New formulations for the controlled release of local anesthetics in dentistry: from development to clinical tests

Abstract

The structure and physicochemical features of local anesthetics (LA) are determinant fort heir potency and toxicity (Araújo et al, 2003). Water solubility is, for instance, an essential parameter for the transport of the anesthetic molecule to the nerve fibers as well as to the ionization equilibrium that guarantees the existence of both ionized and non-ionized LA forms. On the other hand lipid solubility is also crucial for drug partitioning into the axon, so that enough amounts of LA molecules will sit inside that membrane in order to keep the sodium channel in its non-conducting state (Butterworth & Strichartz, 1990). In general, the potency of an LA molecule is proportional to its toxicity, an impediment to the development of more potent drugs. The development of new LA formulations is nowadays a challenge in dentistry. For topical anesthesia, for instance, new therapeutic forms that allow mucous absorption leading to deeper and longer anesthetic effects are highly desirable since infiltrative anesthesia could be replaced for topical products, reducing the aversive responses associated with infiltrative procedures. Liposomes have been shown to be interesting drug-delivery systems for LA since they enhance the availability of compounds, reduce their systemic toxicity and increase their half-life in vivo (Boogaerts et al, 1994; Grant, 2002). Similar advantages have been claimed for cyclodextrin formulations of poorly water-soluble anesthetics (Dollo et al, 1996, Pinto et al, 2004), for hydrogel formulations (Hillingso et al, 2002) and, more recently, for LA in polymers. The team of researchers joined together in this thematic proposal has a large experience in the development of liposomal and cyclodextrin LA preparations (Biomembranas group, Instituto de Biologia-Unicamp) and also in the odontology, specifically in the terapeuthics of local anesthetics (Anesthesia Lab., Faculdade de Odontologia de Piracicaba-Unicamp). We intend with this project to develop new pharmaceutical forms for the controlled release of classic LA molecules, in vehicles such as liposomes, cyclodextrins, gels and polymers. Our aim is to enhance de pharmacological actions and to reduce the local and systemic toxicity of LA, looking forward to a future application in dentistry. The potentiality of projects designed to the development of new LA formulations for human application can be understood by the dimensions of the LA market in Brazil: ca. US$ 12.5 billion per year, according to the Brazilian's Pharmaceutical Industry Association. A fraction of that, ca. US$ 2 billion/year, represents the sales only in LA for topical use... (AU)