Background: The Topicon patch is a needle-free novel platform technology developed to achieve truly passive transdermal delivery of insulin. Here we report pharmacodynamic (PD) and pharmacokinetic (PK) studies comparing needle injection (s.c.) vs Topicon mediated patch delivery of the insulin analog glargine (LANTUS®) in streptozotocin-induced hairless rats.
Objective and hypotheses: We sought to develop a convenient, affordable, and needle-free transdermal patch formulation capable of achieving passive delivery of large molecule drugs such as insulin and insulin-analogues for multiple days.
Method: Male CD® hairless rats were induced with type 1 diabetes (T1DM) by i.p. injection of streptozotocin (65 mg/kg). Plasma insulin glargine was determined by ELISA (Mercodia Iso-Insulin Kit). PK calculations are based on extravascular non-compartmental analysis (NCA) using PKSolver 2.0 for Microsoft Excel. The first-order elimination rate constant (Kel) was calculated as 0.693/T1/2. Required input rate of insulin (k0) to reach Cmax was calculated by Cmax*Vd*Kel)/(1−e^Kel*t). Amount of LANTUS® delivered by Topicon patch per unit surface area over time (t) was Jss*t, where Jss is the steady-state flux rate.
Results: A single s.c. injection of 10 U/kg of LANTUS® resulted in an unexpectedly rapid rise to a peak plasma glargine concentration (Cmax) of ~120 mU/ml at 1 h, rapid elimination with plasma half-life (t1/2) of 2 h and a return to baseline level by 5 h. Blood glucose (BG) lowering was observed from baseline mean of ~375 mg/dl to ~7080 mg/dl for 0.55 h. Administration of LANTUS® 20 U/kg in a 1 cm2 patch resulted in a Cmax of 5.3 mU/ml at 2 h, a t1/2 of 1.7 h. Euglycemia was achieved in 4 h and maintained for 67 h. PK modeling was done to assess whether a Topicon glargine patch can achieve a clinically meaningful therapeutic response by combining in vitro EpidermFT permeation data with the reported Cmax of 22 mU/ml at 12 h after injection of LANTUS® 0.4 mg/kg in T1DM.
Conclusion: Our in vivo studies support the feasibility of developing an effective Topicon extended-wear basal insulin patch that can achieve BG lowering comparable to s.c. injection. Within 10 h, a 3×3 cm2 patch containing ~200 U of LANTUS® can achieve and maintain a target Cmax of 22 mU/ml continuously for >7 days.
01 Oct 2015 - 03 Oct 2015