可注射式雙性幾丁聚醣奈米凝膠用於糖尿病治療之開發與研究

Abstract

根據國際糖尿病協會(I.D.F)統計，西元2013年全球糖尿病患人數約有3.82億人，並預估在2035年，糖尿病人口總數將大幅成長達5.92億。糖尿病無法完全被治癒，病患須藉由居家血糖管控來維持身理機能健康，並藉此降低由糖尿病所引起慢性併發症的風險。多數患有第一型糖尿病的患者，終身都須仰賴胰島素的治療，依據患者的病況，醫生將給予不同的胰島素注射處方，注射頻率最低仍需一天一次，給患者帶來諸多的不便與額外的苦痛。為了提升糖尿病患者的生活品質，我們成功地開發了一種新型可注射式雙性幾丁聚醣奈米凝膠，能夠長時效且緩慢持續釋放胰島素，進而降低皮下注射頻率。在本實驗中，對於此奈米凝膠進行一系列且有系統的評估；經由FT-IR、1H-高解析核磁共振光譜儀分析其結構，發現在其降解過程中，並無生成其他副產物。在降解過程中，環境溶液的酸鹼值也由pH-meter檢測，其酸鹼值並無明顯變化，由此可推測在奈米凝膠降解過程中不會因為酸鹼值的改變而影響生物相容性。另外，實驗中也針對不同組成的凝膠在胰島素釋放行為的差異做進一步的探討，我們觀察到凝膠中胰島素的釋放行為深深受到凝膠降解的影響，藉由控制凝膠的降解程度，可進一步掌控胰島素在凝膠中的釋放。為了進一步探討此奈米凝膠對於糖尿病的治療效果，在給予糖尿病小鼠一劑奈米凝膠皮下注射後，監控其血糖值變化。在動物實驗結果觀察到包覆在凝膠中的胰島素確實釋放，使小鼠血糖降低到正常範圍內並維持長達10天之久。從這些實驗結果，可以證實此注射型奈米凝膠，在未來糖尿病治療的應用上具有相當大的潛力，此凝膠的開發可減少患者的胰島素注射頻率，提高患者的生活品質。

Diabetes is a predominant public health concern, according to International Diabetes Federation (I.D.F), 382 million people are diagnosed with diabetes worldwide in 2013 and this number estimate increase to 592 million in 2035. Since diabetes cannot be cured, diabetic patient require maintaining blood glucose level in normal range through self-management to diminish the risk of complications, such as cardiovascular disease, blindness, kidney failure, and lower limb amputation. Insulin plays an essential role in blood glucose management for both type 1 and some type2 patient. Actually, patients receive insulin treatment via subcutaneous injection more than once a day, which bring suffering and inconvenience. To improve the life quality of diabetic, we successfully developed a novel hydrogel, chitosan based injectable anti-diabetic nanogel. To investigate the degradation behavior, retention weight of nanogel were measure at pre-determined time interval and the degraded products were characterized by FT-IR and 1H magnetic resonance. In vitro drug release studies using insulin revealed that the nanogels exhibited sustained and controllable release. The stability of insulin release from nanogel was investigated by High performance liquid chromatography and circular dichroism. In vitro cell cytotoxicity with HS68 cell shows nanogel exhibit excellent bio-compatibility. The anti-diabetic effect of the nanogel was further explored in diabetic mice, blood glucose levels were measured after s.c injection. The animal experiment result indicated that this anti-diabetic nanogel has a great potential in improving patient compliance, which can reduce the injection frequency.