Novel Lipid Formulation Increases Absorption of Oral Cannabidiol (CBD)
Abstract
Background: Cannabidiol (CBD) is an approved treatment for childhood epilepsies and a candidate treatment for several other CNS disorders. However, it has poor oral bioavailability. We investigated the effect of a novel lipid formulation on its absorption in humans and on its tissue distribution in mice.
Methods: In a double-blind crossover study in fasting healthy volunteers, we compared the pharmacokinetics of a single dose of 1000 mg of CBD in the lipid formulation and in a powder formulation (ClinicalTrials.gov: NCT05032807). In a second study, male CD1 mice were administered CBD in either the lipid formulation or dissolved in water, via oral gavage (n = 1 per timepoint). The tissue distribution of CBD was assessed using matrix-assisted laser desorption/ionization mass spectrometric imaging.
Results: Plasma exposure (AUC0–48) of CBD was nine times greater for the lipid formulation than the powder formulation (611.1 ng·h/mL [coefficient of variation {CV%}: 104.6] and 66.8 ng·h/mL [CV%: 50.7], respectively). With the powder formulation, the AUC0–48 was related to the concentration of specific gastrointestinal bacteria and bile acids. These associations were attenuated with the lipid formulation. In the animal study, after treatment with the lipid formulation, measurable concentrations of CBD were identified in all organs. For the aqueous formulation, tissue concentrations of CBD were below the limit of quantification.
Conclusions: Administering oral CBD in a lipid formulation was associated with an increase in its gastrointestinal absorption, as well as an attenuation of the relationship between its absorption and features of the gut microbiome.
Introduction
Cannabidiol (CBD) is an approved treatment for childhood epilepsies [1] and a promising candidate treatment for psychosis, Parkinson’s disease, anxiety, addiction, and insomnia [2,3,4,5,6,7,8,9]. It has a relatively benign adverse effect profile and is highly accepted by patients compared to existing psychiatric treatments [10,11]. CBD is a highly lipophilic molecule that is not readily absorbed when administered orally, and undergoes substantial first-pass hepatic metabolism. As a result, it has poor oral bioavailability (5–10%) [12]. However, this can be improved if CBD is administered with food, especially food with a high fat content [13,14,15].
The only form of CBD approved for clinical use is Epidiolex, which is formulated with sesame oil. The latter is mainly composed of polyunsaturated fatty acids such as linoleic and oleic acid, and increases CBD’s bioavailability [12,13]. Izgelov and colleagues compared the effects of CBD dissolved in sesame oil and CBD in a ‘self-nano-emulsifying drug delivery system’ (SNEDDS) on its bioavailability. Relative to a powder formulation of CBD, the sesame oil formulation increased its peak concentration (Cmax) by 17× and the plasma exposure over time (AUCt) by 8×, while the SNEDDS formulation increased the Cmax by 22× and the AUC by 7× [16]. Knaub and colleagues found that, compared to a medium-chain triglyceride formulation, a ‘novel self-emulsifying drug delivery system’ increased the Cmax by 4.4× and the AUC by 1.8–2.9× [17].
The pharmacokinetic properties of CBD may also affect its distribution and ability to target organs. A few studies have investigated the tissue distribution of CBD after a single dose [18,19,20,21]. Child and Tallon administered 0, 30, 115, or 230 mg/kg CBD (dissolved in medium chain triglyceride oil) to adult male and female rats (n = 6/group) once daily for 28 days [22]. The concentrations of CBD in adipose tissues were 10–100× higher than in either liver or skeletal muscle.
Here, we investigated whether a lipid formulation that has previously been used to enhance the oral absorption of ibuprofen [23] could enhance the bioavailability of CBD. The formulation, which is solid at room temperature, contains Maisine® CC, Gelucire® 43/01, and polyethylene glycol 400, which have been melted and mixed with CBD. All ingredients used in the formulation have been used as inactive ingredients in previous approved medicines in the same or lower concentrations. We first examined its effects on healthy volunteers, and tested the hypothesis that the absorption of CBD, as indexed by its Cmax and the AUC, would be significantly increased by administration in the lipid formulation.
The gut microbiome is understood to have an important role in drug absorption and metabolism [24]. Bacteria can produce secondary bile acids, which aid in the formation of micelles and may therefore influence the absorption of lipophilic drugs such as CBD [24]. Commensal gut bacteria can also affect the activity of CYP3A4, an enzyme involved in CBD metabolism [25]. To investigate the contribution of the gut microbiome to inter-individual variations in the absorption of CBD [26,27], we collected stool samples before the administration of the lipid and the control formulations. Because some effects of CBD may be mediated by endocannabinoids [28,29], we measured the plasma concentrations of endocannabinoids, as well as those of CBD and its metabolites.
We then conducted a parallel study in mice to investigate the effect of the lipid formulation on the distribution of CBD to putative target organs. Matrix-assisted laser desorption/ionization (MALDI) mass spectrometric imaging was used to assess the tissue distribution of CBD at steady state [30], comparing the plasma and whole-body pharmacokinetics of CBD after repeat dosing. We compared the lipid formulation with a formulation in which CBD was dissolved in water. Our hypotheses were that administering CBD in the lipid formulation would be associated with increased concentrations of CBD in the brain and peripheral tissues, as well as with increased gastrointestinal absorption (as indexed by its Cmax and the AUC).
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Materials Study 2
Both formulations contained naturally derived CBD (>99% pure; BSPG Laboratories, Sandwich, Kent, UK). The lipid matrix formulation contained Maisine® CC, Gelucire® 43/01, and polyethylene glycol 400. The aqueous formulation comprised CBD powder dissolved in water.
Chesney, E.; Mazibuko, N.; Oliver, D.; Minichino, A.; Lamper, A.D.; Chester, L.; Reilly, T.J.; Lloyd, M.; Kråkström, M.; Dickens, A.M.; et al. Novel Lipid Formulation Increases Absorption of Oral Cannabidiol (CBD). Pharmaceutics 2024, 16, 1537. https://doi.org/10.3390/pharmaceutics16121537
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