Designing synergistic crystallization inhibitors: Bile salt derivatives of cellulose with enhanced hydrophilicity
Designing synergistic crystallization inhibitors: Bile salt derivatives of cellulose with enhanced hydrophilicity
复制标题
设计协同结晶抑制剂：亲水性增强的纤维素胆盐衍生物
DOI：
10.1016/j.carbpol.2022.119680
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发表时间：
2022
影响因子：
11.2
通讯作者：
Edgar, Kevin J.
中科院分区：
文献类型：
--
作者：
Novo, Diana C.;Gao, Chengzhe;Qi, Qingqing;Mosquera-Giraldo, Laura I.;Spiering, Glenn A.;Moore, Robert B.;Taylor, Lynne S.;Edgar, Kevin J.
无定形固体分散体（ASD）中的结晶抑制剂能够使亚稳定的过饱和药物溶液持续生理相关的时间。烯烃交叉复分解（CM）已成功地提供了多功能纤维素基衍生物作为候选ASD基质聚合物。在概念验证研究中，我们用天然存在的胆汁盐通过CM制备了疏水性胆汁盐/纤维素加合物。我们假设增加亲水性将增强这些缀合物最大化生物活性过饱和的能力。它们的选择性制备提出了一个重大的合成挑战，多糖反应性和多糖和胆盐的复杂性。我们使用更亲水的羟丙基纤维素（HPC）骨架制备了这样的衍生物，采用了一种用于附加胆汁酸的α-4-烯基系链（Pen）。我们通过改变胆汁酸取代基（石胆酸或脱氧胆酸）的性质和取代度来探索结构-性质关系。这些共轭物确实是协同抑制剂，如快速结晶的前列腺癌药物恩杂鲁胺所证明的。与单独药物相比，石胆酸甲酯衍生物AcrMLC-PenHHPCPen（0.64）的诱导时间增加了68倍。
Crystallization inhibitors in amorphous solid dispersions (ASD) enable metastable supersaturated drug solutions that persist for a physiologically relevant time. Olefin cross-metathesis (CM) has successfully provided multifunctional cellulose-based derivatives as candidate ASD matrix polymers. In proof of concept studies, we prepared hydrophobic bile salt/cellulose adducts by CM with naturally occurring bile salts. We hypothesized that increased hydrophilicity would enhance the ability of these conjugates to maximize bioactive supersaturation. Their selective preparation presents a significant synthetic challenge, given polysaccharide reactivity and polysaccharide and bile salt complexity. We prepared such derivatives using a more hydrophilic hydroxypropyl cellulose (HPC) backbone, employing a pent-4-enyl tether (Pen) for appending bile acids. We probed structure-property relationships by varying the nature and degree of substitution of the bile acid substituent (lithocholic or deoxycholic acid). These conjugates are indeed synergistic inhibitors, as demonstrated with the fast-crystallizing prostate cancer drug, enzalutamide. The lithocholic acid methyl ester derivative, AcrMLC-PenHHPCPen (0.64), increased induction time 68 fold vs. drug alone.