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Percutaneous penetration characteristics of amethocaine from novel bioadhesive and pressure‐sensitive patch devices

Percutaneous amethocaine gels have been shown to provide clinically effective local anaesthesia of intact skin for up to six hours, following a forty minute application (McCafferty and Woolfson 1988; Woolfson et al 1990). Recently, Woolfson and coworkers (1 998) formulated an integrated bioadhesive amethocaine patch and demonstrated that this exhibits a similar clinical profile to established gel formulations. The aim of this study is to determine the percutaneous penetration profile of amethocaine from candidate patch formulations across excised porcine skin in vitro and compare them to amethocaine gels and drug release from novel pressure-sensitive transdermal patches. Bioadhesive films were cast from aqueous gels as described previously (Woolfson et al 1998). Pressure-sensitive patches were constructed from acrylic adhesives in either acetone or ethyl acetate. Flux across excised neonatal porcine skin was measured via modified Frau-type diffusion cells. The effect of several formulation parameters on amethocaine flux (as mg cm-2 min-l) was investigated. Amethocaine and its degradation products were determined by HPLC (Woolfson et al 1992). The statistical significance of results was determined by single-factor analysis of variance. In general, several distinct trends were observed. For a total of 29 bioadhesive systems, increasing the concentration of bioadhesive (poly(methy1 vinyl ethedmaleic anhydride) PMVE/MA (1 :1)) from 1% w/w to 5% w/w significantly decreased flux from 0.142 to 0.031 (p < 0.05). Increasing the concentration of viscosity builder (hydroxyethylcellulose HEC) from 0.5% to 2.5% also significantly (p < 0.05) decreased flux from 0.191 to 0.041. Both changes are probably due to the increase in viscosity and its relationship with flux, as described by the Stokes-Einstein equation. Varying the casting gel pH from pH 5 to pH 10 yielded two significantly different sets of results. Patches formulated at pH 5 to pH 7 demonstrated comparable flux (0.055 to 0.071). Patches formulated at pH 8 to pH 10 demonstrated comparable flux (0.082 to 0.139). Both sets of results are significantly different from each other (p < 0.05). These results correspond to the percentage drug ionised at each pH. Gels formulated at pH 8 10, where amethocaine is predominantly present as the lipophilic, insoluble free base, produced significantly better flux than gels formulated at pH 5 7 where amethocaine is present predominantly as a water-soluble salt. Addition of glycerol to the patch (up to 2.5% w/w) had no significant effect on flux. As expected, increasing drug loading significantly (p < 0.05) increased flux, from 0.051 (0.5% w/w amethocaine) to 2.035 (10% w/w amethocaine). Lag times of formulations exhibited similar trends. The maximum flux observed from a total of 16 different pressure-sensitive drug-in-adhesive formulations was 0.012 mg cm-2 min-I. Flux from bioadhesive amethocaine films containing 2% w/w PMVE/MA, 1.5% HEC and 1 % amethocaine at pH 9 exhibited similar flux to amethocaine gels (Woolfson et al 1992). These results indicate that novel bioadhesive amethocaine patch formulations exhibit a similar drug release profile to amethocaine gel formulations, whereas pressure-sensitive systems demonstrate significantly lower flux (p < 0.05). This difference may be accounted for by the absence of the amethocaine phase-change system (Woolfson and McCafferty 1993) in the pressure-sensitive formulations, ensuring that the drug does not undergo a depression in melting point (from 42°C to 29°C) and hence may not penetrate skin at body temperature as readily as bioadhesive or gel systems that do exhibit such a depression in melting point.