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. A
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.
대표청구항▼
1. A dry powder composition comprising a plurality of particles, wherein the particles comprise an active agent and a di- or tripeptide comprising at least two leucines, wherein said di- or tripeptide is present in an amount effective to increase the emitted dose of the composition over the emitted
1. A dry powder composition comprising a plurality of particles, wherein the particles comprise an active agent and a di- or tripeptide comprising at least two leucines, wherein said di- or tripeptide 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. 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 from about 1% by weight to about 99% by weight di- or tripeptide. 4. The composition of claim 3, comprising from about 5% to about 75% by weight di- or tripeptide. 5. The composition of claim 4, comprising from about 5% to about 50% by weight di- or tripeptide. 6. The composition of claim 1, wherein the particles further comprise a pharmaceutically acceptable excipient or carrier. 7. The composition of claim 6, wherein said excipient is selected from the group consisting of carbohydrates, amino acids, peptides, proteins, organic acid salts, and polymers. 8. The composition of claim 1 in combination with a dry powder inhaler device, wherein the dry powder composition and inhaler device combination have an emitted dose of at least about 30%. 9. The composition of claim 1 in combination with a dry powder inhaler device, wherein the dry powder composition and inhaler device have an emitted dose of at least about 45%. 10. The composition of claim 1, wherein the di- or tripeptide comprises the dipeptide dileucine. 11. The composition of claim 1, wherein the di- or tripeptide comprises 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). 12. The composition of claim 11, wherein said di- or tripeptide comprises trileucine. 13. The composition of claim 1, wherein the particles have an MMD of less than about 10 microns. 14. The composition of claim 1, wherein the particles have an MMD of less than about 4.0 microns. 15. The composition of claim 1, wherein the particles have an MMAD of less than about 10 microns. 16. The composition of claim 1, wherein the particles have an MMAD of less than about 4 microns. 17. The composition of claim 1, wherein the di- or tripetide possesses a glass transition temperature greater than about 40° C. 18. The dry powder composition of claim 1, wherein the dry powder composition has 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. 19. The dry powder composition of claim 1, wherein the dry powder composition has a 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. 20. 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. 21. The dry powder composition of claim 1, wherein the particles have a bulk density from 0.1 to 10 grams per cubic centimeter. 22. The dry powder composition of claim 21, wherein the particles have a bulk density from 0.5 to 2.0 grams per cubic centimeter. 23. 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 tripeptide comprising at least two leucines, anddrying said liquid formulation such that a dry powder containing particles that comprise the active agent and the di- or tripeptide 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 tripeptide. 24. The method of claim 23, wherein the di- or tripeptide that is incorporated into the liquid formulation comprises dileucine. 25. The method of claim 23, wherein the di- or tripeptide that is incorporated into the liquid formulation comprises 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). 26. The method of claim 23, wherein said liquid formulation is an aqueous formulation. 27. The method of claim 23, wherein a pharmaceutically acceptable excipient or carrier is also incorporated into said liquid formulation. 28. The method of claim 23, wherein said drying step is selected from the group consisting of spray-drying, freeze-drying, and spray-freeze drying. 29. The method of claim 23, 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 tripeptide. 30. The method of claim 29, 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. 31. The method of claim 23, wherein said dry powder is characterized by an emitted dose of at least about 30%. 32. The method of claim 23, 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. 33. 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. 34. A dry powder composition comprising a plurality of particles, wherein the particles comprise an active agent and a di- or tripeptide comprising at least two leucines, wherein the di-or tripeptide comprises the dipeptide dileucine. 35. The dry powder composition of claim 34, wherein said composition is suitable for delivery to the lung or deep lung by inhalation. 36. The composition of claim 34, wherein the particles have an MMAD of less than about 10 microns. 37. A dry powder composition comprising a plurality of particles, wherein the particles comprise an active agent and a di- or tripeptide comprising at least two leucines, wherein said di- or tripeptide comprises trileucine. 38. The dry powder composition of claim 37, wherein said composition is suitable for delivery to the lung or deep lung by inhalation. 39. The composition of claim 37, wherein the particles have an MMAD of less than about 10 microns.
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