Sadeghi Fatemeh, Eidizade Atie, Saremnejad Farinaz, Hadizadeh Farzin, Khodaverdi Elham, Akhgari Abbas
Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Iran J Basic Med Sci. 2020 Jun;23(6):781-787. doi: 10.22038/ijbms.2020.41152.9736.
4-aminosalicylic acid (4-ASA) is an isomer of mesalazine that has recently been shown to be effective against inflammatory bowel disease (IBD), and more specifically, ulcerative colitis. However, the majority of orally administered 4-ASA is readily and extensively absorbed from the stomach and small intestine, so only a small amount is transported to the colon. A mutual ester and azo prodrug of 4-ASA was synthesized with polyethylene glycol (PEG) and dimethylaniline, respectively , to overcome this issue.
The 4-ASA prodrug was synthesized via a two-step process and then characterized by 1H-NMR. The stability of the prodrug was evaluated in simulated gastric fluid (pH 1.2). Furthermore, the release profiles of the drug conjugate was evaluated at pH 1.2, as well as pH 6.8 in the absence or presence of rat cecal content.
The prepared prodrug was stable at pH 1.2, indicating that it could be protected from the acidic environment of the stomach. Also, the results of drug release at pH 6.8 showed that the amount of 4-ASA released was 63% within 12 hr in the absence of rat cecal content, while in the presence of rat cecal content, 97% of 4-ASA was released from the prodrug in 6 hr.
Overall, the synthesized PEGylated azo-based 4-ASA prodrug could be a potential candidate for targeted drug delivery to the inflamed gut tissue in IBD.
4-氨基水杨酸（4-ASA）是美沙拉嗪的一种异构体，最近已被证明对炎症性肠病（IBD）有效，更具体地说，对溃疡性结肠炎有效。然而，口服的4-ASA大部分很容易从胃和小肠被广泛吸收，因此只有少量被转运到结肠。分别用聚乙二醇（PEG）和二甲基苯胺合成了4-ASA的互酯和偶氮前药，以解决这个问题。
通过两步法合成4-ASA前药，然后用1H-NMR进行表征。在前药在模拟胃液（pH 1.2）中评估其稳定性。此外，在不存在或存在大鼠盲肠内容物的情况下，在pH 1.2以及pH 6.8下评估药物缀合物的释放曲线。
制备的前药在pH 1.2下稳定，表明它可以免受胃酸性环境的影响。此外，在pH 6.8下的药物释放结果表明，在不存在大鼠盲肠内容物的情况下，12小时内释放的4-ASA量为63%，而在存在大鼠盲肠内容物的情况下，97%的4-ASA在6小时内从前药中释放出来。
总体而言，合成的聚乙二醇化偶氮基4-ASA前药可能是IBD中靶向药物递送至炎症肠道组织的潜在候选物。
