Levobupivacaine-Loaded Liposome Associated with Thermogel for Prolonged Analgesia.

ABSTRACT

Pain is a phenomenon present in the majority of the population, affecting, among others, the elderly, overweight people, and especially recently operated patients, analgesia being necessary. In the specific case of relief of postoperative pain, different kinds of anesthetics are being used, among them bupivacaine, a widely used drug which promotes long-lasting analgesic effects. However, cardiotoxicity and neurotoxicity are related to its repetitive use. To overcome these shortcomings, Novabupi® (a racemic mixture) was developed and is marketed as an injectable solution. This formulation contains an enantiomeric excess of the levogyre isomer, which has reduced toxicity effects. Seeking to rationalize its use by extending the duration of effect and reducing the number of applications, the objectives of this work were to develop and evaluate liposomes containing Novabupi (LBPV), followed by incorporation into thermogel. Liposomes were prepared using the lipid hydration method, followed by size reduction using sonication, and the developed formulations were characterized by hydrodynamic diameter, polydispersity index (PDI), surface zeta potential, and encapsulation efficiency. The selected optimal liposomal formulation was successfully incorporated into a thermogel without loss of thermoresponsive properties, being suitable for administration as a subcutaneous injection. In the ex vivo permeation studies with fresh rodent skin, the thermogel with liposomes loaded with 0.5% LBPV (T-gel formulation 3) showed higher permeation rates compared to the starting formulation, thermogel with 0.5% LBPV (T-Gel 1), which will probably translate into better therapeutic benefits for treatment of postoperative analgesia, especially with regard to the number of doses applied.