基于计算药剂学的索拉非尼—姜黄素联合用药纳米胶束给药系统研究
发布时间：2018-12-08 14:40
【摘要】：“癌中之王”原发性肝癌恶性度高、病情恶化快,治疗难度极大。索拉非尼是第一个批准的可用于临床原发性肝癌治疗的多靶点、多激酶抑制剂,但是索拉非尼的溶解性较差,生物利用度较低。而且索拉非尼的毒副作用较为常见,更严重的是会出现耐药性,此时会出现无药可医的局面。这就使得需要通过改进给药方式或其他手段来提高索拉非尼的生物利用度。联合用药是现有的常用的可以增强索拉非尼的治疗效果和降低毒副作用的常用方法之一。姜黄素具有抗肿瘤作用,还具有化学增敏效果,能够逆转化疗药物的耐药性,因而与索拉非尼联用有增强疗效的效果[1-3]。聚合物纳米胶束给药是解决难溶药物生物利用度低的新型给药方法之一,利用两亲性聚合物的特性,制备成具有纳米粒径的核壳结构的聚合物胶束,亲水性外壳可以将难溶性药物包裹在疏水性内核中,增加溶解度同时,还可以通过主/被动将药物输送到目标位置,提高生物利用度,增强疗效。本课题设计将索拉非尼和姜黄素制备成聚合物胶束进行联合用药,并结合三嵌段聚合物PCL-PEG-PCL自组装纳米胶束的被动靶向和长循环效果,将索拉非尼和姜黄素制备成三嵌段聚合物纳米胶束,用于静脉注射给药,以期在增强索拉非尼和姜黄素的溶解性的同时,提高索拉非尼的生物利用度,降低毒副作用。本课题首先对姜黄素和索拉非尼联合用药效果进行考察,并通过计算药剂学对所用的聚合物载体PCL-PEG-PCL进行了模拟筛选,随后通过实际实验印证模拟结果,筛选出最优的适合制备三嵌段聚合物纳米胶束的载体材料为PCL30-PEG135-PCL30,并且通过具体实验考察了薄膜水化法制备三嵌段聚合物纳米胶束的条件。最终制备的聚合物纳米胶束外观澄清透明,有胶束溶液特有的乳光;粒径为194.9±4.6nm,透射电镜图从微观层面也显示了自组装制备的胶束的粒径在100~160nm左右,形状为形态均一的核-壳同心球型结构;姜黄素和索拉非尼的包封率分别为75.62±1.08%和91.20±0.41%;载药量分别为22.6±0.64%和13.73±0.35%,在4℃下考察,5周内稳定性良好,体外溶出释放持久缓慢。在随后进行的体外抗肿瘤活性研究研究,同姜黄素和索拉非尼原料药给药方式相比,随时间增长,制备成聚合物纳米胶束给药组的抑制活性提高;药代动力学研究显示,同直接使用原料药的聚氧乙烯(35)蓖麻油溶液尾静脉给药相比,纳米胶束给药组的姜黄素和索拉非尼的半衰期分别提高13.75倍和1.116倍;AUC0-∞分别提高15.44倍和2.74倍;MRT0-∞分别提高了15.3倍和1.28倍;CL分别降低到原来的0.087倍和0.39倍,说明制备的聚合物纳米胶束具有长循环效果。
[Abstract]:The King of Cancer has a high degree of malignancy, rapid deterioration and great difficulty in treatment. Solafenib is the first approved multi-target, multi-kinase inhibitor for the treatment of primary liver cancer, but sorafenib has poor solubility and low bioavailability. And the side effects of sorafenib are more common, more serious, drug resistance, and there is no cure. This makes it necessary to improve the bioavailability of Solafenib by improving drug delivery or other means. Combination therapy is one of the commonly used methods to enhance the efficacy and reduce the side effects of sorafenil. Curcumin has antitumor effect and chemically sensitized effect, which can reverse the resistance of chemotherapeutic drugs. Polymer nano-micelle delivery is one of the new methods to solve the low bioavailability of insoluble drugs. Using the properties of amphiphilic polymers, polymer micelles with nanometer-size core-shell structure have been prepared. The hydrophilic shell can encapsulate insoluble drugs in the hydrophobic core, increase solubility and transport the drugs to the target through active / passive transport, improve bioavailability and enhance the efficacy. In this paper, the preparation of solafenil and curcumin into polymer micelles was designed to combine with the passive targeting and long cycle effects of triblock polymer PCL-PEG-PCL self-assembled nano-micelles. Solafenil and curcumin were prepared into triblock polymer nanomicelles for intravenous administration in order to enhance the solubility of solafenil and curcumin and to increase the bioavailability and reduce the side effects of sorafenil. In this paper, the effect of curcumin and sorafenil was investigated, and the polymer carrier PCL-PEG-PCL was screened by computer pharmacology, and then the simulation results were verified by practical experiments. The best carrier material for the preparation of triblock polymer nano-micelles was selected as PCL30-PEG135-PCL30,. The conditions of preparing triblock polymer nano-micelles by thin film hydration were investigated. The final prepared polymer nano-micelles have clear and transparent appearance and have the unique emulsion light of micelle solution. The particle size is 194.9 卤4.6 nm, and the microstructure of the self-assembled micelles is about 100~160nm, and the morphology of the micelles is homogeneous and core-shell concentric spherical structure. The entrapment efficiency of curcumin and sorafenil were 75.62 卤1.08% and 91.20 卤0.41, respectively, and the drug loading amounts were 22.6 卤0.64% and 13.73 卤0.35, respectively. Compared with curcumin and solafenil, the inhibitory activity of polymer nano-micelles was increased with time. The pharmacokinetic study showed that the half-life of curcumin and sorafenil in nano-micelle group was 13.75 and 1.116 times higher than that of polyoxyethylene (35) castor oil solution. AUC0- 鈭，
本文编号：2368525
[Abstract]:The King of Cancer has a high degree of malignancy, rapid deterioration and great difficulty in treatment. Solafenib is the first approved multi-target, multi-kinase inhibitor for the treatment of primary liver cancer, but sorafenib has poor solubility and low bioavailability. And the side effects of sorafenib are more common, more serious, drug resistance, and there is no cure. This makes it necessary to improve the bioavailability of Solafenib by improving drug delivery or other means. Combination therapy is one of the commonly used methods to enhance the efficacy and reduce the side effects of sorafenil. Curcumin has antitumor effect and chemically sensitized effect, which can reverse the resistance of chemotherapeutic drugs. Polymer nano-micelle delivery is one of the new methods to solve the low bioavailability of insoluble drugs. Using the properties of amphiphilic polymers, polymer micelles with nanometer-size core-shell structure have been prepared. The hydrophilic shell can encapsulate insoluble drugs in the hydrophobic core, increase solubility and transport the drugs to the target through active / passive transport, improve bioavailability and enhance the efficacy. In this paper, the preparation of solafenil and curcumin into polymer micelles was designed to combine with the passive targeting and long cycle effects of triblock polymer PCL-PEG-PCL self-assembled nano-micelles. Solafenil and curcumin were prepared into triblock polymer nanomicelles for intravenous administration in order to enhance the solubility of solafenil and curcumin and to increase the bioavailability and reduce the side effects of sorafenil. In this paper, the effect of curcumin and sorafenil was investigated, and the polymer carrier PCL-PEG-PCL was screened by computer pharmacology, and then the simulation results were verified by practical experiments. The best carrier material for the preparation of triblock polymer nano-micelles was selected as PCL30-PEG135-PCL30,. The conditions of preparing triblock polymer nano-micelles by thin film hydration were investigated. The final prepared polymer nano-micelles have clear and transparent appearance and have the unique emulsion light of micelle solution. The particle size is 194.9 卤4.6 nm, and the microstructure of the self-assembled micelles is about 100~160nm, and the morphology of the micelles is homogeneous and core-shell concentric spherical structure. The entrapment efficiency of curcumin and sorafenil were 75.62 卤1.08% and 91.20 卤0.41, respectively, and the drug loading amounts were 22.6 卤0.64% and 13.73 卤0.35, respectively. Compared with curcumin and solafenil, the inhibitory activity of polymer nano-micelles was increased with time. The pharmacokinetic study showed that the half-life of curcumin and sorafenil in nano-micelle group was 13.75 and 1.116 times higher than that of polyoxyethylene (35) castor oil solution. AUC0- 鈭，
本文编号：2368525
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