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

Abstract

Abstract. Cilostazol (CLZ) is an anti-platelet agent that is generally used after the onset of cerebral infarction. However, CLZ is a poorly water-soluble drug and a strategy for increasing its bioavailability is required. In the present study, novel oral formulations were designed containing CLZ solid nanoparticles to improve bioavailability. The present study investigated the therapeutic effect of the oral formulations containing CLZ nanoparticles on ischemic stroke using a cerebral ischemia/reperfusion-induced injury model (MCAO/reperfusion mice). The oral formulation containing CLZ nanoparticles (CLZ/R nano tablet) was prepared using a combination of recrystallization and ball milling with the following ingredients: CLZ, docusate sodium, methylcellulose, 2-hydoxypropyl-β-cyclodextrin, gum arabic, polyvinylpyrrolidone, and mannitol. The particle size after re-dispersion of the CLZ/R nano tablet was 64±47 nm (mean ± standard deviation). The CLZ areas under the concentration-time curve (AUC) and mean residence time (MRT) in rats that were administered CLZ/R nano tablets were significantly greater compared with those in rats that were administered CLZ/R micro tablets. Results indicated, the AUC after administration of CLZ/R nano tablets was 3.1-fold higher compared with that after administration of the commercially available CLZ OD tablet. In addition, oral administration with CLZ/R nano tablets ameliorated neurological deficits caused by ischemic stroke in MCAO/reperfusion mice. It is possible that the oral formulation containing CLZ nanoparticles will be useful for the treatment of patients with ischemic stroke and that these findings will provide significant information that can be used to improve the drug with low bioavailability.

Enhanced percutaneous absorption of cilostazol nanocrystals using aqueous gel patch systems and clarification of the absorption mechanism

“…It is reported that nanoparticles from organic compounds are able to move through the spaces between the cells (28). In a previous study, we reported that recrystallization was suitable for the preparation of nanocrystals by using mill methods (16). These results suggested that the CLZ released from the CLZ nano gel patches was in a nanocrystal state.…”

“…We have previously designed drug nanocrystals by a combination of recrystallization and the breakdown method using a ball mill (16) and shown that CLZ nano enhanced drug bioavailability in the small intestine of rats (16).…”

“…Recrystallized CLZ was prepared as follows (16): CLZ (0.5 g) was dissolved in 50% ethanol (50 ml) at 120˚C, and the extracted CLZ was placed in a sonicator (Yamato Science Co., Ltd, Tokyo, Japan) for 5 sec and allowed to stand for 24 h. Thereafter, CLZ was collected by filtration (recovery rate: 92.3%). Nanocrystals of CLZ (CLZ nano ) were prepared by using zirconia balls and a Pulverisette 7 Planetary Micro Mill (Fritsch Corp., Kanagawa, Japan).…”

An overview on Pharmacokinetics of Polymeric Nanoparticles Intended for Oral Delivery

“…The BA of the drugs carried by the nanoparticles shown to be increasing many folds. [26][27][28][29][30] The BA concept, blood levels will not be corroborated to the effect when the nanoparticles are developed for targeting specific organs or tissues in the body. In targeted nanoparticles, the drug might not appear in reasonable quantities in the blood, but the action would be mightier than the free drug.…”

Effect of Polymer Type on the Dissolution Profile of a Solid Dispersion of Cilostazol

“…[1][2][3] Cilostazol is used for the treatment of chronic arterial occlusive disease and intermittent claudication; cilostazol was developed by Otsuka Pharmaceutical Co., Ltd., and is commercially available as immediate-release (50 and 100 mg) or controlled-release tablets (200 mg) for the treatment of intermittent claudication. 6,7 In addition, a relatively large inter-subject variability is observed in the bioavailability of cilostazol after oral administration, and the coefficients of variation are approximately 40-60% for the area under the curve (AUC) and maximum concentration (C max ). 6,7 In addition, a relatively large inter-subject variability is observed in the bioavailability of cilostazol after oral administration, and the coefficients of variation are approximately 40-60% for the area under the curve (AUC) and maximum concentration (C max ).…”