Category: Formulation and Quality
Purpose: Cannabidiol (CBD) is a non-psychoactive phytocannabinoid which has therapeutic potential for a number of indications, including autoimmune diseases, pain and cancer. CBD is a highly lipophilic compound and has substantial first-pass metabolism which leads to low oral bioavailability. Lipid-based formulations can increase the systemic bioavailability of CBD by facilitating drug uptake via the intestinal lymphatic transport [1.2]. Natural vegetable oils are commonly used for lipid-based formulations. They consist mostly of long-chain triglycerides which lead to the enhancement of the intestinal lymphatic transport. However, substantial variability in fatty acid composition and ratio exists between different vegetable oils. This might affect the efficiency of lipid absorption, as well as the bioavailability of co-administered drug. Moreover, the degree of digestibility of each oil can also affect the overall absorption of lipids and the co-administered drug. The aim of this study is to compare the efficiency of different natural vegetable oils and pre-digested lipid formulations in enhancement of oral bioavailability of cannabidiol.
Methods: All formulations were prepared by solubilizing CBD in corresponding lipid vehicle at a concentration of 12 mg/mL. Lipid vehicles assessed in this work included pre-digested and digestible lipids. Pre-digested lipids vehicles included linoleic acid, oleic acid, 2-oleoylglycerol with oleic acid, and oleic acid with glycerol. Digestible lipid vehicles included trioleate glycerol, sesame oil, soybean oil, sunflower oil, peanut oil and olive oil. All formulations were administered by oral gavage to rats at a dose of 12 mg/kg CBD. Plasma pharmacokinetics and intestinal lymphatic transport were assessed. Blood samples were withdrawn at predetermined time points following the administration. The concentrations of CBD were determined by means of a validated HPLC-UV method . The pharmacokinetic parameters were analysed by a non-compartmental approach using Phoenix WinNolin 6.3 software (Pharsight, Mountain View, CA, USA, Version 6.3). All data were presented as mean ± standard deviation (SD). One-way analysis of variance (ANOVA) followed by post-hoc Tukey multiple comparison test was applied for statistical analysis.
Results: The area under curves (AUC) of plasma CBD concentrations following oral administration of pre-digested lipid formulations were 604±140 h.ng/mL (oleic acid), 670±204 h.ng/mL (linoleic acid), 512±163 h.ng/mL (2-oleoylglycerol with oleic acid) and 584±160 h.ng/mL (oleic acid). The AUC of plasma CBD concentrations following oral administration of digestible lipid formulations was 829±296 h.ng/mL (sesame oil), 775±164 h.ng/mL (soybean oil), and 737±130 h.ng/mL (peanut oil). The total uptake of CBD following oral administration of olive oil formulation (835±130 h.ng/mL) was significantly higher than sunflower oil formulation (551±136 h.ng/mL) and trioleate glycerol formulation (560±229 h.ng/mL), with p< 0.05 (Table 1).
Conclusion: The digestible lipid-based formulations of CBD showed higher drug uptake compared to pre-digested lipid-based formulations. This suggests that lipid digestion in gastro-intestinal tract is not the key step in the overall absorption of highly lipophilic drug such as CBD administered orally in lipid-based formulations. Moreover, the differences in performance between natural vegetable oils as formulation vehicle do not indicate a clear trend in regards to fatty acid composition. It is possible that additional small molecule components of natural vegetable oils could be responsible for difference in enhancement of the absorption of CBD.
Chaolong Qin– PhD student, University of Nottingham, Nottingham, England, United Kingdom
Yenju Chu– Nottingham, England, United Kingdom
Joseph Ali– PhD student, University of Nottingham, Nottingham, England, United Kingdom
Mattia Berton– Abingdon, England, United Kingdom
Sara Bettonte– Abingdon, England, United Kingdom
Jong Bong Lee– Postdoctoral Researcher, Rutgers - The State University of New Jersey, Rutgers, New Jersey
Atheer Zgair– Lecturer, University of Anbar, Ramadi, Al Anbar, Iraq
Cris Constantinescu– Nottingham, England, United Kingdom
David Barrett– Nottingham, England, United Kingdom
Peter Fischer– Professor of Medicinal Chemistry, University of Nottingham, Nottingham, England, United Kingdom
Pavel Gershkovich– Assistant Professor, University of Nottingham, Nottingham, England, United Kingdom