Design and optimization of novel in situ gel of mercaptopurine for sustained drug delivery

Mercaptopurine is a purine antagonist, belonging to the class of antimetabolites. Its oral absorption is erratic and variable throughout GIT, with bioavailability of 5-37% and belongs to Biopharmaceutical Classification System (BCS) class IV. The focus of the present study was to improve solubility of mercaptopurine and to release the drug uniformly throughout the GIT by formulating into a novel in situ gel tablet. By in vitro swelling studies, xanthan gum was selected as the best gelling polymer and the tablets were prepared by direct compression. Sodium chloride was used as a release modifier to improve the release of drug from the tablet. A 32 full factorial design was applied to optimize the percentage of xanthan gum and sodium chloride to get desired swelling index and release profile. Tablets were evaluated for weight variation, hardness, friability, disintegration time, drug content, in vitro swelling studies and in vitro dissolution studies. The best optimized formulation showed good swelling index and extended the release up to 12 h, where as conventional tablet released the drug within 45 min. The results indicate that mercaptopurine loaded in situ gel tablet could be effective in sustaining drug release for a prolonged period of time throughout the GIT, which can possibly improve the oral bioavailability.

巯嘌呤（Mercaptopurine）属于嘌呤拮抗剂，归为抗代谢物类药物。其口服吸收在胃肠道（gastrointestinal tract, GIT）内不稳定且个体差异显著，生物利用度为5%~37%，属于生物药剂学分类系统（Biopharmaceutical Classification System, BCS）IV类。本研究旨在通过制备新型原位凝胶片剂，提升巯嘌呤的溶解度，并实现药物在胃肠道内的均匀释放。通过体外溶胀试验，筛选出黄原胶作为最优凝胶载体，并采用直接压片法制备片剂；以氯化钠作为释放调节剂，改善药物从片剂中的释放行为。采用32全因子设计优化黄原胶与氯化钠的用量占比，以获得理想的溶胀度与药物释放曲线。对制备的片剂开展多项质量评价，包括重量差异、硬度、脆碎度、崩解时限、药物含量、体外溶胀试验及体外溶出试验。最优处方不仅展现出良好的溶胀性能，还可将药物释放时长延长至12小时，而普通片剂仅能在45分钟内完成药物释放。研究结果表明，负载巯嘌呤的原位凝胶片剂可实现药物在胃肠道内的长时间缓释，有望提升其口服生物利用度。