两亲性梳形高分子材料用于改善口服固体脂质纳米粒稳定性的研究

Solid lipid nanoparticle (SLN) is widely used as the vehicle for oral drug delivery. However, because of the poor stability performance, it is necessary to improve the stabilities of SLN, including the physical stability during storage. Expulsion of encapsulated drug of SLN may take place during storage due to formation of a perfect crystalline lattice. Additionally, the glycerides, usually used as the lipid matrix materials in SLN, tend to be degraded in the gastrointestinal tract due to hydrosis catalyzed by lipase enzyme, which leads to the exposure of encapsulated drug of SLN in the gastrointestinal digestive environment. To overcome the limitations of SLN, comb-shaped amphiphilic macromolecular materials (CAM) with hydrophilic backbone and hydrophobic branches, are synthesized as emulsifying agents to prepare SLN for oral drug delivery in the research project. Physical stability of SLN during storage may be improved by CAM instead of common straight chain surfactants, especially in term of the inhibition of the crystal transition of the lipids in SLN. Meanwhile, the lipid matrix of SLN may be shielded from the degradation of lipase enzyme due to the steric hindrance effect of the hydrophilic toothlike loops on the surface of nanoparticles formed by CAM. Based on the promising results from our preliminary experiments, some factors which may effect on the storage physical stability and the lipolysis of SLN in the gastrointestinal tract, including electronic charge, molecular weight, chain length of branched alkyl groups and the degree of alkylation substitution of CAM, will be investigated systematically after three kinds of CAMs, amphiphilic chitosan, hyaluronic acid and inulin derivatives are synthesized, respectively. Quercetin and insulin are selected as representive model drug of the poor aqueous solubility and protein/peptide drugs, respectively. The promising scheme may overcome two main stability limitations of SLN greatly. To our knowledge, there is no research report on SLN prepared using CAM as emulsifier. This research project provides an effective idea regarding the search work for new generation emulsifier to improve the performance of SLN. Therefore, it is novel, innovative, valuable, and highly worthy of accomplishing.

固体脂质纳米粒（SLN）常用作口服给药载体，但需解决稳定性问题。一是贮存物理稳定性，尤其是在贮存过程中脂质晶型转变，导致药物析出。二是口服后易被肪酶消化降解，使药物暴露于消化液。本项目采用主链亲水、支链疏水的两亲性梳形高分子材料（CAM）为乳化剂制备修饰SLN，用作口服药物的载体。一方面，以CAM代替传统直链表面活性剂，提高SLN的贮存物理稳定性。另一方面，SLN表面的齿状高分子亲水基团，对脂酶起立体屏障作用，保护脂质材料免遭降解。本项目拟在前期工作的基础上，合成两亲性壳聚糖、透明质酸和菊糖衍生物并以槲皮素和胰岛素为模型药物，研究CAM的荷电性、分子量、烷基链长度、烷基化度等因素对SLN贮存物理稳定性和在胃肠道中稳定性的影响，有希望解决口服SLN的两大稳定性问题。目前尚未发现以CAM作为乳化剂制备SLN的报道，本项目对探索寻找改善SLN性能的新一代乳化剂提供了新的思路。

固体脂质纳米粒（SLN）常用作口服给药载体，但需解决两个稳定性问题。一是贮存物理稳定性，尤其是在贮存过程中脂质晶型转变，导致药物析出。二是口服后易被脂酶消化降解，使药物暴露于消化液。为此，本项目采用主链亲水、支链疏水的两亲性梳形高分子材料（CAM）为乳化剂制备修饰SLN（CAM-SLN）。一方面，以CAM代替传统直链表面活性剂，提高SLN的贮存物理稳定性。另一方面，SLN表面形如向日葵花瓣的CAM亲水基团，对脂酶起立体屏障作用，保护脂质材料免遭降解。本项目首先合成了不同烷基链取代的N-三甲基-N-烷基壳聚糖、烷基化菊糖和烷基化透明质酸三类CAM，即：N-三甲基-N-辛烷壳聚糖、N-三甲基-N-硬脂酰基壳聚糖（STMC）、N-三甲基-N-亚油酰基壳聚糖、十二烷基菊糖、十八烷基菊糖（Inu18）、辛烷基透明质酸（OHA）、十二烷基透明质酸（DHA）和十六烷基透明质酸。然后，通过处方和工艺优化，制备了各种CAM-SLN并研究其理化性质。结果表明，相较于直链表面活性剂Poloxamer 188（P188）和Tween-80，各种CAM均能更好地降低SLN的脂质晶格有序性，减小脂质结晶度。SLN贮存稳定性试验研究结果表明，与P188和Tween-80相比，各种CAM均能更好地抑制SLN在贮存过程中的脂质晶型转变，减少粒子增长，尤其是STMC、OHA和Inu18。在考察SLN用量、胰酶活力、Ca2+、胆酸盐及卵磷脂浓度等因素对SLN脂质降解的影响基础上，建立体外脂解模型，以模拟体内消化道环境，对SLN在消化道中的稳定性进行了研究。结果表明，与P188和Tween-80相比，所合成的CAM几乎都能更好地抑制SLN在消化道中的脂质降解，减少药物暴露与沉淀，尤其是DHA、Inu18和STMC。本项目圆满完成研究计划，执行过程中已发表SCI论文6篇，申请国家发明专利3项。