ESPE Abstracts

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 (K_el) was calculated as 0.693/T_1/2. Required input rate of insulin (k₀) to reach C_max was calculated by C_max*V_d*K_el)/(1−e^K_el*t). Amount of LANTUS® delivered by Topicon™ patch per unit surface area over time (t) was J_ss*t, where J_ss 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 (C_max) of ~120 mU/ml at 1 h, rapid elimination with plasma half-life (t_1/2) 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 ~70–80 mg/dl for 0.5–5 h. Administration of LANTUS® 20 U/kg in a 1 cm² patch resulted in a C_max of 5.3 mU/ml at 2 h, a t_1/2 of 1.7 h. Euglycemia was achieved in 4 h and maintained for 6–7 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 C_max 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 C_max of 22 mU/ml continuously for >7 days.