Patent EA-003476-B1 (EA)
Title: Dry powder active agent pulmonary delivery
Inventor: CLARK ANDREW
IPC: A61K47/44
Filed: 1999-09-13
Abstract: 1. Particles for delivery of an active agent to the alveoli of a human patient, said particles comprising the active agent and a hygroscopic growth inhibitor, wherein the hygroscopic growth inhibitor is incorporated within the particles in an amount not less than 40% and selected from the group consisting of beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cyclodextrin, dextranomer, hydroxyethylstarch, and maltodextrin, and wherein the particles exhibit a drop in emitted dose under simulated lung conditions of no more than about 25%. 2. The particles of claim l, wherein the hygroscopic growth inhibitor is selected from the group consisting of hydroxyethylstarch, dextranomer and maltodextrins. 3. The particles of claim l, wherein the cyclodextrin is used as the hygroscopic growth inhibitor selected from the group consisting of beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutylether beta-cyclodextrin. 4. The particles of claim l, wherein the hydroxyethylstarch is used as the hygroscopic growth inhibitor. 5. The particles of any of claims 1 to 4, wherein the hygroscopic growth inhibitor is present in the powder at an amount sufficient for the powder to exhibit a rate of moisture uptake of no greater than about 0.50% as a function of relative humidity 6. The particles of any of claims 1 to 5, wherein the hygroscopic growth inhibitor is present in the powder in an amount sufficient for the powder to exhibit an overall extent of water uptake of no greater than about 30 weight percent at a relative humidity of 80%. 7. The particles of any of claims 1 to 6, having an emitted dose under ambient conditions of at least 60%. 8. The particles of any of claims 1 to 7, containing from about 40 percent to about 99 percent by weight hygroscopic growth inhibiting agent. 9. The particles of any of claims 1 to 8, which when delivered pulmonarily, are deposited in the deep lung to an extent greater than 20% of the nominal dose. 10. The particles of any of claims 1 to 9, wherein said hygroscopic growth inhibitor is effective to increase the bioavailability of said active agent when delivered to the lung by at least 5%, when compared to the bioavailability observed for the active agent contained in the same particles absent said hygroscopic growth inhibitor and delivered to the lung. 11. Particles for delivery of an active agent to the alveoli of a human patient, said particles comprising the active agent and a hygroscopic growth inhibitor incorporated within the particles in an amount not less than 40%, wherein the particles have a sorption index of less than about 6.5 and the hygroscopic growth inhibitor is selected from the group consisting of beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutylether beta-cyclodextrin, dextranomer, hydroxyethylstarch, and maltodextrin. 12. The particles of claim l1, wherein the hygroscopic growth inhibitor is selected from the group consisting of hydroxyethylstarch, dextranomer and maltodextrins. 13. The particles of claim l1, wherein the hydroxyethylstarch is used as the hygroscopic growth inhibitor. 14. The particles of any of claims 11 to 13, having an emitted dose under ambient conditions of at least 60%. 15. The particles of any of claims 11 to 14, containing from about 40 percent to about 99 percent by weight hygroscopic growth inhibiting agent. 16. Particles for delivery of an active agent to the alveoli of a human patient, said particles comprising the active agent and a hygroscopic growth inhibitor, wherein the hygroscopic growth inhibitor is incorporated within the particles in an amount not less than 40% and selected from the group consisting of beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutylether beta-cyclodextrin, dextranomer, hydroxyethylstarch, and maltodextrin, wherein the particles maintain an aerosol particle size distribution below 3 microns MMAD when delivered to the alveoli. 17. A method for preparing particles for delivery of an active agent to the alveoli of a human patient, comprising: preparing a mixture of a hygroscopic growth inhibitor selected from the group consisting of beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutylether beta-cyclodextrin, dextranomer, hydroxyethylstarch, and maltodextrin, an active agent, and a solvent, wherein the amount of the inhibitor is at least 40% of the total powder weight; and spray drying the mixture to obtain homogenous particles of the hygroscopic agent and the active agent; wherein the particles exhibit a drop in emitted dose under simulated lung conditions of no more than about 25%. 18. The method of claim 17, wherein the hygroscopic growth inhibitor is selected from the group consisting of beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutylether beta-cyclodextrin. 19. The method of claim l7, wherein the hydroxyethylstarch is used as the hygroscopic growth inhibitor. 20. The method of any of claims 17 to 19, where the solvent is water. 21. The method of any of claims 17 to 20, wherein the homogeneous particles contain from about 40 percent to about 99 percent by weight hygroscopic growth inhibiting agent. 22. Powder prepared by the method of claim 17. 23. The powder of any of claims 1 to 16 in an aerosol form for delivering the active agent to the lungs of a human patient. 24. The powder of any of claims 1 to 16 for delivering the active agent to the lungs of a human patient by means of a dry powder inhaler.