New “drug-in cyclodextrin-in deformable liposomes” formulations to improve the therapeutic efficacy of local anaesthetics

The combined approach of cyclodextrin complexation and entrapment in liposomes was investigated to develop a topical formulation of local anaesthetics. For both benzocaine (BZC) and butamben (BTM), hydroxypropyl-β-cyclodextrin (HPβCD) was a better partner than βCD; drug–HPβCD coevaporated products showed the best solubility and dissolution properties, and were selected for loading into liposomes. Addition of stearylamine to the phosphatidylcholine–cholesterol mixture of the vesicle bilayer allowed obtainment of deformable liposomes with improved permeation and in vivo drug anaesthetic effect (P < 0.05). Double-loaded deformable liposomes were obtained by adding the drug–HPβCD complex at its maximum aqueous solubility in the vesicles hydrophilic phase, and the remaining amount up to 1% as free drug in the lipophilic phase. The properties of double-loaded liposomes were compared with those of classic single-loaded ones, obtained by adding 1% free drug in the aqueous or lipophilic phase of the vesicles. Size, charge, morphology and entrapment efficiency of the different batches were investigated, respectively, by light scattering, confocal laser scanning microscopy and dialysis, while their therapeutic efficacy was evaluated in vivo on rabbits. For both drugs, double-loaded liposomes, exploiting the favourable effects of drug–CD complexation, allowed a significant (P < 0.05) enhancement of intensity and duration of anaesthetic effect with respect to those single-loaded.