α-Arbutin (Arb) has earned widespread attention in the whitening cosmetics, however, its poor drug permeability and short function time exert tremendous challenges for formulations. Herein, we endeavored to screen the compounds that simultaneously enhanced the topical permeability and anti-melanogenic effect of α-arbutin. Ten whitening compounds were selected to evaluate their permeation-enhancing effect to Arb on the porcine skin. We found that Glabridin (Gla) and undecylenoyl phenylalanine (UP) were superior to enhancing the skin retention of α-arbutin than other compounds, and encouraged more α-arbutin accumulation in the epidermis and dermis layers. Furthermore, Gla and UP exhibited a remarkable capability of altering the secondary conformation of keratin and inducing the disorganization of SC surface alignments, thereby achieving permeation enhancement on Arb. Molecularly, Gla and UP possessed a higher intermolecular energy with keratin than α-arbutin, as elucidated by computational simulations. Remarkably, Gla reinforced the activities of inhibiting tyrosinase and melanin production, exhibiting a synergistic whitening effect at cellular and animal pigmentation models with Arb. More importantly, Gla and Arb were biocompatible drug combination for skin whitening. Collectively, Gla was an ideal candidate for enhanced drug permeability and anti-melanogenic effect of Arb, which was a promising drug compatible in pharmaceutical and cosmetics industry.

α-熊果苷（Arb）在美白化妝品領域廣受關注，然而其藥物滲透性差及功效持續(xù)時間短的特性，為配方設計帶來了巨大挑戰(zhàn)。在此，我們旨在篩選出那些既能提高α-熊果苷的局部滲透性，又能增強其抗色素生成作用的化合物。選取十種美白化合物，評估其在豬皮上對α-熊果苷滲透促進的效果。研究表明光甘草定（Gla）和十一烯酰苯丙氨酸（UP）在增強α-熊果苷在皮膚中的留存方面比其他化合物效果更顯著，并且能夠促使更多的α-熊果苷在表皮和真皮層中積累。此外，Gla 和 UP 具有顯著的能力來改變角蛋白的二級結構，并導致基底膜表面排列的紊亂，從而提高了 Arb 的滲透性。在分子層通過計算模擬可知，Gla和UP與角蛋白形成的分子間能量高于α-熊果苷。值得注意的是，Gla在細胞和動物色素沉著模型中與Arb協(xié)同發(fā)揮美白功效，顯著增強了抑制酪氨酸酶活性和黑色素生成的作用。Gla與Arb這兩種物質是一種適用于皮膚美白的生物相容性藥物組合。總的來說，Gla 具有促進藥物滲透和增強Arb抗色素生成作用的雙重優(yōu)勢，而Arb是一種在制藥和化妝品行業(yè)都頗具前景的藥物。

The in vitro permeation and retention performance of Arb in the presence of different enhancers in the porcine skin within 48 h. (a) In vitro permeation pro?les and (b) Retention amount of Arb in the presence of 3-OEA, GH, PB, RG, and ADE; (c) In vitro permeation curves and (d) Accumulation amount of Arb in the presence of Glu, CD, Gla, TA, and UP; (e) Arb retention amount in SC layer and subcutaneous layers (n = 4, Data are expressed as mean values ± SD, **p < 0.01, ****p < 0.0001, compared with Arb).

α-arbutin；Permeation enhancer；Anti-melanogenic；Topical drug delivery；Glabridin

α-熊果苷   滲透促進劑   抗黑色素生成   局部藥物遞送   光甘草定

The molecular mechanisms underlying Glabridin enhancing the topical permeability and anti-melanogenic effect of α-arbutin.pdf