上市公司生产灭蚊剂（a股生产口罩的上市公司）
胰岛素注射制剂的尴尬迫使人类探索新的给药方式
1922 年 Banting 发现胰岛素以来，胰岛素一直是广大糖尿病患者最为有效的治疗手段之一。尽管人类通过改变胰岛素的结构改变胰岛素的药代动力学，但无论是动物胰岛素、人胰岛素还是胰岛素类似物都无法避开皮下注射的尴尬，随之而来的皮下硬结乃至感染等问题也层出不穷，也因此患者注射胰岛素的依从性并不尽如意。因此，人类也在不断探索胰岛素新的给药方式来造福广大患者，口服胰岛素似乎就能避免上述的尴尬。
胰岛素蛋白质的本质是口服胰岛素需要克服的关键关卡
众所周知，胰岛素的本质是蛋白质，属于大分子蛋白，如果胰岛素经口服给药，由肠胃道吸收进入血液，需要克服胃液的强酸性环境（极低的pH值）能降解或破坏胰岛素蛋白质，使其失去生物活性；小肠内存在的大量蛋白酶能分解胰岛素蛋白质、使其失活，此外，大分子蛋白质药物分子很难通过肠道上皮细胞吸收。因此，想要胰岛素安全到达靶器官发挥作用，首先需要克服的是胰岛素不被消化道消化，即便胰岛素不被消化道消化，这部分胰岛素又如何通过消化系统到达作用靶点也是一大难题，最后还需要克服药物吸收的个体差异性。
现行口服胰岛素的工作原理
目前已通过各种工艺尝试了不同的方法来克服上述障碍，也各有利弊，主要的方法有：
将胰岛素粘接在聚合物包裹的纳米颗粒中，如壳聚糖、聚乳酸-乙醇酸(PLGA)和藻酸盐[1-6]，允许肠道的淋巴循环吸收[7]，这种方法取决于结肠中胰岛素的吸收，但这种方法因吸收太迟并无法纠正胰岛素第一时相的分泌不足；另一种方法是将胰岛素与蛋白酶抑制剂（如杆菌肽，甘胆酸钠和迷彩灭蚊剂甲磺酸盐）共同给药[8]，这样可提高胰岛素的吸收率。但是，这种方法的长期疗效尚不清楚；最后一种方法是将胰岛素进行聚乙二醇化或添加聚乙二醇进行修饰，从而改变胰岛素药代动力学，防止消化酶酶的降解，增加胰岛素的吸收[9]。其他的方法还有利用渗透增强剂，例如脂肪酸盐[10]，紧密连接毒素（ZOT）[11]，和N-(4-氯水杨酸)-4-氨基丁酸(4-CNAB)[12]。这些渗透促进剂可能导致局部炎症和胃肠感染[12]。
新进展：口服胰岛素临床研究百花齐放
目前部分口服胰岛素已完成了临床研究，并且已经取得了良好的研究结果（详细见表1）。总而言之，口服胰岛素是目前糖尿病治疗的福音，但也面临极大的挑战，即口服胰岛素吸收的生理障碍，低生物利用度和低生物效力以及患者间的差异性。然而，现行的验证性的研究和早期临床研究让我们对口服胰岛素发挥效用充满希望！
表1 当前口服胰岛素的临床研究及进展
参考文献：
1. Aspden TJ, Mason JD, Jones NS: Chitosan as a nasal delivery system: the effect of chitosan solutions on in vitro and in vivo mucociliary transport rates in human turbinates and volunteers. J Pharm Sci 1997, 86:509-513.
2. Mathiowitz E, Jacob JS, Jong YS, et al: Biologically erodible microspheres as potential oral drug delivery systems. Nature 1997, 386:410-414.
3. Damge C, Michael C, Aprahamian M, Couvreur P: New approach for oral administration of insulin with polyalkylcyanoacrylate nanocapsules as oral carrier. Diabetes 1988, 37:247-251.
4. Takka S, Acarturk F: Calcium alginate microparticles for oral administration. I: effect of sodium alginate type on drug release and drug entrapment efficiency. J Microencapsul: Micro Nano Carriers 1999,16:275-290.
5. Rowsen Moses L, Dileep KJ, Sharma CP: Beta cyclodextrininsulinencapsulated chitosan/alginate matrix: oral delivery system. J Appl Polym Sci 2000, 75:1089-1096.
6. Dapergolas G, Gregoriadis G: Hypoglycaemic effect of liposomeentrapped insulin administered intragastrically into rats. Lancet 1976,2:824-827.
7. Pappo J, Ermak TH: Uptake and translocation of fluorescent latex particles by rabbit Peyer’s patch follicle epithelium: a quantitative model for M cell uptake. Clin Exp Immunol 1989, 76:144-148.
8. Yamamoto A, Taniguchi T, Rikyuu K, et al: Effects of various protease inhibitors on the intestinal absorption and degradation of insulin in rats. Pharm Res 1994, 11:1496-1500.
9. Clement S, Still JG, Kosutic G, et al: Oral insulin product hexyl-insulin monoconjugate 2 (HIM2) in type 1 diabetes mellitus: the glucose stabilization effects of HIM2. Diabetes Technol Ther 2002, 4:459-466.
10. Palin KJ, Phillips AJ, Ning A: The oral absorption of cefoxitin from oil and emulsion vehicles in rats. Int J Pharm 1986, 33:99-104.
11. Fasano A, Uzzau S: Modulation of intestinal tight junctions zona
occludens toxin permits enteral administration of insulin and other
macromolecules in an animal model. J Clin Invest 1997, 99:1158-1164.
12. Kaptiza C, Zijlstra E, Heinemann L, Castelli MC, Riley G, Heise T: Oral insulin:
A comparison with subcutaneous regular human insulin in patients with
type 2. Diabetes Care 2010, 33(6):1288-1290
13.Khedkar A, Iyer H, Anand A, Verma M, Krishnamurthy S, Savale , et al: A dose range finding study of novel oral insulin (IN-105) under fed conditions in type 2 diabetes mellitus subjects. Diabetes, Obesity and Metabolism 2010, 12:659-664.
14. Phillips J, Russel-Jones DL, Wright J, Brackenridge A, New R, Bansal G: Early evaluation of a novel oral insulin delivery system in healthy volunteers. Diabetes 2004, 53(Suppl 2):A113.
15. Luzio S, Dunseath G, Lockett A, Broke-Smith TP, New RR, Owens D:Comparison of an oral insulin (Capsulin) and Actrapid during an isoglycemic clamp study in persons with type 2 diabetes. Diabetes 2008,56(Suppl 1):A10.
16.Heinemann L, Jacques Y: Oral insulin and buccal insulin: a critical reappraisal. J Diabetes Sci Technol 2009, 3:568-584.
17. Schwartz S, Geho B, Rosenberg L, Lau J: A 2-week randomized active comparator study of two HDV-Insulin routes (SC and oral) and SC human insulin in patients with type 1 diabetes. Diabetes 2008, 57(Suppl1):A124.
18.ROY ELDOR, G. ALEXANDER FLEMING, JOEL NEUTEL, etal.1004-P: Oral Insulin (ORMD-0801) Effects on Glucose Parameters in Uncontrolled T2DM on OADs.Diabetes 2020 Jun; 69(Supplement 1): -.
19.A Two Part Trial Investigating NN1952 in Healthy Subjects and Subjects With Type 1 and Type 2 Diabetes This study has been completed. Study NCT01028404.
本文由锦鲤发布，不代表本站立场，转载联系作者并注明出处：/showinfo-5-131240-0.html