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.

Cucurbituril‐Based Biomacromolecular Assemblies

“…Very recently, complexation‐stabilized diabetes drugs have been developed by the co‐administration of insulin and pramlintide with PEGylated CB[7] in diabetic rats and pigs (Figure 6 a). [52] The therapeutic windows of insulin and pramlintide overlap sufficiently with each other upon the complexation of PEGylated CB[7] with the aromatic amino acid residues of insulin and pramlintide at their protonated N‐ and amidated C‐termini, respectively. This supramolecular dual‐hormone therapy improves the pharmacokinetic biocompatibility, suppresses postprandial glucagon secretion, and might eventually relieve the burden of multiple daily doses reliant on medication.…”

“… a) Co‐formulation of CB[7]‐PEGylated insulin and pramlintide to improve the pharmacokinetic profiles and therapeutic effect in diabetes management [52] . b) Crosslinked MT aggregation by CB[8] and antimitotic peptide to enhance cell apoptosis [53] .…”

Full closed loop open‐source algorithm performance comparison in pigs with diabetes

“…Insulin-deficient diabetes was induced in pigs (25-30 kg) using streptozotocin (STZ) (MedChemExpress), as previously reported. 19,20 STZ was infused intravenously at a dose of 125 mg/kg and animals were monitored for 24 h. Food and administration of 5% dextrose solution was given as needed to prevent hypoglycemia. Diabetes was defined as fasting blood glucose greater than 300 mg/dl.…”

“…The comparison of the algorithms in pigs, which have similar physiological glucose ranges but demonstrate faster insulin kinetics than humans, allows for algorithm performance to be evaluated as if using next-generation ultra-fast insulins that are in the pipeline but not yet available for use in humans. [19][20][21] This is useful because it is hypothesized that ultrafast insulin kinetics may enable fully closed loop delivery without the requirement of additional therapeutics (glucagon or amylin) or sensors (accelerometers). Exploiting the faster insulin kinetics in pigs allows us to understand the important features of full closed loop algorithm design in the context of future ultra-fast insulins.…”

Selective Recognition of Amino Acids and Peptides by Small Supramolecular Receptors

“…As can be seen by this example, CB[n]’s can be used for the detection of proteins, due to its specificity towards aromatic and cationic residues. Control over protein assembly and function is another route that is being explored for this supramolecular system [ 9 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 ]. Brunsveld and co-workers have used CB8 as a tool to aid in the dimerization of proteins, making use of the target Phe-Gly-Gly motif as an N -terminal modification, in order to better control enzyme activity [ 149 ] and protein assemblies [ 142 ].…”