# Oil-based and oil-free formulations for enhancing cannabidiol bioavailability

## TL;DR

This study shows that CBD absorption can be significantly improved using specific oil-based or oil-free formulations, with optimal droplet size and surfactant balance being key factors.

## Contribution

The study introduces formulation strategies that significantly enhance CBD bioavailability through controlled droplet size and surfactant optimization.

## Key findings

- CBD emulsions with 16 μm droplet size achieved 291% and 455% higher AUClast and Cmax than the reference.
- Oil-free nanoparticles improved CBD absorption due to their amorphous structure, with minimal size dependency.
- Excessive surfactant (Tween 20) or lecithin reduced overall CBD bioavailability.

## Abstract

Cannabidiol (CBD) exhibits therapeutic potential due to its analgesic, anxiolytic, anti-inflammatory, and anticonvulsant effects. However, its oral bioavailability is limited by poor water solubility and extensive first-pass metabolism. Formulation strategies such as oil-based emulsions and oil-free particles may overcome these limitations by enhancing solubilization and promoting lymphatic absorption. This study aimed to evaluate the effects of oil droplet and particle size, and surfactant concentration on CBD bioavailability.

CBD emulsions were produced using membrane emulsification, high-pressure homogenization, while particles were produced via solvent emulsification–evaporation method. Physicochemical properties were assessed using microscopy and light-scattering techniques. In a randomized, cross-over study, male Wistar rats (n = 75) received single oral doses of ten test formulations, while a CBD solution in sunflower oil served as the reference. Serum concentrations were determined using validated UHPLC–MS/MS. Pharmacokinetic parameters (AUClast, Cmax, Tmax) were estimated by non-compartmental analysis and statistically compared using ANOVA.

All tested formulations enhanced CBD absorption relative to the reference, CBD in sunflower oil. Among emulsions, droplet size significantly influenced bioavailability: the 16 μm formulation yielded the highest exposure, with AUClast and Cmax values reaching 291% and 455% of the reference, respectively. Both sunflower and sesame oil emulsions enhanced bioavailability against the oil solution, though sunflower oil showed a slight advantage. Oil-free nanoparticles and microparticles also improved absorption due to their amorphous character, with size exerting minimal effect. Higher concentrations of Tween 20 accelerated absorption but reduced overall exposure, while an excess of lecithin decreased bioavailability.

CBD bioavailability can be substantially enhanced by formulation design. Medium-sized emulsions (≈ 16 μm) provided the most pronounced improvement, while oil-free particles offered additional but less size-dependent benefits. Excessive surfactant (Tween 20) or lecithin content negatively impacted systemic exposure, underscoring the need for balanced formulation strategies. These findings contribute to the understanding of oral delivery of lipophilic compounds and support the rational development of optimized CBD formulations for therapeutic applications.

The online version contains supplementary material available at 10.1186/s42238-025-00371-y.