Department of Industrial and Physical Pharmacy, College of Pharmacy , Purdue University , West Lafayette , Indiana , United States.
Department of Chemistry, College of Science , Purdue University , West Lafayette , Indiana , United States.
Biomacromolecules. 2018 Dec 10;19(12):4593-4606. doi: 10.1021/acs.biomac.8b01280. Epub 2018 Nov 12.
Amorphous solid dispersions are widely used to enhance the oral bioavailability of poorly water-soluble drugs. Polymeric additives are commonly used to delay crystallization of the drug from the supersaturated solutions formed upon ASD dissolution by influencing the nucleation and growth of crystals. However, there is limited evidence regarding the mechanisms by which polymers stabilize supersaturated drug solutions. The current study used experiments and computational modeling to explore polymer-drug interactions in aqueous solutions. Nucleation induction times for supersaturated solutions of nine drugs in the presence of five newly synthesized cellulose-based polymers were evaluated. The polymers had carboxylic acids substituents with additional variations in the side-chain structure: (1) one with a single side chain and a carboxylic acid termination, (2) three with a branched side chain terminated with a carboxylic and an alcohol group (varying the cellulose linkage and the length of the hydrocarbon side chain), and (3) one with a branched side chain with two carboxylic acid end groups. The polymers with a short side chain and one carboxylic acid were effective, whereas the polymers with the two carboxylic acids or a long hydrocarbon chain were less effective. Atomic force microscopy experiments, evaluating polymer adsorption onto amorphous drug films, indicated that the effective polymers were uniformly spread across the surface. These results were supported by molecular dynamics simulations of a polymer chain in the presence of a drug aggregate in an aqueous environment, whereby the effective materials had a higher probability of establishing close contacts and more negative estimated free energies of interaction. The insights provided by this study provide approaches to design highly effective polymers to improve oral drug delivery.
无定形固体分散体被广泛用于提高水溶性差的药物的口服生物利用度。聚合物添加剂通常用于通过影响晶体的成核和生长来延迟 ASD 溶解后形成的过饱和溶液中药物的结晶。然而，关于聚合物稳定过饱和药物溶液的机制的证据有限。本研究使用实验和计算建模来探索水溶液中聚合物-药物相互作用。评估了在五种新合成的基于纤维素的聚合物存在下，九种药物的过饱和溶液的成核诱导时间。这些聚合物具有羧酸取代基，在侧链结构上有额外的变化：（1）一个带有单链和羧酸端基，（2）三个带有支链，末端带有羧酸和醇基（改变纤维素键和碳氢侧链的长度），（3）一个带有两个羧酸端基的支链。带有短侧链和一个羧酸的聚合物是有效的，而带有两个羧酸或长碳氢链的聚合物则不太有效。评估聚合物在无定形药物膜上吸附的原子力显微镜实验表明，有效的聚合物均匀地分布在表面上。这些结果得到了在水相环境中聚合物链存在药物聚集体的分子动力学模拟的支持，其中有效材料更有可能建立紧密接触，并且相互作用的估计自由能更负。这项研究提供的见解为设计提高口服药物递送的高效聚合物提供了方法。
