Formulation and Characterization of Amphotericin B±Polyethylenimine±Dextran Sulfate Nanoparticles WAREE TIYABOONCHAI, 1 JAMES WOISZWILLO, 2 C. RUSSELL MIDDAUGH 1 1 Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas 66047 2 Sedum Laboratories, Inc., 51 Francis Avenue, Mans®eld, Massachusetts 02048 Received 5 June 2000; revised 28 November 2000; accepted 29 November 2000 ABSTRACT: A new aqueous nanoparticle system has been developed using complex coacervation employing the oppositely charged polymers polyethylenimine (PEI) and dextran sulfate (DS), with zinc sulfate as a stabilizing agent. Amphotericin B (AmB) was loaded into the nanoparticles as a model drug. The nanoparticles contained PEI and DS in the weight ratio of 1:2. They possessed a zeta potential of approximately  30 mV and demonstrated a narrow size distribution in the range 100±600 nm with a polydispersity index of 0.2. Electron microscopy revealed spherical nanocapsules with a smooth surface. Very favorable drug entrapment and recovery ef®ciencies of up to 85% were routinely observed. Processing parameters, such as the pH of the PEI solutions, ratio of the two polymers, as well as the concentrations of DS and zinc sulfate, all played a signi®cant role in controlling particle size. Dissolution studies demonstrated a fast release that is dependent on the model drug solubility. The AmB-loaded nanoparticles displayed no toxicity in tissue culture in contrast to free drug and were almost as ef®cacious as free drug in killing Candida albicans. Advantages of this simple technique are (1) ease of manufacturing and mild preparation conditions, (2) employment of completely aqueous processing conditions, (3) use of biocompatible polymers that can be prepared aseptically, (4) ability to control their size, and (5) a high level of drug entrapment. ß 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:902±914, 2001 Keywords: nanoparticles; complex coacervation; amphotericin B; polyethylenimine; dextran sulfate INTRODUCTION Much effort has been expended to develop delivery systems that can deliver drugs to target organs with improved therapeutic ef®ciency and reduced toxicity. Nanoparticle delivery systems are one approach that has been extensively inves- tigated. It is clear that nanoparticles adminis- tered by various routes can often provide a prolonged circulation time and therefore im- proved drug bioavailability. 1±4 Methods used to form nanoparticles include solvent evaporation, interfacial polymerization, and emulsion poly- merization. Unfortunately, such processes fre- quently employ organic solvents or heat, which are undesirable processing steps for a variety of reasons. 1,5 In contrast, complex coacervation is usually a simpler and milder encapsulation process. 6 This approach generally employs water-soluble poly- mers and a relatively straightforward method of induction of complex formation. Coacervation or phase separation is usually induced by electro- static interaction between oppositely charged polymers. 7 This electrostatic interaction results 902 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 90, NO. 7, JULY 2001 Correspondence to: C.R. Middaugh (Telephone: 785-864- 5813; Fax: 785-864-5814; E-mail: middaugh@ku.edu) Journal of Pharmaceutical Sciences, Vol. 90, 902±914 (2001) ß 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association