Effect of molecular weight of hypromellose on mucin diffusion and oral absorption behavior of fenofibrate nanocrystal

We investigated the effect of variation in the molecular weight of hypromellose (HPMC) on the oral absorption of fenofibrate (FFB) nanocrystal. Four types of HPMC with different molecular weights and sodium dodecyl sulfate (SDS) were used as dispersion stabilizers for FFB nanocrystal suspension. Wet-milling of FFB crystal with HPMC and SDS formed diamond-shaped FFB nanocrystals with approximately 150 nm diameter. HPMC was strongly adsorbed onto the FFB nanocrystal interface, and the amount of HPMC adsorbed was not dependent on the molecular weight of HPMC. However, the decrease in the molecular weight of adsorbed HPMC led to an improvement in the permeability of FFB nanocrystal through the mucin layer. The decrease in molecular weight of HPMC enhanced the flexibility of FFB nanocrystal interface and effectively inhibited its interaction with mucin. This led to faster diffusion of FFB nanocrystal through mucin. In vivo oral absorption studies showed rapid FFB absorption from FFB nanocrystal formulations using HPMC of low molecular weights. The present study revealed that the molecular weight of the dispersion stabilizer for drug nanocrystal formulation should be taken into consideration to achieve improved absorption of poorly water-soluble drugs after oral administration.