伊维菌素脂质体的制备及其在山羊体内药动学、驱虫效果的研究
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摘要
本研究旨在研制出包封率高、稳定性好、安全、高效的伊维菌素脂质体,并对其在山羊体内的药物动力学过程以及对山羊的驱虫效果进行研究。
1.伊维菌素脂质体的制备本试验利用正交试验设计,筛选、优化处方和工艺,最后采用改良薄膜分散法制备出了包封率高、稳定性好的伊维菌素脂质体。试验结果表明:影响伊维菌素脂质体稳定性的主要因素为磷脂与胆固醇的配比,其次为药脂比。其制备方法的最佳处方工艺组合为卵磷脂与胆固醇质量比为9︰1,IVM与卵磷脂质量比为1︰10,缓冲液PBS的pH为7.0,超声裂解时间为5 min,蒸发温度为40℃,冻融3次。按以上最佳处方制备,3次包封率平均达(90.71±0.8) %,符合中华人民共和国药典规定。
2.伊维菌素脂质体的理化性质用透射电镜、激光粒度分布仪等对其理化性质进行研究。结果表明,伊维菌素脂质体是乳白色均一稳定的牛奶状液体,其平均粒径为(91.8±1.5) nm,符合脂质体的要求,粒径分布范围窄,且比较均匀。均证明,制备的伊维菌素脂质体具有较好的稳定性,对光不稳定,应该避光保存。
3.伊维菌素脂质体的稳定性考察用紫外可见分光光度法测定伊维菌素脂质体中伊维菌素的含量,并通过高湿度试验、加速试验、长期试验、留样观察试验考察其稳定性。试验结果表明,伊维菌素在250 nm处有最大吸收,在2μg/mL~48μg/mL范围内线性关系良好,其平均回收率为96.51 %,RSD为0.03 %。平均包封率为(90.71±0.8) %,该方法可用于伊维菌素脂质体的包封率和含量的测定,外观和含量未发生明显变化。
4.伊维菌素脂质体急性毒性试验通过急性毒性试验对伊维菌素脂质体进行安全性评价。结果表明,伊维菌素脂质体对小鼠的LD50为103.04 mg/kg。
5.伊维菌素脂质体在山羊体内的药物动力学试验健康山羊皮下注射伊维菌素脂质体,不同时间点采血,高效液相色谱法测定血药浓度,残数法拟合药时曲线,计算药动学参数。6只山羊皮下注射伊维菌素脂质体(0.2 mg/kg)后,其药动学配置符合有吸收因素二室模型特征。最佳药时曲线方程为:C=41.2768·e-0.6564·t+4.9744·e-0.0809·t-46.2512·e-0.7244·t。伊维菌素在山羊体内的吸收半衰期(t1/2Ka)为0.499±0.264 d,消除半衰期(t1/2Ke)为6.859±1.002 d,药时曲线下面积(AUC)为77.066±17.315 (ng/mL)·d。表明伊维菌素脂质体在山羊体内吸收迅速,消除相对较慢。
6.伊维菌素脂质体在山羊体内驱虫效果的研究在山羊体内通过皮下注射伊维菌素脂质体三个不同治疗剂量(0.2 mg/kg、0.5 mg/kg、1.0 mg/kg)进行驱虫,与伊维菌素普通注射剂(0.2 mg/kg)相比发现伊维菌素脂质体具有良好的缓释作用,且以1.0 mg/kg剂量皮下注射效果最好。
The purpose of this study was to prepare a high encapsulation efficiency ivermectin liposome that is stable, secure and efficient and to study pharmacokinetics process of ivermectin liposome in the goats.
1. Preparation of ivermectin liposome: Modified thin-film dispersion method was adopted to prepare the IVML. The optimal prescription for preparation of IVML were as follows: Lecithin︰Cholesterol=9︰1, IVM︰Lecithin=1︰10, pH of PBS is 7.0, conducting ultrasonic toward 5 minutes, evaporating at 40℃, and freezing and thawing 3 times. Its diameter was distributed mainly in 86～115 nm and the average grain size was (91.8±1.5) nm. The encapsulation efficiency of prepared IVML has reached (90.71±0.8)%(n=3), and it was stable fo heat, but unstable for light. The results shows the encapsulation efficiency was comply with a standard.
2. The physico-chemical property of ivermectin liposome: The physico-chemical property was detected by electron microscope, photon correlation spectroscope. The results showed that ivermectin liposome was milky white liquid. Its average diameter was (91.8±1.5) nm. The disposition of diameter was narrow and uniformity.
3. The stability of ivermectin liposome: The content of ivermectin liposome were measured by ultraviolet spectrophotometer. The stability of ivermectin liposome was evaluated by centrifuging, acceleration, light and long-term. The results showed that ivermectin had the maximal absorption in 250 nm. It had a good linear range in 2μg/mL~48μg/mL, its mean recovery was 97.60%, and its average entrapment efficiency was (90.71±0.8)%. The method of determining was convenient, sensitive, accurate and suitable for determining the entrapment efficiency and content of the liposome. The appearance and content of liposome did not change by constant temperature acceleration and long-term.
4. The acute toxicity experiment of ivermectin liposome: The safety of ivermectin liposome was evaluated by acute toxicity experiment. The results showed that the accmumulation LD50 of the ivermectin liposome test on mouse was 103.04 mg/kg.
5. Pharmacokinetics of ivermectin liposome in goats: Goats were treated with ivermectin liposome (0.2 mg/kg) for hypodermic injection. The concentrations of ivermectin liposome in blood were determined by high performance liquid chromatography(HPLC). Concentration-time is fitted by method of residual and pharmacokinetic parameters is calculated. The results showed that the two-compartment open model with absorption factor adequately describes concentrations of ivermectin liposome(0.2 mg/kg)for hypodermic injection in 6 goats’blood disposition and the best concentration-time equations are: C=41.2768·e-0.6564·t+4.9744·e-0.0809·t-46.2512·e-0.7244·t. The primary pharmacokinetic parameters of ivermectin liposome are: t1/2Kα=0.499±0.264 d, t1/2Ke=6.859±1.002 d, AUC=77.066±17.315 ng·mL-1·d. It will be seen that the distribution of ivermectin liposome in vivo is rapid, and the elimination of thiamphenicol nanoemulsion in vivo is slowly and relatively.
6. Treatments in goats of ivermectin liposome: Iivermectin liposome was administrated to goats by subcutaneous injection and divide them into three different dose (0.2 mg/kg, 0.5 mg/kg, 1.0 mg/kg)for de-worming, liposomal ivermectin and the ivermectin injection (0.2 mg/kg) were carried on contrast to experiment, observing the treatment result. The results of treatment showed the cure rates of high and low dose liposomal ivermectin were significantly higher than that of conventional ivermectin, liposomal ivermectin can reduce consumption, prolong drug effect and cut down medicine remaining as well and to 1.0 mg/kg dose of subcutaneous injection of the best.
1.伊维菌素脂质体的制备本试验利用正交试验设计,筛选、优化处方和工艺,最后采用改良薄膜分散法制备出了包封率高、稳定性好的伊维菌素脂质体。试验结果表明:影响伊维菌素脂质体稳定性的主要因素为磷脂与胆固醇的配比,其次为药脂比。其制备方法的最佳处方工艺组合为卵磷脂与胆固醇质量比为9︰1,IVM与卵磷脂质量比为1︰10,缓冲液PBS的pH为7.0,超声裂解时间为5 min,蒸发温度为40℃,冻融3次。按以上最佳处方制备,3次包封率平均达(90.71±0.8) %,符合中华人民共和国药典规定。
2.伊维菌素脂质体的理化性质用透射电镜、激光粒度分布仪等对其理化性质进行研究。结果表明,伊维菌素脂质体是乳白色均一稳定的牛奶状液体,其平均粒径为(91.8±1.5) nm,符合脂质体的要求,粒径分布范围窄,且比较均匀。均证明,制备的伊维菌素脂质体具有较好的稳定性,对光不稳定,应该避光保存。
3.伊维菌素脂质体的稳定性考察用紫外可见分光光度法测定伊维菌素脂质体中伊维菌素的含量,并通过高湿度试验、加速试验、长期试验、留样观察试验考察其稳定性。试验结果表明,伊维菌素在250 nm处有最大吸收,在2μg/mL~48μg/mL范围内线性关系良好,其平均回收率为96.51 %,RSD为0.03 %。平均包封率为(90.71±0.8) %,该方法可用于伊维菌素脂质体的包封率和含量的测定,外观和含量未发生明显变化。
4.伊维菌素脂质体急性毒性试验通过急性毒性试验对伊维菌素脂质体进行安全性评价。结果表明,伊维菌素脂质体对小鼠的LD50为103.04 mg/kg。
5.伊维菌素脂质体在山羊体内的药物动力学试验健康山羊皮下注射伊维菌素脂质体,不同时间点采血,高效液相色谱法测定血药浓度,残数法拟合药时曲线,计算药动学参数。6只山羊皮下注射伊维菌素脂质体(0.2 mg/kg)后,其药动学配置符合有吸收因素二室模型特征。最佳药时曲线方程为:C=41.2768·e-0.6564·t+4.9744·e-0.0809·t-46.2512·e-0.7244·t。伊维菌素在山羊体内的吸收半衰期(t1/2Ka)为0.499±0.264 d,消除半衰期(t1/2Ke)为6.859±1.002 d,药时曲线下面积(AUC)为77.066±17.315 (ng/mL)·d。表明伊维菌素脂质体在山羊体内吸收迅速,消除相对较慢。
6.伊维菌素脂质体在山羊体内驱虫效果的研究在山羊体内通过皮下注射伊维菌素脂质体三个不同治疗剂量(0.2 mg/kg、0.5 mg/kg、1.0 mg/kg)进行驱虫,与伊维菌素普通注射剂(0.2 mg/kg)相比发现伊维菌素脂质体具有良好的缓释作用,且以1.0 mg/kg剂量皮下注射效果最好。
The purpose of this study was to prepare a high encapsulation efficiency ivermectin liposome that is stable, secure and efficient and to study pharmacokinetics process of ivermectin liposome in the goats.
1. Preparation of ivermectin liposome: Modified thin-film dispersion method was adopted to prepare the IVML. The optimal prescription for preparation of IVML were as follows: Lecithin︰Cholesterol=9︰1, IVM︰Lecithin=1︰10, pH of PBS is 7.0, conducting ultrasonic toward 5 minutes, evaporating at 40℃, and freezing and thawing 3 times. Its diameter was distributed mainly in 86～115 nm and the average grain size was (91.8±1.5) nm. The encapsulation efficiency of prepared IVML has reached (90.71±0.8)%(n=3), and it was stable fo heat, but unstable for light. The results shows the encapsulation efficiency was comply with a standard.
2. The physico-chemical property of ivermectin liposome: The physico-chemical property was detected by electron microscope, photon correlation spectroscope. The results showed that ivermectin liposome was milky white liquid. Its average diameter was (91.8±1.5) nm. The disposition of diameter was narrow and uniformity.
3. The stability of ivermectin liposome: The content of ivermectin liposome were measured by ultraviolet spectrophotometer. The stability of ivermectin liposome was evaluated by centrifuging, acceleration, light and long-term. The results showed that ivermectin had the maximal absorption in 250 nm. It had a good linear range in 2μg/mL~48μg/mL, its mean recovery was 97.60%, and its average entrapment efficiency was (90.71±0.8)%. The method of determining was convenient, sensitive, accurate and suitable for determining the entrapment efficiency and content of the liposome. The appearance and content of liposome did not change by constant temperature acceleration and long-term.
4. The acute toxicity experiment of ivermectin liposome: The safety of ivermectin liposome was evaluated by acute toxicity experiment. The results showed that the accmumulation LD50 of the ivermectin liposome test on mouse was 103.04 mg/kg.
5. Pharmacokinetics of ivermectin liposome in goats: Goats were treated with ivermectin liposome (0.2 mg/kg) for hypodermic injection. The concentrations of ivermectin liposome in blood were determined by high performance liquid chromatography(HPLC). Concentration-time is fitted by method of residual and pharmacokinetic parameters is calculated. The results showed that the two-compartment open model with absorption factor adequately describes concentrations of ivermectin liposome(0.2 mg/kg)for hypodermic injection in 6 goats’blood disposition and the best concentration-time equations are: C=41.2768·e-0.6564·t+4.9744·e-0.0809·t-46.2512·e-0.7244·t. The primary pharmacokinetic parameters of ivermectin liposome are: t1/2Kα=0.499±0.264 d, t1/2Ke=6.859±1.002 d, AUC=77.066±17.315 ng·mL-1·d. It will be seen that the distribution of ivermectin liposome in vivo is rapid, and the elimination of thiamphenicol nanoemulsion in vivo is slowly and relatively.
6. Treatments in goats of ivermectin liposome: Iivermectin liposome was administrated to goats by subcutaneous injection and divide them into three different dose (0.2 mg/kg, 0.5 mg/kg, 1.0 mg/kg)for de-worming, liposomal ivermectin and the ivermectin injection (0.2 mg/kg) were carried on contrast to experiment, observing the treatment result. The results of treatment showed the cure rates of high and low dose liposomal ivermectin were significantly higher than that of conventional ivermectin, liposomal ivermectin can reduce consumption, prolong drug effect and cut down medicine remaining as well and to 1.0 mg/kg dose of subcutaneous injection of the best.
引文
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