Sultan Muhammad H, Mahdi Wael A, Kwon Young M
Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan, Kingdom of Saudi Arabia.
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia.
Bioimpacts. 2021;11(1):59-64. doi: 10.34172/bi.2021.08. Epub 2020 Dec 12.
Neutral protamine Hagedorn (NPH) insulin is an intermediate-acting basal insulin with a long history of clinical use, consisting native human insulin. Its rather undesirable action profile, characterized by a peak release within a few hours, followed by insufficient insulin delivery upon a single subcutaneous (s.c.) dose, is well-documented. This may have been caused by the inherent microcrystal structure involving the basic peptide protamine, as well as the presence of tissue enzyme activities that readily act on protamine at the injection site. This issue may be circumvented by utilizing thermosensitive, erodible Pluronic F127 (PF127) to modulate the kinetics of insulin release from NPH over a period of 24 hours in which the hydrogel is completely eroded. Previously, we have shown that insulin release rates from NPH/PF127 formulations (0-25% PF127) markedly reduced the initial insulin release, especially in the presence of enzyme activity that selectively degraded protamine at 1-5 U/mL. Insulin release over the course of 20 hours was better modulated in the presence of increasing PF127 content. In this study, the insulin formulations (0, 20, and 25% PF127) were administered s.c. (4 U/kg) to streptozotocin (STZ)-induced diabetic rats and blood glucose levels were monitored over 24 hours. blood glucose depression profiles in STZ-induced diabetic rats exhibited a similar pattern of control to data at the single s.c. dose of 4 U/kg, apparently extending the duration of action of NPH over a 24-hour period in the presence of PF127. Our findings suggest that the undesirable kinetics of insulin release from NPH is significantly influenced by tissue enzyme activity and that the presence of PF127 provided a timely modulation of insulin release from NPH microcrystals in the STZ-induced diabetic rat model.
中性鱼精蛋白锌（NPH）胰岛素是一种临床应用历史悠久的中效基础胰岛素，由天然人胰岛素组成。其相当不理想的作用特征已得到充分证明，表现为在数小时内出现峰值释放，随后单次皮下注射剂量后胰岛素递送不足。这可能是由于涉及碱性肽鱼精蛋白的固有微晶结构，以及注射部位存在易于作用于鱼精蛋白的组织酶活性。通过利用热敏性、可侵蚀的泊洛沙姆F127（PF127）来调节NPH在24小时内胰岛素释放的动力学，在此期间水凝胶完全被侵蚀，这个问题可能会得到解决。此前，我们已经表明，NPH/PF127制剂（0-25% PF127）的胰岛素释放速率显著降低了初始胰岛素释放，特别是在存在1-5 U/mL选择性降解鱼精蛋白的酶活性时。在存在增加的PF127含量的情况下，20小时内的胰岛素释放得到了更好的调节。在这项研究中，将胰岛素制剂（0、20和25% PF127）皮下注射（4 U/kg）给链脲佐菌素（STZ）诱导的糖尿病大鼠，并在24小时内监测血糖水平。STZ诱导的糖尿病大鼠的血糖降低曲线显示出与单次皮下注射4 U/kg剂量时的数据相似的控制模式，在存在PF127的情况下，显然在24小时内延长了NPH的作用持续时间。我们的研究结果表明，NPH胰岛素释放的不理想动力学受到组织酶活性的显著影响，并且PF127的存在为STZ诱导的糖尿病大鼠模型中NPH微晶的胰岛素释放提供了及时的调节。
