坦西莫司脂质体冻干剂的制备及大鼠药代动力学
Preparation of lyophilized temsirolimus-loaded liposomes and their pharmacokinetics in rats
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摘要: 制备坦西莫司脂质体冻干剂，优化其处方及工艺，并进行大鼠药代动力学研究。用薄膜分散法制备坦西莫司脂质体，采用冷冻干燥法制备脂质体冻干剂，单因素实验考察最佳处方为:磷脂浓度24 mg/mL，药物与磷脂质量比1∶40，磷脂与胆固醇质量比10∶1，冻干保护剂蔗糖与磷脂的质量比2∶1。复溶后粒径(100.8±6.74)nm，包封率(95.24±3.58)%。透析法研究脂质体的体外释放行为，37 ℃下，在pH 7.4的磷酸盐缓冲液中24 h释放不到30 %。用高效液相色谱法研究最佳处方脂质体的大鼠药代动力学，其最高血药浓度为市售制剂Torisel®；的3.06倍，生物利用度为Torisel®；的2.49倍。实验结果显示，经过处方工艺优化后的坦西莫司脂质体冻干剂包封率较高，具有缓释效果，可以显著提高坦西莫司在大鼠体内的生物利用度。Abstract: Lyophilized temsirolimus-loaded liposomes were prepared; the formulations were optimized; and the pharmacokinetics in rats was investigated. The lyophilized temsirolimus-loaded liposomes were prepared by film dispersion, followed by freeze drying. Formulations were optimized by single-factor design. The optimized formulation contained 24 mg/mL phosphatidyl choline(PC), a weight ratio of 1 ∶40 between drug loading and PC, and a weight ratio of 10 ∶1 between PC and cholersterol. Sucrose was determined as an optimal lyoprotectant, and the weight ratio between sucrose and PC was 2 ∶1. The optimized liposomes had a particle size of(100. 8±6. 74)nm and an entrapment efficiency of(95. 24±3. 58)%. Dialytic method was used to investigate the drug release profile. Less than 30% of entrapped drug was released after 24 h at pH 7. 4 under 37 °C. In addition, pharmacokinetics of temsirolimus in rats receiving commercial product Torisel® and temsirolimus-loaded liposomes was evaluated after HPLC determination of temsirolimus in rat plasma. cmax and AUC of the liposomes were 2. 06- and 1. 49-fold improved relative to that of Torisel® , respectively. In conclusion, the optimized lyophilized temsirolimus-loaded liposomes with high entrapment efficiency achieved sustained release and significantly increased bioavailability of temsirolimus in rats.
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Keywords:
- temsirolimus /
- liposome /
- film dispersion method /
- freeze-drying /
- pharmacokinetics
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