Intraventricular drug delivery system for improving outcome after a brain injury affecting cerebral blood flow

Abstract

The described invention provides a flowable sustained release microparticulate composition effective to improve cerebral perfusion and to treat a delayed complication of a brain injury mediated by decreased cerebral perfusion that deposits blood in a subarachnoid space of the brain. The described invention also provides a method for preparing a flowable sustained release microparticulate composition.

1 - 20 . (canceled) 
     
     
         21 . A flowable sustained release microparticulate composition, comprising:
 (i) a suspension of microparticles comprising a biodegradable polymer matrix comprising a therapeutic amount at least one therapeutic agent selected from the group consisting of a calcium channel antagonist, an endothelin (ET) receptor antagonist, and a transient receptor potential (TRP) channel antagonist, and   (ii) a pharmaceutically acceptable carrier that affects viscosity of the suspension of microparticles,
 the composition being characterized by 
 1) dispersal of the therapeutic amount of the therapeutic agent throughout each microparticle, 
 2) an initial drug load of about 40% to about 80% by weight of the therapeutic agent; 
 3) gradual release of the therapeutic agent from the composition over an extended period of time, and 
 4) release of one half of the therapeutic agent from the microparticulate suspension within 1 day to 30 days in vivo, 
 wherein 
 the composition is effective to improve cerebral perfusion and to treat a delayed complication of a brain injury mediated by decreased cerebral perfusion that deposits blood in a subarachnoid space of the brain; and 
 the delayed complication comprises a delayed cerebral ischemia (DCI) comprising formation of a plurality of microthromboemboli, a cortical spreading ischemia, an angiographic vasospasm, or a combination thereof. 
   
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . The composition according to  claim 21 , wherein the flowable sustained release microparticulate composition, upon delivery into a cerebral ventricle, is effective to flow from cerebrospinal fluid (CSF) in the cerebral ventricle into cerebrospinal fluid (CSF) in the subarachnoid space before sustained release of the therapeutic agent in the subarachnoid space. 
     
     
         25 . The composition according to  claim 21 , wherein the calcium channel antagonist is selected from the group consisting of an L-type voltage dependent calcium channel inhibitor, an R-type voltage dependent calcium channel inhibitor, an N-type voltage dependent calcium channel inhibitor, a P/Q-type voltage dependent calcium channel inhibitor, a T-type voltage dependent calcium channel inhibitor, and a combination thereof. 
     
     
         26 . The composition according to  claim 25 , wherein the L-type voltage dependent calcium channel inhibitor is a dihydropyridine, selected from the group consisting of amlodipine, aranidipine, azelnidipine, bamidipine, benidipine, cinaldipine, efonidipine, felodipine, isradipine, lacidipine, lemildipine, lercanidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, manidipine, pranidipine, or a combination thereof. 
     
     
         27 . The composition according to  claim 26 , wherein the dihydropyridine is nimodipine. 
     
     
         28 . The composition according to  claim 21 , wherein the suspension of microparticles comprises a powder suspension of microparticles. 
     
     
         29 . The composition according to  claim 21 , wherein the suspension of microparticles further comprises a slow-release compound. 
     
     
         30 . The composition according to  claim 29 , wherein the slow release compound is a biodegradable polymer. 
     
     
         31 . The composition according to  claim 30 , wherein the biodegradable polymer is selected from the group consisting of polylactide, polyglycolide, polycaprolactone, polylactide-polyglycolide, poly(orthoester), and poly(anhydride). 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . (canceled) 
     
     
         35 . The composition according to  claim 21 , wherein the flowable sustained release microparticulate composition is effective to produce a predominantly localized effect around the cerebral artery in the subarachnoid space. 
     
     
         36 . The composition according to  claim 21 , wherein the therapeutic amount of the therapeutic agent is effective to increase the internal diameter of a cerebral artery in the subarachnoid space. 
     
     
         37 . The composition according to  claim 21 , wherein the pharmaceutical carrier comprises a buffer solution. 
     
     
         38 - 65 . (canceled) 
     
     
         66 . The composition according to  claim 21 , wherein the pharmaceutical carrier comprises hyaluronic acid. 
     
     
         67 . The composition according to  claim 21 , wherein the suspension of microparticles comprises microparticles of a uniform distribution of microparticle size. 
     
     
         68 . The composition according to  claim 21 , wherein the composition is formulated for intraventricular delivery.