Department of Pharmaceutical Products, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Department of Aliments, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Eur J Pharm Sci. 2018 Jan 1;111:57-64. doi: 10.1016/j.ejps.2017.09.037. Epub 2017 Sep 27.
Mesalamine (5-ASA) consists of the first-line therapy for the treatment of ulcerative colitis; however, it has low bioavailability, can cause several systemic adverse events, and has low treatment adherence due to the inconvenient dosing scheme. In this work, a new drug delivery system consisting of chondroitin sulfate linked to 5-ASA was synthesized using a carbodiimide as conjugating agent. The system was characterized by spectroscopic techniques (UV, ATR-FTIR, XRD, and NMR H) and thermal analysis (TG/DTG and DSC), suggesting the conjugation between the drug and the polymer. The in vitro release and the corresponding kinetics were also evaluated, revealing that approximately 40% of the drug linked was released at pH9 for up to 50h, following Higuchi's model. The conjugate did not show cytotoxicity for the human monocytic cell line at the doses tested, and an in vivo biodistribution study showed that the conjugate remained in the lower GIT for up to 8h with no uptake in the upper GIT. These data corroborate with the radiation found per segment of GIT and in blood. For this last test the conjugate was radiolabeled with Technetium-99m to allow the scintigraphy evaluation and radiation quantification. In conclusion, the polymeric conjugate was successfully synthesized and demonstrated a mucoadhesiveness on the colon as desired, thus supporting its potential use in the treatment of ulcerative colitis.
美沙拉嗪（5-ASA）是溃疡性结肠炎治疗的一线药物；然而，由于其生物利用度低、可能引起多种全身不良反应以及不便的给药方案，导致治疗顺应性较差。在这项工作中，使用碳二亚胺作为偶联剂合成了一种由硫酸软骨素连接到 5-ASA 的新型药物传递系统。该系统通过光谱技术（UV、ATR-FTIR、XRD 和 NMR H）和热分析（TG/DTG 和 DSC）进行了表征，表明药物与聚合物之间发生了共轭。还评估了体外释放及其相应的动力学，结果表明，在 pH9 下，约 40%的药物连接物在长达 50 小时的时间内释放，符合 Higuchi 模型。该缀合物在测试剂量下对人单核细胞系没有细胞毒性，体内分布研究表明，该缀合物在大肠的下消化道中可保持 8 小时，而在上消化道中没有摄取。这些数据与在每个肠道段和血液中发现的放射性相吻合。对于最后一项测试，用锝-99m 对该缀合物进行放射性标记，以允许进行闪烁成像评估和放射性定量。总之，成功合成了该聚合物缀合物，并表现出对结肠的理想的黏膜黏附性，因此支持其在溃疡性结肠炎治疗中的潜在应用。
