(M0930-02-08) Evaluation of Amorphous and Lipid-Based Formulation Strategies to Increase Oral Cannabidiol Bioavailability

Purpose: The aim of this study was to improve the oral bioavailability of BCS II class molecule cannabidiol (CBD), a promising terpenophenolic compound with antioxidant and anti-inflammatory properties. Its oral bioavailability is estimated at 6%, linked to a poor aqueous solubility and high first-pass metabolism [1]. The purpose of this work was to investigate the enhancement of CBD oral bioavailability by administering a CBD-loaded mesoporous silica formulation, a CBD lipid-based system and crystalline CBD, to fasted piglets in a cross-over study. The simultaneous quantification of 7-COOH-CBD, an inactive secondary metabolite, was used to evaluate the effect of the formulation on the CBD metabolization.

Methods: The optimized amorphous CBD formulation consisted of non-ordered mesoporous silica Silsol^® (pore size of 6.6 nm) loaded with 40% of CBD by using subcritical CO₂ (50 bars and 60 °C) as loading method [2]. The selected lipid-based system consisted of an eutectic mixture composed with CBD and Gelucire^® 50/13, loaded in non-ordered mesoporous silica Syloid^® XDP (pore size of 25 nm) to provide a free flowing-powder [3]. Amorphous CBD formulation, lipid-based CBD system and crystalline CBD were characterized in vitro by using HPLC-UV assays, DSC analysis and dissolution tests in FaSSIF medium under sink condition. These three formulations were then administered orally to fasted piglets (n=5; 2.5 mg CBD/kg). Blood samples were collected (0h to 24h) and analyzed by validated UPLC-MS/MS method, allowing simultaneous quantification of CBD and 7 – COOH – CBD [4]. Plasma concentration versus time curves and pharmacokinetic parameters (C_max, T_max, AUC_last) were calculated using Phoenix^TM WinNonlin 8.4 (Certara, Princeton, USA). In addition, intravenous injection of CBD solution in piglets provided Unit Impulse Response (UIR) allowing determination of absolute bioavailability and a better understanding of kinetics of CBD metabolism.

Results: Amorphous and lipid-based CBD formulations followed a diffusion release mechanism in FaSSIF medium, confirmed by both Weibull (r² >0.99; slope factor determined at 0.82 and 0.77 for the amorphous and lipid-based formulations respectively) and Korsmeyer-Peppas equations (r² >0.97; n-values below 0.43). Descriptive pharmacokinetic analysis showed an increase in oral bioavailability of up to 10-fold and 6-fold for the amorphous (144.47 ± 72.55 ng*h*mL^-1) and the lipid-based (89.97 ± 46.00 ng*h*mL^-1) formulations respectively, compared with crystalline CBD (13.25 ± 8.82 ng*h*mL^-1). Absorption of CBD from amorphous formulation was high but variable with entero-hepatic cycles occurring independently of food intake (Figure 1). The absorption of CBD from the lipid-based formulation was lower but more homogenous in terms of AUC and C_max. This formulation provided different populations of T_max mono-peak. Quantification of 7 – COOH – CBD showed higher metabolization with lipid-based formulation than with the amorphous one.

Conclusion: In conclusion, this study proves the in vivo enhancement of CBD oral bioavailability from two in vitro optimized CBD solid formulations in piglets. Higher AUC and C_max are provided by the amorphous formulation, partially explained by lower metabolization and complex pharmacokinetic events such as the entero-hepatic cycle, but suffers from a greater variability than the lipid-based formulation.

References: 1. Millar SA, Maguire RF, Yates AS, O’sullivan SE. Towards better delivery of cannabidiol (Cbd). Pharmaceuticals. 2020;13:1–15.
2. 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.
3. 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.
4. 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).

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 - Mean pharmacokinetic curves of CBD and 7-COOH-CBD from lipid-based, crystalline and amorphous formulations (n=5).