A STRATEGY TO MODULATE INSULIN RELEASE FROM NPH BASAL FORMULATION

Atrium

Objective. To develop a method to extend insulin release from NPH (Neutral Protamine Hagedorn) formulation, an intermediate-acting basal insulin. Background. Despite the prevalence of genetically altered basal products in recent years, the long-term safety of such insulins is in controversy. NPH insulin still represents a well-established basal formulation by its long history of use, featuring native form of human insulin. However, release kinetics in vivo upon single subcutaneous injection of NPH is characterized by a peak within a few hours and declining levels < 1 > day, which is often insufficient to provide daily basal insulin requirement upon single subcutaneous injection. Methods. In vitro release of NPH insulin in phosphate buffer (pH 7.4, 0.01% of Tween 80) was conducted at 37 degree-C in 1-mL dialysis cartridges (MW-cutoff 1,000,000-Da) without diffusion barriers. Amounts of released insulin were quantified chromagraphically at 280 nm, using human insulin as a standard. Results. Insulin release occurred continuously over 3-4 days in vitro. This is in sharp contrast to its in vivo kinetics. We hypothesize that such discrepancy is attributed to subcutaneous enzymes that rapidly degrades protamine on microcrystal surfaces, thereby accelerating drug release. Cathepsin-B is a likely candidate responsible for this process, which recognizes two arginyl residues in series, which are abundant in protamine. Conclusion. Therefore, strategies to protect the surface of NPH crystals will likely lead to "peakless" insulin release. Study is ongoing to investigate effects of protamine degrading enzymes and additives on NPH insulin release kinetics. Grants. This work was supported in part by HPD Research Grant.