Department of Pharmacy, Birla Institute of Technology and Science (BITS PILANI), Pilani, Rajasthan, India.
Department of Pharmacy, Birla Institute of Technology and Science (BITS PILANI), Pilani, Rajasthan, India
J Pharmacol Exp Ther. 2024 Jan 2;388(1):81-90. doi: 10.1124/jpet.123.001679.
Dysregulation of various glucoregulatory hormones lead to failure of insulin monotherapy in patients with diabetes mellitus due to various reasons, including severe hypoglycemia, glycemic hypervariability, and an increased risk of microvascular complications. However, pramlintide as an adjunct to insulin therapy enhances glucagon suppression and thereby offers improved glycemic control. Clinical studies have shown that pramlintide improves glycemic control, reduces postprandial glucose excursions, and promotes weight loss in patients with type 1 and type 2 diabetes. Although clinical benefits of pramlintide are well reported, there still exists a high patient resistance for the therapy, as separate injections for pramlintide and insulin must be administered. Although marketed insulin formulations generally demonstrate a peak action in 60-90 minutes, pramlintide elicits its peak concentration at around 20-30 minutes after administration. Thus, owing to the significant differences in pharmacokinetics of exogenously administered pramlintide and insulin, the therapy fails to elicit its action otherwise produced by the endogenous hormones. Hence, strategies such as delaying the release of pramlintide by using inorganic polymers like silica, synthetic polymers like polycaprolactone, and lipids have been employed. Also, approaches like noncovalent conjugation, polyelectrolyte complexation, and use of amphiphilic excipients for codelivery of insulin and pramlintide have been explored to address the issues with pramlintide delivery and improve patient adherence to the therapy. This approach may usher in a new era of diabetes management, offering patients multiple options to tailor their treatment and improve their quality of life. SIGNIFICANCE STATEMENT: To our knowledge, this is the first report that summarizes various challenges in insulin and pramlintide codelivery and strategies to overcome them. The paper also provides deeper insights into various novel formulation strategies for pramlintide that could further broaden the reader's understanding of peptide codelivery.
各种糖调节激素的失调导致糖尿病患者因各种原因（包括严重低血糖、血糖波动大以及微血管并发症风险增加）无法单独使用胰岛素治疗。然而，普兰林肽作为胰岛素治疗的辅助药物，可增强胰高血糖素的抑制作用，从而改善血糖控制。临床研究表明，普兰林肽可改善 1 型和 2 型糖尿病患者的血糖控制，减少餐后血糖波动，并促进体重减轻。尽管普兰林肽的临床益处已有充分报道，但由于需要分别注射普兰林肽和胰岛素，患者对该疗法的接受程度仍然很高。尽管市售胰岛素制剂通常在 60-90 分钟内达到峰值作用，但普兰林肽在给药后约 20-30 分钟达到峰值浓度。因此，由于外源性给予的普兰林肽和胰岛素的药代动力学存在显著差异，该疗法无法发挥内源性激素产生的作用。因此，已经采用了一些策略，例如使用无机聚合物（如二氧化硅）、合成聚合物（如聚己内酯）和脂质来延迟普兰林肽的释放。此外，还探索了非共价偶联、聚电解质络合以及使用两亲性赋形剂共递送胰岛素和普兰林肽等方法来解决普兰林肽递送问题，并提高患者对治疗的依从性。这种方法可能开创糖尿病管理的新时代，为患者提供多种选择来定制治疗方案，提高生活质量。
据我们所知，这是第一篇总结胰岛素和普兰林肽共递送所面临的各种挑战以及克服这些挑战的策略的报告。本文还深入探讨了普兰林肽的各种新型制剂策略，这可能会进一步拓宽读者对肽共递送的理解。
