Transdermal Delivery of a DTPA Penta-ethyl Ester Prodrug for Continuous Decorporation of Transuranic Elements

Zhang, Yong

Download PDF

Request Version for Screen Reader

Last Modified

March 20, 2019

Creator

Zhang, Yong
- Affiliation: Eshelman School of Pharmacy

Abstract

The penta-ethyl ester of diethylenetriamine pentaacetic acid (DTPA), a DTPA prodrug designated as C2E5, was designed for transdermal delivery for radionuclide decorporation. The C2E5 was first screened with a prototype cream formulation and a hydrocarbon base ointment. C2E5 experienced rapid degradation in the cream matrix and C2E5 ointment formulations underwent phase separation due to components incompatibility. Non-aqueous gel matrix comprised of ethyl cellulose/Miglyol 840® was utilized to formulate C2E5. The C2E5 non-aqueous gel prepared by direct mixing method failed to yield a uniform and pharmaceutically acceptable gel. Solvent evaporation method was conceived and applied to prepare the C2E5 non-aqueous gels. The thermal, rheological and in vitro release studies of a formulation containing 40% C2E5, 20% ethyl cellulose and 40% Miglyol 840 prepared using the solvent evaporation method demonstrated that the gel had acceptable content uniformity, flow properties and C2E5 release profile suitable for transdermal delivery. Topical application of the gel at a 200 mg C2E5/kg dose level in rats achieved higher plasma exposures of several active metabolites compared with neat C2E5 oil at the same dose level. The C2E5 non-aqueous gels comprised of 40% C2E5, 40-45% Miglyol 840 and 15-20% ethyl cellulose prepared by solvent evaporation method were further evaluated by mass balance study and in vivo decorporation study in rodents. When the aforementioned C2E5 gels were spiked with [14C]-C2E5 and applied to rat skin at a dose of 200 mg C2E5/kg, over 60% of the applied dose was absorbed within a 24 h period. Radioactivity was observed in urinary and fecal excretions for over three days after removal of the gel. Using an 241Am wound contamination model, transdermal C2E5 gels were able to enhance total body elimination and reduce the liver and skeletal burden of 241Am in a dose-dependent manner. The efficacy achieved by a single 1000 mg/kg dose to contaminated rats was statistically comparable to the intravenous Ca-DTPA treatment. In conclusion, transdermal delivery of the DTPA penta-ethyl ester prodrug achieved enhanced decorporation of 241Am in contaminated rats. The effectiveness of this treatment, favorable sustained release profile and ease of administration support its use following nuclear and radiological emergencies.

Date of publication