Ultra‐Fast Insulin–Pramlintide Co‐Formulation for Improved Glucose Management in Diabetic Rats

Abstract

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, amphiphilic acrylamide copolymers are used 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 h under stressed aging conditions, whereas commercial insulin lispro (Humalog) aggregates in 8 h. The faster pharmacokinetics of monomeric insulin in this co‐formulation result in increased insulin–pramlintide overlap of 75 ± 6% compared to only 47 ± 7% for separate injections. The co‐formulation results in similar delay in gastric emptying compared to pramlintide delivered separately. In a glucose challenge, in rats, the co‐formulation reduces deviation from baseline glucose compared to insulin only, or separate insulin and pramlintide administrations. Further, comparison of interspecies pharmacokinetics of monomeric pramlintide suggests that pharmacokinetics observed for the co‐formulation will be well preserved in future translation to humans. Together these results suggest that the co‐formulation has the potential to improve mealtime glucose management and reduce patient burden in the treatment of diabetes.

Formulation excipients and their role in insulin stability and association state in formulation

“…The solution was then concentrated using Amicon Ultra 3K centrifugal units (Millipore) and reformulated with glycerol, phenoxyethanol, metacresol, methylparaben, and/or propylparaben in 10 mM phosphate buffer (pH=7.4) at an insulin concentration of 3.45 mg/mL (100 U/mL) (excipient concentrations specified in Table 1-2). For zinc-free formulations glycerol was added at 2.6 wt.% to be consistent with our previously reported monomeric lispro formulations, 18,19,22 however a reduction of glycerol to 1.6% to match Humalog is not expected to affect insulin association states (Figure S1). All other reagents were purchased from Sigma-Aldrich unless otherwise specified.…”

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

“…Further, co-formulation showed an increased overlap of pharmacokinetics with the ratio of AUC of serum pramlintide to Aspart increasing (0.75 ± 0.06) as compared to separate injections (0.47 ± 0.07). Thus, these results demonstrate that developed co-formulation more closely resembled the endogenous behaviour of insulin-pramlintide secretion at meal times (Maikawa, Chen, et al, 2021).…”

“…Due to individual administration of pramlintide and insulin, there is a lack of patient compliance with only 1.5% patients adopting to pramlintide administration owing to discomfort and increased economic strain on the patient (Figure 2) (Maikawa, Chen, et al, 2021). The current form of pramlintide, SYMLIN ® , administered via multiple injections, poses a challenge for patients as it requires twice a day dosing (before meals).…”

Deep Eutectic Solvents for Subcutaneous Delivery of Protein Therapeutics

“…This could make a significant difference especially for patients who use continuous subcutaneous insulin infusion (insulin pumps) that allows blood glucose level within the target ranges for a higher percentage of the day. [ 15 ] While insulin analogs have been used to improve absorption kinetics in the clinic, significant research in academia has also focused on polymer [ 21 ] and polypeptide [ 48 ] excipients, polymer conjugation, [ 24 ] and protein coformulation. [ 49 ] While these strategies have shown success in vivo, DESs and ILs offer an appealing alternative since they can easily be manufactured at scale with fewer steps and lower costs to allow for simpler fast‐acting insulin formulation.…”