Patent EA-002055-B1 (EA)
Title: Stable glassy state powder formulations
Inventor: FOSTER LINDA C
IPC: A61K9/12
Filed: 1997-10-14
Abstract: 1. An aerosolized powder composition for pulmonary administration that, prior to aerosolization, has been stored for a minimum period of 3 weeks at a storage temperature (Ts) that is at least 10 degree C lower than the glass transition temperature (Tg) of said composition, said composition (i) comprising a mixture of a pharmaceutically-acceptable glassy matrix and a pharmacologically active material inside said matrix, characterized by an MMAD between about 1-5 microns both before and after storage. 2. A powdered, dispersible composition suitable for inhalation and which maintains a stable dispersibility over time, comprising a pharmaceutically-acceptable glassy matrix mixed with a pharmacologically active material inside said matrix, wherein said stable dispersibility over time is characterized by a delivered dose efficiency (DDE) of at least 30 percent, when said composition is stored at a storage temperature Ts, that is at least 10  degree C lower than Tg over a time course of one month. 3. The composition of Claim 2 in aerosolized form. 4. The composition of either Claim 1 or Claim 2, characterized by a delivered dose efficiency (DDE) of at least 40%. 5. The composition of either Claim 1 or Claim 2, characterized by a delivered dose efficiency of at least 50%. 6. The composition of either Claim 1 or Claim 2, characterized by a delivered dose efficiency of at least 60%. 7. The composition of either Claim I or Claim 2, wherein the difference between Tg and Ts is at least about 20  degree C. 8. The composition of either Claim 1 or Claim 2, wherein the difference between Tg and Ts is at least about 30  degree C. 9. The composition of either Claim 1 or Claim 2, wherein the Tg is from about 35 degree C to about 200 degree C. 10. The composition of either Claim 1 or Claim 2, wherein the Tg is greater than about 45 degree C. 11. The composition of Claim 6, wherein the Tg is greater than about 55 degree C. 12. The composition of either Claim 1 or Claim 2, wherein the Ts is from about 2 degree C to about 30 degree C and Tg is from about 22 degree C to about 200 degree C. 13. The composition of Claim 1 or Claim 2, wherein the glassy matrix comprises a glass former selected from the group consisting of carbohydrates, carbohydrate derivatives, carbohydrate polymers, organic carboxylic acid salts, synthetic organic polymers, proteins, peptides, amino acids and polyamino acids. 14. The composition of Claim I or Claim 2, wherein the glassy matrix comprises a glass former selected from the group consisting of sodium citrate, raffinose, lactose, trehalose, maltotriose, maltodextrin, maltose, glucopyranosyl-sorbitol, glucopyranosyl-mannilol, polydextrose, sucrose, cycloclodextrin, casein, HSA, oxyethylated starch, stachyose, magnesium gluconale, and cellobiose. 15. The composition of Claim 14, wherein the glass former is selected from the group consisting of sodium citrate, raffinose, lactose, trehalose, maltodextrin, maltose, sucrose, stachyose, magnesium gluconate, and gluocopyranosyl-mannitol. 16. The composition of Claim 14, wherein the glass former is raffinose or sucrose. 17. The composition of Claim 1, which prior to aerosolization, is in unit dosage form. 18. The composition of Claim 2, in unit dosage form. 19. A spray-dried composition of Claim 1 or Claim 2. 20. The composition of any one of Claims 1-19, wherein the pharmacologically active material comprises a macromolecule. 21. The composition of Claim 20, wherein said macromolecule is selected from the group consisting of proteins, peptides, polypeptides and nucleic acids. 22. The composition of any one of Claims 1-19, wherein the pharmacologically active material comprises a non-macromolecule. 23. The composition of any one of Claims 1-19, wherein said pharmacologically active material is selected from the group consisting of insulin, inlerleukin-1 receptor, alpha-1-antitrypsin, albuterol, calcitonin, and elcatonin. 24. The composition of Claim 2, characterized by a DDE of at least 30% when stored at a storage temperature, Ts, that is at least 10 degree C lower than Tg over a time course of 3 months. 25. The composition of Claim 2, further characterized by an initial DDE which remains substantially unchanged over said time course. 26. The composition of Claim 1, further characterized by an initial MMAD which remains substantially unchanged over said time course. 27. The composition of Claim 1 or Claim 2, further characterized by a moisture uptake profile which allows absorption of up to about 5% moisture while maintaining a difference between Tg and Ts of at least 10 degree C. 28. A process for maintaining the aerosol performance of a powder composition over time, said process comprising: (a) removing solvent from a solution comprising a solvent, a glass former and a pharmacologically active material under conditions effective to form a glassy matrix, composition suitable for pulmonary administration, said composition having the pharmacologically active material within the matrix, (ii) a glass transition temperature (Tg), and (iii) an MMAD from 1-5 microns, (b) storing the composition at a storage temperature (Ts) that is at least 10 degree C lower than said Tg, such that the composition maintains an MMAD from 1-5 microns when stored at said Ts for a minimum period of 3 weeks, and (c) dispersion of said composition. 29. A process for maintaining the dispersibility of a powdered composition over time, comprising: (i) forming a solution comprising a solvent, a glass former capable of forming a glassy matrix, and a pharmacologically active material, (ii) removing the solvent from said solution under conditions effective to form a powdered composition suitable for inhalation, said composition comprising a glassy matrix containing the pharmacologically active material and (iii) storing the composition over a time course of at least one month, at a storage temperature, Ts, that is at least 10 degree C lower than the Tg value of said composition. 30. The process of Claim 29, effective to form a powdered composition, which, after said storing, is characterized by a delivered dose efficiency of at least 30 percent. 31. The process of Claim 28 or Claim 29, wherein the solvent is removed by spray drying. 32. The process of Claim 28 or Claim 29, wherein the solvent is removed by evaporative drying. 33. The process of Claim 28 or Claim 29, wherein the solvent is removed by chemical precipitation. 34. The process of Claim 28 or Claim 29, wherein the solvent is water. 35. The process of Claim 28 or Claim 29, wherein the solvent is ethanol. 36. The process of any of Claims 28 to 35, wherein the difference between Tg and Ts (Tg-Ts) is at least 20 degree C. 37. The process of any of Claims 28 to 35, wherein the difference between Tg and Ts (Tg-Ts) is at least 30 degree C; 38. The process of any of Claims 28 to 35, wherein the Tg value of said composition is greater than 45 degree C. 39. The process of any of Claims 28 to 35, wherein the Tg value of said composition is greater than 55 degree C. 40. The process of any of Claims 28 to 35, wherein said storing step comprises storing the composition at a storage temperature, Ts, ranging from 2 degree C to 30 degree C. 41. The process of any one of Claims 28 to 40, wherein the glassy matrix comprises a glass former selected from the group consisting of carbohydrates, carbohydrate derivatives, carbohydrate polymers, organic carboxylic acid salts, synthetic organic polymers, proteins, peptides, amino acids and polyarnino acids. 42. The process of any one of Claims 28 to 40, wherein the glassy matrix comprises a glass former selected from the group consisting of sodium citrate, raffinose, lactose, trehalose, maltotriose, maltodextrin, maltose, glucopyranosyl-sorbitol, glucopyranosyl-mannitol, polydextrose, sucrose, cycloclodextrin, casein, HSA, oxyethylated starch, stachyose, magnesium gluconate, and cellobiose. 43. The process of any one of Claims 28 to 40, wherein the glass former is selected from the group consisting of sodium citrate, raffinose, lactose, trehalose, maltodextrin, maltose, sucrose, stachyose, magnesium gluconate, and gluocopyranosyl-mannitol. 44. The process of any one of Claims 28 to 40, wherein the glass former is raffinose or sucrose. 45. The process of any one of Claims 28 to 44, wherein the pharmacologically active material comprises a macromolecule. 46. The process of any one of Claims 28 to 44, wherein said macromolecule is selected from the group consisting of proteins, peptides, potypeptides, and nucleic acids. 47. The process of any one of Claims 28 to 44, wherein the pharmacologically active material comprises a non-macromolecule. 48. An aerosolized powdered composition having a stable aerosol performance over time, comprising: (i) a first respirable powdered component comprising the composition of Claim 1, and (ii) a second, nonrespirable powdered component comprising a powdered pharmaceutically acceptable carrier. 49. A powdered composition having a stable dispersibility over time, comprising: (i) a first respirable powdered component comprising the composition of Claim 2, and (ii) a second, nonrespirable powdered component comprising a powdered pharmaceutically acceptable carrier. 50. The composition of Claim 49 or Claim 49, wherein said first respirable component comprises particles having a maximum particle size of about 10 microns, with the majority of particles in a size range from about 1 to 5 microns, and wherein said second, nonrespirable component comprises particles in a size range from about 15 to 100 microns.