Intravenous Administration of Cilostazol Nanoparticles Ameliorates Acute Ischemic Stroke in a Cerebral Ischemia/Reperfusion-Induced Injury Model

Abstract

It was reported that cilostazol (CLZ) suppressed disruption of the microvasculature in ischemic areas. In this study, we have designed novel injection formulations containing CLZ nanoparticles using 0.5% methylcellulose, 0.2% docusate sodium salt, and mill methods (CLZnano dispersion; particle size 81 ± 59 nm, mean ± S.D.), and investigated their toxicity and usefulness in a cerebral ischemia/reperfusion-induced injury model (MCAO/reperfusion mice). The pharmacokinetics of injections of CLZnano dispersions is similar to that of CLZ solutions prepared with 2-hydroxypropyl-β-cyclodextrin, and no changes in the rate of hemolysis of rabbit red blood cells, a model of cell injury, were observed with CLZnano dispersions. In addition, the intravenous injection of 0.6 mg/kg CLZnano dispersions does not affect the blood pressure and blood flow, and the 0.6 mg/kg CLZnano dispersions ameliorate neurological deficits and ischemic stroke in MCAO/reperfusion mice. It is possible that the CLZnano dispersions will provide effective therapy for ischemic stroke patients, and that injection preparations of lipophilic drugs containing drug nanoparticles expand their therapeutic usage.

An oral formulation of cilostazol nanoparticles enhances intestinal drug absorption in rats

“…Recently, Kasahara et al (25) reported that treatment with CLZ suppressed the disruption of the microvasculature in ischemic areas. In addition, we reported that the intravenous administration of CLZ attenuated brain damage when administered immediately after the onset of ischemic stroke symptoms in MCAO/reperfusion mice (15). From these findings, we investigated whether the oral administration of CLZ/R tablets prevented ischemic stroke in MCAO/reperfusion mice and found that CLZ/R nano tablets attenuated ischemic stroke (Fig.…”

“…We previously designed drug nanoparticles by the breakdown method using a ball and bead mill (13)(14)(15)(16)(17)(18) and showed that indomethacin solid nanoparticles enhanced drug bioavailability in the small intestine of rats (17). In this study, we designed new oral formulations containing CLZ solid nanoparticles using a combination of recrystallization and breakdown methods.…”

“…Focal cerebral ischemia/reperfusion was caused by middle cerebral artery occlusion (MCAO), which was completed following the method described in our previous reports (15). MCAO was induced by the insertion of a silicone-coated 8-0 nylon monofilament into the left middle cerebral artery under isoflurane anesthesia.…”

“…We also reported a method for producing drug nanoparticles using the ball and bead mill (13)(14)(15)(16)(17)(18) and showed that indomethacin solid nanoparticles exhibited enhanced drug bioavailability after oral administration (17). We hypothesized that an oral formulation of CLZ nanoparticles would provide high drug absorption and that enhancing the bioavailability of CLZ would increase its effectiveness for preventing neuronal cell death after transient cerebral ischemia.…”

Novel Sustained-Release Drug Delivery System for Dry Eye Therapy by Rebamipide Nanoparticles

“…Solid drug nanoparticles come with the added benefits of possible cellular targeting and improvement in cellular uptake and have been used widely as nanotechnology-based delivery systems. We previously designed solid nanoparticles created by a breakdown method (bead mill), and reported on their low toxicity and high transdermal penetration via endocytosis when used in nano-formulations [12][13][14][15][16]. It is expected that the application of solid nanoparticles to the eyelid may be a possible route to sustained drug supplementation to the ocular surface and provide a novel strategy for ophthalmic DDS.…”