A co-formulation of supramolecularly stabilized insulin and pramlintide enhances mealtime glucagon suppression in diabetic pigs.

Abstract

In diabetic patients, treatment with insulin and pramlintide (an amylin analogue) is more effective than treatment with insulin only. But because mixtures of insulin and pramlintide are unstable and have to be injected separately, amylin analogues are only used by 1.5% of diabetics needing rapid-acting insulin. Here, we show that the supramolecular modification of insulin and pramlintide with cucurbit[7]uril-conjugated polyethylene glycol improves the pharmacokinetics of the dual-hormone therapy and enhances post-prandial glucagon suppression in diabetic pigs. The co-formulation is stable for over 100 hours at 37 ºC under continuous agitation, whereas commercial formulations of insulin analogues aggregate after 10 hours under similar conditions. In diabetic rats, the administration of the stabilized co-formulation increased the area-of-overlap ratio of the pharmacokinetic curves of pramlintide and insulin to 0.7 ± 0.1 from 0.4 ± 0.2 (mean ± s.d.) for the separate administration of the hormones. The co-administration of supramolecularly stabilized insulin and pramlintide better mimics the endogenous kinetics of co-secreted insulin and amylin, and holds promise as a dual-hormone replacement therapy.