Micelles-in-Liposome Systems Obtained by Proliposomal Approach for Cannabidiol Delivery: Structural Features and Skin Penetration

Deformable liposomes represent valuable drug carriersfor cutaneousadministration. Nevertheless, the fluid lipid membrane can favor thedrug leakage during storage. Proliposomes may represent a suitablestrategy to solve this issue. As an alternative, a novel carrier,which encloses hydrophobic drugs in the inner core of vesicles, namely,a drug-in-micelles-in-liposome system (DiMiL), has been proposed.In this work, we investigated the possible advantages of combiningthese two approaches to obtain a formulation able to enhance the skinpenetration of cannabidiol (CBD). Proliposomes were prepared by spray-dryingor slurry method testing lactose, sucrose, and trehalose as carriersat different sugar/lipid weight ratios. The ratio between soy-phosphatidylcholine(main lipid) and Tween 80 was instead fixed at 85:15 w/w. DiMiL systemswere extemporaneously obtained by the hydration of proliposomes witha Kolliphor HS 15 micellar dispersion (containing CBD, when appropriate).Based on the technological properties, sucrose and trehalose at 2:1sugar/lipid ratio resulted in the best carriers for spray-dried and"slurried" proliposomes, respectively. Cryo-EM imagesclearly showed the presence of micelles in the aqueous core of lipidvesicles and the presence of sugars did not alter the structural organizationof DiMiL systems, as demonstrated by SAXS analyses. All formulationswere highly deformable and able to control CBD release regardlessof the presence of sugar. The permeation through human epidermis ofCBD carried by DiMiL systems was significantly improved comparedto that obtained loading the drug in conventional deformable liposomeswith the same lipid composition or in an oil solution. Furthermore,the presence of trehalose led to a further slight increase of theflux. Altogether, these results demonstrated that proliposomes maybe a valuable intermediate for the preparation of deformable liposome-basedcutaneous dosage forms, improving the stability without compromisingthe overall performances.