Pramlintide an Adjunct to Insulin Therapy: Challenges and Recent Progress in Delivery.

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.