(T1130-05-34) Digestion Is an Important Element for Absorption of Cinnarizine from Supersaturated Lipid-Based Type II Formulations

Purpose: Lipid-based formulations (LBFs), composed of lipids, surfactants and/or cosolvents, are means to deliver poorly water-soluble, especially lipophilic, compounds. The Lipid Formulations Classification System (Pouton, 2006) classifies LBFs according to their composition and hydrophilicity into five subtypes. The administered dose in LBFs may be limited by the lipid solubility of the compound. Thus, especially for preclinical toxicity studies that require high doses, the administration of supersaturated LBFs has been suggested. LBFs are prone to lipase-mediated digestion in the gastrointestinal tract. Digestion products form micelles with endogenous bile, solubilizing the drug compound (Pouton, 2006). In contrast to type I LBFs, that only consist of lipids, type II LBFs can self-emulsify due to the presence of a surfactant. Therefore, the dependency of lipid digestion on drug absorption for LBFs type II formulations is generally described as less important compared to type I LBFs (Pouton, 2000), but this has to the best of our knowledge never been systematically investigated in vivo. The purpose of the following study was therefore to investigate the impact of lipid digestion on drug absorption from supersaturated type II LBFs, loaded with cinnarizine, in rats.

Methods: For evaluation of the supersaturation potential for cinnarizine, its solubility was investigated in two type II LBFs, based on medium-chain lipids (MC) and on long-chain lipids (LC), at 20, 37 and 60 °C. For the in vivo study, Sprague-Dawley rats (n=6) received 1.0 mL/kg of the LBFs containing different doses of cinnarizine, depending on the solubility in the vehicle used, by oral gavage. The following formulation parameters were investigated: lipid chain length (MC versus LC), non-supersaturated versus supersaturated at 37 °C, and lipase inhibition (pre-dosing of a suspension of the lipase inhibitor orlistat or a placebo suspension-vehicle). Plasma samples were taken up to 24 h post administration and analyzed by LC-MS. Further data analysis of the log₁₀-transformed pharmacokinetic parameters were done by applying a multiple linear regression analysis (p = 0.05) with the three factors lipid chain length, supersaturation, and lipase inhibition.

Results: The equilibrium solubility of cinnarizine at 60 °C was more than 1.5-fold the equilibrium solubility at 37 °C, suggesting a great supersaturation potential (Figure 1). The solubility in MC was higher than in LC. In vivo, the lipid chain length did not have an impact on the AUC (Figure 2). The administration of supersaturated systems resulted in a significantly higher AUC than non-supersaturated formulations (Figure 2). Lipase inhibition reduced the AUC, showing statistically significant results in the multiple linear regression model, whereas any interaction of the parameters lipid chain length, supersaturation, and lipase inhibition did not have a significant impact on the AUC (Figure 2).

Conclusion: The increased solubility of cinnarizine in LBFs type II at 60 °C compared to the solubility at 37 °C suggests a great supersaturation potential in these formulations. The in vivo study highlights the importance of lipid digestion for drug absorption from type II LBFs, with a significant decrease in AUC upon lipase inhibition. In all formulations tested, supersaturated LBFs showed an increased AUC when compared to non-supersaturated LBFs.

References: 1. Pouton, C. W. (2006). Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. European journal of pharmaceutical sciences, 29(3-4), 278-287.
2. Pouton, C. W. (2000). Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and ‘self-microemulsifying’ drug delivery systems. European journal of pharmaceutical sciences, 11, S93-S98.

Acknowledgements: The employees in the animal facility at Janssen Pharmaceutica (Beerse, Belgium) are highly acknowledged for the skillful handling of the animals. The in vivo study followed the Belgian Royal Decree of May 29, 2013 for the protection of laboratory animals. The protocol was approved by the animal ethics committee of the institution in accordance with the European convention for the protection of vertebrate animals used for experimental and other scientific purposes (ETS no. 123). Felix Paulus and Jef Stappaerts are employees of Janssen Pharmaceutica NV in Beerse, Belgium. The other authors report no conflicts of interest.

Figure 1: Solubility of cinnarizine in type II-LBFs based on medium-chain (MC) and long-chain (LC)-lipids

Figure 2: Parameter estimates of LiC (Lipid chain length), S (Supersaturation), LI (Lipase inhibition) and their interactions (shown as “:”) from a multiple linear regression model following oral administration of LBFs type II. The reference level for LC is “medium-chain triglyceride”, for S “no supersaturation”, and for LI “no lipase inhibition”. The data is shown as estimates ± standard error. Statistical significance is indicated by “**” (p ≤ 0.01).