Combination therapy intravaginal rings
The present invention provides improved intravaginal drug delivery devices, i.e., intravaginal rings, useful for the prophylactic administration of dapivirine in combination with either an antimicrobial compound or a contraceptive to a human. The present invention also provides methods of blocking DNA polymerization by an HIV reverse transcriptase enzyme, methods of preventing HIV infection in a female human, methods of treating HIV infection in a female human, methods of preventing unintended pregnancy in a female human, and methods of preparing intravaginal rings.
1. An intravaginal ring comprising 10 mg to 800 mg of dapivirine and 10 mg to 800 mg of a contraceptive,
wherein 60 μg to 7 mg of dapivirine is released in vitro from said ring during an initial 24 hour period of release, and
wherein the release rate of the contraceptive from the intravaginal ring in vitro is increased as compared to the release rate of the contraceptive from an intravaginal ring comprising the contraceptive without dapivirine, and
wherein the intravaginal ring is a matrix-type ring, or a reservoir-type ring comprising a core and a sheath.
2. An intravaginal ring comprising 10 mg to 800 mg of dapivirine and 10 mg to 800 mg of a contraceptive,
wherein less than about 60 μg to 7 mg of dapivirine is released in vitro from said ring during an initial 24 hour period of release, and
wherein the dapivirine in the intravaginal ring increases the solubility of the contraceptive as compared to the solubility of the contraceptive in an intravaginal ring comprising the contraceptive without dapivirine, and
wherein the intravaginal ring is a matrix-type ring, or a reservoir-type ring comprising a core and a sheath.
3. An intravaginal ring comprising a eutectic composition comprising 10 mg to 800 mg of dapivirine and 10 mg to 800 mg of a contraceptive, wherein 60 μg to 7 mg of dapivirine is released in vitro from said ring during an initial 24 hour period of release, and wherein the intravaginal ring is a matrix-type ring, or a reservoir-type ring comprising a core and a sheath.
4. The intravaginal ring of claim 1 , wherein between 100 μg and 700 μg of dapivirine is released in vitro each day for 23 days after an initial 7 day period of release.
5. The intravaginal ring of claim 1 , wherein the intravaginal ring is a matrix-type ring, and wherein the contraceptive is released in vitro at a rate of 35 μg per day to 70 μg per day for 53 days after an initial 7 day period of release.
6. The intravaginal ring of claim 5 , wherein the contraceptive is released in vitro at a rate of 35 μg per day to 70 μg per day for 53 days after an initial 7 day period of release.
7. The intravaginal ring of claim 1 , wherein the intravaginal ring is a reservoir-type ring, and wherein 0 μg to 2 mg of the contraceptive is released from the ring during an initial 24 hour period of release, and wherein 20 μg per day to 290 μg per day of the contraceptive is released in vitro after an initial 7 day period of release.
8. The intravaginal ring of claim 7 ,
wherein 0 μg to 1 μg of the contraceptive is released in vitro from the ring during the initial 24 hour period of release,
wherein 35 μg per day to 70 μg per day of the contraceptive is released in vitro after the initial 7 day period of release for 23 days, or
wherein 35 μg per day to 70 μg per day of the contraceptive is released in vitro after the initial 7 day period of release for 53 days.
9. The intravaginal ring of claim 1 , wherein 2 μg to 100 μg per day of the contraceptive is released in vitro after the initial 7 day period of release for 23 days or for 53 days.
10. The intravaginal ring of any one of claims 1 , 2 and 3 , wherein 2 μg to 15 μg per day of the contraceptive is released in vitro after the initial 7 day period of release for 23 days or for abut 53 days.
11. The intravaginal ring of claim 1 , wherein the ring is a platinum-catalyzed ring.
12. The intravaginal ring of claim 1 , wherein the ring comprises a silicone polymer, an ethyl vinyl acetate (EVA) polymer, or a polyurethane polymer.
13. The intravaginal ring of claim 1 , wherein the dapivirine and the contraceptive are present in the core of the reservoir-type ring, and the sheath is blank.
14. The intravaginal ring of claim 1 , wherein the dapivirine and the contraceptive are present in two separate half-length cores, and the sheath is blank.
15. The intravaginal ring of claim 1 , wherein the contraceptive is present in the core, and the dapivirine is present in the sheath.
16. The intravaginal ring of claim 1 , wherein the core is platinum-catalyzed.
17. The intravaginal ring of claim 1 , wherein the core comprises a silicone polymer, an ethyl vinyl acetate (EVA) polymer, or a polyurethane polymer.
18. The intravaginal ring of claim 1 , wherein the contraceptive is levonorgestrel.
19. The intravaginal ring of claim 1 , wherein the contraceptive is estradiol, etonorgestrel or nestorone.
20. The intravaginal ring of claim 1 , wherein the dapivirine is present in the ring in a therapeutically effective amount or a prophylactically effective amount.
21. The intravaginal ring of claim 1 , wherein 10 mg to 30 mg or 10 mg to 200 mg of dapivirine is loaded in the ring.
22. The intravaginal ring of claim 1 , wherein 15 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, or 200 mg of dapivirine is loaded in the ring.
23. The intravaginal ring of claim 1 , wherein the contraceptive is present in the ring in a therapeutically effective amount or a prophylactically effective amount.
24. The intravaginal ring of claim 1 , wherein 10 mg to 100 mg or 100 mg to 700 mg of the contraceptive is loaded in the ring.
25. The intravaginal ring of claim 24 , wherein 16 mg, 25 mg, 32 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg or 400 mg of the contraceptive is loaded in the ring.
26. The intravaginal ring of claim 2 wherein release rates are stable following 3 months of storage, 6 months of storage, 12 months of storage, or 36 months of storage.
27. The intravaginal ring of claim 1 , wherein the intravaginal ring has an outer diameter of 54 mm, 55 mm, 56 mm, 57 mm, or 58 mm.
28. A method of blocking DNA polymerization by an HIV reverse transcriptase enzyme in a female human, comprising the step of inserting the intravaginal ring of claim 1 into the vagina of the female human.
29. A method of preventing HIV infection in a female human, comprising the step of inserting the intravaginal ring of claim 1 into the vagina of the female human.
30. A method of treating HIV infection in a female human, comprising the step of inserting the intravaginal ring of claim 1 into the vagina of the female human.
31. A method of preventing pregnancy and blocking DNA polymerization by an HIV reverse transcriptase enzyme in a female human, comprising the step of inserting the intravaginal ring of claim 1 into the vagina of the female human.
32. A method of preventing pregnancy and preventing HIV infection in a female human, comprising the step of inserting the intravaginal ring of claim 1 into the vagina of the female human.
33. A method of preventing pregnancy treating HIV infection in a female human, comprising the step of inserting the intravaginal ring of claim 1 into the vagina of the female human.
34. The intravaginal ring of claim 1 , wherein the intravaginal ring has a cross-sectional diameter of 7.0 mm, 7.1 mm, 7.2 mm, 7.3 mm, 7.4 mm, 7.5 mm, 7.6 mm, 7.7 mm, 7.8 mm, 7.9 mm, 8.0 mm, 8.1 mm, 8.2 mm, 8.3 mm, 8.4 mm, or 8.5 mm.