Details for Patent: 7,244,451

Title:	Methods of making nanoparticulate drug compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers
Abstract:	The present invention is directed to nanoparticulate compositions comprising a poorly soluble drug and at least one copolymer of vinyl pyrrolidone and vinyl acetate as a surface stabilizer adsorbed to the surface of the drug. Also encompassed by the invention are pharmaceutical compositions comprising a nanoparticulate composition of the invention, methods of making and using such nanoparticulate and pharmaceutical compositions.
Inventor(s):	Bosch; H. William (Bryn Mawr, PA), Ryde; Niels P. (Malvern, PA)
Assignee:	Elan Pharma International Ltd. (Athlone County Westmeath, IE)
Filing Date:	Aug 30, 2005
Application Number:	11/213,765
Claims:	1. A method of making a nanoparticulate drug composition comprising an organic drug having at least one copolymer of vinyl pyrrolidone and vinyl acetate as a surface stabilizer adsorbed on the surface thereof in an amount sufficient to maintain the drug at an effective average particle size of less than about 2000 nm, said method comprising contacting said drug with at least one copolymer of vinyl pyrrolidone and vinyl acetate for a time and under conditions sufficient to provide a nanoparticle/copolymer composition having an effective average particle size of less than about 2000 nm. 2. The method of claim 1, wherein the copolymer of vinyl pyrrolidone and vinyl acetate has from about 40% up to about 99.9% vinyl pyrrolidone and about 0.1% up to about 60% vinyl acetate. 3. The method of claim 1, wherein the drug is present in an amount selected from the group consisting of from about 99.9% to about 0.1%, from about 80% to about 5.0%, and from about 50% to about 10%, by weight based on the total combined weight of the drug substance and surface stabilizer, not including other excipients. 4. The method of claim 1, wherein the at least one copolymer of vinyl pyrrolidone and vinyl acetate is present in an amount selected from the group consisting of from about 0.1 to about 90%, from about 1 to about 75%, from about 10 to about 60%, and from about 10 to about 55%, by weight based on the total combined weight of the drug substance and surface stabilizer, not including other excipients. 5. The method of claim 1, wherein the drug is selected from the group consisting of a crystalline phase drug and an amorphous phase drug. 6. The method of claim 1, further comprising at least one surface stabilizer which is not a copolymer of vinyl pyrrolidone and vinyl acetate. 7. The method of claim 1, comprising two or more copolymers of vinyl pyrrolidone and vinyl acetate. 8. The method of claim 1, wherein the effective average particle size of the drug present in the nanoparticulate composition is selected from the group consisting of less than about 1500 nm, less than about 1000 nm, less than about 800 nm, less than about 600 nm, less than about 400 nm, less than about 300 nm, less than about 200 mm, less than about 100 nm, and less than about 50 nm. 9. A method of making a nanoparticulate drug composition, wherein the nanoparticulate composition comprises an organic drug having at least one copolymer of vinyl pyrrolidone and vinyl acetate as a surface stabilizer adsorbed on the surface thereof in an amount sufficient to maintain the drug at an effective average particle size of less than about 2000 nm, said method comprising (a) dissolving the drug in a solvent; (b) adding the solubilized drug to a solution comprising at least one copolymer of vinyl pyrrolidone and vinyl acetate to form a clear solution; and (c) precipitating the solubilized drug having a copolymer of vinyl pyrrolidone and vinyl acetate as a surface stabilizer using a non-solvent, wherein said method produces a nanoparticulate drug composition having at least one copolymer of vinyl pyrrolidone and vinyl acetate as a surface stabilizer and an effective average particle size of less than about 2000 nm. 10. The method of claim 9, wherein the copolymer of vinyl pyrrolidone and vinyl acetate has from about 40% up to about 99.9% vinyl pyrrolidone and about 0.1% up to about 60% vinyl acetate. 11. The method of claim 9, wherein the drug is present in an amount selected from the group consisting of from about 99.9% to about 0.1%, from about 80% to about 5.0%, and from about 50% to about 10%, by weight based on the total combined weight of the drug substance and surface stabilizer, not including other excipients. 12. The method of claim 9, wherein the at least one copolymer of vinyl pyrrolidone and vinyl acetate is present in an amount selected from the group consisting of from about 0.1 to about 90%, from about 1 to about 75%, from about 10 to about 60%, and from about 10 to about 55%, by weight based on the total combined weight of the drug substance and surface stabilizer, not including other excipients. 13. The method of claim 9, wherein the drug is selected from the group consisting of a crystalline phase drug and an amorphous phase drug. 14. The method of claim 9, further comprising at least one surface stabilizer which is not a copolymer of vinyl pyrrolidone and vinyl acetate. 15. The method of claim 9, comprising two or more copolymers of vinyl pyrrolidone and vinyl acetate. 16. The method of claim 9, wherein the effective average particle size of the drug present in the nanoparticulate composition is selected from the group consisting of less than about 1500 nm, less than about 1000 nm, less than about 800 nm, less than about 600 nm, less than about 400 nm, less than about 300 nm, less than about 200 nm, less than about 100 nm, and less than about 50 nm. 17. The method of claim 1, wherein the drug has a solubility in at least one liquid dispersion medium of less than about 1 mg/mL. 18. The method of claim 17, wherein the liquid dispersion medium is selected from the group consisting of water, safflower oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane, and glycol. 19. The method of claim 1, wherein the drug is selected from the group consisting of proteins, peptides, nucleotides, anti-obesity drugs, nutraceuticals, corticosteroids, elastase inhibitors, analgesics, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives, astringents, beta-adrenoceptor blocking agents, blood products, blood substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin, parathyroid biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic agents, stimulants, anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines. 20. The method of claim 1, wherein the drug is selected from the group consisting of naproxen, nifedipine, ketoprofen, triamcinolone acetonide, and WIN 68209. 21. The method of claim 6, wherein the at least one surface stabilizer which is not a copolymer of vinyl pyrrolidone and vinyl acetate is selected from the group consisting of cetyl pyridinium chloride, gelatin, casein, lecithin, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, tyloxapol, poloxamers, poloxamines, a charged phospholipid, dioctylsulfosuccinate, Tetronic 1508.RTM., dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, an alkyl aryl polyether sulfonate, a mixture of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), Crodestas SL-40.RTM., decanoyl-N-methylglucamide, n-decyl .beta.-D-glucopyranoside, n-decyl .beta.-D-maltopyranoside, n-dodecyl .beta.-D-glucopyranoside, n-dodecyl .beta.-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-.beta.-D-glucopyranoside, n-heptyl .beta.-D-thioglucoside, n-hexyl .beta.-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl .beta.-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-.beta.-D-glucopyranoside, and octyl .beta.-D-thioglucopyranoside. 22. The method of claim 6, wherein the at least one surface stabilizer which is not a copolymer of vinyl pyrrolidone and vinyl acetate is selected from the group consisting of sodium lauryl sulfate and dioctylsulfosuccinate.