In Vitro-In Vivo Correlation in Cocrystal Dissolution: Consideration of Drug Release Profiles Based on Coformer Dissolution and Absorption Behavior.

This study assessed the in vitro-in vivo correlation in cocrystal dissolution based on the coformer behavior. 4-Aminobenzoic acid (4ABA) was used as a coformer. Cocrystals of poorly water-soluble drugs with 4ABA, ketoconazole cocrystal (KTZ-4ABA), posaconazole cocrystal (PSZ-4ABA), and itraconazole cocrystal (ITZ-4ABA) were used. These three cocrystals generated supersaturated solutions in fasted state simulated intestinal fluid (FaSSIF) in a small-scale, 8 mL dissolution vessel. The time profile of the dissolved amount of 4ABA, an indicator of cocrystal dissolution, was significantly different among the three cocrystals. Under the conditions utilized, half of the KTZ-4ABA cocrystal solid rapidly dissolved within 5 min and the dissolved amount (% of applied amount) of KTZ and 4ABA was the same. Then, even though the residual solid cocrystal gradually dissolved, KTZ precipitated with time. The PSZ-4ABA cocrystal dissolved in a linear fashion with time but the dissolved concentration of PSZ reached a plateau in the supersaturated state and was maintained for at least 2 h. The dissolution rate of ITZ-4ABA was very slow compared to those of the other cocrystals, but a similar tendency was observed between cocrystal dissolution and the dissolved amount of ITZ. The rank order of the cocrystal dissolution rate based on the conformer concentration was KTZ-4ABA > PSZ-4ABA > ITZ-4ABA. Furthermore, cocrystallization of the three drugs with 4ABA significantly enhanced the oral drug absorption in rats. The rank order of the in vivo cocrystal dissolution rate by a deconvolution analysis with the plasma concentration-time profile of 4ABA was KTZ-4ABA > PSZ-4ABA > ITZ-4ABA, which corresponded well with the in vitro dissolution profiles of the cocrystals. These results indicate that analysis of cocrystal dissolution based on the coformer behavior may be useful to evaluate the in vitro and in vivo cocrystal dissolution.

Maximizing the Oral Bioavailability of Poorly Water-Soluble Drugs Using Novel Oil-Like Materials in Lipid-Based Formulations.

Lipid-based formulations, such as self-microemulsifying drug-delivery systems (SMEDDSs), are promising tools for the oral delivery of poorly water-soluble drugs. However, failure to maintain adequate aqueous solubility after coming into contact with gastrointestinal fluids is a major drawback. In this study, we examined the use of a novel cinnamic acid-derived oil-like material (CAOM) that binds drugs with a high affinity through π-π stacking and hydrophobic interactions, as an oil core in a SMEDDS for the oral delivery of fenofibrate in rats. The use of the CAOM in the SMEDDS resulted in an unprecedented enhancement in fenofibrate bioavailability, which exceeded the bioavailability values obtained using SMEDDSs based on corn oil, a conventional triglyceride oil, or Labrasol, an enhancer of intestinal permeation. Further characterization revealed that the CAOM SMEDDS does not alter the intestinal permeability and has no inhibitory activity on P-glycoprotein-mediated drug efflux. The results reported herein demonstrate the strong potential of CAOM formulations as new solubilizers for the efficient and safe oral delivery of drugs that have limited water solubility.