Details for Patent: 6,630,169

Title:	Particulate delivery systems and methods of use
Abstract:	Compositions and methods are provided for the administration of particulates comprising at least one bioactive agent which, in selected embodiments, may comprise and immunoactive agent. In this respect, the invention provides for both topical and systemic delivery of the bioactive agent using, for example, the respiratory, gastrointestinal or urogenital tracts. The particulates may be in the form of dry powders or combined with a non-aqueous suspension medium to provide stabilized dispersions. In preferred embodiments, the disclosed compositions will be used in conjunction with inhalation devices such as metered dose inhalers, dry powder inhalers, atomizers or nebulizers for targeted delivery of the agent to mucosal surfaces.
Inventor(s):	Bot; Adrian I. (San Diego, CA), Tarara; Thomas E. (San Diego, CA), Weers; Jeffry G. (San Diego, CA), Kabalnov; Alexev (Corvalis, OR), Schutt; Ernest G. (San Diego, CA), Dellamary; Luis A. (San Marcos, CA)
Assignee:	Nektar Therapeutics (San Carlos, CA)
Filing Date:	Dec 22, 2000
Application Number:	09/720,536
Claims:	1. A medicament for the modulation of the immune system of a subject comprising a plurality of microstructures associated with one or more immunoactive agents, wherein said microstructures comprise at least about 5% w/w of a biocompatible surfactant selected from the group consisting of saturated and unsaturated lipids, nonionic detergents, nonionic block copolymers, ionic surfactants, cationic surfactants, biocompatible fluorinated surfactants, and combinations thereof; and wherein the immune response elicited by the composition of the present invention is greater than the immune response provoked by intravenous or intraperitoneal administration of the same antigen solubilized or suspended in an aqueous carrier. 2. The medicament of claim 1, wherein said microstructures further comprise at least one penetration enhancing excipient selected from the group consisting of: chelating agents, surfactants, fatty acids, bile salts, and combinations thereof. 3. The medicament of claim 2, wherein said at least one penetration enhancing excipient is a short-chain phospholipid with a chain length of 10 carbons or less. 4. The medicament of claim 1, wherein said biocompatible surfactant is selected from the group consisting of phospholipids, poloxamers, and combinations thereof. 5. The medicament of claim 4, wherein said phospholipid is selected from the group consisting of dilauroylphosphatidylcholine, dioleylphosphatidylcholine, dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, dibehenoylphosphatidylcholine, diarachidoylphosphatidylcholine, and combinations thereof. 6. The medicament of claim 1, wherein said microstructures comprise at least about 25% w/w of said biocompatible surfactant. 7. The medicament of claim 1, wherein said microstructures are dispersed in a nonaqueous suspension medium. 8. The medicament of claim 7, wherein said nonaqueous suspension medium comprises a compound selected from the group consisting of hydrofluoroalkanes, fluorocarbons, perfluorocarbons, fluorocarbon/hydrocarbon diblocks, hydrocarbons, alcohols, ethers, and combinations thereof. 9. The medicament of claim 7, wherein said nonaqueous suspension medium comprises a compound selected from the group consisting of liquid fluorochemicals and hydrofluoroalkane propellants. 10. The medicament of claim 1, wherein the mean aerodynamic diameter of said microstructures is between about 0.5 and about 5 .mu.m. 11. The medicament of claim 1, wherein said microstructures have a mean geometric diameter of between about 1 and about 30 .mu.m. 12. The medicament of claim 1, wherein said microstructures have a mean geometric diameter of less than about 5 .mu.m. 13. The medicament of claim 1, wherein said microstructures are selected from the group consisting of particulates, microparticulates, perforated microstructures, and combinations thereof. 14. The medicament of claim 1, wherein said microstructures are perforated microstructures. 15. The medicament of claim 14, wherein said perforated microstructures comprise hollow porous microstructures. 16. The medicament of claim 1, wherein said immunoactive agent is selected from the group consisting of immunoactive peptides, polypeptides, proteins, carbohydrates, genetic material, and microbes. 17. The medicament of claim 1, wherein said immunoactive agent comprises a vaccine. 18. The medicament of claim 17, wherein said vaccine is selected from the group consisting of inactivated microbes, live attenuated microbes, phages, subunit vaccine proteins, subunit vaccine peptides, subunit vaccine carbohydrates, replicons, viral vectors, plasmids, and combinations thereof. 19. The medicament of claim 1, wherein said modulation of the immune system of a subject comprises an immune response selected from the group consisting of: eliciting an immune response to a foreign antigen or pathogenic particle; inducing localized or systemic passive immunity; stimulating an immune response; and down regulating an immune reaction. 20. The medicament of claim 1, wherein said modulation of the immune system of a subject comprises mucosal immunity. 21. The medicament of claim 1, wherein said medicament is formulated so as to be capable of being administered to said subject using a delivery methodology selected from the group consisting of topical, intramuscular, transdermal, intradermal, intraperitoneal, nasal, pulmonary, vaginal, rectal, aural, oral or ocular administration. 22. A vaccine for eliciting an enhanced immune response in a subject comprising a plurality of microstructures associated with one or more immunoactive agents, wherein said microstructures comprise at least 5% w/w of a biocompatible surfactant selected from the group consisting of saturated and unsaturated lipids, nonionic detergents, nonionic block copolymers, ionic surfactants, cationic surfactants, biocompatible fluorinated surfactants, and combinations thereof, wherein said vaccine is formulated so as to be capable of being administered to the respiratory tract of said subject; and wherein said enhanced immune response is enhanced relative to the immune response elicited by a comparable immunoactive agent delivered via an aqueous carrier in the substantial absence of said microstructures. 23. The vaccine of claim 22, wherein said biocompatible surfactant is selected from the group consisting of phospholipids, poloxamers, and combinations thereof. 24. The vaccine of claim 23, wherein said phospholipid is selected from the group consisting of dilauroylphosphatidylcholine, dioleylphosphatidylcholine, dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, dibehenoylphosphatidylcholine, diarachidoylphosphatidylcholine, and combinations thereof. 25. The vaccine of claim 22, wherein said immunoactive agent is selected from the group consisting of inactivated microbes, live attenuated microbes, phages, subunit vaccine proteins, subunit vaccine peptides, subunit vaccine carbohydrates, replicons, viral vectors, plasmids, other immunoactive genetic and recombinant materials, and combinations thereof. 26. The vaccine of claim 22, wherein said vaccine is compatible with administration via a dry powder inhaler. 27. The vaccine of claim 22, wherein said microstructures are dispersed in a nonaqueous suspension medium. 28. The vaccine of claim 27, wherein said nonaqueous suspension medium comprises a compound selected from the group consisting of liquid fluorochemicals and hydrofluoroalkane propellants. 29. The vaccine of claim 27, wherein said vaccine is administered using a metered dose inhaler, a nebulizer, an atomizer, a nasal pump, or a spray bottle. 30. The vaccine of claim 22, wherein said microstructures are selected from the group consisting of: particulates, microparticulates, and perforated microstructures. 31. The vaccine of claim 22, wherein said microstructures comprise perforated microstructures. 32. The vaccine of claim 31, wherein said perforated microstructures comprise hollow porous microstructures. 33. The vaccine of claim 22, wherein the mean aerodynamic diameter of said microstructures is between about 0.5 and about 5 .mu.m. 34. The vaccine of claim 22, wherein said microstructures have a mean geometric diameter of between about 1 and about 30 .mu.m. 35. The vaccine of claim 22, wherein said microstructures have a mean geometric diameter of less than about 5 .mu.m. 36. The vaccine of claim 22, wherein said elicited immune response comprises mucosal and/or systemic immunity. 37. The vaccine of claim 22, wherein said microstructures further comprise an immunogenicity modifying excipient. 38. The vaccine of claim 37, wherein said immunogenicity modifying excipient is selected from the group consisting of mannans, cell-binding polysaccharides, cofactors, cytokines, and combinations thereof. 39. The vaccine of claim 22, wherein said immune response is enhanced by at least about 25% relative to the immune response elicited by a comparable immunoactive agent delivered via an aqueous carrier in the substantial absence of said microstructures. 40. A method for providing enhanced active immunization comprising administering to a patient a therapeutically or prophylactically effective amount of a medicament that comprises a plurality of microstructures associated with one or more vaccines, wherein said microstructures comprise at least about 5% w/w of a biocompatible surfactant selected from the group consisting of saturated and unsaturated lipids, nonionic detergents, nonionic block copolymers, ionic surfactants, cationic surfactants, biocompatible fluorinated surfactants, and combinations thereof; and wherein said enhanced active immunization is enhanced relative to the immune response elicited by comparable vaccines delivered via an aqueous carrier in the substantial absence of said microstructures. 41. The method of claim 40, wherein said biocompatible surfactant is selected from the group consisting of phospholipids, poloxamers, and combinations thereof. 42. The method of claim 40, wherein said vaccine is selected from the group consisting of inactivated microbes, live attenuated microbes, phages, subunit vaccine proteins, subunit vaccine peptides, subunit vaccine carbohydrates, replicons, viral vectors, plasmids, other immunoactive genetic and recombinant materials, and combinations thereof. 43. The method of claim 40, wherein said medicament is formulated so as to be capable of being delivered to or via the respiratory tract. 44. The method of claim 40, wherein said microstructures further comprise an immunogenicity modifying excipient. 45. The method of claim 44, wherein said immunogenicity modifying excipient is selected from the group consisting of mannans, cell-binding polysaccharides, cofactors, cytokines, and combinations thereof. 46. A method for providing enhanced passive immunization comprising administering to a patient a therapeutically or prophylactically effective amount of a medicament that comprises a plurality of microstructures associated with one or more immunoglobulins or immunoglobulin-like molecules, wherein said microstructures comprise at least about 5% w/w of a biocompatible surfactant selected from the group consisting of saturated and unsaturated lipids, nonionic detergents, nonionic block copolymers, ionic surfactants, cationic surfactants, biocompatible fluorinated surfactants, and combinations thereof; and wherein said enhanced passive immunization is enhanced relative to the immune response elicited by comparable immunoglobulins or immunoglobulin-like molecules delivered via an aqueous carrier in the substantial absence of said microstructures. 47. The method of claim 46, wherein said biocompatible surfactant is selected from the group consisting of phospholipids, poloxamers, and combinations thereof. 48. The method of claim 46, wherein said medicament is formulated so as to be delivered to or via the respiratory tract. 49. A method for treating an autoimmune disease or disorder comprising administering to a patient a therapeutically or prophylactically effective amount of a medicament that comprises a plurality of microstructures associated with one or more immunomodulators, wherein said microstructures comprise at least about 5% w/w of a biocompatible surfactant selected from the group consisting of saturated and unsaturated lipids, nonionic detergents, nonionic block copolymers, ionic surfactants, cationic surfactants, biocompatible fluorinated surfactants, and combinations thereof; and wherein said treatment for an autoimmune disease or disorder is enhanced relative to the treatment elicited by comparable immunomodulators delivered via an aqueous carrier in the substantial absence of said microstructures. 50. The method of claim 49, wherein said immunomodulators are selected from the group consisting of: foreign antigens, self-antigens, antigen epitope peptides, immunoglobulins, autoimmune related-ligands, cytokines, and combinations thereof. 51. The method of claim 49, wherein said biocompatible surfactant is selected from the group consisting of phospholipids, poloxamers, and combinations thereof. 52. The method of claim 49, wherein said medicament is formulated so as to be capable of being delivered to or via the respiratory tract.