Drug delivery system for the prevention of cerebral vasospasm

1. A method of treating a cerebral vasospasm in a human subject, the method comprising the steps:

a) providing a flowable pharmaceutical composition for sustained release comprising a therapeutic amount of a therapeutic agent and a carrier, wherein the therapeutic agent comprises an L-type voltage-gated calcium channel inhibitor and the carrier comprises a plurality of microparticles, wherein the L-type voltage-gated calcium channel inhibitor is dispersed throughout each microparticle;

b) administering the pharmaceutical composition to the human subject locally via surgical injection into the subarachnoicl space in a cistern closest to a cerebral artery at risk for vasospasm, such that the composition flows around the cerebral artery without entering the systemic circulation in an amount to cause unwanted side effects;

wherein the pharmaceutical composition produces a localized pharmacologic effect: and

wherein the therapeutic amount is effective to treat the cerebral vasospasm.

2. The method of claim 1 , wherein the therapeutic agent comprises a calcium channel antagonist.

3. The method of claim 1 , wherein the therapeutic agent comprises a transient receptor potential protein blocker.

4. The method of claim 1 , wherein the therapeutic agent comprises an endothelin receptor antagonist.

5. The method of claim 1 , wherein the carrier is a gel compound.

6. The method of claim 1 , wherein the carrier is a semisolid compound.

7. The method of claim 1 , wherein the carrier is a slow-release solid compound.

8. The method of claim 1 , wherein the therapeutic agent is selected from the group consisting of amlodipine, aranidipine, azelnidipine, bamidipinc, benidipine, bepridil, cinaldipine, diltiazem, efonidipine, felodipine, gallopamil, isradipine, lacidipine, lemildipine, lercanidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, manidipine, pranidipine, verapamil or a combination thereof.

9. The method of claim 1 , wherein the therapeutic agent is selected from the group consisting of A-127722, ABT-627, BMS 182874, BQ-123, BQ-153, BQ-162, BQ-485, BQ-518, BQ-610, EMD-122946, FR 139317, IPI-725, L-744453, LU 127043, LU 135252, PABSA, PD 147953, PD 151242, PD 155080, PD 156707, RO 611790, SB-247083, clazosentan, atrasentan, sitaxsentan sodium, TA-0201, TBC 11251, TTA-386, WS-7338B, ZD-1611, aspirin, A-182086, CGS 27830, CP 170687, J-104132, L-751281, L-754142, LU 224332, LU 302872, PD 142893, PD 145065, PD 160672, RO-470203, bosentan, RO 462005, RO 470203, SB 209670, SB 217242, TAK-044, A-192621, A-308165, BQ-788, BQ-017, IRL 1038, IRL2500, PD-161721, RES 701-1, and RO 468443.

10. The method of claim 1 , wherein the therapeutic agent is selected from the group consisting of SKF 96365 and LOE 908.

11. The method of claim 1 , wherein the cistern closest to a cerebral artery at risk for vasospasm in step (b) is from about 0.001 mm to about 10 mm from the cerebral artery.

12. A method of treating a human subject for vasospasm after subarachnoid hemorrhage in at least one cerebral artery, the method comprising the steps of:

a) providing a flowable pharmaceutical composition for sustained release comprising a therapeutic amount of a therapeutic agent and a carrier, wherein the therapeutic agent comprises an L-type voltage-gated calcium channel inhibitor and the carrier comprises a plurality of microparticles, wherein the L-tvpe voltage-gated calcium channel inhibitor is dispersed throughout each microparticle;

b) administering the pharmaceutical composition to the human subject via surgical injection into the subarachnoid space in a cistern closest to a cerebral artery at risk for vasospasm, such that the composition flows around the cerebral artery without entering the systemic circulation in an amount to cause unwanted side effects;

wherein the pharmaceutical composition produces a localized therapeutic effect; and wherein the therapeutic amount is effective to treat the cerebral vasospasm.

13. The method of claim 12 , wherein the therapeutic agent comprises a transient receptor potential protein blocker.

14. The method of claim 12 , wherein the therapeutic agent comprises an endothelin receptor antagonist.

15. The method of claim 12 , wherein the carrier is a gel compound.

16. The method of claim 12 , wherein the carrier is a semisolid compound.

17. The method of claim 12 , wherein the carrier is a slow-release solid compound.

18. The method of claim 12 , wherein the therapeutic agent is selected from the group consisting of amlodipine, aranidipine, azelnidipine, bamidipine, benidipine, bepridil, cinaldipine, diltiazem, efonidipine, felodipine, gallopamil, isradipine, lacidipine, lemildipine, lercanidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, manidipine, pranidipine, verapamil or a combination thereof.

19. The method of claim 12 , wherein the therapeutic agent is selected from the group consisting of A-127722, ABT-627, BMS 182874, BQ-123, BQ-153, BQ-162, BQ-485, BQ-518, BQ-610, EMD-122946, FR 139317, IPI-725, L-744453, LU 127043, LU 135252, PABSA, PD 147953, PD 151242, PD 155080, PD 156707, RO 611790, SB-247083, clazosentan, atrasentan, sitaxsentan sodium, TA-0201, TBC 11251, TTA-386, WS-7338B, ZD-1611, aspirin, A-182086, CGS 27830, CP 170687, J-104132, L-751281, L-754142, LU 224332, LU 302872, PD 142893, PD 145065, PD 160672, RO-470203, bosentan, RO 462005, RO 470203, SB 209670, SB 217242, TAK-044, A-192621, A-308165, BQ-788, BQ-017, IRL 1038, IRL 2500, PD-161721, RES 701-1, and RO 468443.

20. The method of claim 12 , wherein the therapeutic agent is selected from the group consisting of SKF 96365 and LOE 908.

21. The method of claim 12 , wherein the cistern closest to the cerebral artery in step (b) is from 0.001 mm to about 10 mm from the cerebral artery.

22. The method of claim 1 , wherein the therapeutic agent further comprises at least one of a calcium channel antagonist, a, a transient receptor potential protein antagonist, or an endothelin receptor antagonist.

23. The method of claim 12 , wherein the therapeutic agent further comprises at least one of a calcium channel antagonist, a, a transient receptor potential protein antagonist, or an endothelin receptor antagonist.

24. The method of claim 1 , wherein the pharmaceutical carrier is a liquid pharmaceutical carrier, wherein the liquid pharmaceutical carrier transitions to a semisolid compound upon administration to the subarachnoid space.

25. The method of claim 12 , wherein the pharmaceutical carrier is a liquid pharmaceutical carrier, wherein the liquid pharmaceutical carrier transitions to a semisolid compound upon administration to the subarachnoid space.

26. The method according claim 7 , wherein the slow-release solid compound is a biodegradable polymer.

27. The method according to claim 26 , wherein the biodegradable polymer is polylactide-polyglycolide.

28. The method according to claim 26 , wherein the slow-release solid compound is a microencapsulated matrix.

29. The method according to claim 17 , wherein the slow-release solid compound is a biodegradable polymer.

30. The method according to claim 29 , wherein the biodegradable polymer is polylactide-polyglycolide.

31. The method according to claim 29 , wherein the slow-release solid compound is a microencapsulated matrix.

32. The method according to claim 1 , wherein the L-type voltage-gated calcium channel inhibitor is a dihydropyridine L-type calcium channel antagonist.

33. The method according to claim 1 , wherein the L-type voltage-gated calcium channel inhibitor is nimodipine.

34. The method according to claim 12 , wherein the L-typc voltage-gated calcium channel inhibitor is a dihydropyridine L-type calcium channel antagonist.

35. The method according to claim 12 , wherein the L-type voltage-gated calcium channel inhibitor is nimodipine.

36. The method according to claim 1 , wherein the composition further comprises an R-type voltage-gated calcium channel inhibitor.

37. The method according to claim 12 , wherein the composition further comprises an R-type voltage-gated calcium channel inhibitor.