Delivered by Publishing Technology to: University of Houston IP: 129.7.158.43 On: Sun, 28 Sep 2014 02:06:42 Copyright: American Scientific Publishers Copyright © 2006 American Scientific Publishers All rights reserved Printed in the United States of America Journalof NanoscienceandNanotechnology Vol. 6, 3193–3202, 2006 Surface-Modified and Conventional Nanocapsules as Novel Formulations for Parenteral Delivery of Halofantrine Vanessa Carla Furtado Mosqueira 1 2 , Philippe Legrand 1† , and Gillian Barratt 1 ∗ 1 UMRCNRS8612,FacultédePharmacie,UniversitéParis-Sud,92296ChâtenayMalabry,France 2 DepartamentodeFarmácia,UniversidadeFederaldeOuroPreto,35400000-MG,Brazil The aim of this work was to develop a stable injectable formulation of the antimalarial drug halo- fantrine (Hf) based on nanocapsules (NC) prepared from biodegradable polymers with Miglyol  810N as the oily core. Poly(D,L-lactide) PLA and its copolymers with poly(ethyleneglycol) (PLA- PEG) were used together with the surfactants poloxamer 188 and lecithin to yield NC with different surface properties. Highly efficient loading of the free base form of Hf was obtained; zeta potential measurements indicated that a part of the associated Hf was at the NC surface, interacting with the lecithin. NC were 150–250 nm in diameter and more stable on storage than nanoemulsions formed from oil and lecithin without polymer. The most stable NC, showing minimal size changes and floc- culation, were those with a high density of 20-kDa PEG chains covalently grafted at the surface. Hf release from NC occurred mainly by partition with the external medium. In PBS, even when Tween 80 was added, release was limited to 20% of the total content, whatever the formulation. Addition of serum to the medium allowed complete and rapid release from PLA NC stabilized with adsorbed poloxamer 188, because of the high affinity of Hf for lipoproteins. However, the presence of cova- lently grafted PEG chains at the surface limited release by providing a hydrophilic steric barrier at the particle surface. A dense coverage with long PEG chains provided the best reduction of release. Such systems could constitute a long-circulating intravenous formulation of Hf for treating severe malaria. Keywords: Halofantrine Base, Malaria, Poly-D,L-Lactide, Drug Release, Nanocapsules, Poly- D,L-Lactide-co-Polyethylene Glycol. 1. INTRODUCTION Malaria is a very widespread disease and its severe forms are life-threatening. In particular, cerebral malaria causes mortality in children even with intensive therapy. 1 Such severe malaria is a medical emergency, in which the fast achievement of active drug concentrations is a priority and parenteral administration is the rule. Thus, the develop- ment of a safe intravenous formulation of an effective drug which could be rapidly active in cases of cerebral malaria when the patient is unconscious would be advantageous. Halofantrine is a well-tolerated and effective antimalar- ial drug, prescribed by the oral route for the treatment of malaria attacks caused by multidrug-resistent strains of Plasmodium falciparum. However, halofantrine exhibits unpredictable bioavailability since its intestinal absorption ∗ Author to whom correspondence should be addressed. † Present address: UMR CNRS/ENSCM/UMI 5618, Ecole de chimie de Montpellier, 34000 Montpellier, France. is limited by low rates of dissolution and by poor solubility in aqueous media. 2 Furthermore, it has dose-dependent cardiotoxic side effects due to its propensity to prolong the QT interval. These physicochemical and biological prop- erties of halofantrine render the formulation of an intra- venous preparation difficult and none is yet commercially available. Such a formulation would be useful to achieve a rapid therapeutic effect in treatment of cerebral malaria, since halofantrine acts more rapidly than quinine or meflo- quine in P. falciparum infections. 3 A single parenteral formulation of halofantrine has been tested clinically in humans; however it was not without adverse effects. Seri- ous local irritation with strong erythema and the possibil- ity of halofantrine aggregation immediately upon infusion, together with additional toxicity of the solvents used in intravenous preparation restrict its use. 4 Therefore, this poorly soluble drug would benefit from being associated with a new delivery system that would both provide sus- tained circulating concentrations and reduce toxicity. J. Nanosci. Nanotechnol. 2006, Vol. 6, No. 9/10 1533-4880/2006/6/3193/010 doi:10.1166/jnn.2006.444 3193