Development And Study Of A New PH-sensitive Cyclosporine A Nanoparticles

The main purpose of this paper was to develop a new pH-sensitive Cyclosporine A -loaded nanoparticles and its freeze-drying formulation, investigate on the physico-chemical characteristics, pharmacokinetics as well as hypersensitivity reaction of them.In order to improve the bioavailability of lipophilic Cyclosporine A(CyA) and lessen the hypersensitivity reaction of its commercial preparation, a new pH-sensitive CyA nanoparticles consisting of enteric dissolved material Eudragit? S100 (CyA-NP) was prepared with quasi-emulsion solvent diffusion technique. The particle size, polydispersity index and encapsulation efficiency were introduced as indexes to optimize the compositions and conditions for the process in orthogonal design experiments; the morphological characteristic, size distribution, encapsulation efficiency and in vitro released characteristic from vehicles of CyA were studied individually. The results showed that the CyA-NP looked round and regular under transmission electron microscopy; the particle size was 44.8±3.2nm, and distributed between 20 and 82nm; a polydispersity index of 0.59±0.11 and a maximum encapsulation efficiency up to (99.7±0.1)%; the signification pH-dependant release profiles were revealed when the medium pH was above 6.0. It was found in the influencing facter tests that high temperature and high light can cause the aggregation of CyA-NP, which indicated it should be tightly preserved from light and stored at low temperature; the CyA-NP colloids was stored at 25℃and 4℃for 3 months respectively, and the particle size increased to 75.3 nm and 66.2nm accompanied with some flocculate.Vacuum freeze-drying technique was bring to make the nanoparticle colloids into freeze dried CyA-NP power to improve its permanent stability. The particle size and encapsulation efficiency of Fd-CyA-NP remained relative stable by using 3% lactose (W/N) as cryoprotective agent (Lac-CyA-NP) before freeze-drying and after dissolving. the mean size of Lac-CyA-NP was 52.7±4.6nm and the encapsulation efficiency up to (99.8±0.1)%. The morphological characteristic of Lac-CyA-NP was regular spherical, and having the same in vitro release behavior as CyA-NP which was pH sensitive and could rapidly released when pH>6.0.CyA-NP and Lac-CyA-NP were oral administrated to rats respectively, using Neoral as reference to study on their pharmacokinetics. As a result, the two nanopartilces showed higher Cmax and AUC, significantly improved the relative bioavailability of CyA to 162.1% and 130.1%(P﹤0.01)respectively. The AUC of CyA-NP was higher than that from Lac-CyA-NP, but there was no statistical significance between them. Thus, Lac-CyA-NP gave the bioavailability similar to that of CyA-NP in rats.(P>0.05).Moreover, the hypersusceptibility of the two nanoparticles was tested with guinea pig by using Neoral as reference. The results proved that because of the replacement of Poloxamer 188 for Cremophor EL, the two nanoparticle's incidence of hypersensitivity reaction and toxic symptom was weaker than Neoral.