Abstract

Paromomycin, an aminoglycoside antibiotic, is used to treat visceral leishmaniasis as an intramuscular injection daily for 21 days since it has limited oral bioavailability. The objective of this investigation is to improve the oral bioavailability through formulation development for increased patient compliance and convenience. Comparative pharmacokinetic studies of intravenous and oral administration of paromomycin in mice to evaluate different formulation approaches to increase oral bioavailability were carried out. Following intravenous injection of 15 mg/kg to mice, paromomycin exhibited low plasma clearance (8 ml/min/kg) with elimination half-life of 2.6 h. Following oral administration of 500 mg/kg of a suspension formulation using carboxymethylcellulose to mice, referred to as formulation 1, paromomycin showed very low or negligible oral bioavailability (%F=0.3). Different formulation approaches were made by employing a variety of FDA-approved novel excipients belonging to glycols, fatty acids, alcohols and surfactants alone and in various combinations. In vivo pharmacokinetic studies with these formulations demonstrated improved oral bioavailability of paromomycin in mice. Formulation approaches tested in the present research project were successful in improving the oral bioavailability of paromomycin from 0.3% to a maximum of 9%. Overall, the increase in paromomycin bioavailability ranged 1-30 fold with different formulations compared to carboxymethylcellulose formulation. Formulation with 10% Gelucire 44/14, 10% Solutol HS 15, 30% propylene glycol and 50% normal saline showed higher bioavailability compared to formulation 1. This research provided evidence that improved bioavailability of paromomycin can be achieved through formulation development which eventually could result in making the most tedious and painful intramuscular therapy redundant.