The invention provides a composition comprising microparticles of a water-insoluble or poorly soluble compound, at least one phospholipid, and at least one surfactant, produced by applying an energy to a mixture comprising particles of the compound, the at least one phospholipid, and the at least on
The invention provides a composition comprising microparticles of a water-insoluble or poorly soluble compound, at least one phospholipid, and at least one surfactant, produced by applying an energy to a mixture comprising particles of the compound, the at least one phospholipid, and the at least one surfactant so as to obtain the microparticles. The invention also provides a process for preparing microparticles of a water-insoluble or poorly soluble compound. The process includes mixing particles of a water-insoluble or poorly soluble compound with at least one phospholipid and at least surfactant to form a mixture and applying energy to the mixture sufficient to produce microparticles of the compound. The methods of the invention allow for the production of microparticles smaller than particles produced through previously known methods and the microparticles exhibit advantageous properties including remarkable resistance to particle size growth during storage.
대표청구항▼
1. A process for preparing solid microparticles of a water-insoluble or poorly water-soluble compound in an aqueous medium, which process consists essentially of: (a) adding particles of the water-insoluble or poorly water-soluble compound with at least one phospholipid and at least one surfactant t
1. A process for preparing solid microparticles of a water-insoluble or poorly water-soluble compound in an aqueous medium, which process consists essentially of: (a) adding particles of the water-insoluble or poorly water-soluble compound with at least one phospholipid and at least one surfactant that is not a phospholipid to a container to form a pre-mixture;(b) homogenizing the pre-mixture;(c) sonicating the pre-mixture to produce stable solid microparticles at a temperature between 16° C.-20° C.; and(d) adjusting the pH of the mixture during step b, step c or during both steps b and c˜wherein said water-insoluble or poorly water-soluble compound is a drug. 2. The process of claim 1, wherein the at least one surfactant consists of two or more surfactants, the at least one phospholipid consists of two or more phospholipids, or the at least one surfactant consists of two or more surfactants and the at least one phospholipid consists of two or more phospholipids. 3. The process of claim 1, wherein the at least one surfactant comprises (a) one or more cationic surfactants; (b) one or more nonionic surfactants; (c) an anionic surfactant selected from the group consisting of sodium dodecylsulfate, sodium deoxycholate, dioctyl sodium sulfosuccinate, potassium laurate, sodium lauryl sulfate, an alkyl polyoxyethylene sulfate, sodium alginate, a negatively charged glyceryl ester, and combinations thereof; or (d) a combination of such cationic, nonionic, and/or anionic surfactants. 4. The process of claim 1, wherein average particle size of said stable microparticles of after four months is about 1.033× the particle size of said particle when formed. 5. A process for preparing solid microparticles of a water-insoluble or poorly water-soluble compound in an aqueous medium, which process consists essentially of: (a) adding particles of the water-insoluble or poorly water-soluble compound with at least one phospholipid and at least one surfactant that is not a phospholipid to a container to form a pre-mixture;(b) homogenizing the pre-mixture;(c) microfluidizing the pre-mixture to produce stable solid microparticles at a temperature between 16° C.-20° C.; and(d) adjusting the pH of the mixture during step b, step c or during both steps b and c˜wherein said water-insoluble or poorly water-soluble compound is a drug. 6. The process of claim 5, wherein the process comprises precipitating the particles of the water-insoluble or poorly water-soluble compound in the presence of the at least one phospholipid and the at least one surfactant, followed by subjecting the precipitated particles, the at least one phospholipid, and the at least one surfactant to microfluidization. 7. The process of claim 6, wherein the at least one phospholipid comprises one or more synthetic phospholipids, semisynthetic phospholipids, phospholipids of egg or plant origin, or a combination of any thereof. 8. The process of claim 7, wherein the at least one phospholipid comprises one or more phospholipids selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidyiglycerol, dimyristoyl phosphatidylglycerol sodium salt, phosphatidic acid, lysophospholipids, and combinations thereof. 9. The process of claim 8, wherein the at least one phospholipid includes phosphatidylcholine. 10. The process of claim 9, wherein the at least one phospholipid consists of egg phosphatidyicholine. 11. The process of claim 7, wherein the at least one phospholipid includes at least one phospholipid in desalted or salt form. 12. The process of claim 7, wherein the at least one phospholipid includes at least one phospholipid in fully hydrogenated or partly hydrogenated form. 13. The process of claim 6, wherein the process comprises formulating the microparticles for oral, inhalation, ocular, nasal, or injectable administration. 14. The process of claim 13, wherein the process comprises formulating the microparticles in the form of an aqueous suspension. 15. The process of claim 5, wherein the at least one surfactant comprises one or more nonionic surfactants. 16. The process of claim 5, wherein the at least one surfactant comprises one or more surfactants selected from the group consisting of poloxamers, poloxamines, sorbitan esters, alkyl aryl polyether sulfonates, polyethylene glycols, sodium dodecylsulfate, sodium deoxycholate, cholesterol esters, glycerol monostearate, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, polyoxyethylene fatty acid esters, polyvinyl alcohol, potassium laurate, triethanolamine stearate, polyvinylpyrrolidone, alkyl polyoxyethylene sulfates, dioctyl sodium sulfosuccinate, negatively charged glyceryl esters, quaternary ammonium cationic surfactants, chitosans, and combinations thereof. 17. The process of claim 16, wherein the at least one surfactant comprises one or more quaternary ammonium cationic surfactants selected from the group consisting of benzalkonium chloride, lauryldimethylbenzylammonium chloride, cetyltrimethylammonium bromide, and combinations thereof. 18. The process of claim 16, wherein the at least one surfactant comprises one or more sorbitan fatty esters. 19. The process of claim 18, wherein the at least one surfactant comprises one or more polyoxyethylene sorbitan fatty acid esters. 20. The process of claim 16, wherein the at least one surfactant comprises polyoxyethylene stearate. 21. The process of claim 16, wherein the at least one surfactant comprises a block copolymer of ethylene oxide and propylene oxide. 22. The process of claim 5, wherein the at least one surfactant comprises a surfactant selected from the group consisting of casein, gelatin, tragacanth, acacia, cholesterol, and combinations thereof. 23. The process of claim 5, wherein the mean particle size of the microparticles is at least 50% smaller than the mean particle size of particles of the water-insoluble or poorly water-soluble compound produced by subjecting a mixture of the particles of the water insoluble or poorly water-soluble compound and a phospholipid, without the at least one surfactant, to precipitation, microfluidization, or precipitation and microfluidization, applying the same energy input used to produce the microparticles. 24. The process of claim 5, wherein the water-insoluble or poorly water-soluble compound is selected from the group consisting of an immunosuppressive agent, an immunoactive agent, an antiviral agent, an antifungal agent, an antineoplastic agent, an analgesic agent, an antiinflammatory agent, an antibiotic, an anti-epileptic agent, an anesthetic, a hypnotic, a sedative, an antipsychotic agent, a neuroleptic agent, an antidepressant, an anxiolytic, an anticonvulsant agent, an antagonist, a neuron blocking agent, an anticholinergic agent, a cholinomimetic agent, an antimuscarinic agent, a muscarinic agent, an antiadrenergic, an antiarrhythmic, an antihypertensive agent, a hormone, and combinations thereof. 25. The process of claim 24, wherein the water-insoluble or poorly water-soluble compound is an antifungal agent. 26. The process of claim 5, wherein the at least one surfactant comprises at least one surfactant in a concentration above its critical micelle concentration. 27. The process of claim 5, wherein the particles of the water-insoluble or poorly water-soluble compound are 5-100 μm size. 28. The process of claim 5, wherein the process comprises reducing the size of the particles of the water-insoluble or poorly water-soluble compound by antisolvent/solvent precipitation. 29. The process of claim 5, wherein the process comprises reducing the size of the particles of the water-insoluble or poorly water-soluble compound by precipitation from supercritical fluids. 30. The process of claim 5, wherein the process comprises formulating the microparticles for oral, inhalation, ocular, nasal, or injectable administration. 31. The process of claim 30, wherein the process comprises formulating the microparticles in injectable form for intravenous, intra-arterial, intra-muscular, intradermal, subcutaneous, intra-articular, cerebrospinal, epidural, intracostal, intraperitoneal, intratumor, intrabladder, intra-lesion, or subconjunctival administration. 32. The process of claim 5, wherein the process comprises drying the microparticles. 33. The process of claim 32, wherein the process comprises drying the microparticles by lyophilization, fluid drying, or spray drying. 34. The process of claim 32, wherein the process comprises drying the microparticles in the presence of a stabilizing agent. 35. The process of claim 34, wherein the stabilizing agent is mannitol. 36. A process for preparing solid microparticles of a water-insoluble or poorly water-soluble compound in an aqueous medium, the process consisting essentially of: (1) adding solid particles of a water-insoluble or poorly water-soluble compound with at least one phospholipid and at least one surfactant that is not a phospholipid to a container to form a pre-mixture prior to forming a dispersion, wherein the pre-mixture;(2) homogenizing the pre-mixture;(3) applying energy to the mixture sufficient to produce stable solid microparticles of the compound at a temperature of between 16° C.-20° C., wherein applying energy includes subjecting the mixture to sonication, homogenization, milling, microfluidization, precipitation, recrystallization or combination thereof; and(4) adjusting the pH of the mixture during step 2, step 3 or during both steps 2 and 3˜wherein said water-insoluble or poorly water-soluble compound is a drug. 37. The process of claim 36, wherein applying energy includes subjecting the mixture to precipitation, microfluidization, or precipitation and microfluidization. 38. The process of claim 36, wherein the at least one surfactant is present in a concentration above its critical micelle concentration. 39. The process of claim 36, wherein the at least one phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidyiglycerol, dimyristoyl phosphatidyiglycerol sodium salt, phosphatidic acid, lysophospholipids, and combinations thereof. 40. The process of claim 36, wherein the at least one surfactant consists of two or more surfactants, the at least one phospholipid consists of two or more phospholipids, or the at least one surfactant consists of two or more surfactants and the at least one phospholipid consists of two or more phospholipids. 41. The process of claim 36, wherein the at least one surfactant is one or more nonionic surfactants. 42. The process of claim 36, wherein the particles of the water-insoluble or poorly water-soluble compound are 5-100 μm in size. 43. The process of claim 36, wherein the process comprises drying the microparticles. 44. The process of claim 43, wherein the process comprises drying the microparticles by lyophilization, fluid dying, or spray drying. 45. The process of claim 43, wherein the process comprises drying the microparticles in the presence of a stabilizing agent. 46. The process of claim 45, wherein the stabilizing agent is mannitol. 47. A composition comprising stable solid microparticles of a water-insoluble or poorly water-soluble compound, at least one phospholipid, and at least one surfactant, produced by adding particles of the water-insoluble or poorly water-soluble compound with the at least one phospholipid and the at least one surfactant to a container to form a pre-mixture prior to forming a dispersion; wherein the pre-mixture is formed and is homogenized, and applying an energy to the mixture so as to obtain the microparticles, wherein the energy includes subjecting the mixture to sonication, homogenization, milling, microfluidization, precipitation, recrystallization or combination thereof at a temperature better 16° C.-20° C. and wherein the at least one surfactant is not a phospholipid and (a) the volume-weighted mean particle size of the microparticles after one week of storage in an aqueous medium at 4-25° C. is less than 50% more than the volume-weighted mean particle size of the microparticles before storage,(b) the volume-weighted mean particle size of the microparticles after six days of storage is about 80% smaller than the volume-weighted mean particle size of particles of the water-insoluble or poorly water-soluble compound produced without the presence of the at least one surfactant by applying the same energy input, or(c) the volume-weighted mean particle size of the microparticles after one week of storage in an aqueous medium at 4-25° C. is less than 50% more than the volume-weighted mean particle size of the microparticles before storage and the volume-weighted mean particle size of the microparticles after six days of storage is about 80% smaller than the volume-weighted mean particle size of particles of the water-insoluble or poorly water-soluble compound produced without the presence of the at least one surfactant by applying the same energy input, wherein said water-insoluble or poorly water-soluble compound is a drug. 48. The composition of claim 47, wherein the microparticles exhibit no detectable increase in volume-weighted mean particle size when stored for one week at 4° C. 49. A process for preparing solid microparticles of a water-insoluble or poorly water-soluble compound which process consists essentially of: (a) adding particles of the water-insoluble or poorly water-soluble drug with at least one phospholipid and at least one surfactant to a container to form a pre-mixture prior to forming a dispersion;(b) subjecting the mixture to precipitation, microfluidization, or precipitation and microfluidization to produce stable solid microparticles at a temperature 16° C.-20° C.; and(c) adjusting the pH of the mixture during step a, step b or during both steps a and b wherein the at least one surfactant is not a phospholipid, wherein said water-insoluble or poorly water-soluble compound is a drug. 50. A process for preparing solid microparticles of a water-insoluble or poorly water-soluble compound in an aqueous medium, which process comprises: (a) adding particles of the water-insoluble or poorly water-soluble compound with at least one phospholipid and at least one surfactant that is not a phospholipid to a container to form a pre-mixture;(b) homogenizing the pre-mixture;(c) sonicating the pre-mixture to produce solid microparticles at a temperature between 16° C.-20° C.; and(d) adjusting the pH of the mixture during step b, step c or during both steps b and c˜wherein said water-insoluble or poorly water-soluble compound is a drug. 51. A process for preparing solid microparticles of a water-insoluble or poorly water-soluble compound in an aqueous medium, which process comprises: (a) adding particles of the water-insoluble or poorly water-soluble compound with at least one phospholipid and at least one surfactant that is not a phospholipid to a container to form a pre-mixture;(b) homogenizing the pre-mixture;(c) microfluidizing the pre-mixture to produce solid microparticles at a temperature between 16° C.-20° C.; and(d) adjusting the pH of the mixture during step b, step c or during both steps b and c, wherein said water-insoluble or poorly water-soluble compound is a drug. 52. A process for preparing solid microparticles of a water-insoluble or poorly water-soluble compound in an aqueous medium, the process comprises: (1) adding solid particles of the water-insoluble or poorly water-soluble compound with at least one phospholipid and at least one surfactant that is not a phospholipid to a container to form a pre-mixture prior to forming a dispersion;(2) homogenizing the pre-mixture;(3) applying energy to the mixture sufficient to produce solid microparticles of the compound at a temperature of between 16° C.-20° C., wherein applying energy includes subjecting the mixture to sonication, homogenization, milling, microfluidization, precipitation, recrystallization or combination thereof; and(4) adjusting the pH of the mixture during step 2, step 3 or during both steps 2 and 3, wherein said water-insoluble or poorly water-soluble compound is a drug. 53. A process for preparing solid microparticles of a water-insoluble or poorly water-soluble compound which process consists of: (a) adding particles of the water-insoluble or poorly water-soluble drug with at least one phospholipid and at least one surfactant to a container to form a pre-mixture prior to forming a dispersion, and wherein the mixture is formed and homogenized;(b) subjecting the mixture to precipitation, microfluidization, or precipitation and microfluidization to produce solid microparticles at a temperature of between 16° C.-20° C.; and(c) adjusting the pH of the mixture during step a, step b or during both steps a and b wherein the at least one surfactant is not a phospholipid,wherein said water-insoluble or poorly water-soluble compound is a drug.
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