Absorption of cinnarizine from type IIIb lipid-based formulations: Impact of supersaturation, digestion and precipitation inhibition

In line with previous studies using a similar protocol for the more lipophilic type I, type II and type IIIa lipid-based formulations (LBFs), the impact of supersaturation, lipase inhibition, and precipitation inhibition on type IIIb LBFs containing the poorly water soluble drug cinnarizine was investigated after oral administration to rats. Supersaturated type IIIb LBFs outperformed non-supersaturated LBFs, with statistically significant 58 – 124 % increases in the area under the curve (AUC_0-24h) and 26 – 82 % increases in the maximal plasma concentration (C_max), which also were significant in most cases. The advantage of supersaturated LBFs in terms of AUC_0-24h vanished upon dose-normalization, but C_max still tended to be higher for the supersaturated formulations. Lipase inhibition only had a minor impact on cinnarizine absorption from type IIIb LBFs, as similar AUC_0-24h and C_max were observed from formulations investigated with or without co-administration of a lipase inhibitor. The addition of the amphiphilic polymer Soluplus® did not bring a benefit in terms of drug exposure for type IIIb LBFs, despite high drug loads in supersaturated formulations containing Soluplus®. This study therefore clearly shows the benefit of supersaturated type IIIb LBFs as compared to non-supersaturated LBFs. Along with general learnings about LBFs type IIIb the study also shows that lipase activity is less critical for both – saturated or supersaturated formulations as compared to formulations with a higher glycerol ester content.