Development, characterization and in vitro assessment of a novel self-microemulsifying drug delivery system to...

A new self-microemulsifying drug delivery system (SMEDDS) was developed as a rational alternative to the conventional oral forms of cannabidiol (CBD). The pseudoternary phase diagram was built after excipient screening based on solubility studies; Capryol 90 and isopropyl myristate were selected as the oily phase. Kolliphor HS 15 and Transcutol HP were chosen as surfactant and co-surfactant, respectively. SMEDDS were loaded with 2 % w/w CBD whose recovery resulted 99.86 %. SMEDDS was stable during one-month storage. SMEDDS were diluted with water and simulated physiological media to evaluate their performance. Cloud point of ME obtained by SMEDDS dilution was higher than 37 °C. Transmittance test assessed the formation of microemulsions (ME) upon SMEDDS dilution and the robustness to dilution study evidenced the high stability of ME in the range from 50- to 1000-folds dilution. Droplet sizes less than 30 nm and a high homogeneity of the formulation (PdI < 0.2) were found in water and in simulated gastric and intestinal fluids stability studies. In addition, the ME obtained with media containing enzymes was chemically and physically stable. In the same conditions, unformulated CBD (FREE-CBD) recovery was significantly decreased. Parallel Artificial Membrane Permeability Assay (PAMPA) demonstrated that SMEDDS upon dilution in water or physiological media showed optimal apparent permeability with a very high CBD recovery (99.50 %) with respect to the unformulated CBD which displayed high membrane retention. Moreover, Caco2 studies evidenced that CBD formulation and FREE-CBD displayed a similar permeation across the cell monolayer over 2 h incubation (P_app of 2.45 ± 0.10*10^-5 cm/s vs 2.30 ± 0.25*10^-5 cm/s), indicating that the formulation did not alter the CBD permeability property. The study evidenced also that, although FREE-CBD initially permeates faster, SMEDDS reached comparable permeability values at later time points. Remarkably, at 127 µM concentration, FREE-CBD almost completely reduced Tight junction protein 1 (TJP1) gene expression, a membrane-associated cytosolic protein important for cell-cell communication in intercellular barriers in epithelial and non-epithelial cells. By contrast, ME generated from SMEDDS at the same CBD concentration partially counteracts this negative effect of CBD at this concentration, while maintaining a comparable apparent permeability through the cell monolayer.