Bioadhesive Films Containing Benzocaine: Correlation Between In Vitro Permeation and In Vivo Local Anesthetic Effect

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)The aim of this work was to develop anesthetic bioadhesive films containing benzocaine and study their in vitro skin permeation and in vivo performance, in comparison with commercial formulations. Films containing 3% and 5% w/w of benzocaine were prepared and characterized by weight, drug content, thickness and morphology. In vitro permeation assays were performed in vertical diffusion cells using full-thickness pig ear skin as barrier. Intensity and duration of analgesia were evaluated in rats by tail-flick test, and skin histological analysis was carried out. Tail-flick test showed that the duration of benzocaine-induced analgesia was significantly prolonged with the films compared to commercial creams, in agreement with the higher in vitro permeation. Histological analysis of the rat tail skin did not reveal morphological tissue changes nor cell infiltration signs after application of the commercial creams or films. Results from our study indicate that the films developed in this work can be considered as innovative dermal/transdermal therapeutic systems for benzocaine local delivery.27816771686Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)CAPES [0115-070]FAPESP [06/00121-9

Transdermal delivery of butamben using elastic and conventional liposomes

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Gel formulations containing the local anesthetic butamben (BTB) encapsulated in either conventional (BTBLUV) or elastic (BTBLUV-EL) liposomes were prepared and characterized, and then evaluated in terms of their skin permeability. Parameters measured included vesicle size and surface charge, BTB fluorescence anisotropy, encapsulation efficiency, partition coefficient and liposomal membrane organization. Encapsulation efficiencies and membrane/water partition coefficients were determined using a phase separation. The partition coefficients of the elastic and conventional formulations were 2025 +/- 234 and 1136 +/- 241, respectively. The sizes of the elastic and conventional liposomes did not change significantly (p>0.05) following incorporation of the anesthetic. As expected, the elastic liposomes presented order parameters that were lower than those of the conventional liposomes, as determined by electron paramagnetic resonance with a 5-stearic acid nitroxide probe incorporated into the bilayer. After 8 h, the fluxes into the receiving solution (mu g/cm(2)/h) were 6.95 +/- 1.60 (10% BTB), 23.17 +/- 6.09 (10% BTBLUV) and 29.93 +/- 6.54 (10% BTBLUV-EL). The corresponding time lags (h) were 1.90 +/- 0.48, 1.23 +/- 0.28 and 1.57 +/- 0.38, respectively. The permeability coefficients (10(-3) cm/h) were 1.02 +/- 0.23, 2.96 +/- 0.77 and 4.14 +/- 0.9, for 10% BTB, 10% BTBLUV and 10% BTBLUV-EL, respectively. The results demonstrate that anesthetic access through the skin can be considerably enhanced using liposomal gel formulations, compared to plain gel formulations.233228234Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)CAPES [Proc. 2611/09-0]FAPESP [Proc. 06/00121-9

Bupivacaine in alginate and chitosan nanoparticles: an in vivo evaluation of efficacy, pharmacokinetics, and local toxicity

Cíntia Maria Saia Cereda,1 Daniel Sebbe Mecatti,2 Juliana Zampoli Boava Papini,1 Diego Valério Bueno,2 Michelle Franz-Montan,3 Thalita Rocha,2 José Pedrazzoli Júnior,2 Eneida de Paula,4 Daniele Ribeiro de Araújo,5 Renato Grillo,6 Leonardo Fernandes Fraceto,7 Silvana Aparecida Calafatti,2 Giovana Radomille Tofoli1 1Institute and Research Center São Leopoldo Mandic, Campinas, São Paulo, Brazil; 2UNIFAG, São Francisco University, Bragança Paulista, São Paulo, Brazil; 3Department of Physiological Sciences, University of Campinas, Piracicaba, São Paulo, Brazil; 4Department of Biochemistry and Tissue Biology, University of Campinas, Campinas, São Paulo, Brazil; 5Human and Natural Science Centre, Federal University of ABC, Santo André, São Paulo, Brazil; 6Department of Physics and Chemistry, School of Engineering, São Paulo State University (UNESP), Ilha Solteira, São Paulo, Brazil; 7Department of Environmental Engineering, São Paulo State University (UNESP), Sorocaba, São Paulo, Brazil Objective: This study reports a preclinical evaluation of an alginate/chitosan nanoparticle formulation containing NovaBupi®, a racemic bupivacaine (BVC) containing 25% dextrobupivacaine and 75% levobupivacaine. Methods: New Zealand White rabbits (n=6) received intraoral or intrathecal injections of BVC 0.5% or BVC 0.5%-loaded alginate–chitosan nanoparticles (BVCALG). BVC plasma levels and pharmacokinetic parameters were determined in blood samples of these rabbits. An infraorbital nerve blockade was performed in male Wistar rats (n=7) with the same formulations and the vehicle (NPALG). Histological evaluation of local toxicity after 6 hours and 24 hours of the treatments was performed in rats’ (n=6) oral tissues. Results: No statistically significant difference was observed between plasma concentrations and pharmacokinetic parameters (p>0.05) after intraoral injections. However, after intrathecal injection BVCALG changed approximately three times the values of volume of distribution and area under the curve (AUC0–t; p<0.05). The total analgesic effect of BVC after infraorbital nerve blockade was improved by 1.4-fold (p<0.001) with BVCALG. BVC and BVCALG did not induce significant local inflammatory reaction. Conclusion: The encapsulation of BVC prolongs the local anesthetic effect after infraorbital nerve blockade and altered the pharmacokinetics after intrathecal injection. Keywords: local anesthetics, bupivacaine, polymeric nanoparticle, drug delivery, preclinical stud