Bioadhesive film for the delivery of local anesthetics to the buccal mucosa: ex-vivo and in-vivo evaluation

The aim of this work was the preparation and characterization of two bioadhesive films (with different drug loadings) containing a combination of lidocaine and prilocaine hydrochloride to be applied on the buccal mucosa to reduce the pain sensation associated with needle insertion during dental procedures. The films were tested ex- vivo to determine the amount of drug permeated/retained in buccal mucosa, and, in-vivo to assess the extent and duration of anesthetic effect on the mucosa and pharmacokinetic parameters. As a reference, the commercial formulation EMLA (R) cream was used. Ex-vivo studies were conducted on porcine esophageal epithelium, an accepted model for buccal mucosa, and in-vivo studies on human volunteers. The ex-vivo results obtained show that the retention of both drugs into the mucosa resulted comparable after the application of the films or EMLA (R) cream for 10 min; on the contrary, the amounts of drug permeated from the commercial formulation was higher, suggesting the possibility to achieve systemic effect. In-vivo experiments showed that the intensity of anesthesia, evaluated by VAS during needle insertion, was much higher for EMLA (R) cream (the median value was zero for EMLA (R) and 0.15-0.3 cm for the two films); however, the film and EMLA (R) cream resulted equivalent in terms of duration of anesthesia, from 25 to 40 min. The pharmacokinetic study showed that both films tested produced very low plasma concentration (zero for most of experimental data point), thus guaranteeing no risk of systemic effects, whereas EMLA (R) cream demonstrated measurable plasma levels for both drugs (lidocaine Cmax was 4 ng/ ml, prilocaine Cmax was 1.5 ng/ml). Moreover, a correlation between ex-vivo drug tissue concentration and duration of the anesthetic effect in-vivo was found. Although this correlation is limited to a small number of formulations, it supports the validity of pig esophageal epithelium in the development of formulation to be used on human buccal mucosa.