(W1230-06-35) Freeze-Dried Self-Microemulsifying Drug Delivery Systems and Lipidic Nanoparticles for Enhancing Oral Delivery of Cannabidiol

Purpose: Cannabis sativa, contains over 1,200 compounds, including more than 100 cannabinoids. One of these derivatives> is cannabidiol (CBD), which has drawn growing interest by scientists, and policymakers. It is widely used for its anti-inflammatory properties and in the management of seizures, anxiety, schizophrenia, pain/spasticity, and symptoms of Parkinson's disease [1]. However, CBD presents several challenges, including low water solubility (0.01 μg/mL), poor permeability, extensive first-pass metabolism, and conversion to Δ9-THC (which may have psychoactive and addictive effects) and cannabinol (CBN) at low pH (stomach pH ≈ 1.2), resulting in an estimated oral bioavailability of just 6%. Therefore, enhancing its oral bioavailability through solid formulations, offering greater stability and patient compliance compared to liquid formulations [2]. It was found that ω-3 fatty acids enhance the levels of cannabinoid CB1 receptors (~30%) showing that it can potentially have synergistic action with simultaneous administration of CBD [3]. The purpose of this study was to develop lyophilized lipidic nanoparticles incorporating ω-3 fatty acids with CBD, as well as self-microemulsifying drug delivery systems (SMEDDS) containing CBD. In addition, the lyophilized powders were used to prepare tablets, which were then filled into enteric-coated capsules to increase the solubility, bioavailability and stability of CBD after oral administration.

Methods: Two different lipidic nanoparticle formulations were developed by the thin film hydration method followed by sonication. The first formulation consisted of EPC lipid and ω-3 fatty acids at a molar ratio of 8:2 (VE3). The second was composed of DMPC lipid and ω-3 fatty acids at the same molar ratio (V3). These nanosystems were used to incorporate CBD at a final concentration of 1mg/ml. Moreover, two SMEDDS formulations were prepared. The first consisted of Gelucire 44/14 (surfactant), Capryol 90 (co-surfactant), and Labrafil M1944 CS (oil) at a weight ratio of 50:30:20 (S1), whilst the second was composed of Labrasol (surfactant), Plurol® Oleique CC 497 (co-surfactant), and Labrafil® M1944 CS (oil) at a weight ratio of 70:10:20 (S2). To form SMEDDS, 1 g of each mixture was added to 200 mL of distilled water at room temperature. The developed lipidic nanoparticles and SMEDDS were characterized with respect to their physicochemical properties (hydrodynamic diameter, polydispersity index, z-potential) by using dynamic and electrophoretic light scattering (DLS, ELS). Sucrose was used as lyoprotectant, and nanoparticles were lyophilized in a freeze-drier. The freeze-dried powders were reconstituted to the original volume of the preparation and the physicochemical properties were determined to study the effects of lyophilization. Tablets (5 mm in diameter) were prepared using the lyophilized final products of the above formulations, along with the excipients StarLac, Polyplasdone™ XL, and magnesium stearate to develop immediate-release formulations. A conventional tablet containing CBD powder was also prepared for comparison. The matrix tablets were then placed into enteric-coated capsules, and used for the dissolution test, utilizing an USP I dissolution apparatus equipped with a basket at 50 rpm and 37 ± 0.5^oC. Two aqueous media were used, first a pH 1.2 (450 mL) medium, for 2 hours and then a pH 6.8 buffer solution (450 mL) for another 8 hours. The CBD content was determined using UV–Vis spectrophotometry.

Results: The physicochemical properties of both empty and CBD-loaded nanoparticles were measured on the day of preparation. Regarding lipidic nanoparticles, VE3 formulation exhibited a mean size of approximately 150 nm, which was greater compared to V3 nanoparticles. The polydispersity index (PDI) was below 0.3 for both formulations indicating great homogeneity, whereas both SMEDDS exhibited greater size and PDI (Figure 1). The results indicate that CBD is incorporated into the lipidic nanoparticles effectively, and SMEDDS can solubilize CBD at the same concentration. Lyophilization and reconstitution studies were performed, showing the potential of the formulations for in situ nanoparticle formation at the small intestine. During the first two hours (pH=1.2), all formulations showed no CBD release, due to the use of enteric-coated capsules. At pH 6.8, both liposomes and SMEDDS demonstrated a significant increase in CBD dissolution, compared to the conventional tablet containing CBD powder (Figure 2). Specifically, at t=720 min, the liposomal formulation VE3 showed the highest release (94%), followed by V3 (81%). This result can be correlated with the more fluid phase of EPC at 37^oC compared to DMPC, which has a higher phase transition temperature. The two SMEDDS formulations, S1 and S2, exhibited similar release rates of 69% and 66%, respectively. Conversely, the conventional formulation with unprocessed CBD powder showed a mere 28% release, markedly lower than the nanocarrier-based formulations.

Conclusion: By incorporating CBD into nanocarriers (liposomes and SMEDDS), several of its limitations were circumvented. Thus, the use of these nanocarriers improved both solubility and permeability, while the enteric-coated capsules enhanced CBD stability by protecting it from the acidic environment of the stomach. Additionally, the presence of ω-3 in the formulations, could, by acting synergistically, enhance CBD’s therapeutic activity.

References: 1. White CM. A Review of Human Studies Assessing Cannabidiol’s (CBD) Therapeutic Actions and Potential. J Clin Pharmacol. 2019;59:923–34.
2. Jennotte O, Koch N, Lechanteur A, Evrard B. Formulation and quality consideration of cannabidiol printed forms produced by fused-deposition modeling. J Drug Deliv Sci Technol [Internet]. 2023;87:104837. Available from: https://doi.org/10.1016/j.jddst.2023.104837
3. Serrano M, Saumell-Esnaola M, Ocerin G, García del Caño G, Puente N, Sallés J, et al. Impact of Omega-3 on Endocannabinoid System Expression and Function, Enhancing Cognition and Behavior in Male Mice. Nutrients . 2024;16:1–21.

Acknowledgements: The research work was supported by the Hellenic Foundation for Research and Innovation (HFRI) under the 5th Call for HFRI PhD Fellowships grant to C.P. (Fellowship Number: 20610)


The hydrodynamic diameter (Dh) of the developed nanocarriers on the day of preparation (t=0d).


Dissolution profiles of CBD capsules containing the lyophilised powders at pH 1.2 (0–120 min) and at pH 6.8 (120–720 min). Results represent the mean value (n = 3, SD < 2).