Lipid-based nanocarriers (SLN/NLC and remote-loading liposomes) used to improve the upload and potency of local anesthetics

Abstract

Local anesthetics (LA) are amphiphile compounds that interact with the sodium channel protein reversibly blocking the action potential of excitable membranes. The more potent the anesthetic (as for instance bupivacaine, which is the drug-of-choice for surgical procedures) the more toxic it is to the Central Nervous and Cardiovascular systems. Our research group has been working in the development of sustained release systems for local anesthetics, with encouraging results in animals and human, regarding the use of liposomes, cyclodextrins and polymers as drug delivery systems (de Paula E. et al., Exp. Op. Drug Delivery 9:1505, 2012). Liposomes are the most well-known drug-delivery system but they have a limited encapsulation efficiency caused by the low amounts used for injection (ca. 10-2 M lipids, i.e. in the same magnitude of LA clinical doses). Such limitation curbs liposomes use as quantitative LA reservoirs for sustained release purposes. Here we intend to employ two novel drug-delivery strategies to enhance the encapsulation of long acting LA such as bupivacaine (e.g., ropivacaine, dibucaine, tetracaine, etidocaine&) by preparing and characterizing: 1) ion-gradient (or remote-loading) liposomes and 2) Nanostructured lipid carriers (SLN/NLC), able to upload higher amount of LA in the particle core. Two approaches will be adopted to form the ionic gradient: kosmotropic ions such as sufalte and citrate and acid medium in the liposomes core. Liposome type (uni or multivesicullar) and composition will be also evaluated in terms of their effect on the sustained LA delivery since there is a report in the literature of as much as 48h anesthesia after intradermic bupivacaine injection in humans (Grant GJ et al., Anesthesiol. 101:133, 2004). Solid lipid nanoparticles and nanostructured lipid carriers will be prepared through high pressure hot homogenization or sonication, from solid matrices of cetyl palmitate or myristyl myristate plus Pluronic F68 as a colloidal stabilizer; LiponateGC (a mixture of triglycerides of caprylic and capric acids) will sere as the liquid lipid component of NLC. The in vitro and in vivo effect of the formulations will be compared to those evoked by the equivalent commercial product of the LA. Looking forward the development of pharmaceutical products, pharmacokinectic studies, lyoprotection tests for shelf-life extension and hydrogel preparations for parental and topic uses will be performed. These innovative and of technological potential approaches will provide significant increase in the upload of anesthetic in the lipid-based particles, prolonging the anesthesia duration of action to avoid the need for re-administration in the (surgical or post-operative procedures) treatment of pain. (AU)