Biocompatibility, permeation profile and anesthetic efficacy of articaine-loaded poly(epsilon-caprolactone) nanocapsules formulations

Articaine is a local anesthetic thar presents good diffusion after maxillary and mandibular infiltration, and fast biotransformation. However, it is associated to higher paresthesia prevalence than lidocaine. Delivery systems, such as nanocapsules, have been used to improve availability and to reduce toxicity of drugs. The aims of this study were to evaluate an articaine-loaded poli(?-caprolactone) formulation in relation to toxicity (in vitro viability of human keratinocyte cells), in vitro permeation capacity (through the mucosal epithelium of pig esophagus), and anesthetic efficacy (postoperative pain model in rats). The formulations tested were: articaine (ATC), articaine with 1:200,000 epinephrine (ATCepi), articaine loaded-nanocapsules of poly(?-caprolactone) (ATCnano), articaine loaded-nanocapsules of poly(?-caprolactone) with 1:200,000 epinephrine (ATCnanoepi) and the respective controls. HaCaT cells were exposed to formulations at various concentrations for 1 h and 24 h for MTT and fluorescence microscopy tests. Permeation profiles (flux and permeation coefficient) of ATC and ATCnano across pig esophageal epithelium were performed in Franz-type vertical diffusion cells. Anesthetic efficacy was evaluated 24 h after development of hypernociception in the hind paw of rats. The animals received, laterally to the wound, 0.1 mL of articaine or control formulations. Local anesthesia was evaluated with von Frey anesthesiometer. Results were evaluated by non-linear regression analysis (MTT test), Mann-Whitney (flux and permeation coefficient) and Log-Rank, ANOVA and t LSD tests (anesthesia success and duration) (a=5%). Encapsulation of articaine did not change nanoparticles size and polidispersion index, which remained at low levels (0.11 ± 0.04). Encapsulation and epinephrine lowered articaine toxicity (p<0.0001) on HaCaT cells. In the permeation study ATCnano presented higher flux (p=0.0007) and permeation coefficient (p=0.0004) than ATC. In the postoperative pain model in rats 2% and 4% articaine (both associated to epinephrine did not differ (p>0.05) and showed higher anesthesia success and duration (p<0.05) than the other articaine formulations. In conclusion, articaine encapsulation and epinephrine addition (isolated or associated) lower articaine toxicity and the encapsulation increases permeation and could provide a future use of articaine for topical anesthesia. However, encapsulation does not improve articaine anesthetic efficacy in inflamed tissues, even with epinephrine addition. Epinephrine addition to articaine is essential to improve its anesthetic success and duration. Due to the similar anesthetic efficacy, when associated to epinephrine, articaine could be used in inflamed tissues at the lower concentration tested, 2% (AU)