Effects of Lipid Digestion and Drug Permeation/Re-Dissolution on Absorption of Orally Administered Ritonavir as Different Lipid-Based Formulations.

The aim of this study is to clarify absorption mechanisms after oral administration of ritonavir (RTV) from different types of lipid-based formulations (LBFs) with particular emphasis on the effect of lipid digestion and drug permeation/re-dissolution on the oral absorption. Four LBFs were prepared; three contained either long-chain (LC) or medium-chain (MC) lipids [lipid formulation classification system (LFCS) Type II-LC, Type IIIA-MC, and Type IIIB-MC] and the fourth contained only surfactant and co-solvent (Type IV). The solubility of RTV in those LBFs was determined and drug subsequently loaded at 85% w/w of the saturated solubility in the formulations. Then, each LBF containing drug was added into a model rat intestinal fluid at approximately 2.5% w/v for evaluation using an in vitro digestion model. In vitro digestion study showed the ability of Type II-LC and Type IIIA-MC to support continued solubilization of RTV, and moderate supersaturation was observed in Type IIIA-MC. In contrast, RTV partly precipitated in the Type IIIB-MC during digestion, and the Type IV formulation lost its solubilization capacity rapidly upon dispersion, leading to drastic precipitation. Oral administration of RTV as Type IIIA-MC to rats showed significantly higher area under the plasma concentration-time curve compared to control suspension, whereas it was not improved with Type II-LC administration despite complete solubilization of RTV during digestion. From the results of in vitro permeation across dialysis membrane (a molecular weight cutoff of > 1000 Da), this may be attributed to the lowered free concentration in the gastrointestinal tract owing to incorporation of RTV into the undigested LC lipid. Oral absorption drastically increased with Type IIIB-MC and Type IV despite the observed moderate and drastic precipitation, respectively. Powder X-ray diffraction analysis revealed that the precipitate was amorphous. Therefore, improved re-solubilization may partly contribute to improved absorption. The present study revealed detailed absorption mechanisms from LBFs with different compositions. Our findings may be useful for selecting appropriate excipients to design optimal LBFs for poorly water-soluble drugs.