Mesalamine suppository
View Patent ↗The present invention relates to a mesalamine rectal suppository designed to provide improved comfort of use. One embodiment of the invention is a mesalamine rectal suppository comprising mesalamine and one or more pharmaceutically acceptable excipients, wherein the drug load of the suppository ranges from 35% to 50%. Yet another embodiment of the invention is a mesalamine rectal suppository comprising mesalamine having a tap density ranging from about 600 to about 800 g/L (as measured by USP <616>) and a hard fat having an ascending melting point of 32 to 35.5° C. Yet another embodiment is a mesalamine rectal suppository comprising mesalamine particles and one or more pharmaceutically acceptable excipients, where the mesalamine particles have a surface area of from about 0.1 m 2 /g to about 2.8 m 2 /g (e.g., from about 0.1 m 2 /g to about 1.3 m 2 /g). Methods of preparing and methods of treatment with mesalamine suppositories are also provided. The invention further provides a method of determining a dissolution parameter (such as dissolution rate) of a mesalamine rectal suppository, such as a 1 g mesalamine suppository, by measuring its dissolution with USP Apparatus #2 at 40° C. and a paddle rotation speed of 125 rpm in 0.2 M phosphate buffer at a pH of 7.5.
1. A mesalamine rectal suppository comprising from about 400 to about 1600 mg mesalamine and an oily or fatty base, wherein the mesalamine has a tap density ranging from about 600 to about 800 g/L (as measured by USP <616>), wherein the suppository has a drug load ranging from 35% to 50%, and the suppository releases at least about 75% by weight of the mesalamine within 2 hours of dissolution as measured with USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
2. The mesalamine suppository of claim 1 , wherein the suppository comprises from about 1450 to about 1550 mg of mesalamine.
3. The mesalamine suppository of claim 1 , wherein the oily or fatty base has an ascending melting point ranging from 32 to 33.5° C.
4. The mesalamine suppository of claim 1 , wherein the oily or fatty base has an ascending melting point ranging from 33 to 35.5° C.
5. The mesalamine suppository of claim 1 , wherein the oily or fatty base is hard fat.
6. The mesalamine suppository of claim 3 , wherein the oily or fatty base is hard fat.
7. The mesalamine suppository of claim 1 , wherein the drug load ranges from about 39 to about 45%.
8. The mesalamine suppository of claim 7 , wherein the drug load ranges from about 41 to about 43%.
9. The mesalamine suppository of claim 1 , wherein the suppository releases at least about 80% by weight of the mesalamine within 2 hours of dissolution as measured with USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
10. The mesalamine suppository of claim 1 , wherein the suppository releases at least about 80% by weight of the mesalamine within 1 hour of dissolution as measured with USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
11. The mesalamine suppository of claim 1 , wherein the suppository releases at least 90% by weight of the mesalamine within 30 minutes of dissolution as measured with USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
12. A method of treating active ulcerative proctitis in a patient in need thereof comprising administering the mesalamine rectal suppository of claim 1 to the patient.
13. The method of claim 12 , wherein the mesalamine rectal suppository is administered once a day.
14. The method of claim 13 , wherein the mesalamine rectal suppository is administered once a day at bedtime.
15. A mesalamine rectal suppository comprising from about 950 to about 1600 mg mesalamine and an oily or fatty base, wherein the mesalamine has a tap density ranging from about 600 to about 800 g/L (as measured by USP <616>), and the suppository releases at least about 75% by weight of the mesalamine within 2 hours of dissolution as measured with USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
16. The mesalamine rectal suppository of claim 15 , wherein the suppository comprises from about 1450 to about 1550 mg of mesalamine.
17. The mesalamine rectal suppository of claim 15 , wherein the suppository comprises about 1500 mg of mesalamine.
18. A mesalamine rectal suppository comprising from about 950 to about 1600 mg mesalamine and an oily or fatty base, wherein the suppository has a drug load ranging from 35% to 46%, and the suppository releases at least about 75% by weight of the mesalamine within 2 hours of dissolution as measured with USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
19. A mesalamine rectal suppository comprising mesalamine particles and an oily or fatty base, wherein the mesalamine particles have a surface area of from about 0.1 m 2 /g to about 2.8 m 2 /g, the suppository has a drug load ranging from 35% to 50%, and the suppository releases at least about 85% by weight of the mesalamine within 1 hour of dissolution as measured with USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
20. The mesalamine rectal suppository of claim 19 , wherein the mesalamine particles have a surface area of from about 0.1 m 2 /g to about 1.3 m 2 /g.
21. The mesalamine rectal suppository of claim 19 , wherein the suppository comprises about 500 mg mesalamine.
22. The mesalamine rectal suppository of claim 19 , wherein the suppository comprises about 1 g mesalamine.
23. The mesalamine rectal suppository of claim 19 , wherein the suppository comprises about 1.5 g mesalamine.
24. The mesalamine suppository of claim 19 , wherein the oily or fatty base has an ascending melting point ranging from 32 to 33.5° C.
25. The mesalamine suppository of claim 19 , wherein the oily or fatty base has an ascending melting point ranging from 33 to 35.5° C.
26. The mesalamine suppository of claim 18 , the oily or fatty base is hard fat.
27. The mesalamine suppository of claim 19 , the oily or fatty base is hard fat.
28. The mesalamine suppository of claim 19 , wherein the drug load ranges from about 39 to about 45%.
29. The mesalamine suppository of claim 28 , wherein the drug load ranges from about 41 to about 43%.
30. The mesalamine suppository of claim 19 , wherein the suppository releases at least 90% by weight of the mesalamine within 30 minutes of dissolution as measured with USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
31. The mesalamine rectal suppository of claim 20 , wherein the suppository releases
(a) at least 41.4% (w/w) of the mesalamine after 20 minutes of dissolution, and
(b) at least 62.3% (w/w) of the mesalamine after 30 minutes of dissolution, as measured with USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
32. A method of treating active ulcerative proctitis in a patient in need thereof comprising administering the mesalamine rectal suppository of claim 19 to the patient.
33. A mesalamine rectal suppository comprising mesalamine particles and an oily or fatty base, wherein the mesalamine particles have a surface area of from about 0.1 m 2 /g to about 2.8 m 2 /g, the suppository has a drug load ranging from 35% to 50%, and the suppository releases
(a) between 15.0% and 95.1% (w/w) of the mesalamine after 10 minutes of dissolution,
(b) at least 27.9% (w/w) of the mesalamine after 20 minutes of dissolution, and
(c) at least 32.5% (w/w) of the mesalamine after 30 minutes of dissolution, as measured with USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
34. The mesalamine rectal suppository of claim 33 , wherein the surface area of the mesalamine particles ranges from about 1.3 m 2 /g to about 2.8 m 2 /g.
35. The mesalamine rectal suppository of claim 34 , wherein the suppository releases
(a) between 19.1% and 40.3% (w/w) of the mesalamine after 10 minutes of dissolution,
(b) between 27.9% and 70.7% (w/w) of the mesalamine after 20 minutes of dissolution, and
(c) between 32.5% and 94.8% (w/w) of the mesalamine after 30 minutes of dissolution, as measured with USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
36. A mesalamine rectal suppository comprising mesalamine particles and an oily or fatty base, wherein the mesalamine particles have a surface area of from about 0.1 m 2 /g to about 2.8 m 2 /g and a tap density ranging from about 600 to about 800 g/L (as measured by USP <616>), and the suppository releases at least about 85% by weight of the mesalamine within 1 hour of dissolution as measured with USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
37. The mesalamine rectal suppository of claim 36 , wherein the surface area of the mesalamine particles ranges from about 0.1 m 2 /g to about 1.3 m 2 /g.
38. The mesalamine rectal suppository of claim 36 , wherein the suppository has a drug load ranging from 35% to 50%.
39. The mesalamine rectal suppository of claim 36 , wherein the suppository comprises about 500 mg mesalamine.
40. The mesalamine rectal suppository of claim 36 , wherein the suppository comprises about 1 g mesalamine.
41. The mesalamine rectal suppository of claim 36 , wherein the suppository comprises about 1.5 g mesalamine.
42. A mesalamine rectal suppository comprising from 1.1 to 2.5 g mesalamine particles and an oily or fatty base, wherein the mesalamine particles have (i) a surface area of from about 0.1 m 2 /g to about 2.8 m 2 /g, (ii) a tap density ranging from about 600 to about 800 g/L (as measured by USP <616>), or (iii) both, and the suppository releases at least about 85% by weight of the mesalamine within 1 hour of dissolution as measured with USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
43. A mesalamine rectal suppository comprising mesalamine particles and an oily or fatty base, wherein the mesalamine particles have (i) a surface area of from about 0.1 m 2 /g to about 2.8 m 2 /g, (ii) a tap density ranging from about 600 to about 800 g/L (as measured by USP <616>), or (iii) both, the suppository having a drug load ranging from 25% to 50%, and the suppository releases at least about 85% by weight of the mesalamine within 1 hour of dissolution as measured with USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
44. The mesalamine rectal suppository of claim 43 , wherein the suppository comprises about 400 to about 800 mg mesalamine.
45. The mesalamine rectal suppository of claim 1 , wherein the suppository is a moulded suppository.
46. The mesalamine rectal suppository of claim 15 , wherein the suppository is a moulded suppository.
47. The mesalamine rectal suppository of claim 18 , wherein the suppository is a moulded suppository.
48. The mesalamine rectal suppository of claim 19 , wherein the suppository is a moulded suppository.
49. The mesalamine rectal suppository of claim 33 , wherein the suppository is a moulded suppository.
50. The mesalamine rectal suppository of claim 36 , wherein the suppository is a moulded suppository.
51. The mesalamine rectal suppository of claim 42 , wherein the suppository is a moulded suppository.
52. The mesalamine rectal suppository of claim 43 , wherein the suppository is a moulded suppository.