Formulation and administration of ramipril prodrug for improving bioactivity significantly: In vitro and in vivo correlation

Abstract

Ramipril (RAM), a prodrug is converted to the active metabolite, ramiprilat (RAT) after de-esterification in the liver for pharmacologic activity. RAM is advisable for the control of ocular hypertension after oral administration. The absolute oral bioavailability of RAM is 15% as its unchanged form and 44% as ramiprilat (RAT) in plasma. Film formulations have been prepared for the delivery of RAM transdermally for sustained activity using ethyl cellulose (EC) and hydroxypropyl methylcellulose (HPMC) at different ratios by casting and solvent evaporation method, and compared with conventional oral and intravenous administration. Bioavailability has been assessed by measuring intraocular pressure (IOP) on normotensive rabbit eye model. The study revealed a sustained diffusion-controlled release of RAM exceeding 24 h. Ocular hypotensive action was continued for more than 30 h and the maximum reduction of IOP was found to be 33% after transdermal application of the formulation. Bioactivity has been increased about 9 times and 18 times compared to conventional oral and intravenous administration respectively. The elimination rate was found to be very much lower in the films compared to iv and oral administration. Formulation and transdermal administration of ramipril could improve bioactivity significantly.