Novel Findings about Double-Loaded Curcumin-in-HPβcyclodextrin-in Liposomes: Effects on the Lipid Bilayer and Drug Release

In this study, the encapsulation of curcumin (Cur) in “drug-in-cyclodextrin-in-liposomes (DCL)” by following the double-loading technique (DL) was proposed, giving rise to DCL–DL. The aim was to analyze the effect of cyclodextrin (CD) on the physicochemical, stability, and drug-release properties of liposomes. After selecting didodecyldimethylammonium bromide (DDAB) as the cationic lipid, DCL–DL was formulated by adding 2-hydroxypropyl-α/β/γ-CD (HPβCD)–Cur complexes into the aqueous phase. A competitive effect of cholesterol (Cho) for the CD cavity was found, so cholesteryl hemisuccinate (Chems) was used. The optimal composition of the DCL–DL bilayer was obtained by applying Taguchi methodology and regression analysis. Vesicles showed a lower drug encapsulation efficiency compared to conventional liposomes (CL) and CL containing HPβCD in the aqueous phase. However, the presence of HPβCD significantly increased vesicle deformability and Cur antioxidant activity over time. In addition, drug release profiles showed a sustained release after an initial burst effect, fitting to the Korsmeyer-Peppas kinetic model. Moreover, a direct correlation between the area under the curve (AUC) of dissolution profiles and flexibility of liposomes was obtained. It can be concluded that these “drug-in-cyclodextrin-in-deformable” liposomes in the presence of HPβCD may be a promising carrier for increasing the entrapment efficiency and stability of Cur without compromising the integrity of the liposome bilayer.