Background <p>Transdermal drug delivery (TDD) offers a convenient administration for treating local or systemic diseases. However, the dense “brick–mortar” structure of the stratum corneum hinders the skin permeation of most of bioactive molecules, which highly constrained the application of TDD.</p> Methods <p>This study analyzed stratum corneum disruption and enhanced permeation by gently rubbing calcium hydrogen phosphate (Chp) particles of varying sizes on skin. Enhanced anesthetic efficacy of Chp-containing microemulsion gel (MG) loaded with lidocaine-tetracaine eutectic was evaluated in guinea pigs using a needle-prick model.</p> Results <p>Using Chp as dermabrasion particle could effectively disrupt the barrier of stratum corneum after applying gently rubbing on the skin, which resulted in increasing skin permeation of both FITC, FITC-Dextran4000 and MG loaded with lidocaine-tetracaine eutectic. The enhanced skin permeation depended not only on the increase of particle size and amount of Chp in the MG, but also on the increase of rubbing pressure and duration after being applied to the skin, finally shortening the onset time and improving the efficacy of local anesthetics.</p> Conclusions <p>The incorporation of Chp into the topical formulation, followed by rubbing them on the skin with appropriate pressure and a certain duration, can significantly disrupt the stratum corneum, enhance drug permeation through the skin, and shorten the onset time of local anesthetics. This study provided a potential strategy for improving the skin permeation with well tolerance, which could be further used to expand the range of bioactive molecules for TDD.</p>