Lipophilic drug loaded nanospheres prepared by nanoprecipitation: effect of formulation variables on size, drug recovery and release kinetics

The nanoprecipitation method of nanosphere preparation offers several important advantages, such as readily adjustable and reproducible carrier size in the nanometer range and use of ingredients with low toxic potential, especially important for intravascular delivery. The applicability of the method to encapsulation of strongly lipophilic drugs has not been adequately addressed to date. In this study we applied nanoprecipitation to prepare PLA nanospheres loaded with a lipophilic tyrphostin compound, AG-1295, a potent antirestenotic agent. The effect of several formulation variables on the nanosphere basic properties (carrier size, drug release rate and drug recovery yield) was investigated. The nanosphere size was shown to be readily controlled by modifying the PLA and PLA non-solvent amounts in the organic phase. Carrier size and organic solvents' elimination rate are the main determinants of the drug release rate. The stability and drug recovery yield in the formulation depend on the drug to polymer ratio. Nanoprecipitation protocol modifications were suggested to produce nanospheres combining ultrasmall size (<100 nm) with high drug recovery yield, and to reduce the surfactant amount in the formulation. (C) 2002 Elsevier Science B.V. All rights reserved.