阿托伐他汀自微乳释药系统的制备和评价

Preparation and evaluation of self-microemulsifying drug delivery systems containing atorvastatin

目的制备阿托伐他汀自微乳,为自微乳释药系统的处方设计和体内外评价提供参考。方法采用伪三元相图法研究不同乳化剂、助乳化剂和油相形成微乳的能力和区域,绘制不同处方组成的相图,在此基础上制备阿托伐他汀自微乳,比较温度、介质、稀释等因素对自微乳效率的影响,进行自微乳时间、所成微乳的形态、粒径分布、zeta电位、含量和稳定性等体外评价Beagle犬体内药代动力学研究。结果理想的处方经分散后可得到平均粒径在100nm以下、呈高斯分布的微乳,稳定性好,自微乳效率高,在Beagle犬体内的吸收明显高于市售片剂。结论本文首次研制阿托伐他汀自微乳,稳定性好,在Beagle犬体内的生物利用度高。

Aim To prepare self-mieroemulsifyiug drug delivery system （SMEDDS） containing atorvastatin,and decrease its size to improve the solubility in the stomach. And to study the effect of the resultant mieroenulsion in reducing the presystemic clearance in the gastrointestinal mucosa and hepatic first-pass metabolism, improving the oral hioavailability, and redueing side effect and expenditure. Methods Pseudoternary phase diagrams were used to evaluate the self-mieroemulsifieation existence area. The HPLC analyses in vitro and in vivo were set up. Solubility in various vehicles was determined. The self-microemulsification efficiency was assessed, such as self-microcnulsifieation time, stability, particle size and zeta potential. SMEDI）S containing atorvastatin, non-ionlc surfactant and lipid were prepared. Droplet size/ distributions arid zeta potential of the resultant microemulsion were determined. Photos were taken with transmission electron microscope. Oral bioavailability uas studied on prepared SMEDDS hard capsules and compared with that of the conventional tablet in Beagle dogs in vivo. Results The optimal formulations had wide microemulsion existent field and had good self-mieroemulsifying efficiency. Droplet size was within 100 nm and showed Gaussian distribution. After oral administration of SMEDDS capsules and the conventional tablet to fasted Beagle dogs, the C from SMEDDS was greater than that of the conventional tablet. AUC from zero to 24 h of SMEDDS was ahout 1.5-fold higher than that of the conventional tablet. Oral bioavailability of atorvastatin SMEDDS was greater than that of the conventional tablet. Conclusion The resuhs indicated the potential use of SMEDDS for the delivery of atorvastatin to increase its oral hioavailability.