Claims for Patent: 6,518,239

Summary for Patent: 6,518,239

Title:	Dry powder compositions having improved dispersivity
Abstract:	The present invention provides a highly dispersible formulation comprising an active agent and a dipeptide or tripeptide comprising at least two leucyl residues. The composition of the invention possesses superior aerosol properties and is thus preferred for aerosolized administration to the lung. Also provided are a method for (i) increasing the dispersibility of an active-agent containing formulation for administration to the lung, and (ii) delivery of the composition to the lungs of a subject.
Inventor(s):	Kuo; Mei-Chang (Palo Alto, CA), Lechuga-Ballesteros; David (Santa Clara, CA)
Assignee:	Inhale Therapeutic Systems, Inc. (San Carlos, CA)
Application Number:	09/548,759
Patent Claims:	1. A dry powder composition comprising an active agent and a di- or tripeptide comprising at least two leucines. 2. The dry powder composition of claim 1, wherein said composition is suitable for delivery to the lung or deep lung by inhalation. 3. The composition of claim 1 comprising dry powder particles, wherein the concentration of said di- or tri-peptide on the surface of the particles is greater than in the bulk powder. 4. The composition of claim 1, wherein said di- or tri-peptide is present in an amount effective to increase the emitted dose of the composition over the emitted dose of the composition absent said di- or tripeptide. 5. The composition of claim 1, comprising from about 1% by weight to about 99% by weight di- or tripeptide. 6. The composition of claim 5, comprising from about 5% to about 75% by weight di- or tripeptide. 7. The composition of claim 6, comprising from about 5% to about 50% by weight di- or tripeptide. 8. The composition of claim 1, further comprising a pharmaceutically acceptable excipient or carrier. 9. The composition of claim 8, wherein said excipient is selected from the group consisting of carbohydrates, amino acids, peptides, proteins, organic acid salts, and polymers. 10. The composition of claim 1, characterized by an emitted dose of at least about 30%. 11. The composition of claim 1, characterized by an emitted dose of at least about 45%. 12. The composition of claim 1, comprising a dipeptide where said dipeptide is dileucine. 13. The composition of claim 1, comprising a tripeptide comprising two leucines and an amino acid selected from the group consisting of leucine (leu), valine (val), isoleucine (isoleu), tryptophan (try) alanine (ala), methionine (met), phenylalanine (phe), tyrosine (tyr), histidine (his), and proline (pro). 14. The composition of claim 13, wherein said tri-peptide is trileucine. 15. The composition of claim 1, comprising particles having an MMD of less than about 10 microns. 16. The composition of claim 1, comprising particles having an MMD of less than about 4.0 microns. 17. The composition of claim 1, comprising particles having an MMAD of less than about 10 microns. 18. The composition of claim 1, comprising particles having an MMAD of less than about 4 microns. 19. The composition of claim 1, wherein the di- or tri-peptide possesses a glass transition temperature greater than about 40.degree. C. 20. The dry powder composition of claim 1 having stable dispersivity over time, as characterized by a drop in emitted dose of no more than about 10% when said composition is stored under ambient conditions for a period of three months. 21. The dry powder composition of claim 1 having chemical stability over time, as characterized by degradation of less than about 5% by weight of the active agent upon storage of said composition under ambient conditions for a period of three months. 22. The dry powder composition of claim 1, wherein said active agent is selected from the group consisting of insulin, cyclosporin, parathyroid hormone, follicle stimulating hormone, VLA-4 inhibitors, interleukin-4R, thrombopoietin, c-peptide, amylin, pro-insulin, interleukin-1, interleukin-2, alpha-1-antitrypsin, budesonide, human growth hormone, growth hormone releasing hormone, interferon alpha, interferon beta, growth colony stimulating factor, keratinocyte growth factor, glial growth factor, tumor necrosis factor, leutinizing hormone releasing hormone, calcitonin, low molecular weight heparin, somatostatin, respiratory syncytial virus antibody, erythropoietin, Factor VIII, Factor IX, ceredase, cerezyme and analogues, agonists and antagonists thereof. 23. The dry powder composition of claim 1, comprising particles having a bulk density from 0.1 to 10 grams per cubic centimeter. 24. The dry powder composition of claim 23, comprising particles having a bulk density from 0.5 to 2.0 grams per cubic centimeter. 25. A method for enhancing the aerosol performance of a dry powder, said method comprising: incorporating into a liquid formulation comprising an active agent, a di- or tri-peptide comprising at least two leucines, and drying said liquid formulation such that a dry powder containing the active agent and the di- or tri-peptide is produced, whereby the resultant dry powder possesses an emitted dose that is increased over the emitted dose of a dry powder having the same components but absent said di- or tri-peptide. 26. The method of claim 25, wherein said incorporating step comprises incorporating a dipeptide where the dipeptide is dileucine. 27. The method of claim 25, wherein said incorporating step comprises incorporating a tri-peptide comprising two leucines and an amino acid selected from the group consisting of leucine (leu), valine (val), isoleucine (isoleu), tryptophan (try) alanine (ala), methionine (met), phenylalanine (phe), tyrosine (tyr), histidine (his), and proline (pro). 28. The method of claim 25, wherein said liquid formulation is an aqueous formulation. 29. The method of claim 25, wherein a pharmaceutically acceptable excipient or carrier is also incorporated into said liquid formulation. 30. The method of claim 25, wherein said drying step is selected from the group consisting of spray-drying, freeze-drying, and spray-freeze drying. 31. The method of claim 25, wherein the emitted dose of the dry powder is increased by at least about 5% over that of a dry powder having the same components and absent said di- or tri-peptide. 32. The method of claim 31, wherein the emitted dose of the dry powder is increased by at least about 10% over that of a dry powder having the same components and absent said di- or tripeptide. 33. The method of claim 25, wherein said dry powder is characterized by an emitted dose of at least about 30%. 34. The method of claim 25, wherein said active agent is selected from the group consisting of insulin, cyclosporin, parathyroid hormone, follicle stimulating hormone, VLA-4 inhibitors, interleukin-4R, thrombopoietin, c-peptide, amylin, pro-insulin, interleukin-1, interleukin-2, alpha-1-antitrypsin, budesonide, human growth hormone, growth hormone releasing hormone, interferon alpha, interferon beta, growth colony stimulating factor, keratinocyte growth factor, glial growth factor, tumor necrosis factor, leutinizing hormone releasing hormone, calcitonin, low molecular weight heparin, somatostatin, respiratory syncytial virus antibody, erythropoietin, Factor VIII, Factor IX, ceredase, cerezyme and analogues, agonists and antagonists thereof. 35. A method for increasing the aerosol performance of an active agent-containing formulation suitable for administration to the lung, said method comprising: incorporating a di- or tripeptide comprising at least two leucines into a formulation comprising an active agent, to thereby form a composition comprising said active agent and said di- or tripeptide, whereby as a result of said incorporating, the emitted dose of the composition is increased over the emitted dose of a composition having the same components but absent said di- or tripeptide. 36. The method of claim 35, wherein said composition is a liquid composition suitable for aerosolized administration to the lung. 37. The method of claim 35, wherein said composition is a dry composition suitable for aerosolized administration to the lung. 38. The method of claim 35, wherein said tripeptide comprising two leucines and an amino acid selected from the group consisting of leucine (leu), valine (val), isoleucine (isoleu), tryptophan (try) alanine (ala), methionine (met), phenylalanine (phe), tyrosine (tyr), histidine (his), and proline (pro). 39. A method for delivery of a dry powder composition to the lungs of a mammalian patient, said method comprising administering by inhalation the dry powder composition of claim 1 in aerosolized form. 40. A method for delivery of an active-agent containing formulation to the lungs of a mammalian patient, said method comprising administering by inhalation a liquid composition produced by the method of claim 36.

Details for Patent 6,518,239

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genzyme Corporation	CEREZYME	imiglucerase	For Injection	020367	05/23/1994		2019-10-29
Genzyme Corporation	CEREZYME	imiglucerase	For Injection	020367	09/22/1999		2019-10-29
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2019-10-29