The impact of quantity of lipid based formulations with different compositions on the oral absorption of ritonavir: A trade-off between apparent solubility and permeability

In this study, the effect of the quantity of lipid-based formulations (LBFs) on the oral absorption of ritonavir (RTV), a model for poorly water-soluble drugs, was investigated. Two types of LBFs, comprising short- and medium-chain lipids (LBF-SMC) and long-chain lipids (LBF-LC) loaded with different masses of RTV, were prepared. Then, the respective LBFs were dispersed in distilled water at concentrations of 1.0, 2.0, and 3.0% w/w, which provided the same drug concentration for all formulations. When 1.0% LBF-SMC and LBF-LC were orally administered to rats, the oral absorption was significantly improved compared with that of the suspension (a reference formulation) because of enhanced solubilization of RTV in the gastrointestinal tract; however, this improvement was lower for LBF-LC than for LBF-SMC.

Highlights

• An increase in LBF quantity reduced concentration of free drug in the GI tract.

• The effect of LBF quantity on oral absorption depended on the LBF compositions.

• Solubility-permeability trade-off is key factors for oral absorption from LBFs.

• A new in vitro predictive tool successfully predicted oral absorption from LBFs.

The oral absorption decreased with increasing LBF concentration for both LBF-SMC and LBF-LC. The in vitro permeation in sequence with in vitro digestion revealed that this phenomenon was caused by a reduction in the free drug concentration in the gastrointestinal tract. Moreover, the effect of decreasing the free concentration was more remarkable for LBF-LC than for LBF-SMC because of the greater solubilization capacity of LC digestion products. These findings may be useful for designing improved drug delivery systems.

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Materials:

RTV, tributyrin, a short-chain (SC) triglyceride, Tween 85, egg- lecithin, and 4-bromophenylboronic acid (4-BPB) were obtained from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Saquinavir was purchased from LGM pharma (Erlanger, KY, USA). Capmul MCM C8 EP/ NF, a medium-chain (MC) mono- and di-glyceride, was obtained from Abitec Corporation (Columbus, OH, USA). Maisine CC, a long-chain (LC) mono-, di-, and triglyceride, was purchased from Gattefossé (Lyon, France). Corn oil, a LC triglyceride, and sodium taurocholate (NaTC) were bought from FUJIFILM Wako Pure Chemical Corporation (Osaka, Japan). Porcine pancreatin extract (P7545, 8 ×USP specifications) was obtained from Sigma-Aldrich (St. Louis, MO, USA). All other chemicals were of analytical grade

Yusuke Tanaka, Hirotaka Doi, Takeru Katano, Satoshi Kasaoka,
The impact of quantity of lipid based formulations with different compositions on the oral absorption of ritonavir: A trade-off between apparent solubility and permeability,
European Journal of Pharmaceutical Sciences, Volume 168, 2022, 106079, ISSN 0928-0987,
https://doi.org/10.1016/j.ejps.2021.106079.

See also our short video on Maisine CC:

https://youtu.be/yxXp_LZ2F7M