oil phase is also referred to as the "inner" phase and typically includes vaseline and a fatty alcohol, such as cetyl alcohol or stearyl alcohol. The volume of the aqueous phase typically (although not necessarily) exceeds the oil phase and typically contains a humectant. The emulsifier in the cream formulation can be a nonionic, anionic, cationic or amphoteric surfactant.

[0132] Gels can be semisolid, suspension-type systems. Single-phase gels contain organic macromolecules substantially uniformly distributed throughout a liquid carrier. Suitable gelling agents include, but are not limited to, cross-linked acrylic acid polymers such as carbomers, carboxypolyalkylenes and Hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a uniform gel, a dispersant such as alcohol or glycerin may be added, or the gelling agent may be dispersed by grinding, mechanical mixing, and / or stirring.

[0133] Pharmaceutical compositions provided by the invention can be administered in the form of suppositories, pessaries, bougies, plasters or cataplasms, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays or enemas through the rectum, urethra, vagina or around the vagina. These dosage forms can be manufactured using conventional methods as described in Remington: The Science and Practice of Pharmacy.

[0134] Rectal, urethral and vaginal suppositories are solids for insertion into body orifices, which are solid at room temperature but melt or soften at body temperature to release the active ingredient in the orifice. Pharmaceutically acceptable carriers for rectal and vaginal suppositories include a matrix or medium, such as a hardener, whose melting point is close to body temperature when formulated with the active ingredient; and the above-mentioned antioxidants, including bisulfite and sodium metabisulfite. Suitable media include, but are not limited to, cocoa butter (cocoa butter), glycerol-gelatin, polyethylene glycol (carbowax / polyoxyethylene glycol), spermaceti, paraffin, white wax and yellow wax,, a suitable mixture of monoglycerides, diglycerides and triglycerides of fatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate and polyacrylic acid. Combinations of various media can also be used. Rectal and vaginal suppositories can be prepared by compression or molding. The typical weight of rectal and vaginal suppositories is about 2 to about 3 grams.

[0135] The pharmaceutical compositions provided by the present invention can be administered ophthalmically in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, and ocular inserts and implants.

[0136] The pharmaceutical composition provided by the present invention can be administered intranasally or by inhalation into the respiratory tract. The pharmaceutical composition can be in the form of an aerosol or solution for delivery using the following methods: a pressurized container, a pump, a sprayer, a nebulizer, such as an nebulizer or atomizer that uses electrohydrodynamics to produce a fine mist, which is used alone or in combination with a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical composition can also be in the form of a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and in the form of nasal drops. For intranasal use, the powder can contain a bioadhesive, including chitosan or cyclodextrin.

[0137] Solutions or suspensions for use in a pressurized container, pump, spray, atomizer or nebulizer may contain: ethanol, aqueous ethanol or a suitable substitute to disperse, solubilize or prolong the release of the active ingredient; a propellant as a solvent; and / or a surfactant, for example sorbitan trioleate, oleic acid or oligolactic acid.

[0138] Pharmaceutical composition provided by the invention can be micronized to a size suitable for delivery by inhalation, for example, about 50 microns or less, or about 10 microns or less. Particles of this size can be prepared using pulverization methods known to those skilled in the art, for example spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.

[0139] Capsules, bubbles and cartridges for inhalers or insufflators may contain: a powder mixture of the pharmaceutical composition provided by the present invention; a suitable powder base, such as lactose or starch; and a modifier, such as l-leucine, mannitol or magnesium stearate. Lactose may be in anhydrous or monohydrate form. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. The pharmaceutical composition for inhalation / intranasal administration provided by the present invention may also contain: a suitable flavor enhancer, such as menthol and levomenthol; and / or a sweetener, such as saccharin and saccharin sodium.

[0140] The pharmaceutical composition for topical administration provided by the present invention can be formulated into an immediate release or modified release dosage form, including delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release. D. Modified Release

[0141] The pharmaceutical composition provided by the present invention can be formulated into a modified release dosage form. As used in the present invention, the term "modified release" refers to a dosage form in which the release rate or release position of the active ingredient is different from that of an immediate release dosage form when administered by the same route. Modified release dosage forms include but are not limited to delayed release, extended release, prolonged release, sustained release, pulsed release, controlled release, accelerated release and rapid release, targeted release, programmed release and gastric retention dosage forms. A variety of modified release devices and methods known to those skilled in the art can be used to prepare a pharmaceutical composition of a modified release dosage form, including but not limited to a matrix controlled release device, an osmotic controlled release device, a multi-particle controlled release device, an ion exchange resin, an enteric coating, a multi-layer coating, a microsphere, a liposome and a combination thereof. The release rate of the active ingredient can also be changed by changing the particle size and polymorphism of the active ingredient. 1. Matrix controlled release device

[0142] The pharmaceutical compositions of the modified release dosage form provided by the present invention can be prepared using matrix controlled release devices known to those skilled in the art. See, for example, Takada et al. in Encyclopedia of Controlled Drug Delivery, Mathiowitz Ed.; Wiley, 1999; Vol. 2.

[0143] In certain embodiments, the pharmaceutical compositions provided herein in modified release dosage forms are formulated using an erodible matrix device, wherein the erodible matrix is ​​a water-swellable, erodible, or soluble polymer, including but not limited to synthetic polymers, and natural polymers and derivatives, such as polysaccharides and proteins.

[0144] Materials that can be used to form the erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenan, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches such as dextrin and maltodextrin; hydrophilic colloids such as pectin; phospholipids such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; celluloses such as ethylcellulose (EC), methylethylcellulose (MEC), carboxymethylcellulose (CMC), CMEC, hydroxyethylcellulose (HEC), and hydroxyethylcellulose (HEC). EC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT) and ethyl hydroxyethyl cellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid Poly(2-hydroxyethyl-methacrylate); polylactic acid; copolymers of L-glutamic acid and L-glutamate ethyl ester; degradable lactic acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylic acid and (trimethylaminoethyl) methacrylic acid chloride.

[0145] In certain embodiments, the pharmaceutical compositions provided herein are formulated using a non-erodible matrix device. The active ingredient is dissolved or dispersed in an inert matrix and released primarily by diffusion through the inert matrix after administration. Materials suitable as non-corrodible matrices include, but are not limited to, insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, ethylene / vinyloxyethanol copolymers, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane and silicic acid ester copolymers; hydrophilic polymers such as ethylcellulose, cellulose acetate, crospovidone and partially cross-linked hydrolyzed polyvinyl acetate; and fatty compounds such as carnauba wax, microcrystalline wax and triglycerides.

[0146] In a matrix controlled release system, the desired release kinetics can be controlled, for example, by controlling the type of polymer used, polymer viscosity, particle size of the polymer and / or active ingredient, the proportion of active ingredient in the polymer, and other excipients or carriers.

[0147] The pharmaceutical composition in a modified release dosage form provided by the present invention can be prepared by methods known to those skilled in the art, including direct tableting, dry or wet granulation followed by tableting, and melt granulation followed by tableting. 2. Osmotic controlled release device

[0148] The pharmaceutical composition of the modified release dosage form provided by the present invention can be manufactured using an osmotic controlled release device, including but not limited to a single chamber system, a two-chamber system, an asymmetric membrane technology (AMT) and an extruded core system (ECS), and generally, such a device has at least two components: (a) a core containing an active ingredient; (b) a semipermeable membrane having at least one delivery port, which is used to encapsulate the core. The semipermeable membrane controls water to flow into the core from the aqueous environment used, and is extruded through the delivery port, thereby releasing the drug.

[0149] In addition to the active ingredient, the core of the osmotic device optionally includes an osmotic agent that creates a driving force for transporting water from the environment of use into the device core. One class of osmotic agents are water-swellable hydrophilic polymers, also known as "osmopolymers" and "hydrogels." Water-swellable hydrophilic polymers suitable as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic acid), poly(methacrylic acid), polyvinyl pyrrolidone (PVP), cross-linked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, PVA / PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, cross-linked sodium carboxymethylcellulose, carrageenan, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) and carboxyethylcellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum and sodium starch glycolate.

[0150] Another class of osmogens is osmogens, which are able to absorb water and thus affect the osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

[0151] Osmotic agents with different dissolution rates can affect the rate at which the active ingredient is initially delivered from the dosage form. For example, amorphous sugars (such as MANNOGEM TM EZ) can be used to provide a faster delivery rate in the first few hours to quickly produce the desired therapeutic effect, and gradually and continuously release the remaining amount to maintain the desired therapeutic or preventive effect over a long period of time. In this case, the active ingredient is released at such a rate to replenish the active ingredient that is metabolized and excreted.

[0152] The core may further include various other excipients and carriers as described in the present invention to enhance the performance of the dosage form, or to promote stability or processability.

[0153] Materials that can be used to form the semipermeable membrane include various grades of acrylic resins, vinyl resins, ethers, polyamides, polyesters, and cellulose derivatives that are water permeable and insoluble in water at physiologically relevant pH values, or that are susceptible to being rendered water insoluble by chemical changes, such as crosslinking. Examples of polymers suitable for forming the coating include plasticized or unplasticized, reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, β-glucan acetate, Esters, β-glucan triacetate, dimethyl acetaldehyde acetate, locust bean gum triacetate, hydroxylated ethylene vinyl acetate, EC, PEG, PPG, PEG / PPG copolymer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acid and esters, and poly(methacrylic) acid and esters and their copolymers, starch, dextran, dextrin, chitosan, collagen, gelatin, polyolefins, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes and synthetic waxes.

[0154] The semipermeable membrane may also be a hydrophobic microporous membrane in which the pores are substantially filled with gas and are not wetted by aqueous media but are permeable to water vapor, as described in U.S. Pat. No. 5,798, 119. Such hydrophobic but water vapor permeable membranes are typically composed of hydrophobic polymers such as polyolefins, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0155] The one or more delivery ports on the semipermeable membrane can be formed after coating by mechanical or laser drilling, can also be formed in situ by plug erosion of a water-soluble material, or by rupturing the thinner portion of the membrane at a depression in the core. In addition, the delivery ports can be formed during the coating process, as in the case of asymmetric membrane coatings of the type described in U.S. Patent Nos. 5,612,059 and 5,698,220.

[0156] The total amount of active ingredient released and the rate of release can be regulated substantially by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size and location of the delivery ports.

[0157] The pharmaceutical composition in the form of an osmotic controlled release dosage form may further comprise conventional excipients or carriers as described in the present invention to facilitate the performance or processing of the preparation.

[0158] Osmotic controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release, 1995, 35, 1-21; Verma et al., Drug Dev. Ind. Pharm., 2000, 26, 695-708; Verma et al., J. Controlled Release, 2002, 79, 7-27.

[0159] In certain embodiments, the pharmaceutical composition provided by the present invention is formulated into an AMT controlled release dosage form, which comprises an asymmetric osmotic membrane, the membrane coating a core, the core comprising an active ingredient and other pharmaceutically acceptable excipients or carriers. See, for example, U.S. Patent No. 5,612,059 and WO 2002 / 17918. AMT controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation and dip coating.

[0160] In certain embodiments, the pharmaceutical composition provided by the present invention is formulated into an ESC controlled release dosage form, which comprises a permeable membrane coating a core comprising an active ingredient, hydroxyethylcellulose and other pharmaceutically acceptable excipients or carriers. 3. Multi-particle controlled release device

[0161] The pharmaceutical compositions of the modified release dosage form provided by the present invention can be manufactured as multi-particulate controlled release devices, which contain a plurality of particles, granules or pellets having a diameter ranging from about 10 μm to about 3 mm, from about 50 μm to about 2.5 mm to or from 100 μm to about 1 mm. Such multi-particulates can be prepared by methods known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, roller compaction, melt congealing and strengthening the core by spraying. See, for example, Multiparticulate Oral Drug Delivery; Ghebre-Sellassie Eds.; Drugs and the Pharmaceutical Sciences 65; CRC Press: 1994; and Pharmaceutical Pelletization Technology; Ghebre-Sellassie Eds.; Drugs and the Pharmaceutical Sciences 37; CRCPress:1989.

[0162] Other excipients or carriers described in the present invention can be mixed with the pharmaceutical composition to facilitate processing and form multi-particulates. The resulting particles themselves can constitute a multi-particulate device or can be coated with various film-forming materials, such as enteric polymers, water-swellable and water-soluble polymers. The multi-particulates can be further processed into capsules or tablets. 4. Targeted delivery

[0163] The pharmaceutical compositions provided by the present invention can also be delivered to specific tissues, receptors or other areas of the subject's body to be treated by targeted delivery, including liposome-based delivery systems, re-encapsulated erythrocyte-based delivery systems and antibody-based delivery systems. Examples include, but are not limited to, U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874.

[0164] The present invention will be further understood by the following non-limiting examples. Example

[0165] As used herein, the symbols and conventions used in these processes, schemes, and examples, whether or not specific abbreviations therein are specifically defined, are consistent with the abbreviations used in contemporary scientific literature, such as Journal of the American Chemical Society, Journal of Medicinal Chemistry, or Journal of Medicinal Chemistry. Specifically, for example, but not limited to, the following abbreviations may be used in the examples and throughout the specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); nm (nanometer); h (hour); min (minute); rpm (revolutions per minute); and HPLC (high performance liquid chromatography).

[0166] Unless otherwise stated, all temperatures are expressed in ° C (Celsius). Unless otherwise stated, all processes are carried out at room temperature. The methods described herein are intended to illustrate applicable techniques through the use of specific examples and are not intended to limit the scope of the invention. Example 1 Preparation of mannitol microparticles coated with ibuprofen nanoparticles

[0167] Mannitol microparticles coated with ibuprofen nanoparticles on the surface were prepared using organic vapor phase deposition (OVPD) technology. See, for example, Baldo et al., Adv. Mater. 1998, 10, 1505-1514; KR 100644219B1. Ibuprofen (25 g) was loaded into the sample feed container of the Nanosizer, and mannitol (1,000 g) was placed on the coating pan. The Nanosizer was adjusted to a vacuum pressure of no more than 0.0001 torr using a vacuum pump. The sample feed chamber in the Nanosizer was heated to 100° C. for 1 hour, 150° C. for 1 hour, and 200° C. for 2 hours under vacuum pressure to vaporize ibuprofen, while stirring the coating pan at 90 rpm at ambient temperature without active heating. When the gaseous ibuprofen contacts the stirred mannitol microparticles, it is coated on its surface, thereby forming ibuprofen nanoparticles. After completion, the nanoparticle size analyzer was pressurized to atmospheric pressure, and the coating pan was removed to collect the mannitol microparticles with ibuprofen nanoparticles on the surface. It was calculated that the prepared mannitol microparticles with ibuprofen nanoparticles on the surface had a drug loading of 2% by weight. Example 2 Preparation of mannitol microparticles coated with ibuprofen nanoparticles

[0168] Mannitol microparticles with surface coated with ibuprofen nanoparticles are prepared using organic vapor phase deposition (OVPD) technology. See, for example, the same. Ibuprofen (30 g) is loaded into the sample feed container of the nanoparticle sizer, and mannitol (1,000 g) is placed on the coating pan. The nanoparticle sizer is adjusted to a vacuum pressure of no more than 0.001 torr using a vacuum pump. The sample feed chamber in the nanoparticle sizer is heated to 100 ° C for 1 hour, 150 ° C for 1 hour, and 200 ° C for 2 hours under vacuum pressure to gasify ibuprofen, while stirring the coating pan at 90 rpm at ambient temperature without active heating. When gaseous ibuprofen contacts the stirred mannitol microparticles, it is coated on its surface, thereby forming ibuprofen nanoparticles. After completion, the nanoparticle sizer is pressurized to atmospheric pressure, and the coating pan is removed, and the mannitol microparticles with surface coated with ibuprofen nanoparticles are collected. It was calculated that the prepared mannitol microparticles with surface coated with ibuprofen nanoparticles had a drug loading of 2% by weight. Example 3 In vitro dissolution of ibuprofen nanoparticles

[0169] The in vitro dissolution of ibuprofen nanoparticles was determined by the following measurement: using the USP monograph method for ibuprofen (United States Pharmacopeia, USP31), the average dissolution profile of 6 hard gelatin capsules of size 00# was measured, each capsule containing mannitol microparticles (555 mg) coated with ibuprofen nanoparticles on the surface. The dissolution profile was measured in a phosphate buffer (900 mL) at pH 7.2, using a type 2 apparatus (basket) at 50 rpm, sampling at 5, 10, 15, 30, 45 and 60 minutes. Example 4 Pharmacokinetics of ibuprofen nanoparticles in rabbits

[0170] The pharmacokinetic profile of ibuprofen nanoparticles in rabbits was determined by the following method: using hard gelatin capsules of size 00#, wherein each capsule surface was coated with mannitol microparticles of ibuprofen nanoparticles (total weight 555 mg, ibuprofen nanoparticles 50 mg), the capsules were taken orally, and blood was collected at 0, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours after administration. Rabbit plasma samples (20 μL / injection) were analyzed by C18 reverse phase HPLC. The samples were eluted on an ODS2 column with a UV detector at 223 nm and eluted with acetonitrile and phosphate buffer (50:50 (v:v), pH 4.16) at a flow rate of 1.0 mL / min at ambient temperature. Example 5 Determination of particle size distribution of ibuprofen nanoparticles by optical diffraction

[0171] Mannitol microparticles (1 g) coated with ibuprofen nanoparticles were dissolved in water (1 mL). The particle size distribution of the homogenized aqueous solution containing ibuprofen nanoparticles was analyzed using a Malvern MASTESIZER 3000 particle size analyzer. Three different samples were analyzed separately. Example 6 SEM analysis of the particle size of ibuprofen nanoparticles

[0172] Mannitol microparticles (1 g) coated with ibuprofen nanoparticles were dissolved in water (1 mL). The resulting homogenized aqueous solution containing ibuprofen nanoparticles was analyzed using a scanning electron microscope (SEM). Three different samples were analyzed separately. Example 7 Preparation of glucose microparticles coated with ibuprofen nanoparticles

[0173] The OVPD technique was used to prepare glucose (D-glucose, D-dextrose) microparticles coated with ibuprofen nanoparticles. The reference is the same as above. Ibuprofen (71 g) was loaded into the sample feed container of the nanoparticle sizer, and glucose (915 g) was placed on the coating pan. The sample feed chamber in the nanoparticle sizer was set at 10 -3 The coating pan is heated to 150-200°C under a vacuum pressure of 10 torr to vaporize the ibuprofen, while the coating pan is stirred at 120 rpm at ambient temperature without active heating. When the gaseous ibuprofen contacts the stirred glucose microparticles, it is coated on the surface to form ibuprofen nanoparticles. After completion, the nanoparticle sizer is pressurized to atmospheric pressure, and the coating pan is removed to collect the glucose microparticles coated with ibuprofen nanoparticles on the surface. The prepared glucose microparticles coated with ibuprofen nanoparticles on the surface have a drug loading of 5% by weight, calculated using the measured value measured by the USP monograph method (USP 31) for ibuprofen. Example 8 Particle size distribution of ibuprofen nanoparticles attached to glucose surface

[0174] Glucose microparticles (250 mg) coated with ibuprofen nanoparticles on the surface prepared in Example 7 were dissolved in water to obtain a clear suspension. The suspension was immediately used for negative staining with 2% uranyl acetate to determine the particle size.

[0175] For negative staining, a 100-mesh polyvinyl acetate / carbon-coated Cu grid was glow discharged for 5 minutes. Freshly prepared suspension (5 μL) was incubated on the grid and allowed to adhere for 10 minutes. Excess suspension was wicked away with filter paper. The grid was immediately stained with 2% uranyl acetate (20 μL) twice for 10 seconds each, removing the excess between each step by wicking. The grid was allowed to dry face down on the filter paper for at least 15 minutes before observation. The FEI TECNAI equipped with an AMT camera was used. TM The grids were imaged using a T12TEM. Measurements were obtained using the AMT quantification package and AMT camera software. The particle size of the ibuprofen nanoparticles on the glucose surface was determined twice. The average particle size of the ibuprofen nanoparticles was determined to be 156 ± 26 nm or 174 ± 22 nm. Example 9 Preparation of mannitol microparticles coated with ibuprofen nanoparticles

[0176] Mannitol microparticles coated with ibuprofen nanoparticles were prepared using OVPD technology. Reference is the same as above. Ibuprofen (26.7 g) was loaded into the sample feed container of the nanoparticle sizer, and glucose (1197 g) was placed on the coating pan. The sample feed chamber in the nanoparticle sizer was set at 10 -5The coating pan is heated to 90-130°C under a vacuum pressure of 10 torr to vaporize ibuprofen, while stirring the coating pan at 145 rpm at ambient temperature without active heating. When the gaseous ibuprofen contacts the stirred mannitol microparticles, it is coated on its surface to form ibuprofen nanoparticles. After completion, the nanoparticle sizer is pressurized to atmospheric pressure, and the coating pan is removed to collect the mannitol microparticles coated with ibuprofen nanoparticles on the surface. The prepared mannitol microparticles coated with ibuprofen nanoparticles on the surface have a drug loading of 2% by weight, calculated using the measured values ​​measured by the USP monograph method (USP 31) of ibuprofen. The particle size of the ibuprofen nanoparticles on the surface of mannitol is determined twice using the TEM method described in Example 8. The average particle size of the ibuprofen nanoparticles is determined to be 21 ± 4nm or 18 ± 3nm. Example 10 Preparation of Glucose Microparticles Coated with Nifedipine Nanoparticles

[0177] Glucose microparticles coated with nifedipine nanoparticles were prepared using OVPD technology. The reference is the same as above. Nifedipine (80 g) was loaded into the sample feed container of the nanoparticle sizer, and glucose (1,600 g) was placed on the coating pan. The sample feed chamber in the nanoparticle sizer was set at 10 -3 The coating pan was heated to 250°C under a vacuum pressure of 10 torr to vaporize nifedipine, while stirring the coating pan at 120 rpm at ambient temperature without active heating. When the gaseous nifedipine contacts the stirred glucose microparticles, it is coated on their surface to form nifedipine nanoparticles. After completion, the nanoparticle sizer was pressurized to atmospheric pressure, and the coating pan was removed to collect the glucose microparticles coated with nifedipine nanoparticles on the surface. The prepared glucose microparticles coated with nifedipine nanoparticles on the surface had a drug loading of 3% by weight, calculated using the measured values ​​measured using the USP monograph method for nifedipine. The particle size of the nifedipine nanoparticles on the glucose surface was determined twice using the TEM method described in Example 8. The average particle size of the nifedipine nanoparticles was determined to be 487±33nm or 513±27nm. Embodiment 11 Preparation of MCC microparticles coated with plumbagin nanoparticles

[0178] Microcrystalline cellulose (MCC) microparticles coated with plumbagin nanoparticles were prepared using OVPD technology. The reference is the same as above. Plumbagin (6 g) was loaded into the sample feed container of the nanoparticle sizer, and MCC (62 g) was placed on the coating pan. The sample feed chamber in the nanoparticle sizer was set at 10 -6The coating pan was heated to 85-87°C under a vacuum pressure of 10 torr to vaporize plumbagin, while the coating pan was stirred at 133 rpm at ambient temperature without active heating. When the gaseous plumbagin came into contact with the stirred MCC microparticles, it was coated on the surface to form plumbagin nanoparticles. After completion, the nanoparticle size analyzer was pressurized to atmospheric pressure, and the coating pan was removed to collect the MCC microparticles with plumbagin nanoparticles on the surface. Example 12 Preparation of lactose microparticles coated with piroxicam nanoparticles

[0179] Lactose microparticles coated with piroxicam nanoparticles were prepared using OVPD technology. The reference is the same as above. Piroxicam (5 g) was loaded into the sample feed container of the nanoparticle sizer, and lactose (120 g) was placed on the coating pan. The sample feed chamber in the nanoparticle sizer was set at 10 -6 The coating pan is heated to 120-130°C under a vacuum pressure of 10 torr to vaporize piroxicam, while the coating pan is stirred at 70°C and 120 rpm without active heating. When the gaseous piroxicam contacts the stirred lactose microparticles, it is coated on the surface to form piroxicam nanoparticles. After completion, the nanoparticle sizer is pressurized to atmospheric pressure, the coating pan is removed, and the lactose microparticles coated with piroxicam nanoparticles are collected. Example 13 Preparation of PVP microparticles coated with zileuton nanoparticles

[0180] Polyvinyl pyrrolidone (PVP) microparticles coated with zileuton nanoparticles were prepared using OVPD technology. The reference is the same as above. Zileuton (7 g) was loaded into the sample feed container of the nanoparticle sizer, and PVP (50 g) was placed on the coating pan. The sample feed chamber in the nanoparticle sizer was set at 10 -5 The coating pan is heated to 135-147°C under a vacuum pressure of torr to vaporize zileuton, while the coating pan is stirred at 70°C and 120 rpm without active heating. When the gaseous zileuton contacts the stirred PVP microparticles, it is coated on their surface to form zileuton nanoparticles. After completion, the nanoparticle size analyzer is pressurized to atmospheric pressure, the coating pan is removed, and the PVP microparticles with the surface coated with zileuton nanoparticles are collected. Embodiment 14 Preparation of HPC microparticles coated with carbamazepine nanoparticles

[0181] Hydroxypropyl cellulose (HPC) microparticles coated with carbamazepine nanoparticles were prepared using OVPD technology. The reference is the same as above. Carbamazepine (8 g) was loaded into the sample feed container of the nanoparticle sizer, and HPC (100 g) was placed on the coating pan. The sample feed chamber in the nanoparticle sizer was set at 10 -6The coating pan was heated to 189-192°C under a vacuum pressure of 10 torr to vaporize carbamazepine, while the coating pan was stirred at 70°C and 145 rpm without active heating. When the gaseous carbamazepine came into contact with the stirred HPC microparticles, it was coated on the surface to form carbamazepine nanoparticles. After completion, the nanoparticle sizer was pressurized to atmospheric pressure, and the coating pan was removed to collect the HPC microparticles coated with carbamazepine nanoparticles. Embodiment 15 Preparation of HPMC microparticles coated with verapamil nanoparticles

[0182] Hydroxypropyl methylcellulose (HPMC) microparticles coated with verapamil nanoparticles were prepared using OVPD technology. The reference is the same as above. Verapamil (8 g) was loaded into the sample feed container of the nanoparticle sizer, and HPMC (100 g) was placed on the coating pan. The sample feed chamber in the nanoparticle sizer was set at 10 -6 The coating pan was heated to 130-143°C under a vacuum pressure of 10 torr to vaporize Verapamil, while the coating pan was stirred at 70°C and 145 rpm without active heating. When the gaseous Verapamil came into contact with the stirred HPMC microparticles, it was coated on their surface, thereby forming Verapamil nanoparticles. After completion, the nanoparticle sizer was pressurized to atmospheric pressure, and the coating pan was removed to collect the HPMC microparticles with Verapamil nanoparticles on their surface.

[0183] The purpose of providing the above-mentioned embodiments is to fully disclose and describe the claimed technical solutions to those of ordinary skill in the art, and it does not limit the scope of protection of the present invention. Modifications that are obvious to those of ordinary skill in the art also fall within the scope of the claims. All publications, patents and patent applications cited in the specification are incorporated herein by reference, which is equivalent to each specific publication, patent and patent application being incorporated herein by reference.

Claims

1. A coated particle comprising: (i) microparticles comprising a pharmaceutically acceptable excipient, and (ii) nanoparticles, each nanoparticle comprising a therapeutic agent; wherein the surface of the microparticles is coated with the nanoparticles.

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

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

4. The coated particle of claim 1, wherein the coated particle is prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form the nanoparticles on the surface of the microparticles, thereby forming coated particles.

5. The coated particles of claim 4, wherein the first predetermined temperature is about 50 to about 500°C, about 100 to about 400°C, about 50 to about 300°C, about 100 to about 300°C, about 100 to about 250°C, about 150 to about 300°C, or about 200 to about 300°C.

6. The coated particle of claim 4, wherein the first predetermined temperature is from about 50 to about 250°C.

7. The coated particle of claim 4, wherein the predetermined vacuum pressure is no greater than about 10 -1 torr, not more than about 10 -2 torr, not more than about 10 -3 torr, not more than about 10 -4 torr, not more than about 10 -5 torr, not more than about 10 -6 torr, not more than about 10 -7 torr, not more than about 10 -8 torr or not more than about 10 -9 torr.

8. The coated particle according to claim 4, wherein The predetermined vacuum pressure is about 10-3 torr to about 10-9 torr.

9. The coated particles of claim 4, wherein the predetermined stirring speed is about 10 to about 200 rpm, about 20 to about 150 rpm, about 20 to about 120 rpm, about 50 to about 100 rpm, or about 80 to about 100 rpm.

10. The coated particles of claim 4, wherein the predetermined stirring speed is about 50 to about 100 rpm.

11. The coated particle of claim 4, wherein the second predetermined temperature is 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.

12. The coated particle of claim 4, wherein the second predetermined temperature is no greater than about 100°C.

13. The coated particle of claim 1, wherein the pharmaceutically acceptable excipient is a hydrophilic excipient.

14. The coated particle of claim 1, wherein the pharmaceutically acceptable excipient is a sugar alcohol.

15. The coated particles of claim 1, wherein the pharmaceutically acceptable excipient is arabitol, erythritol, fucitol, dulcitol, iditol, inositol, isomalt, lactitol, maltitol, maltotriitol, mannitol, ribitol, sorbitol, threitol, heptyl alcohol, xylitol, or a mixture thereof.

16. The coated particle according to claim 1, wherein the pharmaceutically acceptable excipient is erythritol, lactitol, maltitol, mannitol, sorbitol, xylitol or a mixture thereof.

17. The coated particle of claim 1, wherein the pharmaceutically acceptable excipient is mannitol, sorbitol, xylitol or a mixture thereof.

18. The coated particle of claim 1, wherein the pharmaceutically acceptable excipient is mannitol.

19. The coated particle of claim 1, wherein the pharmaceutically acceptable excipient is a carbohydrate.

20. The coated particle according to claim 1, wherein the pharmaceutically acceptable excipient is dextrose, fructose, glucose, lactose, maltose, molasses, sucrose, trehalose or a mixture thereof.

21. The coated particle of claim 1, wherein the pharmaceutically acceptable excipient is glucose.

22. The coated particle of claim 21, wherein the pharmaceutically acceptable excipient is D-glucose.

23. The coated particles of claim 1, wherein the pharmaceutically acceptable excipient is glucose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), lactose, mannitol or polyvinyl pyrrolidone (PVP).

24. The coated particle of claim 1, wherein the microparticles have an average particle size of about 1 to about 1,000 μm, about 10 to about 500 μm, about 20 to about 500 μm, about 50 to about 300 μm, or about 100 to about 300 μm.

25. The coated particle of claim 1, wherein the microparticles have an average particle size of about 1 to about 100 μm, about 1 to about 50 μm, or about 1 to about 25 μm.

26. The coated particle of claim 1, wherein the therapeutic agent is a BCS class II compound.

27. The coated particle of claim 1, wherein the therapeutic agent is a BCS class IV compound.

28. The coated particle of claim 1, wherein the therapeutic agent has a melting point of no greater than about 300°C.

29. The coated particles of claim 1, wherein the nanoparticles have an average particle size of about 1 to about 500 nm, about 1 to about 200 nm, about 2 to about 200 nm, about 5 to about 200 nm, about 10 nm to about 200 nm, or about 10 to about 100 nm.

30. The coated particle of claim 1, wherein the nanoparticles have an average particle size of about 10 to about 500 nm.

31. The coated particle of claim 1, wherein the coated particle comprises nanoparticles in an amount of about 0.1 to about 25%, about 0.2 to about 20%, about 0.5 to about 10%, or about 1 to about 10% by weight.

32. The coated particle of claim 1, wherein the coated particle comprises nanoparticles in an amount of about 0.1% to about 10% by weight.

33. The coated particles of claim 1, wherein the coated particles have an average particle size of about 1 to about 1,000 μm, about 10 to about 500 μm, about 20 to about 500 μm, about 50 to about 300 μm, or about 100 to about 300 μm.

34. The coated particles of claim 1, wherein the coated particles have an average particle size of about 1 to about 100 μm, about 1 to about 50 μm, or about 1 to about 25 μm.

35. The coated particle of claim 1, wherein the therapeutic agent is carbamazepine, ibuprofen, nifedipine, piroxicam, plumbagin, verapamil, or zileuton.

36. A pharmaceutical composition comprising the coated particles of any one of claims 1 to 35.

37. The pharmaceutical composition according to claim 36, which is a pharmaceutical composition for oral, parenteral or topical administration.

38. The pharmaceutical composition according to claim 37, which is a pharmaceutical composition for ocular or otic administration, or administration by inhalation.

39. The pharmaceutical composition according to claim 37, which is a pharmaceutical composition for administration by inhalation.

40. A method for preparing coated particles, each of the coated particles comprising: (i) microparticles comprising a pharmaceutically acceptable excipient and (ii) nanoparticles of a therapeutic agent, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form the nanoparticles on the surface of the microparticles, thereby forming coated particles.

41. The method of claim 40, wherein the first predetermined temperature is about 50 to about 500°C, about 100 to about 400°C, about 50 to about 300°C, about 100 to about 300°C, about 100 to about 250°C, about 150 to about 300°C, or about 200 to about 300°C.

42. The method of claim 40, wherein: The first predetermined temperature is about 50 to about 250°C.

43. The method of claim 40, wherein the predetermined vacuum pressure is no greater than about 10 -1 torr, not more than about 10 -2 torr, not more than about 10 -3 torr, not more than about 10 -4 torr, not more than about 10 -5 torr, not more than about 10 -6 torr, not more than about 10 -7 torr, not more than about 10 -8 torr or not more than about 10 -9 torr.

44. The method of claim 40, wherein: The predetermined vacuum pressure is about 10 -3 to about 10 -9 torr.

45. The method of claim 40, wherein the predetermined stirring speed is from about 10 to about 200 rpm, from about 20 to about 150 rpm, from about 20 to about 120 rpm, from about 50 to about 100 rpm, or from about 80 to about 100 rpm.

46. ​​The method of claim 40, wherein: The predetermined stirring speed is about 50 to 100 rpm.

47. The method of claim 40, wherein the second predetermined temperature is 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.

48. The method of claim 40, wherein: The second predetermined temperature is no greater than about 100°C.

49. The method of claim 40, wherein the pharmaceutically acceptable excipient is a hydrophilic excipient.

50. The method of claim 40, wherein the pharmaceutically acceptable excipient is a sugar alcohol.

51. The method of claim 40, wherein the pharmaceutically acceptable excipient is mannitol, sorbitol, xylitol, or a mixture thereof.

52. The method of claim 40, wherein the pharmaceutically acceptable excipient is mannitol.

53. The method of claim 40, wherein the pharmaceutically acceptable excipient is a carbohydrate.

54. The method of claim 40, wherein the pharmaceutically acceptable excipient is glucose.

55. The method of claim 54, wherein the pharmaceutically acceptable excipient is D-glucose.

56. The method of claim 40, wherein the microparticles have an average particle size of about 1 to about 1,000 μm, about 10 to about 500 μm, about 20 to about 500 μm, about 50 to about 300 μm, or about 100 to about 300 μm.

57. The method of claim 40, wherein the microparticles have an average particle size of about 1 to about 100 μm, about 1 to about 50 μm, or about 1 to about 25 μm.

58. The method of claim 40, wherein the therapeutic agent is a BCS class II compound.

59. The method of claim 40, wherein the therapeutic agent is a BCS class IV compound.

60. The method of claim 40, wherein the therapeutic agent has a melting point of no greater than about 300°C.

61. The method of claim 40, wherein the nanoparticles have an average particle size of about 1 to about 500 nm, about 1 to about 200 nm, about 2 to about 200 nm, about 5 to about 200 nm, about 10 nm to about 200 nm, or about 10 to about 100 nm.

62. The method of claim 40, wherein the nanoparticles have an average particle size of about 10 to about 500 nm.

63. The method of claim 40, wherein the coated particles comprise nanoparticles in an amount of about 0.1% to about 25%, about 0.2% to about 20%, about 0.5% to about 10%, or about 1% to about 10% by weight.

64. The method of claim 40, wherein the coated particles comprise nanoparticles in an amount of about 0.1% to about 10% by weight.

65. The method of claim 40, wherein the coated particles have an average particle size of about 1 to about 1,000 μm, about 10 to about 500 μm, about 20 to about 500 μm, about 50 to about 300 μm, or about 100 to about 300 μm.

66. The method of claim 40, wherein the coated particles have an average particle size of about 1 to about 100 μm, about 1 to about 50 μm, or about 1 to about 25 μm.

67. The method of claim 40, wherein the therapeutic agent is carbamazepine, ibuprofen, nifedipine, piroxicam, plumbagin, verapamil, or zileuton.

68. A method for preparing therapeutic agent nanoparticles, comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the microparticles, wherein the microparticles contain a pharmaceutically acceptable excipient.

69. A therapeutic agent nanoparticle prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the microparticles, wherein the microparticles contain a pharmaceutically acceptable excipient.

70. A batch of coated particles, wherein each coated particle comprises: (i) microparticles comprising a pharmaceutically acceptable excipient and (ii) nanoparticles of a therapeutic agent; The coated particles are prepared by the following method, which comprises: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form the nanoparticles on the surface of the microparticles, thereby forming coated particles.

71. A batch of therapeutic agent nanoparticles prepared by the following method, the method comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the microparticles, wherein the microparticles contain a pharmaceutically acceptable excipient.

72. A batch of pharmaceutical compositions comprising coated particles, each coated particle comprising: (i) microparticles comprising a pharmaceutically acceptable excipient and (ii) nanoparticles of a therapeutic agent; The coated particles are prepared by the following method, which comprises: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed to form the nanoparticles on the surface of the microparticles, thereby forming coated particles.

73. A batch of a pharmaceutical composition comprising nanoparticles of a therapeutic agent and a pharmaceutically acceptable excipient, wherein the nanoparticles are prepared by a process comprising: a. gasifying the therapeutic agent at a predetermined vacuum pressure at a first predetermined temperature to form a gaseous therapeutic agent; and b. solidifying the gaseous therapeutic agent on the surface of the microparticles at a predetermined vacuum pressure, a second predetermined temperature and a predetermined stirring speed, thereby forming nanoparticles on the surface of the microparticles, wherein the microparticles contain the pharmaceutically acceptable excipient.

Images