ABSTRACT
Local anesthetics (LA) are among the most important pharmacological compounds used to attenuate or eliminate pain. However, systemic toxicity is still a limitation for LA application, especially for ester-type drugs, such as tetracaine (TTC) that presents poor chemical stability (due to hydrolysis by plasma esterases). Several approaches have been used to improve LA pharmaceutical properties, including the employment of drug-delivery systems. Here we used beta-cyclodextrin (ß-CD) or hydroxypropyl-beta-cyclodextrin (HP-ß-CD) to develop two new TTC formulations (TTC:ß-CD and TTC:HP-ß-CD). The inclusion complexes formation, in a 1:1 stoichiometry, was confirmed by differential scanning calorimetry, X-ray diffraction, UV-VIS absorption and fluorescence. Nuclear magnetic resonance (DOSY experiments) revealed that TTC association with HP-ß-CD is stronger (Ka=1200 mol/L(-1)) than with ß-CD (Ka=845 mol/L(-1)). Moreover, nuclear Overhauser effect (NOE) experiments provided information on the topology of the complexes, where TTC aromatic ring is buried inside the CD hydrophobic cavity. In vitro tests with 3T3 fibroblast cells culture revealed that complexation decreased TTC cytotoxicity. In addition, the total analgesic effect of TTC, tested in rats through the infraorbital nerve test, was improved in 36% with TTC:ß-CD and TTC:HP-ß-CD. In conclusion, these formulations presented potential for future clinical use, by reducing the toxicity and increasing the antinociceptive effect of tetracaine.
Subject(s)
Analgesics/administration & dosage , Cyclodextrins/administration & dosage , Pain Measurement/drug effects , Tetracaine/administration & dosage , Analgesics/chemistry , Animals , Chemistry, Pharmaceutical/methods , Cyclodextrins/chemistry , Male , Mice , NIH 3T3 Cells , Pain Measurement/methods , Rats , Rats, Wistar , Tetracaine/chemistry , X-Ray Diffraction/methodsABSTRACT
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.
