坎地沙坦酯脂质体冻干粉的制备及在大鼠体内药动学研究

Preparation of candesartan cilexetil liposome-lyophilized powder and its pharmacokinetics study in rats

目的制备并评价泊洛沙姆407修饰的坎地沙坦酯脂质体(CC/PLip),考察其口服给药后在大鼠体内药动学过程。方法用薄膜分散法制备坎地沙坦酯脂质体,经冷冻干燥制成冻干粉。动态光散射(DLS)测定其Zeta电位和粒径,透射电镜(TEM)观察其形态,超滤离心法测定包封率;采用口服给药,观察肠道黏膜渗透行为,分析药物在大鼠体内的药代动力学参数。结果泊洛沙姆407修饰的坎地沙坦酯脂质体呈现球形,粒径为(182.67±4.10)nm,Zeta电位为(-8.98±0.19)m V,包封率为98.94%±0.60%;体外释放试验结果表明其具有明显的缓释效果;肠道黏膜渗透试验表明坎地沙坦酯脂质体在小肠易被吸收;药动学实验中,参比坎地沙坦酯片和坎地沙坦酯脂质体的AUC_(0→48 h)分别为(13 112.6±5 343.7)、(19 522.8±3 973.7)ng·h·mL^(-1);C_(max)分别为(656.8±345.0)、(1 199.1±330.7)ng·mL^(-1);T_(max)分别为(7.3±3.0)、(2.7±1.4)h。结论坎地沙坦酯脂质体包封率较高,粒径较小,具有缓释效果,能提高在小肠的吸收,可显著提高在大鼠体内的生物利用度。

Objective To prepare and evaluate poloxamer 407 decorated liposomes of candesartan cilexetil（ CC/PLip）,and investigate the pharmacokinetics in rats.Methods The CC/PLip was prepared by the film dispersion method,and the freeze-dried powder of CC/PLip was obtained by freeze drying.The Zeta potential and particle size were measured by dynamic light scattering（ DLS）.The morphology was observed by transmission electron microscopy（ TEM）,and the encapsulation efficiency was measured by ultrafiltration centrifugation.Intestinal penetration in rats was carried out with FITCloaded liposome by oral administration.Pharmacokinetics study in rats was carried out by oral administration and analysis of rats pharmacokinetic parameters.Results The CC/PLip was spherical,the mean diameter was（ 182.67±4.10） nm,the Zeta potential was（-8.98±0.19） m V,the encapsulation efficiency was 98.94% ± 0.60%. In vitro release test results showed that CC/PLip had significant slow-release effects. Intestinal penetration test results showed that CC/PLip was easily to be absorbed in the small intestine. The pharmacokinetic parameters of reference preparation and CC/PLip were as follows：AUC0→48 h were（ 13 112.6±5 343.7） and（ 19 522.8±3 973.7） ng·h·mL-1; Cmax were（ 656. 8 ± 345. 0） and（ 1 199. 1 ±330.7） ng·mL-1; Tmax were（ 7.3±3.0） and（ 2.7±1.4） h.Conclusion The CC/PLip had the high entrapment efficiency,small particle size and slow-release effects.They can increase the uptake of candesartan cilexetil and significantly improve the bioavailability in rats.