Monomeric Insulin Analog and Stabilizing Excipient Enabled Ultrafast Insulin Formulation

Abstract

ABSTRACT The speed of insulin therapy remains fundamentally constrained by the self‐association of insulin into hexamers. Here, a materials‐based strategy is introduced to stabilize HALQ, a monomeric insulin analog, using a non‐interacting inulin‐derived excipient (BN‐Inu). BN‐Inu markedly mitigates aggregation and maintains HALQ stability for 96 h under stress and for at least 30 days at room temperature. In a porcine model of diabetes, monomeric HALQ exhibits significantly accelerated absorption and a shorter duration of action than the ultrarapid insulin aspart Fiasp. This “fast‐on, fast‐off” profile is consistent with faster clearance from the subcutaneous depot, more closely synchronizes with endogenous prandial insulin physiology. Addition of clinically used absorption enhancers further accelerates its pharmacokinetic profile, producing a faster time‐to‐peak and reduced exposure relative to ultrarapid insulin lispro Lyumjev in this animal model. Furthermore, translation to human physiology was evaluated through pharmacokinetic modeling, which predicts that HALQ could reduce time‐to‐peak from 60 to 39 min and shorten duration of action from 143 to 84 min in humans. These simulations suggest the potential utility of achieving a step‐change in the speed of insulin therapy. These findings demonstrate that monomer‐stabilizing excipients enable next‐generation ultrafast insulin formulations with the potential to improve glycemic control in diabetes.