Department of Pharmaceutics, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.
Department of Pharmacology and Toxicology, School of Pharmacy, Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
Pharm Nanotechnol. 2020;8(3):239-254. doi: 10.2174/2211738508666200628033442.
Insulin, like most peptides, is classified as a hydrophilic and macromolecular drug that is considered as a low permeable and unstable compound in the gastrointestinal (GI) tract. The acidic condition of the stomach can degrade insulin molecules. Moreover, the presence of proteolytic activities of some enzymes such as trypsin and chymotrypsin can hydrolyze amide-bonds between various amino-acids in the structures of peptides and proteins. However, due to its simplicity and high patient compliance, oral administration is the most preferred route of systemic drug delivery, and for the development of an oral delivery system, some obstacles in oral administration of peptides and proteins including low permeability and low stability of the proteins in GI should be overcome.
In this study, the effects of orally insulin nanoparticles (INPs) prepared from quaternerized N-aryl derivatives of chitosan on the biochemical factors of the liver in diabetic rats were studied.
INPs composed of methylated (amino benzyl) chitosan were prepared by the PEC method. Lyophilized INPs were filled in pre-clinical capsules, and the capsules were enteric-coated with Eudragit L100. Twenty Male Wistar rats were randomly divided into four groups: group1: normal control rats, group 2: diabetic rats, group 3: diabetic rats received capsules INPs(30 U/kg/day, orally), group 4: the diabetic rats received regular insulin (5 U/kg/day, subcutaneously). At the end of the treatment, serum, liver and kidney tissues were collected. Biochemical parameters in serum were measured using spectrophotometric methods. Also, oxidative stress was measured in plasma, liver and kidney. Histological studies were performed using H and E staining .
Biochemical parameters, and liver and kidney injury markers in serum of the diabetic rats that received INPs improved significantly compared with the diabetic group. INPs reduced oxidative toxic stress biomarkers in serum, liver and kidney of the diabetic treated group. Furthermore, a histopathological change was developed in the treated groups.
Capsulated INPs can prevent diabetic liver and oxidative kidney damages (similar regular insulin). Therefore oral administration of INPs appears to be safe. Lay Summary: Although oral route is the most preferred route of administration, but oral delivery of peptides and proteins is still a challenging issue. Diabetes Mellitus may lead to severe complications, which most of them are life-threatening. In this study, we are testing the toxicity of oral insulin nanoparticles in kidney and liver of rats. For this investigation, we will prepare insulin nanoparticles composed of a quaternized derivative of chitosan. The nanoparticles will be administered orally to rats and the level of oxidative stress in their liver and kidney will be determined. The data will be compared to the subcutaneous injection of insulin.
胰岛素与大多数肽类一样，被归类为亲水性和大分子药物，被认为是胃肠道（GI）中渗透性差且不稳定的化合物。胃的酸性条件会降解胰岛素分子。此外，一些酶如胰蛋白酶和糜蛋白酶的蛋白水解活性的存在会水解肽和蛋白质结构中各种氨基酸之间的酰胺键。然而，由于其简单性和患者的高顺应性，口服给药是全身药物递送最优选的途径，并且为了开发口服递药系统，应该克服包括蛋白质在胃肠道中的低渗透性和低稳定性在内的口服给予肽和蛋白质的一些障碍。
在这项研究中，研究了由壳聚糖的季铵化 N-芳基衍生物制备的口服胰岛素纳米粒（INPs）对糖尿病大鼠肝脏生化因子的影响。
采用 PEC 法制备由甲基化（氨基苄基）壳聚糖组成的 INPs。将冻干的 INPs 填充在预临床胶囊中，并使用 Eudragit L100 对胶囊进行肠溶包衣。20 只雄性 Wistar 大鼠随机分为四组：第 1 组：正常对照组大鼠，第 2 组：糖尿病大鼠，第 3 组：糖尿病大鼠口服 INPs（30 U/kg/天），第 4 组：糖尿病大鼠皮下注射常规胰岛素（5 U/kg/天）。治疗结束时，收集血清、肝脏和肾脏组织。使用分光光度法测量血清中的生化参数。还测量了血浆、肝脏和肾脏中的氧化应激。使用 H 和 E 染色进行组织学研究。
与糖尿病组相比，接受 INPs 的糖尿病大鼠血清中的生化参数以及肝和肾损伤标志物明显改善。INPs 降低了糖尿病治疗组血清、肝脏和肾脏中的氧化毒性应激生物标志物。此外，在治疗组中还发生了组织病理学变化。
包封的 INPs 可预防糖尿病肝和氧化肾损伤（类似于常规胰岛素）。因此，口服 INPs 似乎是安全的。
虽然口服途径是最优选的给药途径，但肽类和蛋白质的口服递送仍然是一个具有挑战性的问题。糖尿病可能导致严重的并发症，其中大多数是危及生命的。在这项研究中，我们正在测试口服胰岛素纳米粒在大鼠的肾脏和肝脏中的毒性。为此调查，我们将制备由壳聚糖的季铵化衍生物组成的胰岛素纳米粒。将纳米粒口服给予大鼠，并测定其肝脏和肾脏中的氧化应激水平。将数据与胰岛素的皮下注射进行比较。
