Improvement of oxaprozin solubility and permeability by the combined use of cyclodextrin, chitosan, and bile components

The effect of the combined use of randomly methylated β-cyclodextrin (RAMEB), chitosan (CS), and bile components (dehydrocholic (DHCA) or ursodeoxycholic (UDCA) acids and their sodium salts) on solubility and permeability through Caco-2 cells of oxaprozin (a very poorly water-soluble non-steroidal anti-inflammatory drug) has been investigated. Addition of CS, bile acids, and their sodium salts increased the RAMEB solubilizing power of 4, 2, and 5 times, respectively. Drug–RAMEB–CS co-ground systems showed very higher dissolution rate than corresponding drug–RAMEB systems. Addition of bile components further improved drug dissolution rate. The CS presence enabled a significant increase in drug permeability through Caco-2 cells with respect to drug–RAMEB systems. Moreover, CS and NaDHC showed a synergistic enhancer effect, enabling a 1.4-fold permeability increase in comparison with systems without bile salt. However, unexpectedly, no significant differences were found between physical mixtures and co-ground products, indicating that drug permeation improvement was due to the intrinsic enhancer effect of the carriers and not to drug-carrier interactions brought about by co-grinding, as instead found in dissolution rate studies. The combined use of RAMEB, CS, and NaDHC could be exploited to develop effective oral dosage forms of oxaprozin, with increased drug solubility and permeability, and then improved bioavailability.

Dissolution profiles (left) and apparent permeability values (right) of oxaprozin (OXA) alone or as physical mixture (PM) or co-ground product (GR) with RAMEB and chitosan (CS), with and without sodium ursodeoxycholate (NaUDC) or dehydrocholate (NaDHC).Figure optionsDownload as PowerPoint slide