Claims for Patent: 6,375,986

Summary for Patent: 6,375,986

Title:	Solid dose nanoparticulate compositions comprising a synergistic combination of a polymeric surface stabilizer and dioctyl sodium sulfosuccinate
Abstract:	Disclosed are solid dose nanoparticulate compositions comprising a poorly soluble active agent, at least one polymeric surface stabilizer, and dioctyl sodium sulfosuccinate (DOSS). The solid dose compositions exhibit superior redispersibility of the nanoparticulate composition upon administration to a mammal, such as a human or animal. The invention also describes methods of making and using such compositions.
Inventor(s):	Ryde; Niels P. (Malvern, PA), Ruddy; Stephen B. (Schwenksville, PA)
Assignee:	Elan Pharma International Ltd. (Clare, IE)
Application Number:	09/666,539
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,375,986
Patent Claims:	1. A solid dose nanoparticulate composition comprising: (a) an active agent which has a solubility in a liquid dispersion medium of less than about 10 mg/mL; (b) at least one polymeric surface stabilizer adsorbed on the surface of the active agent; and (c) about 0.1% to about 20% w/w, of dioctyl sodium sulfosuccinate (DOSS), wherein the effective average particle size of the nanoparticulate dispersion prior to incorporation in the solid dose formulation, comprising said poorly soluble active agent and at least one polymeric surface stabilizer, is less than about 1 micron, and upon reconstitution in media representative of human physiological conditions, the solid dose nanoparticulate composition redisperses such that 90% of the active agent particles have a particle size of less than about 5 microns. 2. The composition of claim 1, wherein the active agent is present in an amount of about 99.8% to about 0.1% (w/w). 3. The composition of claim 1, wherein the active agent is present in an amount of about 80% to about 5% (w/w). 4. The composition of claim 1, wherein the active agent is present in an amount of about 50% to about 10% (w/w). 5. The composition of claim 1, wherein the at least one polymeric surface stabilizer is present in an amount of about 0.01% to about 90% (w/w). 6. The composition of claim 1, wherein the at least one polymeric surface stabilizer is present in an amount of about 1% to about 75% (w/w). 7. The composition of claim 1, wherein the at least one polymeric surface stabilizer is present in an amount of about 10% to about 60% (w/w). 8. The composition of claim 1, wherein DOSS is present in an amount of about 1% to about 10% (w/w). 9. The composition of claim 1, wherein the effective average particle size of the nanoparticulate dispersion prior to incorporation in the solid dose formulation, comprising said poorly soluble active agent and at least one polymeric surface stabilizer, is less than about 800 nm, and upon reconstitution in media representative of human physiological conditions, the solid dose nanoparticulate composition redisperses such that 90% of the active agent particles have a particle size of less than about 4 microns. 10. The composition of claim 1, wherein the effective average particle size of the nanoparticulate dispersion prior to incorporation in the solid dose formulation, comprising said poorly soluble active agent and at least one polymeric surface stabilizer, is less than about 600 nm, and upon reconstitution in media representative of human physiological conditions, the solid dose nanoparticulate composition redisperses such that 90% of the active agent particles have a particle size of less than about 3 microns. 11. The composition of claim 1, wherein the effective average particle size of the nanoparticulate dispersion prior to incorporation in the solid dose formulation, comprising said poorly soluble active agent and at least one polymeric surface stabilizer, is less than about 400 nm, and upon reconstitution in media representative of human physiological conditions, the solid dose nanoparticulate composition redisperses such that 90% of the active agent particles have a particle size of less than about 2 microns. 12. The composition of claim 1, wherein the effective average particle size of the nanoparticulate dispersion prior to incorporation in the solid dose formulation, comprising said poorly soluble active agent and at least one polymeric surface stabilizer, is less than about 200 nm, and upon reconstitution in media representative of human physiological conditions, the solid dose nanoparticulate composition redisperses such that 90% of the active agent particles have a particle size of less than about 1 micron. 13. The composition of claim 1, wherein the active agent is selected from the group consisting of a crystalline phase drug, a semi-crystalline phase drug, and an amorphous phase drug. 14. The composition of claim 1, wherein the active agent is selected from the group consisting of proteins, peptides, nucleotides, anti-obesity drugs, nutriceuticals, 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 and substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immuriological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines. 15. The composition of claim 1, wherein the at least one polymeric surface stabilizer is selected from the group consisting of polyvinylpyrrolidone (PVP), cellulose ethers, polysaccharides, random copolymers of vinyl acetate and vinyl pyrrolidone, polyvinyl alcohol, and copolymers of vinyl acetate and vinyl alcohol. 16. The composition of claim 15, wherein the at least one polymetric surface stabilizer is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, dextrin, guar gum, starch, and a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a mass proportion of 3:2. 17. A method of making a solid dose nanoparticulate composition having a high redispersibility upon administration to a mammal comprising: (a) dispersing particles of an active agent which has a solubility in a liquid dispersion medium of less than about 10 mg/mL in a liquid dispersion medium; (b) applying mechanical means in the presence of grinding media to reduce the effective average particle size of the active agent in the liquid dispersion medium to less than about 1 micron, wherein at least one polymeric surface stabilizer and dioctyl sodium sulfosuccinate are added to the liquid dispersion medium before or after milling; (c) drying the nanoparticulate dispersion comprising an active agent, at least one polymeric surface stabilizer, and dioctyl sodium sulfosuccinate; and (d) formulating the dry nanoparticulate composition into a solid dose form for administration, wherein upon reconstitution in media representative of human physiological conditions, the solid dose nanoparticulate composition redisperses such that 90% of the active agent particles have a particle size of less than about 5 microns. 18. The method of claim 17, wherein the active agent is present in an amount of about 99.8 to about 0.1% (w/w). 19. The method of claim 17, wherein the at least one polymeric surface stabilizer is present in an amount of about 0.01% to about 90% (w/w). 20. The method of claim 17, wherein DOSS is present in an amount of about 0.1% to about 20% (w/w). 21. The method of claim 17, wherein DOSS is present in an amount of about 1.0% to about 10% (w/w). 22. The method of claim 17, wherein the active agent is selected from the group consisting of a crystalline phase drug, a semi-crystalline phase drug, and an amorphous phase drug. 23. The method of claim 17, wherein the effective average particle size of the nanoparticulate dispersion prior to incorporation in the solid dose formulation, comprising said poorly soluble active agent and at least one polymeric surface stabilizer, is less than about 800 nm, and upon reconstitution in media representative of human physiological conditions, the solid dose nanoparticulate composition redisperses such that 90% of the active agent particles have a particle size of less than about 4 microns. 24. The method of claim 17, wherein the effective average particle size of the nanoparticulate dispersion prior to incorporation in the solid dose formulation, comprising said poorly soluble active agent and at least one polymeric surface stabilizer, is less than about 600 nm, and upon reconstitution in media representative of human physiological conditions, the solid dose nanoparticulate composition redisperses such that 90% of the active agent particles have a particle size of less than about 3 microns. 25. The method of claim 17, wherein the effective average particle size of the nanoparticulate dispersion prior to incorporation in the solid dose formulation, comprising said poorly soluble active agent and at least one polymeric surface stabilizer, is less than about 400 nm, and upon reconstitution in media representative of human physiological conditions, the solid dose nanoparticulate composition redisperses such that 90% of the active agent particles have a particle size of less than about 2 microns. 26. The method of claim 17, wherein the effective average particle size of the nanoparticulate dispersion prior to incorporation in the solid dose formulation, comprising said poorly soluble active agent and at least one polymeric surface stabilizer, is less than about 200 nm, and upon reconstitution in media representative of human physiological conditions, the solid dose nanoparticulate composition redisperses such that 90% of the active agent particles have a particle size of less than about 1 micron. 27. A method of treating a patient in need with a solid dose nanoparticulate composition having high redispersibility of the nanoparticulate composition upon administration to a mammal, comprising administering to a patient in need a therapeutically effective amount of a solid dose nanoparticulate composition comprising: (a) an active agent which has a solubility in a liquid dispersion medium of less than about 10 mg/mL; (b) at least one polymeric surface stabilizer adsorbed on the surface of the active agent; and (c) about 0.1% to about 20% w/w of dioctyl sodium sulfosuccinate (DOSS), wherein the effective average particle size of the nanoparticulate dispersion prior to incorporation in the solid dose formulation, comprising said poorly soluble active agent and at least one polymeric surface stabilizer, is less than about 1 micron, and upon reconstitution in media representative of human physiological conditions, the solid dose nanoparticulate composition redisperses such that 90% of the active agent particles have a particle size of less than about 5 microns. 28. The method of claim 27, wherein the active agent is present in an amount of about 99.8 to about 0.1% (w/w). 29. The method of claim 27, wherein the at least one polymeric surface stabilizer is present in an amount of about 0.01% to about 90% (w/w). 30. The method of claim 27, wherein DOSS is present in an amount of about 1.0% to about 10% (w/w). 31. The method of claim 27, wherein the effective average particle size of the nanoparticulate dispersion prior to incorporation in the solid dose formulation, comprising said poorly soluble active agent and at least one polymeric surface stabilizer, is less than about 800 nm, and upon reconstitution in media representative of human physiological conditions, the solid dose nanoparticulate composition redisperses such that 90% of the active agent particles have a particle size of less than about 4 microns. 32. The method of claim 27, wherein the effective average particle size of the nanoparticulate dispersion prior to incorporation in the solid dose formulation, comprising said poorly soluble active agent and at least one polymeric surface stabilizer, is less than about 600 nm, and upon reconstitution in media representative of human physiological conditions, the solid dose nanoparticulate composition redisperses such that 90% of the active agent particles have a particle size of less than about 3 microns. 33. The method of claim 27, wherein the effective average particle size of the nanoparticulate dispersion prior to incorporation in the solid dose formulation, comprising said poorly soluble active agent and at least one polymeric surface stabilizer, is less than about 400 nm, and upon reconstitution in media representative of human physiological conditions, the solid dose nanoparticulate composition redisperses such that 90% of the active agent particles have a particle size of less than about 2 microns. 34. The method of claim 27, wherein the effective average particle size of the nanoparticulate dispersion prior to incorporation in the solid dose formulation, comprising said poorly soluble active agent and at least one polymeric surface stabilizer, is less than about 200 nm, and upon reconstitution in media representative of human physiological conditions, the solid dose nanoparticulate composition redisperses such that 90% of the active agent particles have a particle size of less than about 1 micron.