Liposomal prilocaine: preparation, characterization, and in vivo evaluation.

PURPOSE. This study reports the development and in vivo evaluation of a liposomal system for the local anesthetic, prilocaine. METHODS. Liposomal prilocaine was prepared with egg phosphatidylcholine, cholesterol and a-tocopherol (4:3:0.07 molar ratio). The size of the liposomes was measured by laser light scattering and the effect of prilocaine on membrane fluidity made use of electron spin resonance (ESR). The anesthetic effect of liposomal prilocaine was compared to that of plain prilocaine solution (with or without vasoconstrictor) in a rat infraorbital nerve blockade model. RESULTS. Laser light-scattering analysis showed one major vesicle population of liposomes with ca 400 run (100%), without size changes after prilocaine incorporation. The ESR results showed a decrease in the orientation of the phospholipid molecules into the liposomes (ca 11%) in the presence of prilocaine, which characterized the prilocaine-liposome interaction. A prolongation of anesthetic effect was produced by liposomal prilocaine in comparison to plain prilocaine (without vasoconstrictor, p<0.001). However, no statistical differences were found after comparison between liposomal prilocaine and vasoconstrictor-containing prilocaine. CONCLUSIONS. We suggest that the encapsulation of prilocaine in liposomes facilitates the controlled release of prilocaine (increasing the time of duration of the sensory nervous blockade) and constitutes a good choice to replace vasoconstrictor-containing local anesthetic formulations.7223524

Liposomal formulations of prilocaine, lidocaine and mepivacaine prolong analgesic duration

Purpose: A laboratory investigation was undertaken to compare the in vivo antinociceptive effects of 2% liposomal formulations of prilocaine (PLC), lidocaine (LDC) and mepivacaine (MVC) compared to plain solutions of each of these three local anesthetics. Methods: Large unilamellar vesicles were prepared by extrusion (400 nm), at pH 7.4. The membrane/water partition coefficients were obtained from encapsulation efficiency values, after incorporation of each local anesthetic to the vesicles. The anesthetic effect of each liposomal formulation was compared to the respective local anesthetic solution in water, using the infraorbital nerve-blockade test, in rats. Results: The partition coefficients were: 57 for PLC, 114 for LDC and 93 for MVC. In vivo results showed that local anesthetic-free liposomes, used as control, had no analgesic effect. In contrast, the encapsulated formulations induced increased intensities of total anesthetic effect (35.3%, 26.1% and 57.1%) and time for recovery (percentage increases of 30%, 23.1% and 56%), respectively, for PLC, LDC and MVC when compared to the plain solutions (P < 0.01). Conclusions: These results indicate that liposomes provide effective drug-delivery systems for intermediate-duration local anesthetics. Mepivacaine was affected to the greatest extent, while LDC benefited least from liposome encapsulation, possibly due to greater vasodilatory properties of LDC.53111092109

Encapsulation of mepivacaine prolongs the analgesia provided by sciatic nerve blockade in mice

Purpose: Liposomal formulations of local anesthetics (LA) are able to control drug-delivery in biological systems, prolonging their anesthetic effect. This study aimed to prepare, characterize and evaluate in vivo drug-delivery systems, composed of large unilamellar liposomes (LUV), for bupivacaine (BVC) and mepivacaine (MVC). Methods: BVC and MVC hydrochloride were encapsulated into LUV (0.4 mum) composed of egg phosphatidylcholine, cholesterol and a-tocopherol (4:3:0.07 molar ratio) to final concentrations of 0.125, 0.25, 0.5% for BVC and 0.5, I, 2% for MVC. Motor function and antinociceptive effects were evaluated by sciatic nerve blockade induced by liposomal and plain formulations in mice. Results: Liposomal formulations modified neither the intensity nor the duration of motor blockade compared to plain solutions. Concerning sensory blockade, liposomal BVC (BVLUV) showed no advantage relatively to the plain BVC injection while liposomal MVC (MVCLUV) improved both the intensity (1.4-1.6 times) and the duration of sensory blockade (1.3-1.7 times) in comparison to its plain solution (P < 0.001) suggesting an increased lipid solubility, availability and controlled-release of the drug at the site of injection. Conclusion: MVCLUV provided a LA effect comparable to that of BVC. We propose MVCLUV, drug delivery as a potentially new therapeutic option for the treatment of acute pain since the formulation enhances the duration of sensory blockade at lower concentrations than those of plain MVC.51656657

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

Development and pharmacological evaluation of ropivacaine-2-hydroxypropyl-beta-cyclodextrin inclusion complex

Ropivacaine (RVC) is an enantiomerically pure local anesthetic (LA) largely used in surgical procedures, which presents physico-chemical and therapeutic properties similar to those of bupivacaine (BPV), but associated to less systemic toxicity This study focuses on the development and pharmacological evaluation of a RVC in 2-hydroxypropyl-beta-cyclodextrin (HP-P-CD) inclusion complex. Phase-solubility diagrams allowed the determination of the association constant between RVC and HP-beta-CD (9.46 M-1) and showed an increase on RVC solubility upon complexation. Release kinetics revealed a decrease on RVC release rate and reduced hemolytic effects after complexation. (onset at 3.7 mM and 11.2 mM for RVC and RVCHP-beta-CD, respectively) were observed. Differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and X-ray analysis (X-ray) showed the formation and the morphology of the complex. Nuclear magnetic resonance (NMR) and job-plot experiments afforded data regarding inclusion complex stoichiometry (1:1) and topology. Sciatic nerve blockade studies showed that RVCHP-beta-CD was able to reduce the latency without increasing the duration of motor blockade, but prolonging the duration and intensity of the sensory blockade (p < 0.001) induced by the LA in mice. These results identify the RVCHP-beta-CD complex as an effective novel approach to enhance the pharmacological effects of RVC, presenting it as a promising new anesthetic formulation. (c) 2007 Elsevier B.V All rights reserved.331607

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

C&iacute;ntia Maria Saia Cereda,1 Daniel Sebbe Mecatti,2 Juliana Zampoli Boava Papini,1 Diego Val&eacute;rio Bueno,2 Michelle Franz-Montan,3 Thalita Rocha,2 Jos&eacute; Pedrazzoli J&uacute;nior,2 Eneida de Paula,4 Daniele Ribeiro de Ara&uacute;jo,5 Renato Grillo,6 Leonardo Fernandes Fraceto,7 Silvana Aparecida Calafatti,2 Giovana Radomille Tofoli1 1Institute and Research Center S&atilde;o Leopoldo Mandic, Campinas, S&atilde;o Paulo, Brazil; 2UNIFAG, S&atilde;o Francisco University, Bragan&ccedil;a Paulista, S&atilde;o Paulo, Brazil; 3Department of Physiological Sciences, University of Campinas, Piracicaba, S&atilde;o 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 Andr&eacute;, S&atilde;o Paulo, Brazil; 6Department of Physics and Chemistry, School of Engineering, S&atilde;o Paulo State University (UNESP), Ilha Solteira, S&atilde;o Paulo, Brazil; 7Department of Environmental Engineering, S&atilde;o Paulo State University (UNESP), Sorocaba, S&atilde;o Paulo, Brazil Objective: This study reports a preclinical evaluation of an alginate/chitosan nanoparticle formulation containing NovaBupi&reg;, 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&ndash;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&rsquo; (n=6) oral tissues. Results: No statistically significant difference was observed between plasma concentrations and pharmacokinetic parameters (p&gt;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&ndash;t; p&lt;0.05). The total analgesic effect of BVC after infraorbital nerve blockade was improved by 1.4-fold (p&lt;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