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

in Journal of Drug Delivery Science and Technology (2006), 16(6, NOV-DEC), 437-442

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 ... [more ▼]

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. [less ▲]

Conformational analysis of the calcium-antagonist gallopamil.

in Biochemical Pharmacology (1983), 32(3), 437-40

Conformational analysis of gallopamil was performed in order to gain insight into the molecular determinant of its calcium-antagonistic property. Whereas the neutral form of gallopamil was characterized ... [more ▼]

Conformational analysis of gallopamil was performed in order to gain insight into the molecular determinant of its calcium-antagonistic property. Whereas the neutral form of gallopamil was characterized by a single, largely predominant configuration, the protonated form of the drugs yielded several conformers, some of which were characterized by a readily accessible ionized site. The capacity of gallopamil to inhibit ionophore-mediated calcium translocation in a two-phase bulk system was inversely related to the pH of the aqueous phase. These findings indicate that the capacity of gallopamil to interfere with the transport of cations is critically dependent on the availability of a protonated configuration of the drug. [less ▲]

Conformational analysis of the calcium--A23187 complex at a lipid--water interface.

in Proceedings of the National Academy of Sciences of the United States of America (1982), 79(9), 2895-7

A possible conformation of the complex formed by one calcium ion and two molecules of the ionophore A23187 at a simulated lipid--water interface was predicted by a variant method for conformational ... [more ▼]

A possible conformation of the complex formed by one calcium ion and two molecules of the ionophore A23187 at a simulated lipid--water interface was predicted by a variant method for conformational analysis. This method takes into account, in addition to the Van der Waals energy, electrostatic interaction, and torsional potential, the alteration of electrostatic forces attributable to changes in dielectric constant at the interface and the transfer energy for each part of the complex as it moves through the lipid-water interface. The most probable conformer was characterized by a two-fold axial symmetry that was maintained during transition to the hydrophobic bulk conformation. Minor changes in the interfacial structure were sufficient to achieve the configuration characteristic of the hydrophobic bulk phase. [less ▲]