氨苯砜-海藻酸缀合物的合成、表征及释放评价

Synthesis and Release of Dapsone-Alginate( DS-Alg) Conjugate

目的合成氨苯砜-海藻酸(DS-Alg)缀合物,确保氨苯砜(DS)无法经皮吸收进入全身血液循环。方法海藻酸(Alg)作为载体、缬氨酸(Val)为连接臂,合成DS-Alg缀合物并优化合成条件。1H-NMR、MS以及FT-IR对产物结构进行确证。以p H7.4、0.05 mol·L^(-1)PBS和乙醇混合液为接受介质,进行DS-Alg缀合物体外释放评价,监测释放介质中缬氨酸-氨苯砜(ValDS)和DS的浓度。大鼠局部烫伤作为模型,对创伤部位涂抹给药,监测血液中药物浓度。结果优化得到DS-Alg合成条件为:缬氨酸-氨苯砜0.277 g、海藻酸钠0.400 g、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐7 eq、N-羟基丁二酰亚胺3 eq、反应溶剂p H为5.5。缀合物释放72 h,接受液中无Val-DS或DS检出,表明DS与Alg共价结合后结构稳定,DS在实验条件下无法解离透皮释放。DS-Alg经皮给药72 h内大鼠血浆中无DS检出,AUC_(0→72 h)为0,说明缀合药物无法经皮肤进入血液。结论 DS-Alg结构稳定,可以避免DS进入血液循环。

OBJECTIVE To synthesize and characterize dapsone-alginate acid （DS-ALG） conjugate. METHODS Alginate （Alg） was selected as the drug carrier and valine （Val） as the linking arm to synthesize DS-Alg, which could be applied to topical ad- ministration. And the synthetic condition of DS-Alg was optimized by changing the amount of 1- （3-dimethylaminopropyl） -3-ethylcarbo- diimide hydrochloride （EDC） and N-hydroxysuccinimide （ NHS）, while the pH of solvent was changed in the range of 4. 0 to 6. 0. The structures of the products were characterized by ^1 H-NMR, MS and FT-IR. Meanwhile, the drug release in vitro of DS-Alg was investi- gated in the mixture of pH 7.4, 0. 05 mol ·L^-1 PBS and ethanol by diffusion cells. The concentration of DS or valine-dapsone in the release medium was detected by HPLC. Taking rats with local scald as model, the drug release in vivo was measured by coating the trauma with DS-Alg conjugate cream and monitoring the drug concentration in blood. RESULTS The optimum synthetic conditions of DS-Alg were as follows ： 0. 277 g valine-dapsone, 0. 400 g sodium alginate, 7 eq EDC, 3 eq NHS, pH of the solvent of 5.5. And dur- ing 72 h, there was no DS detected in the release medium or rat plasma. The AUC0-72 h of DS-Alg was 0. It suggested that DS immobi- lized by Alg with covalent bond was too stable to be released from Alg in vitro and in vivo. The DS-Alg conjugate could effectively pre- vent DS from entering the systemic circulation. CONCLUSION DS-Alg conjugate is successfully synthesized. The conjugate is stable that DS cannot be released from the conjugate to the bloodstream, which can efficiently decrease the side effects of DS and has the po- tential for topical administration.