Using present formulation strategies, insulin and pramlintide are unstable if mixed, and require separate administrations. The disparate pharmacokinetics of insulin and pramlintide following separate subcutaneous administrations does not mimic secretion from the beta-cells and inhibits their potential synergistic effects. Designer excipients that exhibit host-guest supramolecular interactions with protein drugs have potential to improve formulation stability of biologic therapeutics and allow for unprecedented formulation strategies. Here we develop an excipient strategy for simultaneous supramolecular PEGylation of insulin and pramlintide to generate a stable insulin-pramlintide co-formulation that more closely mimics endogenous secretion.
Protein stability when formulated with curcurbit[7]uril-poly(ethylene glycol) (CB[7]-PEG) was determined using a transmittance assay in order to detect the formation of aggregates that scatter light over time. The formulation pharmacokinetics and pharmacodynamics were evaluated in diabetic rat and pig models. Blood glucose levels are monitored and ELISA is used to measure the pharmacokinetics of the two hormones.
CB[7]-PEG enables stable co-formulation of insulin and pramlintide for over 100 hours under stressed aging conditions where commercial formulations of insulin analogues exhibit only 10 hours of stability. Using diabetic rat and pig models, we demonstrate that co-formulation with CB[7]-PEG modifies the pharmacokinetics of both insulin and pramlintide, increasing the overlap between the time-frame of action of the two hormones, thus mimicking endogenous secretion and restoring meal-time glucagon suppression.
This insulin-pramlintide co-formulation more closely mimics endogenous co-secretion of insulin and amylin from the beta-cells and shows promise as a single administration therapy that could reduce patient burden and enhance diabetes management.