Topical delivery of vismodegib using ablative fractional laser and micro-emulsion formulation in vitro

Abstract

Background and Objective: Hedgehog inhibitors such as vismodegib are targeted drugs widely used for the treatment of basal cell carcinomas; however, their use is significantly limited by frequent systemic side effects due to oral administration route. We aim to use ablative fractional laser (AFL) to enable the topical delivery of vismodegib to relevant dermal depths. Materials and Methods: Pig skin was treated in vitro with a fractional 10,600 nm CO 2 laser at 0 or 80 mJ/microbeam and exposed to vismodegib (6.4 mmol/L) in Franz-diffusion cells for 0.5, 4, and 24 hours (n = 54 samples), either formulated in a micro-emulsion composed of soybean oil and Tween 80 or dissolved in ethanol as vehicle control. Vismodegib biodistribution was studied at specific skin depths from 0 to 1,800 µm (incremental steps of 300 µm) by mass spectrometry. Results: Combination of AFL and vismodegib emulsion substantially enhanced the delivery of drug into the skin. Emulsion formulation alone yielded higher vismodegib skin concentrations compared to vehicle control in superficial and mid-dermis (0–900 µm, P = 0.002–0.015). The over-all highest concentration found (554.5 µmol/L) was reached at 24 hours in superficial (0–300 µm) AFL exposed skin, 7.6-fold higher than vehicle control (P = 0.002) and 9.7–101.6 fold higher than previously reported steady-state plasma concentrations in patients treated with oral vismodegib (5.5–56.9 µmol/L). Compared to intact skin, AFL exposure significantly increased skin concentrations of vismodegib even in deep skin layers (24 h, 900–1,800 µm, emulsion: 8.7–74.3 µmol/L vs. 0.0–0.0 µmol/L, P = 0.004–0.048; vehicle control: 23.7–50.6 µmol/L vs. 0.0–1.6 µmol/L, P = 0.002). The total delivery of vismodegib-emulsion into mid-deep dermal skin layers from 600 to 1,800 µm was for AFL exposed skin 8.2 fold higher than intact skin. Also, delivery of emulsion vismodegib by AFL was time-dependent as seen by the continuous increase in concentrations found over time, with highest uptake detected after 24 hours (4–24 hours, 0–900 µm, P = 0.002–0.004). Conclusion: AFL enhances topical delivery of micro-emulsion formulated vismodegib, reaching concentrations similar to or above plasma concentrations previously reported in patients receiving oral vismodegib. Lasers Surg. Med. 51:79–87, 2019. © 2018 Wiley Periodicals, Inc.