Details for Patent: 7,205,343

Title:	Stabilized bioactive preparations and method of use
Abstract:	Stabilized dispersions are provided for the delivery of a bioactive agent. The dispersions preferably comprise a plurality of perforated microstructures dispersed in a suspension medium that typically comprises a liquid fluorochemical. As density variations between the suspended particles and suspension medium are minimized and attractive forces between microstructures are attenuated, the disclosed dispersions are particularly resistant to degradation, such as by settling or flocculation. In particularly preferred embodiments the stabilized dispersions may be directly administered to the lung of a patient using an endotracheal tube or bronchoscope.
Inventor(s):	Dellamary; Luis A. (San Marcos, CA), Tarara; Thomas (Burlingame, CA), Kabalnov; Alexey (Corvalis, OR), Weers; Jeffry (Half Moon Bay, CA), Schutt; Ernest (San Diego, CA)
Assignee:
Filing Date:	Dec 03, 2001
Application Number:	09/999,071
Claims:	1. A method of manufacturing a stabilized dispersion for the pulmonary delivery of a bioactive agent wherein the stabilized dispersion is in a form for direct administration by liquid dose instillation to at least a portion of the nasal or pulmonary air passages of a patient in need thereof, the method comprising: providing a fluorochemical suspension medium, and dispersing a plurality of perforated microstructures in the suspension medium, the perforated microstructures comprising at least one bioactive agent, wherein the suspension medium substantially permeates the perforated microstructures. 2. A method according to claim 1 wherein the perforated microstructures comprise a surfactant. 3. A method according to claim 1 wherein the perforated microstructures comprise a phospholipid. 4. A method according to claim 1 wherein the perforated microstructures comprise hollow porous microspheres. 5. A method according to claim 1 wherein the fluorochemical suspension medium comprises perfluorooctyl bromide. 6. A method according to claim 1 wherein the perforated microstructures comprise an active agent, inorganic salt and a phospholipid, and wherein the gel to liquid crystal phase transition temperature of the perforated microparticles is greater than 40.degree. C. 7. A method according to claim 6 wherein the inorganic salt comprises calcium chloride. 8. A method according to claim 1 wherein the perforated microstructures further comprise a surfactant comprising one or more of phospholipids, nonionic detergents, nonionic block copolymers, ionic surfactants, biocompatible fluorinated surfactants or combinations thereof. 9. A method according to claim 8 wherein the phospholipid comprises a lung surfactant. 10. A method according to claim 8 wherein the phospholipid is a saturated phospholipid. 11. A method according to claim 1 wherein the suspension medium and the perforated microstructures have a refractive index differential of less than 0.5. 12. A method according to claim 1 wherein the bioactive agent comprises one or more of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, leukotriene inhibitors or antagonists, antihistamines, anti-inflammatories, antineoplastics, anticholinergics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antisense agents, proteins, peptides or combinations thereof. 13. A method according to claim 1 wherein the bioactive agent is gentamicin. 14. A method according to claim 1 comprising a nonaqueous suspension medium with at least one liquid fluorochemical. 15. A method according to claim 1 wherein the perforated microstructures have a mean density selected to provide a density differential with that of the suspension medium of less than 0.6 g/cm.sup.3. 16. A method according to claim 1 wherein the dispersion comprises a creaming time of greater than 30 minutes. 17. A method according to claim 1 wherein the perforated microstructures have a mean diameter of 1 30 .mu.m. 18. A method according to claim 1 wherein the liquid fluorochemical has a vapor pressure of 5 760 Torr at 25.degree. C. 19. A method of manufacturing a stabilized dispersion for the pulmonary delivery of a bioactive agent wherein the stabilized dispersion is in a form for direct administration by liquid dose instillation to at least a portion of the nasal or pulmonary air passages of a patient in need thereof, the method comprising: providing a nonaqueous suspension medium with at least one liquid fluorochemical, and dispersing a plurality of perforated microstructures in the suspension medium, the perforated microstructures comprising at least one bioactive agent and phospholipid. 20. A method according to claim 19 wherein the fluorochemical suspension medium comprises perfluorooctyl bromide. 21. A method according to claim 19 wherein the perforated microstructures comprise an inorganic salt and a phospholipid, and wherein gel to liquid crystal phase transition temperature of the perforated microparticles is greater than 40.degree. C. 22. A method according to claim 21 wherein the inorganic salt comprises calcium chloride. 23. A method according to claim 19 wherein the phospholipid comprises a lung surfactant. 24. A method according to claim 19 wherein the suspension medium and the perforated microstructures have a refractive index differential of less than 0.5. 25. A method according to claim 19 wherein the bioactive agent comprises one or more of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, leukotriene inhibitors or antagonists, antihistamines, anti-inflammatories, antineoplastics, anticholinergics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antisense agents, proteins, peptides or combinations thereof. 26. A method according to claim 19 wherein the bioactive agent is gentamicin. 27. A method of manufacturing a stabilized dispersion for the pulmonary delivery of a bioactive agent wherein the stabilized dispersion is in a form for direct administration by liquid dose instillation to at least a portion of the nasal or pulmonary air passages of a patient in need thereof, the method comprising: providing a nonaqueous suspension medium with at least one liquid fluorochemical, and dispersing a plurality of perforated microstructures in the suspension medium, the perforated microstructures comprising at least one bioactive agent, saturated phospholipid, and an inorganic salt. 28. A method according to claim 27 wherein the fluorochemical suspension medium comprises perfluorooctyl bromide. 29. A method according to claim 27 wherein the gel to liquid crystal phase transition temperature of the perforated microparticles is greater than 40.degree. C. 30. A method according to claim 27 wherein the inorganic salt comprises calcium chloride. 31. A method according to claim 27 wherein the suspension medium and the perforated microstructures have a refractive index differential of less than 0.5. 32. A method according to claim 27 wherein the bioactive agent comprises one or more of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, leukotriene inhibitors or antagonists, antihistamines, anti-inflammatories, antineoplastics, anticholinergics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antisense agents, proteins, peptides or combinations thereof.