Continuing along the lipid formulation classification system: Effects of lipid chain length, supersaturation, digestion, and precipitation inhibition on cinnarizine absorption from type IIIa lipid-based formulations.

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 of 72 - 178 % and in C of 45 - 130 %. Upon lipase inhibition, AUC tended to decrease by 28 - 35 % for LC-based formulations. For MC-based formulations, there was an increase in the AUC of up to 31 % compared to the formulations without lipase inhibition, however, if Soluplus® was present, the AUC 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, 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®.