Deguchi Saori, Ogata Fumihiko, Isaka Takumi, Otake Hiroko, Nakazawa Yosuke, Kawasaki Naohito, Nagai Noriaki
Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan.
Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
Pharmaceutics. 2021 Mar 12;13(3):375. doi: 10.3390/pharmaceutics13030375.
Postprandial hyperglycemia, a so-called blood glucose spike, is associated with enhanced risks of diabetes mellitus (DM) and its complications. In this study, we attempted to design nanoparticles (NPs) of protamine zinc insulin (PZI) by the bead mill method, and prepare ophthalmic formulations based on the PZI-NPs with (nPZI/P) or without polyacrylic acid (nPZI). In addition, we investigated whether the instillation of the newly developed nPZI and nPZI/P can prevent postprandial hyperglycemia in a rabbit model involving the oral glucose tolerance test (OGTT). The particle size of PZI was decreased by the bead mill to a range for both nPZI and nPZI/P of 80-550 nm with no observable aggregation for 6 d. Neither nPZI nor nPZI/P caused any noticeable corneal toxicity. The plasma INS levels in rabbits instilled with nPZI were significantly higher than in rabbits instilled with INS suspensions (commercially available formulations, CA-INS), and the plasma INS levels were further enhanced with the amount of polyacrylic acid in the nPZI/P. In addition, the rapid rise in plasma glucose levels in OGTT-treated rabbits was prevented by a single instillation of nPZI/P, which was significantly more effective at attenuating postprandial hyperglycemia (blood glucose spike) in comparison with nPZI. In conclusion, we designed nPZI/P, and show that a single instillation before OGTT attenuates the rapid enhancement of plasma glucose levels. These findings suggest a better management strategy for the postprandial blood glucose spike, which is an important target of DM therapy.
餐后高血糖，即所谓的血糖峰值，与糖尿病（DM）及其并发症风险增加相关。在本研究中，我们尝试通过珠磨法设计精蛋白锌胰岛素（PZI）纳米颗粒（NPs），并制备基于含（nPZI/P）或不含聚丙烯酸（nPZI）的PZI-NPs的眼用制剂。此外，我们研究了新开发的nPZI和nPZI/P滴眼是否能在涉及口服葡萄糖耐量试验（OGTT）的兔模型中预防餐后高血糖。通过珠磨法将PZI的粒径减小至nPZI和nPZI/P均为80 - 550 nm的范围，且6天内无明显聚集。nPZI和nPZI/P均未引起任何明显的角膜毒性。滴注nPZI的兔血浆胰岛素（INS）水平显著高于滴注INS悬浮液（市售制剂，CA-INS）的兔，且nPZI/P中聚丙烯酸的量会进一步提高血浆INS水平。此外，单次滴注nPZI/P可预防OGTT处理兔血浆葡萄糖水平的快速升高，与nPZI相比，其在减轻餐后高血糖（血糖峰值）方面显著更有效。总之，我们设计了nPZI/P，并表明在OGTT前单次滴注可减轻血浆葡萄糖水平的快速升高。这些发现提示了一种针对餐后血糖峰值的更好管理策略，餐后血糖峰值是DM治疗的一个重要靶点。
