Drug delivery system for the prevention of cerebral vasospasm

Abstract

The present invention relates to the treatment and prevention of vasospasm. The present invention provides a system for treating a cerebral vasospasm in a human utilizing a pharmaceutical composition and administrating a therapeutically effective amount of the pharmaceutical composition to a predetermined location in close proximity to a cerebral artery within a subarachnoid space wherein the pharmaceutical composition produces a localized pharmacologic effect thereby treating the cerebral vasospasm.

1 - 32 . (canceled) 
     
     
         33 . A flowable, sustained release pharmaceutical composition for treating cerebral vasospasm in a human subject, the pharmaceutical composition comprising:
 a) a therapeutic amount of a therapeutic agent selected from the group consisting of a calcium channel antagonist, an endothelin (ET) receptor antagonist, a transient receptor potential (TRP) channel antagonist, and a combination thereof; and   b) a pharmaceutically acceptable carrier, wherein the carrier comprises a plurality of microparticles, and wherein the therapeutic agent is dispersed throughout each microparticle,   wherein the composition is formulated for local delivery so that it is capable of flowing around a cerebral artery at risk of vasospasm, and   wherein the therapeutic amount is capable of producing a localized pharmacologic effect and thereby treating the cerebral vasospasm without entering the systemic circulation in an amount to cause unwanted side effects.   
     
     
         34 . The flowable, sustained release pharmaceutical composition of  claim 33 , wherein the calcium channel antagonist 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, and a combination thereof. 
     
     
         35 . The flowable, sustained release pharmaceutical composition of  claim 33 , wherein the calcium channel antagonist is an L-type voltage-gated calcium channel antagonist. 
     
     
         36 . The flowable, sustained release pharmaceutical composition of  claim 35 , wherein the calcium channel antagonist further comprises an R-type voltage-gated calcium channel antagonist. 
     
     
         37 - 39 . (canceled) 
     
     
         40 . The flowable, sustained release pharmaceutical composition of  claim 33 , wherein the pharmaceutically acceptable carrier is a gel compound. 
     
     
         41 . The flowable, sustained release pharmaceutical composition of  claim 33 , wherein the pharmaceutically acceptable carrier is a slow-release solid compound. 
     
     
         42 . The flowable, sustained release pharmaceutical composition of  claim 33 , wherein the pharmaceutically acceptable carrier is a semisolid compound. 
     
     
         43 . The flowable, sustained release pharmaceutical composition according to  claim 35 , wherein the L-type voltage-gated calcium channel antagonist is a dihydropyridine L-type calcium channel antagonist. 
     
     
         44 . The flowable, sustained release pharmaceutical composition according to  claim 35 , wherein the L-type voltage-gated calcium channel antagonist is nimodipine. 
     
     
         45 . The flowable, sustained release pharmaceutical composition according to  claim 41 , wherein the slow-release solid compound is a biodegradable polymer. 
     
     
         46 . The flowable, sustained release pharmaceutical composition according to  claim 45 , wherein the biodegradable polymer is polylactide-polyglycolide. 
     
     
         47 . The flowable, sustained release pharmaceutical composition according to  claim 41 , wherein the slow-release solid compound comprises a microencapsulated matrix. 
     
     
         48 . The flowable, sustained release pharmaceutical composition according to  claim 45 , wherein the composition comprises a bioadhesive polymer. 
     
     
         49 . The flowable, sustained release pharmaceutical composition according to  claim 48 , wherein the bioadhesive polymer is a polyhyaluronic acid. 
     
     
         50 . The flowable, sustained release pharmaceutical composition of  claim 33 , wherein the endothelin (ET) receptor antagonist 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, RO 468443, and a combination thereof. 
     
     
         51 . The flowable, sustained release pharmaceutical composition according to  claim 33 , wherein the transient receptor potential (TRP) channel antagonist is selected from the group consisting of gadolinium chloride, lanthanum chloride, SKF 96365, LOE-908, and a combination thereof. 
     
     
         52 . The flowable, sustained release pharmaceutical composition according to  claim 33 , wherein the local delivery is a surgical injection into subarachnoid space in a cistern closest to a cerebral artery at risk for vasospasm. 
     
     
         53 . The flowable, sustained release pharmaceutical composition according to  claim 50 , wherein the cistern is about 0.001 mm to about 10 mm from the cerebral artery. 
     
     
         54 . The flowable, sustained release pharmaceutical composition according to  claim 33 , wherein the pharmaceutical composition is in a form selected from the group consisting of a powder, a paste, a suspension, and a combination thereof. 
     
     
         55 . The flowable, sustained release pharmaceutical composition according to  claim 33 , wherein the pharmaceutical composition is malleable. 
     
     
         55 . The flowable, sustained release pharmaceutical composition according to  claim 33 , wherein the pharmaceutical composition is a long-term sustained release surgical implant for treatment of a chronic condition. 
     
     
         56 . The flowable, sustained release pharmaceutical composition according to  claim 54 , wherein the surgical implant is capable of delivering the therapeutic amount of the therapeutic agent for about 7 days to about 60 days. 
     
     
         57 . The flowable, sustained release pharmaceutical composition according to  claim 55 , wherein the implant is capable of delivering the therapeutic amount of the therapeutic agent for about 30 days to about 60 days.