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 3032 °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 (Jss) was calculated using Ficks first law of diffusion.
Results: IGF1 Topicon ThermoMatrix formulations over the dose range of 5500 μg/0.6 cm2 achieved and maintained a maximum Jss of 0.8 μg/cm2 per h for 7 days. We observed a doseresponse 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).
01 Oct 2015 - 03 Oct 2015