ESPE Abstracts

Background: There is a need for a convenient and affordable alternative to twice daily s.c. injections for children with IGF1 deficiency (IGFD) and growth failure. We report a novel platform technology, Topicon™ ThermoMatrix™, applied to the transdermal delivery of IGF1 (7649 Da).

Objective and hypotheses: We sought to develop a convenient, non-invasive, and affordable transdermal patch formulation capable of achieving passive delivery of large molecule drugs such as IGF1, insulin, and GH for multiple days.

Method: Lyophilized IGF1 was reconstituted in a Topicon™ ThermoMatrix™ formulation that transitions from solid at 25 °C (room temperature) to gel at 30–32 °C (skin temperature). Formulations containing IGF1 were applied as 50 μl gel to EpidermFT™ tissue inserts, which are barrier-enhanced, full thickness, and metabolically active human skin equivalents (HSEs) when cultured in maintenance medium at 32 °C. Equal volume of medium was sampled and replenished every 24 h. IGF1 concentrations were measured by using a Quantikine® ELISA Kit (R&D Systems). Steady-state IGF1 flux (J_ss) was calculated using Fick’s first law of diffusion.

Results: IGF1 Topicon™ ThermoMatrix™ formulations over the dose range of 5–500 μg/0.6 cm² achieved and maintained a maximum J_ss of 0.8 μg/cm² per h for 7 days. We observed a dose–response effect over the tested dose range, which was non-saturating. The calculated steady-state plasma level in pediatric IGFD patients after twice daily 0.12 mg/kg s.c. injection of Increlex™ is 250 ng/ml. Extrapolated to 7.7 l volume of distribution (30 kg boy) for Increlex (mecasermin), a 64 or 25 cm² patch containing 500 μg/0.6 cm² of IGF1 would achieve the target steady-state plasma level of 250 ng/ml in 1.5 or 4.5 days respectively. MTT assays showed that epidermal cell viability was preserved, independent of dose or time.

Conclusion: These rigorous in vitro studies support the feasibility of developing safe and effective extended-wear IGF1 Topicon™ ThermoMatrix™ patches that replace daily injections and provide constant and consistent drug delivery.

Funding: This work was supported by Prometheon Pharma, LLC, which has no formal business, commercial, or other relationship with the manufacturer (Ipsen) of commercially available IGF1 (Increlex).