Kawaguchi T, Tsugane A, Higashide K, Endoh H, Hasegawa T, Kanno H, Seki T, Juni K, Fukushima S, Nakano M
Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan.
J Pharm Sci. 1992 Jun;81(6):508-12. doi: 10.1002/jps.2600810606.
Drug release was controlled by a combination of prodrug and polymer matrix. Prodrugs of 5-fluoro-2'-deoxyuridine with different physicochemical properties were synthesized by esterification with aliphatic acids (propionate, n-butyrate, and n-pentanoate). Microspheres containing these ester prodrugs were prepared with poly(3-hydroxybutyrate) of three molecular weights (65,000, 135,000, and 450,000). The release rates from the spheres depended on both the lipophilicity of the prodrug and the molecular weight of the polymer. Regardless of the polymer, the relative release rates were propionate greater than butyrate greater than pentanoate. The release of butyrate and pentanoate from the spheres consisting of low-molecular-weight polymer (M(r), 65,000) was faster than that from the spheres of higher molecular weight (M(r), 135,000 or 450,000). A single intraperitoneal injection of spheres of the highest molecular weight polymer containing butyrate or pentanoate resulted in higher antitumor effects against P388 leukemia in mice than did free prodrugs given over a period of five consecutive days. The polymer sphere itself showed low toxicity to and good biocompatibility with mice and rats.
药物释放由前药和聚合物基质共同控制。通过与脂肪酸（丙酸酯、正丁酸酯和正戊酸酯）酯化反应合成了具有不同物理化学性质的5-氟-2'-脱氧尿苷前药。用三种分子量（65,000、135,000和450,000）的聚（3-羟基丁酸酯）制备了含有这些酯前药的微球。微球的释放速率取决于前药的亲脂性和聚合物的分子量。无论聚合物如何，相对释放速率均为丙酸酯大于丁酸酯大于戊酸酯。由低分子量聚合物（M(r)，65,000）组成的微球中丁酸酯和戊酸酯的释放速度比高分子量（M(r)，135,000或450,000）微球的释放速度快。单次腹腔注射含有丁酸酯或戊酸酯的最高分子量聚合物微球对小鼠P388白血病的抗肿瘤效果比连续五天给予游离前药的效果更好。聚合物微球本身对小鼠和大鼠显示出低毒性和良好的生物相容性。
