(M1330-07-41) Impact of Gastric Phase Simulation on the In Vitro Lipolysis of Lipid-Based Formulations Containing Ticagrelor or Fenofibrate

Purpose: In vitro lipolysis is a key approach for helping prediction of the oral performance of lipid-based formulations containing poorly soluble active pharmaceutical ingredients (APIs). This study compares two lipolysis protocols to better understand the impact of an initial gastric phase on the solubilization of two lipophilic drugs, ticagrelor and fenofibrate.

Methods: Two lipolysis protocols were evaluated: Intestinal-only protocol: a standard lipolysis model based on the Lipid Formulation Classification System (LFCS) consortium methodology (1), using porcine pancreatin extract as the digestive enzyme at pH 6.5 and bile salts. Gastrointestinal protocol: including a gastric phase (pH 5.5) containing rabbit gastric lipase and bile salts for 30 minutes, followed by the intestinal phase described above. (2) Two model APIs were evaluated with the two different methods (n=3): ticagrelor, a BCS class IV API and fenofibrate, a BCS a class II API. For ticagrelor, four different lipid-based formulations were tested: 100% Labrasol® ALF, 70% Labrasol® ALF + 30% Labrafac™ MC60, 100% Transcutol® HP, and 70% Tween® 80 + 30% Maisine® CC. For fenofibrate, a single lipid-based formulation composed of Labrasol® ALF:Capryol® 90: Maisine® CC (75/10/15) was evaluated.

Results: For ticagrelor, the addition of a gastric phase significantly improved the percentage of solubilized drug over time, achieving levels between 65% and 100% depending on the formulation, compared to a rapid decline observed in the intestinal-only protocol. For fenofibrate, the implementation of a gastric phase resulted in a two-fold increase in the final amount of solubilized drug compared to the intestinal-only condition. These findings suggest that introducing a simulated gastric phase enhances the solubilization of lipophilic APIs. This effect may be due to the formation of favourable colloidal structures.These results suggest that having a gastric phase enhances the solubilization profiles of lipid-based formulations during the in vitro lipolysis. Further studies are needed to determine which protocol better predicts the in vivo performance.

Conclusion: Incorporating a gastric phase into in vitro lipolysis protocols offers an extra tool to screen oral lipid-based drug delivery systems. Future work will aim to establish in vitro–in vivo correlations supported by PBPK modelling.

References: (1) Williams, HD. et al. (2012) Toward the establishment of standardized in vitro tests for lipid-based formulations, Part 2: The effect of bile salt concentration and drug loading on the performance of type I, II, IIIA, IIIB, and IV formulations during in vitro digestion. In: Molecular pharmaceutics, vol. 9, n° 11, p. 3286–3300
(2) E. Dauphin-Chanard, S. Chevrier, M. Ducros, P. Caisse (2024, October). Toward Improving the In Vitro, In Vivo Correlation of Lipid-Based Formulations Using a Simplified Gastro-Intestinal Lipolysis Protocol [Poster presentation]. AAPS PharmaSci 360, Salt Lake City, UT, United States.


Solubilization profile of ticagrelor from different lipid-based formulations during in vitro intestinal-only lipolysis


Solubilization profile of ticagrelor from different lipid-based formulations during in vitro gastrointestinal lipolysis