Abstract：
Most active pharmaceutical ingredients (APIs) suffer from poor water solubility, often keeping them from reaching patients. To overcome the issues of poor drug solubility and subsequent low bioavailability, amorphous solid dispersions (ASDs) have garnered much attention. Cellulose ester derivatives are of interest for ASD applications as they are benign, sustainable-based, and successful in commercial drug delivery systems, e.g. in osmotic pump systems and as commercial ASD polymers. Synthesis of carboxy-pendant cellulose esters is a challenge, due in part to competing reactions between carboxyls and hydroxyls, forming ester crosslinks. Herein we demonstrate proof-of-concept for a scalable synthetic route to simple, yet highly promising ASD polymers by esterifying cellulose polymers through ring-opening of cyclic succinic or glutaric anhydride. We describe the complexity of such ring-opening reactions, not previously well-described, and report ways to avoid gelation. We report synthesis, characterization, and preliminary in vitro ASD evaluations of fifteen such derivatives. Synthetic routes were designed to accommodate these criteria: no protecting groups, no metal catalysts, mild conditions with standard reagents, simple purification, and one-pot synthesis. Finally, these designed ASD polymers included members that maintained fast-crystallizing felodipine in solution and release it from an ASD at rather high 20 % drug loading (DL).
摘要：
大多数活性药物成分（API）的水溶性差，经常阻止他们接触病人。为了克服药物溶解性差和随后的低生物利用度的问题，无定形固体分散体（ASD）已经引起了很多关注。纤维素酯衍生物对ASD应用感兴趣，因为它们是良性的，可持续的基础上，并在商业药物输送系统中取得成功，例如在渗透泵系统中和作为商业ASD聚合物。羧基-侧基纤维素酯的合成是一个挑战，部分由于羧基和羟基之间的竞争反应，形成酯交联。在这里，我们展示了一种可扩展的合成路线的概念证明，然而，通过环状琥珀酸或戊二酸酐的开环酯化纤维素聚合物，这是非常有前途的ASD聚合物。我们描述了这种开环反应的复杂性，以前没有很好的描述，并报告避免凝胶化的方法。我们报告综合，表征，和15种此类衍生物的初步体外ASD评价。合成路线的设计符合这些标准：没有保护基团，没有金属催化剂，使用标准试剂的温和条件，简单的净化，一锅法合成。最后,这些设计的ASD聚合物包括在溶液中保持快速结晶的非洛地平并以相当高的20％载药量（DL）从ASD中释放的成员。
