(M1430-07-38) Nanotechnological Approach to Cannabidiol Delivery: Production and Characterization of Microemulsion for Oral Administration

Purpose: To develop a cannabidiol-loaded microemulsion (CBD-ME) for oral delivery intended to overcome the biopharmaceutical drawbacks of CBD, such as low bioavailability, chemical instability in the gastrointestinal environment, and susceptibility to first-pass metabolism.

Methods: Initially, an analytical spectrophotometric method was developed for CBD quantification. A CBD solution in methanol (500 μg/mL) was prepared and subsequently diluted to obtain a concentration range of 2.48 - 19.23 μg/mL. Each solution was analyzed by UV-vis spectrophotometry at 274 nm, and the analytical curve was obtained by linear regression. The CBD-ME was produced using Lipoid^® S100 (6.3 %), Tween^® 80 (14.7 %), Miglyol^® 812N (11 %), and purified water (68 %). All components were homogenized by magnetic stirring and submitted to 4 cycles of 1.5 min of sonication using an ultrasound probe (40 % amplitude) followed by 3 min in ultrasound bath. Then, 150 mg of the CBD were added to 10 mL of the microemulsion by the direct incorporation method, under constant stirring for 12h. To determine the CBD loading efficiency, the CBD-ME was centrifuged at 9000 g for 10 min. Aliquots of 50 μL taken before and after centrifugation were diluted in methanol (1:60 v/v) and quantified by UV-vis spectrophotometry using the previously described method. The physicochemical characterization of the CBD-ME included the evaluation of pH, conductivity (μS/cm), hydrodynamic droplet size (nm) and polydispersity index (PdI). Finally, the physiochemical stability was assessed based on droplet size and PdI, while chemical stability was analyzed by CBD quantification. These analyzes were performed over 60 days, with the CBD-ME stored at room temperature (25 ± 2 ºC) in a glass vial.

Results: CBD is the second most abundant phytocannabinoid from Cannabis sativa. The literature suggests CBD’s pharmacological potential as anxiolytic, neuroprotective, antitumor, antidepressant, antipsychotic, anti-inflammatory, and beneficial in managing several neurological disorders. Despite its versatile pharmacological profile, CBD presents low and variable oral bioavailability due to its (i) low water solubility, (ii) high lipophilicity, (iii), instability in gastric pH, and (iv) high susceptibility to first-pass metabolism. Therefore, microemulsions emerge as a nanotechnological approach to overcome these drawbacks and promote a suitable oral delivery for CBD. Prior to CBD-ME production, an analytical spectrophotometric curve was developed, yielding the equation y = 0.0581x + 0.0133 and R² = 0.9999, which allows CBD quantification according to the ICH guidelines for analytical methods. Post-production, the CBD-ME appeared as an optically clear, homogeneous, and translucent system. The physicochemical characterization showed the following results for CBD-ME: pH of 6.16 ± 0.08, which is slightly acid, but physiologically acceptable for oral administration; electrical conductivity of 132 ± 0.23 µS/cm, indicating an oil in water (O/W) microemulsion, composed of oils droplets dispersed on an aqueous medium; droplet size of 27.72 ± 0.052 nm; and polydispersity index (PdI) of 0.25 ± 0.01, suggesting a monodisperse and homogeneous system. Microemulsions are characterized by droplet size smaller than 100 nm, and this data reinforce the successful production of the CBD-ME. Additionally, the loading efficiency was 97.3 ± 0.7 %, corresponding to 14.5 ± 2.7 mg/mL of CBD in the microemulsion. The stability studies showed slight changes in pH and conductivity (Fig. 1) over 60 days, which did not compromise the system’s stability. The droplet size and PdI (Fig. 2) remained unchanged over 60 days, suggesting a suitable stability of the CBD-ME. Finally, the loading efficiency of 97.3 ± 0.7 % at day 1 and 94.4 ± 0.9 % after 60 days (Fig. 3) indicated a slightly decrease in concentration, suggesting high stability of the CBD molecule.

Conclusion: These data indicate the successful production of CBD-ME with desirable features for a microemulsified system. The CBD-ME demonstrated appropriate physicochemical properties and chemical stability over 60 days, suggesting that the produced microemulsion is potentially suitable for use as an advanced oral delivery system for CBD.

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Acknowledgements: This research was funded by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); Coordenação de Aperfeiçoamento de Pessoal de Nível superior—Brasil (CAPES)—Finance code 001; Fundação de Amparo e Promoção da Ciência, Tecnologia e Inovação do Rio Grande do Norte (FAPERN) e Núcleo de Pesquisa em Alimentos e Medicamentos (NUPLAM);

Figure 2: Evaluation of physicochemical stability by measuring droplet size and polydispersity index of the cannabidiol-loaded microemulsion (CBD-ME) stored at 25 °C for 60 days.

Figure 2: Evaluation of physicochemical stability by measuring droplet size and polydispersity index of the cannabidiol-loaded microemulsion (CBD-ME) stored at 25 °C for 60 days.

Figure 3: Evaluation of cannabidiol loading stability of the cannabidiol-loaded microemulsion (CBD-ME) stored at 25 °C for 60 days.