Use of aerosolized cyclosporine for prevention and treatment of pulmonary disease
View Patent ↗The present invention relates to methods and compositions for prevention of graft rejection in lung transplant recipients and for treatment of subjects with pulmonary disorders. Specifically, the methods and compositions of the invention provide a means for inhibiting immune response mediated inflammatory processes in the lungs. The method of the invention comprises the administration of aerosolized cyclosporine for prevention of acute and/or chronic refractory rejection in lung transplant patients. The invention further provides for the use of aerosolized cyclosporine to treat subjects having immunologically mediated inflammatory pulmonary disorders including, but not limited to, asthma, cystic fibrosis, idiopathic pulmonary fibrosis, chronic bronchitis and allergic rhinitis. The present invention, by enabling a method for the use of aerosolized cyclosporine for inhibiting pulmonary inflammation leading to prevention of graft rejection and treatment of pulmonary disorders, provides a safer and less toxic treatment than those methods that utilize systemic administration of cyclosporine.
1. A method for preventing chronic graft rejection in a human lung transplant recipient, comprising administering to a transplant recipient, by inhalation, an aerosolized composition comprising an effective dose of cyclosporine, wherein said aerosolized composition is administered at least three times per week over a period of at least about 3 months, and wherein said transplant recipient does not have grade II or greater acute cellular rejection or active bronchiolitis obliterans.
2. The method of claim 1 , wherein a dose of cyclosporine administered is sufficient to achieve deposition levels ranging between 5 mg and 15 mg in a lung.
3. The method of claim 1 , wherein a dose of cyclosporine administered is sufficient to achieve deposition levels ranging between 15 mg and 30 mg in a lung.
4. The method of claim 1 , wherein the total dose of cyclosporine administered is sufficient to achieve deposition levels ranging between 15 mg and 45 mg per week in a lung.
5. The method of claim 1 , wherein the total dose of cyclosporine administered is sufficient to achieve deposition levels ranging between 45 mg and 90 mg per week in a lung.
6. The method of claim 1 , wherein a dose of cyclosporine administered is sufficient to achieve circulating cyclosporine levels ranging between 50 ng/ml and 250 ng/ml.
7. The method of claim 1 , wherein a dose of cyclosporine administered is between 100 mg and 500 mg.
8. The method of claim 1 , wherein a dose of cyclosporine administered is between 20 mg and 400 mg.
9. The method of claim 1 , wherein a dose of cyclosporine administered is between 50 mg and 300 mg.
10. The method of claim 1 , wherein the first administration occurs within 10 days of transplantation.
11. The method of claim 1 , wherein the aerosolized composition is co-administered with an effective amount of one or more other agents selected from the group consisting of an immunosuppressive agent and an anti-inflammatory agent.
12. The method of claim 1 , wherein the cyclosporine is administered as a dry powder.
13. The method of claim 1 , wherein the cyclosporine is dissolved in an organic solvent.
14. The method of claim 1 , wherein the cyclosporine is dissolved in propylene glycol.
15. A method for preventing chronic graft rejection in a human lung transplant recipient, comprising administering to a transplant recipient, by inhalation, an aerosolized composition comprising an effective dose of cyclosporine, wherein said aerosolized composition is administered at least three times per week over a period of at least 6 months, and wherein said transplant recipient does not have grade II or greater acute cellular rejection or active bronchiolitis obliterans.
16. The method of claim 15 , wherein a dose of cyclosporine administered is sufficient to achieve deposition levels ranging between 5 mg and 15 mg in a lung.
17. The method of claim 15 , wherein a dose of cyclosporine administered is sufficient to achieve deposition levels ranging between 15 mg and 30 mg in a lung.
18. The method of claim 15 , wherein the total dose of cyclosporine administered is sufficient to achieve deposition levels ranging between 15 mg and 45 mg per week in a lung.
19. The method of claim 15 , wherein the total dose of cyclosporine administered is sufficient to achieve deposition levels ranging between 45 mg and 90 mg per week in a lung.
20. The method of claim 15 , wherein a dose of cyclosporine administered is sufficient to achieve circulating cyclosporine levels ranging between 50 ng/ml and 250 ng/ml.
21. The method of claim 15 , wherein a dose of cyclosporine administered is between 100 mg and 500 mg.
22. The method of claim 15 , wherein the total a dose of cyclosporine administered is between 20 mg and 400 mg.
23. The method of claim 15 , wherein a dose of cyclosporine administered is between 50 mg and 300 mg.
24. The method of claim 15 , wherein the first administration occurs within 10 days of transplantation.
25. The method of claim 15 , wherein the aerosolized composition is co-administered with an effective amount of one or more other agents selected from the group consisting of an immunosuppressive agent and an anti-inflammatory agent.
26. The method of claim 15 , wherein the cyclosporine is administered as a dry powder.
27. The method of claim 15 , wherein the cyclosporine is dissolved in an organic solvent.
28. The method of claim 15 , wherein the cyclosporine is dissolved in propylene glycol.
29. A method for preventing chronic graft rejection in a human lung transplant recipient, comprising administering to a transplant recipient, by inhalation, an aerosolized composition comprising an effective dose of cyclosporine, wherein said aerosolized composition is administered at least three times per week over a period of at least 12 months, and wherein said transplant recipient does not have grade II or greater acute cellular rejection or active bronchiolitis obliterans.
30. The method of claim 29 , wherein a dose of cyclosporine administered is sufficient to achieve deposition levels ranging between 5 mg and 15 mg in a lung.
31. The method of claim 29 , wherein a dose of cyclosporine administered is sufficient to achieve deposition levels ranging between 15 mg and 30 mg in a lung.
32. The method of claim 29 , wherein the total dose of cyclosporine administered is sufficient to achieve deposition levels ranging between 15 mg and 45 mg per week in a lung.
33. The method of claim 29 , wherein the total dose of cyclosporine administered is sufficient to achieve deposition levels ranging between 45 mg and 90 mg per week in a lung.
34. The method of claim 29 , wherein a dose of cyclosporine administered is sufficient to achieve circulating cyclosporine levels ranging between 50 ng/ml and 250 ng/ml.
35. The method of claim 29 , wherein a dose of cyclosporine administered is between 100 mg and 500 mg.
36. The method of claim 29 , wherein a dose of cyclosporine administered is between 20 mg and 400 mg.
37. The method of claim 29 , wherein the total a dose of cyclosporine administered is between 50 mg and 300 mg.
38. The method of claim 29 , wherein the first administration occurs within 10 days of transplantation.
39. The method of claim 29 , wherein the aerosolized composition is co-administered with an effective amount of one or more other agents selected from the group consisting of an immunosuppressive agent and an anti-inflammatory agent.
40. The method of claim 29 , wherein the cyclosporine is administered as a dry powder.
41. The method of claim 29 , wherein the cyclosporine is dissolved in an organic solvent.
42. The method of claim 29 , wherein the cyclosporine is dissolved in propylene glycol.
43. A method for preventing chronic graft rejection in a human lung transplant recipient, comprising administering to a transplant recipient, by inhalation, an aerosolized composition comprising an effective dose of cyclosporine, wherein said aerosolized composition is administered at least three times per week over a period of at least 5 years, and wherein said transplant recipient does not have grade II or greater acute cellular rejection or active bronchiolitis obliterans.
44. The method of claim 43 , wherein a dose of cyclosporine administered is sufficient to achieve deposition levels ranging between 5 mg and 15 mg in a lung.
45. The method of claim 43 , wherein a dose of cyclosporine administered is sufficient to achieve deposition levels ranging between 15 mg and 30 mg in a lung.
46. The method of claim 43 , wherein the total dose of cyclosporine administered is sufficient to achieve deposition levels ranging between 15 mg and 45 mg per week in a lung.
47. The method of claim 43 , wherein the total dose of cyclosporine administered is sufficient to achieve deposition levels ranging between 45 mg and 90 mg per week in a lung.
48. The method of claim 43 , wherein a dose of cyclosporine administered is sufficient to achieve circulating cyclosporine levels ranging between 50 ng/ml and 250 ng/ml.
49. The method of claim 43 , wherein a dose of cyclosporine administered is between 100 mg and 500 mg.
50. The method of claim 43 , wherein a dose of cyclosporine administered is between 20 mg and 400 mg.
51. The method of claim 43 , wherein a dose of cyclosporine administered is between 50 mg and 300 mg.
52. The method of claim 43 , wherein the first administration occurs within 10 days of transplantation.
53. The method of claim 43 , wherein the aerosolized composition is co-administered with an effective amount of one or more other agents selected from the group consisting of an immunosuppressive agent and an anti-inflammatory agent.
54. The method of claim 43 , wherein the cyclosporine is administered as a dry powder.
55. The method of claim 43 , wherein the cyclosporine is dissolved in an organic solvent.
56. The method of claim 43 , wherein the cyclosporine is dissolved in propylene glycol.