Microneedle-Assisted Percutaneous Delivery of a Tetramethylpyrazine-Loaded Microemulsion

This study examined the efficacy of the percutaneous delivery of a tetramethylpyrazine-loaded microemulsion (TMP-ME) on skin pretreated with microneedles (MN). The TMP-ME formulation was optimized in vitro with skin permeation experiments, using a uniform experimental design, guided by a pseudo-ternary phase diagram, in which the TMP skin permeation level and mean particle size were indices. The effects of MN pretreatment on skin permeation by TMP-ME were assessed using in vitro skin permeation, in vivo skin microdialysis, and pharmacokinetic studies in rats. The influence of MN pretreatment on the skin barrier function was evaluated by measuring the electrical resistance of rat skin before and after MN insertion. In the optimal formulation of TMP-ME, the weight percentages of Maisine^® 35-1 (oil phase), Labrasol^® (surfactant), and Transcutol^® P (co-surfactant) were 7%, 30% and 10%, respectively, with 1.5% TMP loading. In the in vitro skin permeation study, MN-assisted TMP-ME exhibited a two-fold increase in a 24-h cumulative TMP permeation compared with TMP-ME alone (<i>p</i> < 0.05). In the skin microdialysis study, TMP in MN-assisted TMP-ME exhibited a 1.25-fold increase in C_max, a 0.93-fold decrease in T_max, and a 0.88-fold increase in AUC_0-t (<i>p</i> < 0.05). Similarly, in the pharmacokinetic study, TMP in MN-assisted TMP-ME exhibited a 2.11-fold increase in C_max, a 0.67-fold decrease in T_max, and a 1.07-fold increase in AUC_0-t (<i>p</i> < 0.05). The percutaneous electrical resistance of rat skin before and after MN insertion was 850 ± 50 Ω/cm² and 283 ± 104 Ω/cm² respectively, indicating that MN dramatically compromises the skin barrier. These results suggest that MN assistance increases the skin permeation rate and the extent of percutaneous absorption of TMP-ME, and that the mechanism may involve the reversible barrier perturbation effect. The rate and extent of percutaneous absorption of TMP-ME can be significantly enhanced by MN assistance, possibly because MN causes a reversible barrier perturbation effect on skin.