Development of 2D and 3D mucus models and their interactions with mucus-penetrating paclitaxel-loaded lipid nanocapsules.

PURPOSE: To study, diffusion through mucus (3D model) of different formulations of paclitaxel loaded lipid nanocapsules (Ptx-LNCs), to interpret the results in the light of LNC behavior at air-mucus interface (2D model). METHODS: LNC surface properties were modified with chitosan or poly(ethylene glycol) (PEG) coatings of different size (PEG 2,000 to 5,000 Da) and surface charges. LNC diffusion through 446 µm pig intestinal mucus layer was studied using Transwell(®). LNCs were spread at the air-water-mucus interface then interfacial pressure and area changes were monitored and the efficiency of triglyceride (TG) inclusion was determined. RESULTS: Ptx-LNCs of surface charges ranging from -35.7 to +25.3 mV were obtained with sizes between 56.2 and 75.1 nm. The diffusion of paclitaxel in mucus was improved after encapsulation in neutral or positively charged particles (p < 0.05 vs Taxol(®)). No significative difference was observed in the 2,000-5,000 PEG length for diffusion both on the 2D or 3D models. On 2D model positive or neutral LNCs interacted less with mucus. Highest efficiency of TG inclusion was observed for particles with smallest PEG length. CONCLUSIONS: The results obtained with 2D and 3D model allowed us to select the best candidates for in vivo studies (neutral or positive LNCs with smaller PEG length).

A kinetic study of the formation of beta-cyclodextrin complexes with monomolecular films of fatty acids and glycerides spread at the air/water interface.

The kinetics of formation of inclusion complexes between beta-cyclodextrin and monolayers of one-, two- and three-chained lipid molecules, namely, oleic acid (OA), monoolein (MO), diolein (DO) and triolein (TO), was investigated at various pH using three independent dynamic methods. The formation and solubilization of soluble inclusion beta-CD/OA and beta-CD/MO complexes was detected by measuring the decrease of the surface area and surface pressure of the OA and MO monolayers in the presence of beta-CD within a wide range of concentrations. A third approach, describing the dilatational properties of the monolayers, influenced by the formation and solubilization of the complexes, was developed. Using the three above-mentioned independent methods, the rate constants of formation (k1) and dissociation (k2) of beta-CD/OA and beta-CD/MO, were determined. We observed that solubilization flux i s for OA monolayer increases with pH and at pH 11 reached a value, which is closed to the diffusion flux iD and the process thus becomes diffusion controlled. For MO monolayer no significant effects of pH was observed above pH 6. The surface pressure (Deltapi)--area per molecule (A) and surface potential (DeltaV)--area per molecule (A) isotherms and rheological properties of DO and TO monolayers were measured in the presence or absence of beta-CD. DO and TO form water-insoluble complexes with beta-CD, as visualized by AFM images.