Inclusion of Medium-Chain Triglyceride in Lipid-Based Formulation of Cannabidiol Facilitates Micellar Solubilization In Vitro, but In Vivo Performance Remains Superior with Pure Sesame Oil Vehicle

Abstract

Oral sesame oil-based formulation facilitates the delivery of poorly water-soluble drug cannabidiol (CBD) to the lymphatic system and blood circulation. However, this natural oil-based formulation also leads to considerable variability in absorption of CBD. In this work, the performance of lipid-based formulations with the addition of medium-chain triglyceride (MCT) or surfactants to the sesame oil vehicle has been tested in vitro and in vivo using CBD as a model drug. The in vitro lipolysis has shown that addition of the MCT leads to a higher distribution of CBD into the micellar phase. Further addition of surfactants to MCT-containing formulations did not improve distribution of the drug into the micellar phase. In vivo, formulations containing MCT led to lower or similar concentrations of CBD in serum, lymph and MLNs, but with reduced variability. MCT improves the emulsification and micellar solubilization of CBD, but surfactants did not facilitate further the rate and extent of lipolysis. Even though addition of MCT reduces the variability, the in vivo performance for the extent of both lymphatic transport and systemic bioavailability remains superior with a pure natural oil vehicle.

Keywords: cannabidiol; lipid-based formulation; lymphatic transport; medium-chain triglyceride; sesame oil; surfactant.

Figure 1

Distribution of CBD in sediment, micelle and lipid phases (n = 3, mean ± SD) following the in vitro lipolysis of 6 lipid-based formulations of CBD. One-way ANOVA was used for statistical analysis, followed by Dunnett’s post-hoc test with sesame oil serving as a control group. *, p < 0.05, ****, p < 0.0001. The experiment was terminated when the addition rate of NaOH was slower than 3 μL/min.

Figure 2

The amount of triglyceride, diglyceride and monoglyceride in lipolysis fractions following in vitro lipolysis of six lipid-based formulations (n = 3, mean ± SD). One-way ANOVA was used for statistical analysis, followed by Dunnett’s post-hoc test with sesame oil serving as a control group. * p < 0.05, **, p < 0.01, ***, p < 0.001, ****, p < 0.0001.

Figure 3

Plasma concentration-time profiles of CBD following oral administration of sesame oil-based formulation, Formulation 3 (sesame oil:Tri-C8, 5:5, v/v) and Formulation 4 (sesame oil:Tri-C8:Tween^® 85, 2:2:1, v/v/v with 10 mg/mL TPGS) (n = 5–6, mean ± SD). The concentration of CBD in all formulations was 50 mg/mL, the administered dose of CBD was 25 mg/kg in all treatment groups.

Figure 4

Concentrations of CBD and triglyceride in rat serum. CBD was orally administered in sesame oil, Formulation 3 (F3, sesame oil:Tri-C8, 5:5, v/v) and Formulation 4 (F4, sesame oil:Tri-C8:Tween 85, 4:4:2, v/v/v with 10 mg/mL TPGS) at a dose of 25 mg/kg in rats (50 mg/mL CBD content in each formulation). (a) The concentration of CBD and triglyceride level in rat serum at 1.5 h post-administration. (b) The concentration of CBD and triglyceride level in rat serum at 2.5 h post-administration. All data are shown as mean ± standard deviation (SD) (n = 4). Statistical analysis was performed using one-way ANOVA, followed by Dunnett’s post-hoc test with sesame oil serving as a control group. ****, p < 0.0001.

Figure 5

Concentrations of CBD and triglyceride in lymph fluid. CBD was orally administered in sesame oil, Formulation 3 (F3, sesame oil:Tri-C8, 5:5, v/v) and Formulation 4 (F4, sesame oil:Tri-C8:Tween 85, 4:4:2, v/v/v with 10 mg/mL TPGS) at a dose of 25 mg/kg in rats (50 mg/mL CBD content in each formulation). (a) The concentration of CBD and triglyceride in lymph fluid at 1.5 h post-administration. (b) The concentration of CBD and triglyceride in lymph fluid at 2.5 h post-administration. All data are shown as mean ± SD, n = 4. Statistical analysis was performed using one-way ANOVA followed by Dunnett’s post-hoc test with sesame oil serving as a control group.

Figure 6

Concentrations of CBD in mesenteric lymph nodes (MLNs). CBD was orally administered in sesame oil, Formulation 3 (F3, sesame oil:Tri-C8, 5:5, v/v) and Formulation 4 (F4, sesame oil:Tri-C8:Tween 85, 4:4:2, v/v/v with 10 mg/mL TPGS) at a dose of 25 mg/kg in rats (50 mg/mL CBD content in each formulation). (a) The concentration of CBD in MLNs at 1.5 h post-administration. (b) The concentration of CBD level in MLNs at 2.5 h post-administration. (c) The concentration of CBD in MLNs at 12 h post-administration. All data are shown as mean ± SD, n = 4. Statistical analysis was performed using one-way ANOVA followed by Dunnett’s post-hoc test with sesame oil serving as a control group. *, p < 0.05, **, p < 0.01.