An in vitro cultured monolayer system of alveolar epithelial cells was used as a model to investigate the transport pathway of the peptides and proteins, salmon calcitonin (sCT), insulin (INS), recombinant hirudin (rHAV2), and recombinant human growth hormone (rhGH), in pulmonary epithelium. Human lung adenocarcinoma A549 cells formed continuous monolayers when grown on the polycarbonate filters of Transwell plates. The transport of the peptides and proteins having MW of 3400-22,000 Da was studied under different conditions. The results showed that the apparent permeability coefficients (Papp) of these macromolecules across A549 cell monolayers ranged from 2×10−6 to 5×10−6cm s−1 and exhibited a good inverse correlation with molecular weight. No concentration, direction, or temperature dependence was observed in the permeation of sCT, INS, and rHAV2. While the Papp of rhGH in the BA direction (2.25×10−6cm s−1) was less than that in the AB direction at both concentrations (3.20×10−6 and 3.29×10−6cm s−1). The Papp values of rhGH were concentration and temperature independent in the AB direction. These findings suggest that the hydrophilic peptides and proteins used in this study, sCT, INS, rHAV2, and rhGH, appear to cross the A549 cell monolayers via a paracellular pathway by a passive diffusion mechanism.

The purpose of this work was to improve the oral bioavailability of cyclosporine A (CyA) by preparation the CyA-pH sensitive nanoparticles. The CyA-pH sensitive nanoparticles were prepared by using poly (methacrylic acid and methacrylate) copolymer. The characterization and the dispersion state of CyA at the surface or inside the polymeric matrices of the nanoparticles were investigated. The in vitro release studies were conducted by ultracentrifuge method. The bioavailability ofCyAfrom nanoparticles and Neoral microemulsionwas assessed in Sprague-Dawley (SD) rats at a dose of 15mg/kg. The particle size of the nanoparticles was within the range from 37.4

Based on the clinical fact that paclitaxel injection (Taxol®) frequently causes hypersensitivity reactions, we prepared an alternative paclitaxel microemulsion with small particle size (17.2nm). The hypersensitivity evaluation and pharmacokinetic behavior in rats were conducted to assess the new microemulsion. The results showed that the new microemulsion was negative and the placebo Taxol® solution was positive with regard to allergic reactions. In the pharmacokinetic study, five rats were administrated Taxol® or paclitaxel microemulsion. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 14h and paclitaxel determined by HPLC. The area under the curve (AUC) was significantly higher in the microemulsion group (34.98μg ml-1 h) than that in the Taxol group (21.98μg ml-1h). Also, the K10 was much smaller in the microemulsion group (0.57h-1) compared with the Taxol® group (1.29h-1), showing the elimination rate was much slower in the former than in the latter. Compared with Taxol®, the paclitaxel microemulsion caused less toxicity and had a longer circulation time in rats.

Polybutylcyanoacrylate nanoparticles of 3H labelled gentamicin were used to investigate the possibility of gentamicin nanoparticles as the drug delivery system for intracellular chemotherapy. 3H labelled gentamicin nanoparticles were incubated with mouse peritoneal macrophages or rat hepatocytes for various lengths of time. The cells were then separated from the nanoparticles and the radioactivity of 3H in the cells was measured by a liquid scintillation counter. By comparison with the gentamicin solution, the binding to nanoparticles produced a 5.34-fold increase in the uptake of gentamicin by the macrophages in 30-min incubation and 26.74-, 8.03-and 7.36-fold increase in uptake by the hepatocytes in 1-, 12-and 24-h incubation. The stabilizers used in the preparation of nanoparticles, particle size, surfactant coating and the gentamicin concentration were each found to have an effect on the uptake of the nanoparticles by both types of cells.

The pH-sensitive cyclosporine A (CyA) nanoparticles were prepared by the solvent displacement method with enteric dissolved polymer of hydroxypropyl methylcellulose phthalate (HPMCP; including HP50 and HP55). The CyA nanoparticles were analyzed by HPLC for yield and encapsulation efficiency, dynamic light scattering for particle size and transmission electron microscopy (TEM) for morphology. The bioavailability of CyA-HP50 and CyA-HP55 nanoparticle colloids were evaluated in rats, compared with the current available CyA microemulsion (NeoralR). The bioavailability of CyA-HP55 nanoparticle colloids with various suspending agents was also investigated. The results obtained demonstrated that the pHsensitive CyA nanoparticles with a particle size of 50-60nm and encapsulation efficiency over 95% could be reproducibly prepared. The bioavailability of CyA-HP50 and CyA-HP55 nanoparticle colloids calculated by the AUC0-72 were 82.3% and 119.6%, similar to the reference of Neoral, while the bioavailability of CyA-HP55 nanoparticle colloids was found to be higher than that of CyA-HP50 nanoparticle colloids. The increase of mean residence time (MRT) and the decrease of elimination constant of the central compartment (K10) for both CyA-HP50 and CyA-HP55 nanoparticle colloids compared with the reference indicated significant sustained release of CyA from the nanoparticles. The effects of the suspending agents on the bioavailability of CyA-HP55 nanoparticles were observed, and the bioavailability decreased as the concentration of suspending agents or the viscosity of the nanoparticle colloids increased.