氢化可的松琥珀酸钠口服结肠靶向pH敏感型水凝胶表征与靶向性研究

Characterization of Oral Colon-targeting pH-Sensitive Hydrogel of Hydrocortisone Sodium Succinate and Experiment About Colon-targeting

关键词:  表征|水凝胶|氢化可的松琥珀酸钠|pH敏感性|口服结肠靶向给药系统

Key words:  characterization|hydrogel|hydrocortisone sodium succinate|pH-sensibility|oral colon-targeting drug delivery system

摘要:

目的 对前期制备的氢化可的松琥珀酸钠（hydrocortisone sodium succinate，HSS）口服结肠靶向pH型水凝胶进行表征，并进一步探讨其结肠靶向性。方法 利用差示扫描量热法（differential scanning calorimetry，DSC）对HSS结肠靶向型水凝胶（colon-targeting hydrogel of HSS，HSS-GEL）进行结构分析；对HSS-GEL在不同pH（pH 1.2、pH 6.8、pH 7.4）下的溶胀度进行考察；通过模拟胃肠道环境体外释放试验考察HSS-GEL不同时间内药物在不同介质中的释放度；通过测定HSS-GEL灌胃后不同时间内HSS在消化道不同部位的残留量进一步评价HSS-GEL结肠靶向性；通过在大鼠盲肠的体内孵化试验考察盲肠细菌对HSS-GEL的崩解程度。结果 DSC结果显示魔芋葡甘聚糖与黄原胶以氢键作用结合形成稳定网状结构，将药物包裹于凝胶内部孔穴中；溶胀度试验结果表明HSS-GEL在pH 7.4中溶胀率是在pH 1.2的5倍，在pH 6.8的溶胀率则介于两者之间，表明HSS-GEL具有pH敏感性；胃肠道环境体外释放试验显示HSS-GEL在pH 1.2人工胃液中的释药量为17.63%，在pH 6.8人工肠液中的释药量为25.56%，在pH 7.4的人工结肠液中的释药量为86.14%；大鼠肠段药物残留量试验显示给药后1~3 h，HSS-GEL在胃、小肠及结肠中检测到的HSS量较少，给药后5 h，结肠中检测到的HSS量急剧增加，给药后7 h，结肠内容物中的HSS浓度达到最大值，几乎等于胃及小肠药量的总和，以上胃肠道环境体外释放试验和肠段药物残留量试验均表明HSS-GEL有良好的结肠靶向性与生物降解性；体内孵化试验显示经过克林霉素抑制后，盲肠内药物释放率仅为3.55%，而对照组释放率达82.99%，说明盲肠细菌对HSS-GEL的凝胶材料崩解贡献很大。结论 本实验室所制备的HSS-GEL具有良好的pH敏感性、生物可降解性与结肠靶向性。

Abstract:

OBJECTIVE To characterize the oral colon-targeting pH-sensitive hydrogel of hydrocortisone sodium succinate(HSS) prepared in the previous work and to explore its colon-targeting characteristic. METHODS The structure of colon-targeting hydrogel of HSS(HSS-GEL) was analyzed by differential scanning calorimetry(DSC). The swelling degree of HSS-GEL at different pH(pH 1.2, pH 6.8, pH 7.4) was investigated; then the drug release degree of HSS-GEL in different media at different times through in vitro release experiments in simulated gastrointestinal environment was investigated; finally, the colon targeting of HSS-GEL by measuring the residual amount of HSS in different parts of the digestive tract at different times after intragastric administration of HSS-GEL was evaluated; and the disintegration degree of the cecal bacteria to HSS-GEL by in vivo incubation experiment in rat cecum was investigated. RESULTS The DSC results showed that konjac glucomannan and xanthan gum were combined by hydrogen bonding to form a stable network structure, and the drug was wrapped in the inner cavity of the gel; the swelling test results showed that the swelling rate of HSS-GEL at pH 7.4 was 5 times higher than that at pH 1.2, and the swelling rate at pH 6.8 was between them, which indicated that HSS-GEL had pH sensitivity; gastrointestinal environment in vitro release test showed that the release amount of HSS-GEL in artificial gastric juice was 17.63%, the release amount in pH 6.8 artificial juice was 25.56%, the release amount in artificial colon fluid at pH 7.4 was 86.14%; intestinal drug residue test in rats showed that within 1 to 3 hours after administration, HSS-GEL detected a small amount of HSS in the stomach, small intestine and colon, 5 h after administration, the amount of HSS detected in colon was dramatically increased, 7 hours after administration, the HSS concentration in the colon content reached the maximum, which was almost equal to the sum of the gastric and small intestinal drug doses. The above gastrointestinal environment in vitro release test and intestinal drug residue test all showed that HSS-GEL had good colon targeting and biodegradability; the in vivo incubation test showed that after the inhibition of clindamycin, the drug release rate in the cecum was only 3.55%, while the release rate of the control group was 82.99%, indicating that the cecal bacteria contributed greatly to the disintegration of the HSS-GEL gel material. CONCLUSION The HSS-GEL prepared in laboratory has good pH-sensibility, colon-targeting characteristic and biocompatibility.