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Details for Patent: 6,969,529

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Details for Patent: 6,969,529

Title: Nanoparticulate 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. (Dublin, IE)
Filing Date:Jan 16, 2003
Application Number:10/345,312
Claims:1. A stable nanoparticulate drug composition comprising: (a) a drug having an effective average particle size of less than about 2000 nm, wherein the drug has a solubility in at least one liquid dispersion medium of less than about 10 mg/mL; and (b) at least one copolymer of vinyl pyrrolidone and vinyl acetate adsorbed on the surface thereof as a surface stabilizer.

2. The composition 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 composition of claim 2, wherein the copolymer of vinyl pyrrolidone and vinyl acetate has from about 50% up to about 99.9% vinyl pyrrolidone and about 0.1% up to about 50% vinyl acetate.

4. The composition of claim 2, wherein the copolymer of vinyl pyrrolidone and vinyl acetate has about 60% vinyl pyrrolidone and about 40% vinyl acetate.

5. The composition of claim 2, wherein the copolymer of vinyl pyrrolidone and vinyl acetate has about 80% vinyl pyrrolidone and about 20% vinyl acetate.

6. The composition 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.

7. The composition of claim 1, wherein 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.

8. The composition of claim 1, wherein the drug is selected from the group consisting of a crystalline phase drug and an amorphous phase drug.

9. The composition of claim 1, further comprising at least one surface stabilizer which is not a copolymer of vinyl pyrrolidone and vinyl acetate.

10. The composition of claim 1, comprising two or more copolymers of vinyl pyrrolidone and vinyl acetate.

11. The composition of claim 1, wherein the effective average particle size of the drug present in the nanoparticulate composition is less than about 1500 nm.

12. The composition of claim 11, wherein the effective average particle size of the drug present in the nanoparticulate composition is less than about 1000 nm.

13. The composition of claim 12, wherein the effective average particle size of the drug present in the nanoparticulate composition is less than about 800 nm.

14. The composition of claim 13, wherein the effective average particle size of the drug present in the nanoparticulate composition is less than about 600 nm.

15. The composition of claim 14, wherein the effective average particle size of the drug present in the nanoparticulate composition is less than about 400 nm.

16. The composition of claim 15, wherein the effective average particle size of the drug present in the nanoparticulate composition is less than about 300 nm.

17. The composition of claim 16, wherein the effective average particle size of the drug present in the nanoparticulate composition is less than about 200 nm.

18. The composition of claim 17, wherein the effective average particle size of the drug present in the nanoparticulate composition is less than about 100 nm.

19. The composition of claim 18, wherein the effective average particle size of the drug present in the nanoparticulate composition is less than about 50 nm.

20. A method of treating a patient in need with a stable nanoparticulate drug composition comprising an organic drug, wherein said method comprises: (a) administering to a mammal in need a therapeutically effective amount of the nanoparticulate drug composition comprising: (1) an organic drug having an effective average particle size of less than about 2000 nm wherein the drug has a solubility in at least one liquid dispersion medium of less than about 10 mg/mL; and (2) at least one copolymer of vinyl pyrrolidone and vinyl acetate as a surface stabilizer adsorbed on the surface of the drug.

21. The method of claim 20, 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.

22. The method of claim 20, 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.

23. The method of claim 20, 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.

24. The method of claim 20, wherein the drug is selected from the group consisting of a crystalline phase drug and an amorphous phase drug.

25. The method of claim 20, 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.

26. The composition of claim 1, wherein the drug has a solubility in at least one liquid dispersion medium of less than about 1 mg/mL.

27. The composition of claim 1, 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.

28. The composition 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.

29. The composition of claim 1, wherein the drug is selected from the group consisting of naproxen, nifedipine, ketoprofen, triamcinolone acetonide, and WIN 68209.

30. The composition of claim 9, 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.

31. The composition of claim 9, 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.

32. The method of claim 20, wherein the drug has a solubility in at least one liquid dispersion medium of less than about 1 mg/mL.

33. The method of claim 20, 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.

34. The method of claim 20, 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.

35. The method of claim 20, wherein the drug is selected from the group consisting of naproxen, nifedipine, ketoprofen, triamcinolone acetonide, and WIN 68209.

36. The method of claim 20, wherein the composition further comprises at least one surface stabilizer which is not a copolymer of vinyl pyrrolidone and vinyl acetate.

37. The method of claim 36, 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.

38. The method of claim 36, 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.
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