(T1530-03-17) Preparation and Characterization of Cannabidiol and Cannabidiol-Valine-Hemisuccinate Loaded Lipid-Based Nanoformulations for Ocular Drug Delivery

Purpose: The therapeutic potential of cannabidiol (CBD) has been investigated to treat several ocular disorders. However, CBD is a poorly aqueous soluble molecule making it a challenge to be topically delivered to the back of the eye. CBD’s analog, cannabidiol-valine-hemisuccinate (CBD-VHS), has superior permeation into the ocular tissues compared to CBD due to its physicochemical properties. This research work aimed to develop and evaluate stable mucoadhesive nanoemulsion and nanomicellar formulations of CBD and its analog CBD-VHS for enhanced ophthalmic application.

Methods: The saturation solubility of CBD and CBD-VHS in various excipients of interest was studied at 25ºC. The nanoemulsion and nanomicellar formulations (CBD-NEC, CBD-NMC, and CBD-VHS-NMC) were prepared using hot homogenization followed by probe sonication. The formulations were then studied for physicochemical characteristics, sterilization by autoclaving and filtration, ex-vivo transcorneal permeation, and corneal deposition. In addition, the lead formulations underwent a stability study at refrigerated (5±3ºC), room (25±2ºC), and accelerated (40±2ºC) storage conditions for three months.

Results: The saturation solubility studies revealed that the highest solubility among the surfactants was obtained with Cremophor EL for CBD (23.3±0.1mg/mL) and CBD-VHS (11.2±0.2 mg/mL). Among the lipid/oils evaluated, super-refined sesame oil and sesame oil had the highest solubilizing capacity for CBD and CBD-VHS. CBD showed better solubility values in comparison to its analog in all the evaluated lipids/oils. Based on the results, the oily phase in CBD-NEC formulations was prepared using sesame oil and super-refined sesame oil. The lead CBD-NEC formulation showed a globule size (GS), polydispersity index (PDI), zeta potential (ZP), and assay% of 268.9±7.9 nm, 0.25±0.04, -36.4±0.3 mV, and 103.5±1.2, respectively. The lead CBD-NMC revealed a particle size (PS), PDI, ZP, and assay% of 205.2±2.1 nm, 0.20±0.0, -26.1±0.3 mV, and 100.5±3.1, respectively. CBD-VHS-NEC formulations were not prepared due to the poor solubility of CBD-VHS in the tested oils. The lead CBD-VHS-NMC showed a PS, PDI, ZP, and assay% of 77.8±0.7 nm, 0.44±0.01, -25.7±2.1 mV, and 101.8±1.1, respectively. Sterilization by filtration was achieved for the lead nanomicellar formulations due to their small PS ( < 220 nm). The CBD-NEC formulation was sterilized using autoclaving. Moreover, the autoclaved and filtered formulations, except for CBD-VHS-NMC at 40°C, were stable under the employed storage conditions - PS, GS, PDI, ZP, and assay did not show any significant (p >0.05) change in comparison to the unsterilized (control) formulation for three months. The transcorneal permeation studies (figure 1) demonstrated enhancement in permeability and flux with both formulations; however, a greater improvement was observed with the nanomicellar formulation compared to the nanoemulsion formulation.

Conclusion: CBD-NEC, CBD-NMC, and CBD-VHS-NMC formulations were successfully prepared and characterized. In vivo studies in an animal model are required to demonstrate the differences in ocular surface retention, ocular bioavailability and distribution, and effect on intraocular pressure, as a function of the drug candidate as well as the formulation composition.

Figure 1. Transcorneal flux and permeation (A) and corneal deposition (B) of CBD and CBD-VHS from F25 (CBD-NEC), F30 (CBD-NMC), and F31 (CBD-VHS-NMC) formulations through the corneas isolated from New Zealand White rabbit eyeballs (mean±SD, n=3).