Olesen Uffe Høgh, Clergeaud Gael, Hendel Kristoffer Kjærgaard, Yeung Kelvin, Lerche Catharina Margrethe, Andresen Thomas Lars, Haedersdal Merete
Department of Dermatology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, Denmark.
Department of Microtechnology and Nanotechnology, Technical University of Denmark, Lyngby, Denmark.
J Invest Dermatol. 2020 Oct;140(10):2051-2059. doi: 10.1016/j.jid.2020.01.032. Epub 2020 Mar 2.
Oral administration of vismodegib for basal cell carcinoma treatment is limited by significant class-specific systemic side effects. We investigated the approach of combining ablative fractional laser-assisted drug delivery with an extended-release microemulsion formulation of vismodegib to provide efficient cutaneous delivery in vivo. The developed formulation consisted of an oil-in-water microemulsion stabilized by Tween-80. Pig skin was exposed to ablative fractional laser followed by topical application of vismodegib microemulsion for 4 hours. At 4 hours, 2 days, 5 days, and 9 days, we evaluated vismodegib biodistribution in superficial, mid, and deep dermis and plasma (n = 189 measurements) and assessed local skin reactions. Sustained topical delivery of vismodegib was detected in all depths of ablative fractional laser-exposed skin over the course of the study, with peak concentrations found at 5 days and 9 days. The highest vismodegib concentrations reached 1,409.7 μmol/liter in superficial dermis and 62.3 μmol/liter in deep dermis, exceeding steady-state plasma concentrations previously reported for oral administration of vismodegib (5.5-56.0 μmol/liter). Ablative fractional laser increased vismodegib uptake up to 16.6-fold compared with intact skin. Only mild local skin responses to vismodegib were observed, and no vismodegib was detected in plasma. We report sustained topical delivery of vismodegib in vivo at high concentrations with favorable skin tolerability, suggesting a future safer vismodegib treatment.
维莫德吉口服治疗基底细胞癌受到显著的类特异性全身副作用限制。我们研究了将剥脱性分数激光辅助药物递送与维莫德吉缓释微乳剂配方相结合的方法，以在体内实现有效的皮肤给药。所开发的配方由吐温80稳定的水包油微乳剂组成。猪皮暴露于剥脱性分数激光下，然后局部应用维莫德吉微乳剂4小时。在4小时、2天、5天和9天时，我们评估了维莫德吉在浅表、中层和深层真皮以及血浆中的生物分布（共189次测量），并评估了局部皮肤反应。在研究过程中，在剥脱性分数激光照射皮肤的所有深度均检测到维莫德吉的持续局部递送，在5天和9天时达到峰值浓度。维莫德吉在浅表真皮中的最高浓度达到1409.7 μmol/升，在深层真皮中为62.3 μmol/升，超过了先前报道的维莫德吉口服给药的稳态血浆浓度（5.5 - 56.0 μmol/升）。与完整皮肤相比，剥脱性分数激光使维莫德吉的摄取增加了16.6倍。仅观察到对维莫德吉的轻度局部皮肤反应，血浆中未检测到维莫德吉。我们报告了维莫德吉在体内的持续局部高浓度递送以及良好的皮肤耐受性，提示未来维莫德吉治疗更安全。
