Pharmacokinetic behavior of cyclosporin A in rabbits by oral administration of lecithin vesicle and sandimmun neoral

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Abstract

The present study was undertaken to investigate the incorporation of lipophilic polypeptide, cyclosporin A (CsA) into lecithin vesicular system and to compare its pharmacokinetics behavior with Sandimmun Neoral® (CsA-NEO). Lecithin vesicles of cyclosporin A (CsA-VES) were prepared by the rotary evaporation method, treated further with sonication. Studies were carried out to characterize the vesicles on physical properties, content, entrapment efficiency, particle size, polydispersity and Zeta potential. Pharmacokinetic behaviors were studied in rabbits at dose of 30 mg/kg. Results showed CyA vesicles were spherical particles, with content of 3.137±0.060% mg/ml, entrapment efficiency of 98.91±0.80%, particle size of 63.89±4.75 nm, polydispersity of 43.2±6.1% and Zeta potential of −13 mV. The best model fitting experimental data was a two-compartment open model with first-order kinetics. The relative bioavailability of CsA-VES versus CsA-NEO was 105±21% (n=6) and statistical analysis demonstrated both preparations were bioequivalent. In conclusion, lecithin vesicles are promising carriers in the oral delivery of CsA, considering their absorption enhancement effect and low-toxic property.

Introduction

Nowadays, numerous efforts are being made to enhance the oral bioavailability of polypeptides in order to increase their clinical efficacy. The incorporation of the active component into lipid vesicles is very attractive. Advantages include increased solubility and protection of the polypeptides from the aggressive conditions present in the gastrointestinal tract (Arien et al., 1994, Arien et al., 1995). Furthermore, the biomembrane similarity of the lecithin material and the small particle size of the vesicles may result in rapid absorption (Aungust, 1993). It has been reported that oral administration of liposomes loaded with calcitonin led to hypocalcemic effect in the rat 1 h after the application (Fukunaga et al., 1991).

Cyclosporin A (CsA) is a lipophilic cyclic polypeptide containing 11 amino acids and was reported as a typical drug with the worst and non-regular absorption (Klompmaker et al., 1993). The present study was undertaken to characterize the incorporation of CsA into lecithin vesicular system and to compare its pharmacokinetics behavior in rabbits with Sandiummun Neoral® (CsA-NEO). Sandiummun Neoral® is a highly recommended new microemulsion formulation concentrated CsA (Kovarik et al., 1994).

Section snippets

Materials

Soybean lipid (purity >80%, lot number: 980607) was purchased from Shanghai Fuda pharmaceutical manufacturing factory (China) and lecithin was freshly prepared by column chromatography on aluminum oxide according to the reported method (Singelton et al., 1964). Only lecithin with purity >95% was used in this study. CsA powder (USP 23, lot number: 040396) was obtained from Galena (Czech Republic). Methanol, chloroform, sodium chloride and other reagents, all p.a. were products of Nanjing

Physical properties of vesicles

CsA-VES suspension was transparent colloidal dispersions with average diameter of 77.6 nm and the polydispersity index of 45.6%. Zeta potential was −13 mV.

Fig. 1 showed the transmission electron photomicrographs of vesicles. It was evident that the particles were approximately spherical with obvious whorls.

Determination of CsA

The regression equation for CsA content (μg/ml) in ethanol solution ranging from 0.1 to 4 μg/ml was A=7.52×103C−74.66 (r2=0.9999). The mean recovery was 97.4±5.9% (n=3). Precision assay

Discussion

CsA is a potent immunosuppressive drug and has been utilized clinically in the prevention of organ rejection (Mcevoy, 1995). Due to its high lipophilicity, poor solubility in aqueous fluids, the existence of an absorption window in the small intestine (Reymond et al., 1988) and relatively high molecular weight, the mean absolute bioavailability of CsA is approximately only 30%, when the drug is administered as Sandiummun®, a crude oil-in-water emulsion (Mcevoy, 1995). In order to increase

Acknowledgements

This research work is granted by the National Natural Science Foundation of China, with project number 39930200.

References (13)

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