Compositions and their use to treat complications of aneurysmal subarachnoid hemmorrhage

Abstract

The described invention provides a method for treating an interruption of a cerebral artery in a subarachnoid space at risk of interruption caused by brain injury in a mammal, which reduces signs or symptoms of at least one delayed complication associated with brain injury using a flowable sustained release particulate composition.

1 - 44 . (canceled) 
     
     
         45 . A flowable particulate composition for treating a delayed complication of a brain injury that deposits blood in a subarachnoid space of the brain, wherein the brain injury is mediated by decreased cerebral perfusion, comprising:
 (A) a microparticle suspension comprising a plurality of particles of a uniform distribution of microparticle size, and a therapeutic amount of at least one therapeutic agent, wherein each microparticle comprises a matrix, and wherein the at least one therapeutic agent is a calcium channel antagonist; and   (B) a pharmaceutical carrier comprising an agent that affects viscosity of the suspension, the pharmaceutical composition being characterized by:   (i) dispersal of the at least one therapeutic agent throughout each particle; and   (ii) a drug load of 40%-100% (wt/wt) of the at least one therapeutic agent;   release characteristics as follows:   (a) release of about 50%-100% of the therapeutic agent within 6 days to 14 days;   (b) upon release, the concentration of the therapeutic agent in plasma (PLASMA-C av ) is less than about 30-40 ng/mL; and   (c) upon release, the concentration of the therapeutic agent in cerebrospinal fluid (CSF) (CSF-C av ) is at least about 5 ng/mL to about 5000 ng/mL,   (d) gradual release of the therapeutic agent from the composition over an extended period of time;   (e) as a dispersion, its fluidity around at least one cerebral artery in the subarachnoid space; and   (f) a local therapeutic effect; and   (g) the flowable particulate composition formulated for administration locally, via an injection apparatus, either intracisternally into the subarachnoid space in a cistern;   intraventricularly; or   intrathecally into the spinal subarachnoid space;   so that the microparticulate suspension releases the at least one therapeutic agent in the subarachnoid space to contact the at least one cerebral artery in the subarachnoid space without entering systemic circulation in an amount to cause unwanted side effects,   wherein the therapeutic amount is effective to improve perfusion and to treat the delayed complication comprising a delayed cerebral ischemia (DCI) comprising an angiographic vasospasm, formation of a plurality of microthromboemboli, a cortical spreading ischemia, or a combination thereof.   
     
     
         46 . The flowable particulate composition according to  claim 45 , wherein the cerebral artery is an anterior cerebral artery, a middle cerebral artery, an internal carotid artery, a basilar cerebral artery, a vertebral cerebral artery, or a combination thereof. 
     
     
         47 . The flowable particulate composition according to  claim 45 , wherein each microparticle is of a particle size from about 40 mm to about 100 mm. 
     
     
         48 . The flowable particulate composition according to  claim 47 , wherein the mean size distribution is about 70 mm. 
     
     
         49 . The flowable particulate composition according to  claim 45 , wherein each microparticle is loaded with at least 65% (wt/wt) of the at least one therapeutic agent. 
     
     
         50 . The flowable particulate composition according to  claim 45 , 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, or a combination thereof. 
     
     
         51 . The flowable particulate composition according to  claim 50 , 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. 
     
     
         52 . The flowable particulate composition according to  claim 51 , wherein the dihydropyridine is nimodipine. 
     
     
         53 . The flowable particulate composition according to  claim 45 , wherein the agent that affects viscosity of the suspension comprises between 0% to 5% by weight hyaluronic acid or a derivative thereof, wherein the hyaluronic acid has an average molecular weight of about 500 kDa. 
     
     
         54 . The flowable particulate composition according to  claim 45 , wherein the injection apparatus is a needle, a cannula, a catheter, or a combination thereof. 
     
     
         55 . The flowable particulate composition according to  claim 45 , wherein the viscosity of the suspension at 20° C., when administered intracisternally, is from about 100 cP to about 1,000 cp. 
     
     
         56 . The flowable particulate composition according to  claim 45 , wherein the viscosity of the suspension at 20° C., when administered intraventricularly, is from about 0.5 cP to about 50 cp. 
     
     
         57 . The flowable particulate composition according to  claim 45 , wherein the viscosity of the suspension at 20° C., when administered intrathecally into the spinal subarachnoid space, is from about 0.5 cP to about 50 cp. 
     
     
         58 . The flowable particulate composition according to  claim 45 , wherein maximum tolerated dose of the therapeutic agent when administered intracisternally is from 40 mg to about 1,000 mg. 
     
     
         59 . The flowable particulate composition according to  claim 45 , wherein maximum tolerated dose of the therapeutic agent when administered intraventricularly is from 40 mg to about 1,000 mg. 
     
     
         60 . The flowable particulate composition according to  claim 45 , wherein maximum tolerated dose of the therapeutic agent when administered intrathecally is from 40 mg to about 1,000 mg. 
     
     
         61 . The flowable particulate composition according to  claim 45 , wherein the flowable particulate composition is administered intraventricularly in a lateral ventricle, a third ventricle, a fourth ventricle, or a combination thereof. 
     
     
         62 . The flowable particulate composition according to  claim 45 , wherein the cistern is a carotid cistern, a chiasmatic cistern, a Sylvian cistern, an interhemispheric cistern, an ambient cistern, a crural cistern, an interpeduncular cistern, a prepontine cistern, a lateral medullary cistern, a cisterna magna, or a combination thereof. 
     
     
         63 . The flowable particulate composition according to  claim 45 , wherein the particulate formulation comprises a femtoparticle, a picoparticle, a microparticle, or a nanoparticle. 
     
     
         64 . The flowable particulate composition according to  claim 45 , wherein the matrix comprises a biodegradable polymer. 
     
     
         65 . The flowable particulate composition according to  claim 64 , wherein the biodegradable polymer is a poly(lactide-co-glycolide) (PLGA) polymer, wherein the lactide to glycolide ratio is 65:35 or 50:50. 
     
     
         66 . The flowable particulate composition according to  claim 45 , wherein the pharmaceutically acceptable carrier comprises a matrix. 
     
     
         67 . The flowable particulate composition according to  claim 45 , wherein the pharmaceutically acceptable carrier comprises nanoparticles. 
     
     
         68 . The flowable particulate composition according to  claim 67 , wherein the therapeutic agent is dispersed throughout the nanoparticles, adsorbed into the nanoparticles, in a core of the nanoparticles surrounded by a coating, or a combination thereof. 
     
     
         69 . The flowable particulate composition according to  claim 45 , wherein the pharmaceutically acceptable carrier is a slow release carrier. 
     
     
         70 . The flowable particulate composition according to  claim 45 , wherein the pharmaceutically acceptable carrier is a localized release carrier. 
     
     
         71 . The flowable particulate composition according to  claim 45 , wherein the pharmaceutically acceptable carrier is a depot release carrier. 
     
     
         72 . The flowable particulate composition according to  claim 45 , wherein the pharmaceutically acceptable carrier is a delayed release carrier. 
     
     
         73 . The flowable particulate composition according to  claim 45 , wherein the pharmaceutically acceptable carrier is a long-term release carrier. 
     
     
         74 . The flowable particulate composition according to  claim 45 , wherein the pharmaceutically acceptable carrier is a biphasic release carrier. 
     
     
         75 . The flowable particulate composition according to  claim 45 , wherein the pharmaceutically acceptable carrier is an extended release carrier. 
     
     
         76 . The flowable particulate composition according to  claim 45 , wherein the concentration of the therapeutic agent in plasma (PLASMA-Cav) is from 0.200 ng/ml/day to 30 mg/ml/day for at least 4 days after administration. 
     
     
         77 . The flowable particulate composition according to  claim 45 , wherein the concentration of the therapeutic agent in plasma (PLASMA-Cav) is less than 5 ng/ml/day for at least 14 days after administration. 
     
     
         78 . The flowable particulate composition according to  claim 45 , wherein the concentration of the therapeutic agent in cerebrospinal fluid (CSF) (CSF-Cav) is from 5 ng/ml/day to 30 mg/ml/day for at least 14 days after administration. 
     
     
         79 . The flowable particulate composition according to  claim 45 , wherein the therapeutic amount of the therapeutic agent is effective to decrease angiographic diameter of the cerebral artery at risk of interruption such that percent change in angiographic diameter of at least one cerebral artery is less than 50% compared to baseline. 
     
     
         80 . The flowable particulate composition according to  claim 45 , wherein the therapeutic amount of the therapeutic agent is effective to decrease occurrence of delayed cerebral ischemia (DCI) within 14 days of symptom onset of subarachnoid hemorrhage (SAH). 
     
     
         81 . The flowable particulate composition according to  claim 45 , wherein the therapeutic amount of the therapeutic agent is effective to decrease occurrence of delayed cerebral infarction on CT within 30 days of symptom onset of subarachnoid hemorrhage (SAH). 
     
     
         82 . The flowable particulate composition according to  claim 45 , wherein the therapeutic amount of the therapeutic agent is effective to decrease occurrence of delayed cerebral ischemia. 
     
     
         83 . The flowable particulate composition according to  claim 82 , wherein occurrence of delayed cerebral ischemia is assessable as a decrease of at least 2 points on the modified glasgow coma score or an increase of at least 2 points on the abbreviated National Institutes of Health Stroke Scale lasting for at least 2 hours. 
     
     
         84 . The flowable particulate composition according to  claim 45 , wherein the therapeutic amount of the therapeutic agent is effective to reduce need for rescue therapy.