Cinnarizine

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_maxwere 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.

Lipid-based formulations (LBFs) are classified according to the content of each component and the hydrophilicity of the surfactant into types I - IV, with LBFs type IIIa consisting of 40 - 80 % oils, 20 - 40 % water-soluble surfactant with HLB > 12, and 0 - 40 % cosolvents. In cases where high drug loads are required, e.g. preclinical toxicity-studies, and the solubility of the drug in the vehicle is insufficient, the use of supersaturated LBFs has been suggested. The impact of digestion on drug absorption from cinnarizine-loaded type I and type II LBFs had previously been found to be highly important for the bio-performance, however, the IIIa systems self-emulsify which is why digestion may be less critical. Therefore, the impact of digestion on drug absorption, as well as the impact of lipid chain length, supersaturation and the addition of the precipitation inhibitor Soluplus® has been investigated in the present work for LBF class IIIa formulations using cinnarizine as a model compound in a similar manner as the previous studies on LBF classes I and II. The administration of long-chain (LC) based type IIIa formulations resulted in a similar drug exposure as for medium-chain (MC) based systems. Supersaturation was beneficial in all cases, with an increase in AUC_0-24h of 72 - 178 % and in C_max of 45 - 130 %. Upon lipase inhibition, AUC_0-24h tended to decrease by 28 - 35 % for LC-based formulations. For MC-based formulations, there was an increase in the AUC_0-24h of up to 31 % compared to the formulations without lipase inhibition, however, if Soluplus® was present, the AUC_0-24h for MC-based formulations tended to decrease. The addition of Soluplus® only brought a benefit for non-supersaturated LBFs, with a 26 - 34 % increase in AUC_0-24h, and for supersaturated MC-based formulations without lipase inhibition, but not for the other formulations. This was surprising as the administered dose of cinnarizine in supersaturated LBFs containing the precipitation inhibitor was higher than in supersaturated LBFs without Soluplus®.