Liposomal lidocaine gel for topical use at the oral mucosa: characterization, in vitro assays and in vivo anesthetic efficacy in humans.

OBJECTIVE: To characterize liposomal-lidocaine formulations for topical use on oral mucosa and to compare their in vitro permeation and in vivo anesthetic efficacy with commercially available lidocaine formulations. MATERIALS AND METHODS: Large unilamellar liposomes (400 nm) containing lidocaine were prepared using phosphatidylcholine, cholesterol, and α-tocoferol (4:3:0.07, w:w:w) and were characterized in terms of membrane/water partition coefficient, encapsulation efficiency, size, polydispersity, zeta potential, and in vitro release. In vitro permeation across pig palatal mucosa and in vivo topical anesthetic efficacy on the palatal mucosa in healthy volunteers (double-blinded cross-over, placebo controlled study) were performed. The following formulations were tested: liposome-encapsulated 5% lidocaine (Liposome-Lido5); liposome-encapsulated 2.5% lidocaine (Liposome-Lido2.5); 5% lidocaine ointment (Xylocaina®), and eutectic mixture of lidocaine and prilocaine 2.5% (EMLA®). RESULTS: The Liposome-Lido5 and EMLA showed the best in vitro permeation parameters (flux and permeability coefficient) in comparison with Xylocaina and placebo groups, as well as the best in vivo topical anesthetic efficacy. CONCLUSION: We successfully developed and characterized a liposome encapsulated 5% lidocaine gel. It could be considered an option to other topical anesthetic agents for oral mucosa.

Liposomal formulations of prilocaine, lidocaine and mepivacaine prolong analgesic duration : [Des préparations liposomiques de prilocaïne, de lidocaïne et de mépivacaïne prolongent la durée de l'analgésie].

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. OBJECTIF: Une recherche en laboratoire a été entreprise pour comparer les effets antinociceptifs in vivo de préparations liposomiques de prilocaïne (PLC), de lidocaïne (LDC) et de mépivacaïne (MVC) à 2 %, à des solutions simples de chacun de ces anesthésiques locaux. MéTHODE: De grandes vésicules unilamellaires ont été préparées par extrusion (400 nm), à un pH de 7,4. Les coefficients de partage membrane/eau ont été obtenus des valeurs d'efficacité de l'encapsulation, après l'introduction de chaque anesthésique local dans les vésicules. L'effet anesthésique de chaque préparation liposomique a été comparé à la solution respective d'anesthésique local dans l'eau par le test de blocage du nerf infra-orbitaire chez des rats. RéSULTATS: Les coefficients de partage ont été de : 57 pour la PLC, 114 pour la LDC et 93 pour la MVC. Les résultats in vivo ont montré que les liposomes témoins sans anesthésique local n'avaient pas d'effet analgésique. Par contre, les préparations en capsules ont augmenté l'intensité anesthésique totale (35,3 %, 26,1 % et 57,1 %) et le temps de récupération (30 %, 23,1 % et 56 %) respectivement pour la PLC, la LDC et la MVC comparées aux solutions simples (P < 0,01). CONCLUSION: Ces résultats indiquent que les liposomes sont des systèmes de vecteurs de médicaments efficaces pour les anesthésiques locaux de durée moyenne. La MVC a surtout bénéficié, et la LDC le moins, de l'encapsulation liposomique, peut-être à cause de ses plus importantes propriétés vasodilatatrices.

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 nm (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.

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.

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 micro m) composed of egg phosphatidylcholine, cholesterol and alpha-tocopherol (4:3:0.07 molar ratio) to final concentrations of 0.125, 0.25, 0.5% for BVC and 0.5, 1, 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 (BVC(LUV)) showed no advantage relatively to the plain BVC injection while liposomal MVC (MVC(LUV)) 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: MVC(LUV) provided a LA effect comparable to that of BVC. We propose MVC(LUV) 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.