Avaliação biologica de uma pre-formulação de ropivacaina em hidroxipropil-beta-ciclodextrina produzida em processo escalonavel / Biological evaluation of a Ropivacaine formulation in hydroxypropyl-beta-cyclodextrin prepared in a scaled up process

AUTOR(ES)
DATA DE PUBLICAÇÃO

2007

RESUMO

Long-acting local anesthetics (LA) are worldwide used, mainly for surgical procedures. Ropivacaine (RVC) is a new, long-acting LA, with increased cardiovascular safety, in comparison to other anesthetics. The delivery of LA in carriers such as cyclodextrins has been investigated in order to increase the nonciceptive action and to reduce the systemic toxicity of these compounds. Cyclodextrins are cyclic oligosaccharides with a somewhat lipophilic central cavity that is able to form inclusion complexes with guest molecules, increasing their water solubility. Here we report the preparation, physicochemical characterization and evaluation of the biological activity of an inclusion complex, formed between RVC and hydroxypropyl-beta-cyclodextrin (HP-b-CD). The complex was obtained by mixing appropriate amounts of HP-b-CD and RVC (1:1, molar ratio) in water; the solution was spray-dried and the solid complexes were suspended in 20mM HEPES buffer with 150mM NaCl, pH 7.4. The 1:1 stoichiometry of the complex was determined through the Continuous Variation Method. Differential Scanning Calorimetry, X-Rays and the NMR analysis confirmed the formation of the inclusion complex. The anesthetic effect of the RVC:HP-b-CD complex (0,125%, 0,25 e 0,5%) was compared to that elicited by plain RVC solutions of equivalent concentrations, using the infraorbital nerve-blockade test in rats. The results show that the RVC:HP-b-CD complex improved both the total anesthetic effect (54.5%, 53.3% and 20.0%, respectively) and the time for recovery (42.9%, 44.4% and 18.8%, respectively), in comparison to RVC solutions. The cardiotoxicity was evaluated by electrocardiography, in rats. The results show no enhancement of the heart toxic effect of RVC under complexation, in spite of the increased amount of available (water soluble) RVC and improved anesthetic effect. In conclusion: we found in rats that the RVC:HP b-CD complex is a promising long-acting anesthetic formulation, allowing the use of sub-clinic doses that reach the same anesthetic effects of 0.5% RVC or even ? at the therapeutic doses of 0.5% - to replace Bupivacaine, the drug-of-choice in long term anesthesia, but also the more toxic. Finally, these results were obtained in a scale previous the pilot scale and show the feasibility of the scale up procedure adopted, looking forward the technologic development of a pharmaceutical product.

ASSUNTO(S)

anestesia local ropivacaina local anesthesy ropivacaine ciclodextrinas cyclodextrins

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