Development of a Respirable, Sustained Release Microcarrier for 5-Fluorouracil II: In Vitro and In Vivo Optimization of Lipid Coated Nanoparticles

The release rate of 5-fluorouracil (5-FU) from lipid-coated nanoparticles (LNPs) was determined to develop a respirable delivery system for use as adjuvant (postsurgery) therapy for lung cancer. LNPs were prepared by spray drying, and the in vitro release was measured by microdialysis. The composition of the core and shell affected the release rate. Increasing the core diameter at constant shell thickness and increasing shell thickness at constant core diameter reduced the release rate, suggesting that the lipid shell is the rate limiting step for the release of 5-FU. A model consisting of a sequential zero-order/first-order dependence on time from polydispersed cores within polydispersed shells was developed to describe the release. Based on studies of the effect of geometry of the layered particles, the optimal formulation was identified as a 600-nm diameter 5-FU/poly-(glutamic acid) core with a 200-nm thick tripalmitin/cetyl alcohol shell. This system is readily aerosolized by ultrasonic atomization, which did not change the release properties. Preliminary instillation and inhalation delivery studies to the hamster resulted in lung levels of the particles and 5-FU that were near the desired values. Through this effort, a sustained-release, respirable delivery system for adjuvant therapy of lung cancer in humans may ultimately be realized.