具有温敏变形性与高度变形性特征的中药复合磷脂传递体的构建与透皮机制研究

Except oral route, transdermal route is the most important administration route in traditional Chinese medicine.However, due to the barrier effect of the stratum corneum (SC), it is difficult for most drug molecules to be abosorbed into blood circulation, resulting in poor bioavailability. Transfersomes have been proved to be effective carriers which can defrom and penetrate through SC. Unfortunately, to guarantee the deformability of transfersomes, the lipid bilayers should be in the state of liquid-crystal phase. Therefore, in the long-term storage process, most drug molecules are leaked from the carriers, which leads to serious stability problem. In this project, novel transfersomes are invented and total alkaloids from nux vomica with reduced toxicity are further encapsulated into the carriers. The novel transfersomes are composed of two phosphatidylcholine(PC)s and the phase transition temperature of the transfersome is set between the storage and adminstration site temperatures. Therefore, the deformability can be controlled by the control of the phase behavior. Compared with the conventional transfersomes which are mainly composed of unsaturated PC, there are some more advanced properties of the novel transfersomes possessing thermosensitive deformability. (1)The bilayers are in gel solid phase and the storage stability is significantly enhanced. （2）Following transdermal administration, the bilayers transfer into liquid-crystal phase and the deformability is increased. The skin penetration behavior is further improved. (3) By changing the ratio between the two PCs, the phase transition temperature can be easily modified to eliminate the possible infulence of various components in traditional Chinese medicine on phase transition temperature. Based on the results of the present project, a novel transdermal carrier can be obtained with high bioavailability, high stability and high safety for the delivery of effective fraction in Chinese medicine. Moreover, a new drug which can be applied to treat cancer pain is also inveneted.

经皮给药是传统中药除口服以外最主要的给药途径，但由于角质层的屏障功能而严重限制了生物利用度。传递体是透皮吸收的有效载体，能够通过变形穿透角质层，但为了保证变形性，传递体膜应处于液晶相，通透性高，从而导致了其在存放过程中存在严重的药物泄漏问题。本项目以马钱子减毒总生物碱为模型药物，以复合磷脂技术为核心，将传递体的相变温度设定于存放温度与给药部位温度之间，利用相行为控制载体变形性与稳定性随温度的变化，所构建的具有温敏变形性特征的传递体与目前常用的不饱和磷脂传递体相比，具有以下优势：①存放时处于胶晶相，变形性低，稳定性显著提高；②给药后加温转变为液晶相，变形性升高，透皮吸收效果更好；③能够校正中药多成分因素对传递体Tm的可能影响。本项目的研究将为中药有效部位提供具有高生物利用度、高稳定性与高安全性特征的透皮吸收新型载体，同时为癌性疼痛的治疗提供新的候选药物。

经皮给药是传统中药除口服以外最主要的给药途径，但由于角质层的屏障功能而严重限制了生物利用度。传递体是透皮吸收的有效载体，能够通过变形穿透角质层，但为了保证变形性，传递体膜应处于液晶相，通透性高，从而导致了其在存放过程中存在严重的药物泄漏问题。本项目（一）构建了具有温敏变形性特征的复合磷脂传递体。建立了复合磷脂比例与Tm之间的数学规律，通过控制两种磷脂的摩尔比例，即可获得Tm在30～37℃范围内的传递体，实现了存放时处于胶晶相，稳定性较目前常用的不饱和磷脂传递体相比显著提高，给药后转变为液晶相，变形性升高，透皮吸收效果更好；筛选了边缘活性剂的种类和用量；采用CLSM、FT-IR、DSC对复合磷脂传递体的透皮机制进行了研究。结果表明，DPPC/DMPC（质量比2:3，相变温度为32℃）复合磷脂传递体以司盘80作为边缘活性剂，用量为15%，温敏变形性最高，且稳定性最好；复合磷脂传递体可能通过脂质萃取和增加角质层脂质的流动性增加药物的透皮吸收能力。（二）以马钱子减毒总生物碱为模型药物，构建和评价了马钱子减毒总生物碱复合磷脂温敏变形传递体。体外透皮与在体药动学研究表明，复合磷脂传递体的体外透皮速率是马钱子减毒总碱溶液的80%，54小时的累积透过量是马钱子减毒总碱溶液的114%；药动学研究表明，马钱子减毒总碱复合磷脂传递体凝胶和马钱子减毒总碱凝胶经皮给药后峰浓度分别为246.43±122.91 μg/L和475.45±238.85μg/L，达峰时间分别为3.80±1.10h和1.62±1.11h，马钱子减毒总碱复合磷脂传递体凝胶经皮给药显示出一定的缓释作用，对于治疗窗狭窄的药物，可以避免血药浓度峰谷现象，降低毒副作用。药效学研究表明马钱子减毒总碱传递体有显著的抗肿瘤和镇痛作用，且与阳性对照组相比没有明显的免疫抑制作用。本项目的研究将为中药活性部位提供具有高生物利用度、高稳定性与高安全性特征的透皮吸收新型载体，同时为癌性疼痛的治疗提供新的候选药物。