重组水蛭素Ⅲ口服制剂给药系统的初步研究

 目的探讨重组水蛭素Ⅲ(以下简称rHV3)的口服制剂。方法采用在体原位肠袢法研究小肠和结肠在吸收促进剂作用下对rHV3的吸收情况,寻找促进rHV3肠道吸收的吸收促进剂和吸收位置;合成蛋白酶抑制剂——壳聚糖-EDTA轭合物(chitosan-EDTAconjugates,CEC),考察rHV3在胃蛋白酶和胰蛋白酶中的稳定性;将rHV3和促吸收剂、CEC乳化,考察其抗凝血作用。结果吸收促进剂能提高rHV3在肠道内的吸收水平,其中在0.5%EDTA-Na₂的作用下rHV3经由小肠给药产生的抗凝血作用最强;CEC在消化酶的存在下对rHV3有保护作用;乳化微粒与单用rHV3的抗凝血作用有显著性差异。结论重组水蛭素Ⅲ和促吸收剂以及CEC形成的乳化微粒经灌胃能够发挥其抗凝血作用。

Studies on Oral Preparations of Recombinant Hirudin Ⅲ

OBJECTIVE To study oral preparations of recombinant hirudin Ⅲ. METHODS The absorption of recombinant hirudin Ⅲ in the intestine and colon was evaluated using situ loop method.The absorption enhancer and the absorption position were screened.Chitosan-EDTA conjugates (CEC) was synthesized and the protection of hirudin from peptic and tryptic digestion was studied.The anticoagulant efficacy of emulsionized hirudin with absorption enhancer and CEC was measured by mice model. RESULTS Absorption enhancers promoted the absorption of hirudin both in intestinal and colon, and rHV3 showed the highest anticoagulant activity in small intestine with 0.5%EDTA-Na₂.In peptic and trypic solutions,CEC protected hirudin from digestion. The anticoagulant efficacy of emulsionized hirudin with absorption enhancer and CEC showed significant difference with oral hirudin alone.CONCLUSION The oral emulsifier of recombinant hirudin Ⅲ with absorption promoters and CEC has anticoagulant activity.