Development of cannabidiol nanoemulsion for direct nose to brain delivery: statistical optimization, in vitro and in vivo evaluation

Abstract

Cannabidiol (CBD) is a prescribed drug for epilepsy but has low oral bioavailability and gastric instability. Because of the direct link between the nasal cavity and the central nervous system, intranasal administration of CBD as nanoemulsions which are the small sized lipid carriers seem to improve the bioavailability. CBD-nanoemulsions (NEs) were made using Capryol 90, Tween 80, and Transcutol P as oil, surfactant, and co-surfactant, respectively, following aqueous titration approach. Then, using the Box–Behnken design, CBD-NE was statistically optimised for the selection of desirable excipient concentrations in order to create the optimal CBD-NE formulation. As independent variables in the statistical design, Capryol 90 (oil; coded as A), Tween 80 (surfactant; coded as B), and Transcutol P (co-surfactant; coded as C) were used. The dependent variables were droplet size (DS; coded as R 1) and polydispersity index (PDI; coded as R 2). The average DS, PDI, and the zeta potential of the optimized CBD-NEs were observed to be 88.73 ± 2.67 nm, 0.311 ± 0.015, and −2.71 ± 0.52 mV respectively. Pure CBD and lyophilized CBD-NE Fourier-transform infrared spectra demonstrated no physicochemical interaction between excipients and the drug. Furthermore, differential scanning calorimetry and x-ray diffraction measurements revealed the amorphous CBD in the NE. As compared to pure CBD, the optimised CBD-NE showed considerably better in vitro drug release as well as ex vivo nasal permeability. The drug targeting efficiency and direct transport percentage of the optimised CBD-NEs were found to be 419.64% and 76.17%, respectively, in this research. Additionally, pharmacokinetic investigations after intranasal administration of CBD-NE revealed considerably higher drug concentrations in the brain with better brain targeting efficiency. As a result, the development of CBD-NE may be an excellent alternative for better intranasal delivery.

Formulating Resveratrol and Melatonin Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) for Ocular Administration Using Design of Experiments

“…Furthermore, Capryol ® 90 and, even more, PGMC possess the ability to spontaneously form clear emulsions when mixed with surfactants with high HLB, such as polysorbates (Tween ® ). Both have been extensively investigated for the development of nanoemulsion and SNEDDS, as well as microemulsions and SMEDDS [ 27 , 28 , 29 , 30 ]. The emulsion formed must be clear and limpid and must not allow the drug to precipitate [ 31 ].…”

Strategies to Improve Cannabidiol Bioavailability and Drug Delivery

“…When delivered at the same dose with the same formulation (PEG 400-ES), the AUC of CBD was around 2-fold higher with intravenous administration than with intranasal administration [ 65 ]. Ahmed and colleagues [ 66 ] also showed that the plasma AUC of intranasal CBD delivery (3.1 mg) was approximately half that of intravenous CBD delivery. However, the brain AUC was around 2-fold higher after intranasal administration of a CBD nanoemulsion formulation compared with intravenous or intranasal delivery of non-formulated CBD.…”

“…In dogs, CBD administered intranasally (20 mg) resulted in a C max ~66% and an AUC ~22% of those of oral administration (100 mg) [ 26 ]. The T max with intranasal CBD ranged between 20 and 30 min among studies [ 26 , 65 , 66 ].…”

Cannabinoid-Based Ocular Therapies and Formulations

“…Potentially, those cannabinoid-based formulations not initially developed for ocular administration could be considered for this purpose, providing they are compatible with the requisites of ophthalmic administration. Despite the unfavorable physicochemical properties of cannabinoids, successful cannabinoid encapsulation with adequate physicochemical properties of the resulting nanocarrier was achieved with polymeric NPs [130][131][132]; SLNs [133][134][135]; nanostructured lipid carriers [136]; NEs [137]; micelles [138][139][140]; microemulsions [141]; ethosomes [142]; pickering emulsions [143]; silica NPs [144]; and carbon nanotubes [145], to mention a few.…”