Nifedipine nanocrystals: pharmacokinetic evaluation in the rat and permeability studies in Caco-2/HT29-5M21 (co)-cultures

Poorly water-soluble drugs such as nifedipine (NIF) (similar to 20 mu g/mL) offer challenging problems in drug formulation as poor solubility is generally associated with poor dissolution characteristics and thus with poor oral bioavailability (BCS class H drugs). In order to enhance these characteristics, formulation of NIF as nanocrystals was carried out. NIF nanoparticles (NP) were prepared using high-pressure homogenization (HPH). Solubility and dissolution characteristics have been reported in previous work to be significantly enhanced for NIF NP. Influence of NIF particle size on NIF permeation rate across intestinal cell models (Caco-2 and HT29-5M21 cultures and co-cultures) was investigated in order to complement these promising in vitro data. Apical to basolateral transfer studies were carried out across Caco-2 and HT29-5M21 cultures and co-cultures. Caco-2/HT29-5M21 co-cultures (seeding ratio 3: 1) were evaluated to better represent in vivo intestinal conditions. The influence of chitosan in the NIF NP formulation with regard to in vitro NIF permeation rate was also evaluated. These studies showed that NIF permeation rate across the different in vitro models evaluated can be significantly enhanced (approximate to 6-fold) by formulation of NIF as nanoparticles. No significant difference was observed either in the presence of chitosan in the formulation or between the three cell models evaluated. To complement these observations, preliminary in vivo pharmacokinetic evaluations in Sprague-Dawley rats, in the fed and fasted states, were also carried out for both un-milled NIF and NIF NP.