(M1230-02-08) In Vitro – In Vivo Correlation Studies of Amorphous and Lipid-Based Oral Cannabidiol Formulations

Purpose: The purpose of this work was to investigate the development of in vitro – in vivo correlations of two qualitatively different solid cannabidiol formulations. An amorphous formulation of CBD and a CBD lipid-based system, previously developed and having proven an increased in vivo bioavailability in piglets, were compared in terms of dissolution efficiency in several in vitro dissolution media. Then, a point-by-point relationship correlation between in vitro and in vivo data has been suggested by using a time scaling approach based on the different media so as to be able to rationalize the choice of a dissolution medium to be used to characterize the in vivo behavior of the two different formulations.

Methods: Pharmacokinetic data (C_max, T_max, AUC_last) of an amorphous CBD formulation (CBD: MS Silsol^®; 40:60) [1] and a lipid-based CBD system (CBD: Gelucire^® 50/13: MS Syloid^® XDP; 20:40:40) [2] were obtained from previous works in which the formulations were administered orally to fasted piglets (n=5; 2.5 mg CBD/kg). The two formulations were submitted to various in vitro dissolution tests (HCl 0.1 N and phosphate buffer pH 6.8, ± 0.5% SLS; Biorelevant^® media FaSSGF, FaSSIF and FeSSIF-V2) under sink and non-sink conditions. In vivo data were compared via point-to-point relationships to in vitro dissolution data by using Phoenix^TM WinNonlin 8.4 (Certara, Princeton, USA). In vivo absorption curves were obtained through deconvolution process by using UIR values obtained from a previous intravenous study [3]. In vivo absorption profiles and modeled in vitro data were linked by time scaling approach using the inverse release function (IRF) [4]. The obtained mean time scaling values (specific to the type of formulation or common for both formulations) were used to predict absorption profiles from in vitro data. Model predictability was estimated internally by calculating the prediction errors (%).

Results: Dissolution efficiencies were similar or not depending on the used medium and in vitro dissolution tests highlighted the importance of the presence of surfactant properties to allow CBD solubilization (Figure 1). The most suitable in vitro - in vivo correlations were obtained by using basic media containing surfactant properties. FaSSIF medium under sink condition, FeSSIF medium and phosphate buffer pH 6.8 (+0.5% SLS) medium under non-sink condition allowed appropriate AUC prediction for both formulations. The use of correlation factor common for both formulations gave similar results to the use of a factor specific to each formulation, thus demonstrating the potential of these media for predicting the AUC of formulations as different from each other as those used in this study (Table 1). On the contrary of AUC parameters, predictive C_max values were not systematically conclusive, explained by complex absorption events (essentially entero-hepatic cycles for the amorphous formulation, and the presence of two populations of monopeak for the lipid-based system). FeSSIF medium was the optimal choice for suitable prediction of both AUC and C_max.

Conclusion: This study showed the importance of the choice of dissolution medium when analyzing in vitro results. Furthermore, these tests have shown the need for surfactant to enable CBD solubilization. Level A in vitro – in vivo correlations showed the suitability of FeSSIF to predict in vivo AUC, and C_max, of CBD from different formulations.

References: 1. Koch N, Jennotte O, Gasparrini Y, Vandenbroucke F, Lechanteur A, Evrard B. Cannabidiol aqueous solubility enhancement: Comparison of three amorphous formulations strategies using different type of polymers. Int J Pharm. 2020;589.
2. Koch N, Jennotte O, Toussaint C, Lechanteur A, Evrard B. Production challenges of tablets containing lipid excipients: Case study using cannabidiol as drug model. Int J Pharm. 2023;633.
3. Koch N, Jennotte O, Lechanteur A, Deville M, Charlier C, Cardot J, et al. An Intravenous Pharmacokinetic Study of Cannabidiol Solutions in Piglets through the Application of a Validated Ultra-High-Pressure Liquid Chromatography Coupled to Tandem Mass Spectrometry Method for the Simultaneous Quantification of CBD and Its Carboxylated Metabolite in Plasma. Pharmaceutics 2024;16(1).
4. Cardot JM, Lukas JC, Muniz P. Time Scaling for In Vitro-In Vivo Correlation: the Inverse Release Function (IRF) Approach. AAPS J. 2018;20:1–10.

Acknowledgements: In vivo study was performed within PigForLife® (CER Group Facilities) GLP structure (Marloie, Belgium). The study protocols were approved by the Local Ethical Committee before the start of the study and complied with the Belgian regulation as published in «Royal Decree of May 29, 2013 on the protection of experimental animals, A.G.W. 30.11.2017». Authors received funding from FEDER funds (SOLPHARE project, 884148-329407) and Fonds Léon Frédéricq for the support in project 2021-2022-12. Authors declare no conflict of interest.


Figure 1 - Examples of dissolution efficiencies of lipid-based and amorphous formulations in HCl 0.1 N and FeSSIF media (n=3; ± SD).


Table 1 - Prediction errors (PE%) of Cmax and AUC per formulation and medium