Ultra-fast insulin-pramlintide co-formulation for improved glucose management in diabetic rats
Dual-hormone replacement therapy with insulin and amylin in patients with type 1 diabetes has the potential to improve glucose management. Unfortunately, currently available formulations require burdensome separate injections at mealtimes and have disparate pharmacokinetics that do not mimic endogenous co-secretion. Here, we use amphiphilic acrylamide copolymers to create a stable co-formulation of monomeric insulin and amylin analogues (lispro and pramlintide) with synchronous pharmacokinetics and ultra-rapid action. The co-formulation is stable for over 16 hours under stressed aging conditions that cause a commercial "fast-acting" insulin formulation, Humalog, to aggregate in only 8 hours. The faster insulin pharmacokinetics achieved by delivery of monomeric insulin alongside pramlintide in this new co-formulation resulted in an increased overlap of 75 (s.e. = 6)% compared to only 47 (s.e. = 7)% for separate injections. Pramlintide delivered in the co-formulation resulted in similar delay in gastric emptying compared to pramlintide delivered separately, indicating pramlintide efficacy is maintained in the co-formulation. In a glucose challenge, rats receiving the co-formulation had reduced deviation from baseline glucose compared to treatment with either Humalog alone or separate injections of Humalog and pramlintide. Together these results suggest that a stable co-formulation of monomeric insulin and pramlintide has the potential to improve mealtime glucose management and reduce patient burden in the treatment of diabetes.