Patent EA-000956-B1 (EA)
Title: Dispersible compositions based on macromolecule compounds
Inventor: PLATZ ROBERT M
IPC: A61K31/00
Filed: 1997-05-07
Abstract: 1. A method for preparing dispersible dry powders of biological macromolecules, said method comprising: providing an evaporable liquid medium containing a predetermined concentration of the macromolecule and excipients; atomizing the liquid medium under conditions selected to form droplets having an average size below predetermined maximum; drying the droplets under conditions selected to form dispersible particles of the composite material containing the biological macromolecules, said particles having a moisture content below a predetermined moisture content, and collecting the particles with high yields. 2. A method as in claim 1, wherein the total solids content in the liquid medium is below 10% by weight. 3. A method as in claim 2, wherein the concentration of macromolecule is in the range from 1% to 5% by weight. 4. A method as in claim 1, wherein the liquid medium comprises an aqueous medium. 5. A method as in claim 1, wherein the maximum mean droplet size is 11 μm. 6. A method as in claim 5, wherein the atomizing step comprises flowing the liquid medium and an atomization gas stream through a two fluid nozzle at a predetermined gas:liquid mass flow ratio. 7. A method as in claim 6, wherein the gas:liquid mass flow ratio is above 5. 8. A method as in claim 7, wherein the fluid nozzle has a liquid orifice diameter in the range from 0.015 in. (0.38 mm) to 0.075 in. (1.9mm) and wherein the air pressure upstream of the orifice is maintained above 25 psi. (172.37 pKa). 9. A method as in claim 1, wherein the droplets are dried to form particles having a moisture content below 10% by weight. 10. A method as in claim 9, wherein the drying step comprises flowing the droplets in a heated gas stream. 11. A method as in claim 10, wherein the droplets are flowed concurrently with the gas stream and wherein the gas stream has an inlet temperature above 90 degree C. 12. A method as in claim 11, wherein the gas stream has an inlet temperature above 90 degree C and an outlet temperature above 50 degree C. 13. A method as in claim 1, wherein the droplets are dried under conditions selected to provide particles having a rugosity measured by air permeability above 2. 14. A method as in claim 1, wherein the drying step produces a powder having at least 90% of the mass of particles in the size range from 0.4 μm to 5 5 μm and the particle collecting step comprises separating substantially the entire particle output of the drying step from the gas stream. 15. A method as in claim 14, further comprising packaging a portion of the separated particles in a container, wherein the particles have not been size classified prior to packaging. 16. A method as in claim 15, wherein the portion is packaged in a unit dosage container. 17. A method as in claim 1, wherein the particle separating step comprises passing substantially the entire gas stream through a separator which removes at least about 90% by weight of all particles having a size above 1 μm from said gas stream. 18. A method as in claim 17, wherein the separator is a sintered metal fiber filter. 19. A method as in claim 17, wherein the separator is a bag filter, cartridge filter, or cloth filter. 20. A method as in claim 17, wherein the separator is a high efficiency cyclone. 21. A method as in claim 1, wherein the macromolecule is selected from the list of macromolecules set forth in Table 1. 22. A macromolecule composition prepared by the method of claim 1. 23. A dispersible macromolecule composition for inhalation into the alveolar regions of the lung, said composition comprising particles having an average particle size below 5 μm and a rugosity measured by air permeametry above 2. 24. A dispersible macromolecule composition as in claim 23, wherein the macromolecule is a protein, a nucleic acid, or a high molecular weight polysaccharide. 25. A dispersible macromolecule composition as in claim 24, wherein the macromolecule is a protein selected from the group consisting of proteins set forth in Table 1. 26. A dispersible macromolecule composition as in claim 25, wherein the protein is insulin. 27. A dispersible macromolecule composition as in claim 23, wherein the particles further comprise a pharmaceutical carrier. 28. A dispersible macromolecule composition as in claim 23, wherein the particles have a moisture content below 10% by weight. 29. A dispersible macromolecule composition as in claim 23, wherein over 90% by weight of the composition comprises particles having a particle size in the range from 0.1 μm to 7 μm. 30. A unit dose of a macromolecule comprising a unit dose receptacle having a therapeutically effective amount of a macromolecule composition as in claim 23 therein.