(M1530-03-20) Digestion Is a Critical Element for Absorption of Cinnarizine from Supersaturated Lipid-Based Type I Formulations

Purpose: Lipid-based formulations (LBFs) are composed of lipids, surfactants and/or cosolvents, and are means to deliver poorly water-soluble compounds. The Lipid Formulations Classification System (Pouton, 2006) classifies LBFs according to their composition and hydrophilicity, ranging from type I (very lipophilic) to type IV (hydrophilic). The administered dose in LBFs may be limited by the lipid solubility of the compound. Thus, especially for preclinical toxicity studies, requiring high doses, the application of supersaturated LBFs has been suggested. LBFs are prone to digestion in the gastrointestinal tract. As LBFs type I consist only of lipids and therefore lack the ability to self-emulsify, digestion is thought to be crucial for drug absorption from type I LBFs (Pouton, 2000). However, this has not been proven in vivo for supersaturated LBFs, hence in this study, the impact of lipid digestion on drug absorption from supersaturated type I LBFs, loaded with cinnarizine, was investigated in rats.

Methods: To evaluate the supersaturation potential for cinnarizine, its solubility was investigated in two one-component type I LBFs, a medium-chain triglyceride (MCT) and a long-chain triglyceride (LCT), at 20, 37 and 60 °C using the shake-flask method. For the in vivo study, male Sprague-Dawley rats (n=6) received 1.0 mL/kg of the LBF containing different doses of cinnarizine, dependent upon the solubility in the vehicle used, by oral gavage. The following formulation parameters were investigated: lipid chain length (MCT versus LCT), non-supersaturated versus supersaturated at when dosing 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.

Results: The equilibrium solubility of cinnarizine at 60 °C was more than twice the equilibrium solubility at 37 °C, suggesting a great supersaturation potential (Figure 1). The solubility in MCT was higher than in LCT. In vivo, the supersaturated systems resulted in a higher AUC and C_max than non-supersaturated formulations (Figure 2A). Lipase inhibition greatly affected the in vivo performance of LBFs: As co-administration of the lipase inhibitor significantly reduced C_max and AUC for the LCT formulations and, though statistically not significant for the MCT formulations, a similar trend was observed (Figure 2B, 2C). Also, t_max tended to decrease when compared to the animals not dosed with orlistat. Without lipase inhibition, the LCT in general lead to better absorption of cinnarizine as compared to MCT. The fact that with lipase inhibition a higher decrease in AUC and C_max was observed for cinnarizine administered in LCT than in MCT suggested a higher dependency on lipolysis for LCT (Figure 2A, 2D).

Conclusion: This study showed that LBFs based on LCT performed better in vivo than their medium-chain counterparts. The absorption of cinnarizine from LCT was more dependent on lipolysis, and the study highlights the importance of lipid digestion for drug absorption from type I LBFs. In all formulations tested, supersaturated LBFs showed an increased bioavailability 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 staff in the animal facility at Janssen Pharmaceutica (Beerse, Belgium) are highly acknowledged for their skillful handling of the animals. The study protocol used for the pharmacokinetic study was approved by the institutional animal ethics committee in agreement with the European convention for the protection of vertebrate animals used for experimental and other scientific purposes (ETS no. 123). The study was conducted in accordance with the Belgian law controlling the experiments on animals (Royal Decree of May 29, 2013 for the protection of laboratory animals). Felix Paulus and Jef Stappaerts are employed by Janssen Pharmaceutica NV in Beerse, Belgium. The other authors declare no conflicts of interest.

Figure 1: Solubility of cinnarizine in medium-chain triglycerides (MCT) and long-chain triglycerides (LCT)

Figure 2: Plasma-concentration versus time curves after oral administration of cinnarizine to rats. A) Supersaturated (s) and non-supersaturated lipid-based formulations based on MCT and LCT without lipase inhibition (LI); B) Non-supersaturated lipid-based formulations based on MCT and LCT with and without lipase inhibition (with an enlargement of the plasma curve in the upper right corner); C) Supersaturated lipid-based formulations based on MCT and LCT with and without lipase inhibition; D) Non-supersaturated and supersaturated lipid-based formulations based on MCT and LCT with lipase inhibition (with an enlargement of the plasma curve in the upper right corner). The data is shown as mean ± SEM (n = 6).