摘要
作为一种广谱的免疫抑制药物,雷帕霉素具有低的肾毒性和抗排斥反应活性,可以治疗多种自身免疫性疾病。然而,它的水溶性很差,在每毫升的水中只能溶解2.6微克。无论在临床上还是商业上都限制了其应用范围。因此,增加其水溶性、提高其生物利用率是非常重要的。树状高分子由于特殊的结构,已经广泛应用于药物的载体。
本文以嵌段树状高分子为载体,包裹难溶性的药物雷帕霉素,并对其释放行为进行了研究。
采用透析法,制备了聚合物空心胶束。通过扫描电镜对其形貌的观察,发现它为空心的囊泡结构。通过改变实验的条件,得到了制备胶束的最佳条件。选用疏水嵌段比例不同的树状高分子制备胶束溶液,可以得到不同大小的胶束。
同样采用透析法制备了雷帕霉素缓释胶束,平均包封率和载药量为40%和91%。研究结果显示：所制备的载药胶束同样为中空结构的囊泡；载药胶束的载药量和包封率大大增加；体外释放结果显示其有明显的缓释效果；随着疏水嵌段PLLA比例的增大,药物释放速度减慢,可根据需要合成疏水嵌段比例不同的树状嵌段共聚物载体,得到所需的释放速度。
对雷帕霉素缓释胶束的体外释放行为运用多种药物释放模型进行了拟合。通过拟合发现最佳的模型都为Gompertz二级函数模型,能够较好的预测雷帕霉素缓释胶束真实的体外释放。
本文采用生物可降解树状共聚物制备的雷帕霉素缓释胶束,与文献报道的同类药物缓释胶囊(或胶束)相比,载药量提高了将近一倍,缓释速度更慢,且可通过树状共聚物的结构进行缓释速度调控,具有更大的临床应用前景。
As a broad-spectrum immunosuppressive drugs, Rapamycin has low renal toxicity and anti-rejection activity, can treat a variety of autoimmune diseases. However, the solubility of Rapamycin in water is 2.6μg/ml, the poor water solubility limited its application both in clinical and commercial. Therefore, It is very important to increase its water solubility and increase its bioavailability. Due to the special structure, biodegradable dendrimer has been widely used as drug carrier.
In this paper, the dendrimer was used as a drug carrier to package insoluble Rapamycin, and then we studied its release behavior.
Hollow polymer micelles were prepared by dialysis method. Scanning electron microscopy observation indicate its hollow vesicle structure. We get the best conditions for preparing micelles from changing the experimental conditions. Choosing different structure of dendritic copolymer, the size of micelles would be different.
We prepared Rapamycin micelles by dialysis method. The average drug content and encapsulation efficiency were 40% and 91%. The results showed that:the drug-loaded micelles has the same hollow vesicle structure; the drug content and encapsulation efficiency of the drug-loaded micelles significantly increased; in vitro release results show its obvious sustained release. As the incresing ratio of hydrophobic PLLA segment, the release rate of drug slow down, according to the different need, we can synthesis different dendrimer polymer carrier to obtain the required release rate.
Several models of drug release were used to fit the vitro release of Rapamycin from drug-loaded micelles. From the fitting we found the secondary Gompertz is the best models, which can predict the true release of Rapamycin from drug-loaded micelles in vitro release.
In this paper, the Rapamycin-loaded micelles which used biodegradable dendrimer, compared to the similar drug sustained-release capsules(or micelles) whiich were reported, has nearly double drug content and lower sustained-release, we can change the structure of the dendrimer to control the drug release speed,has greater clinical application.
引文
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