Quantitative Structure-Activity Relationship of Enhancers of Licochalcone A and Glabridin Release and Permeation Enhancement from Carbomer Hydrogel

This study aimed to systematically compare licochalcone A (LicA) and glabridin (Gla) (whitening agents) release and permeation from Carbomer 940 (CP) hydrogels with different enhancers, and evaluate the relationship between the quantitative enhancement efficacy and structures of the enhancers. An in vitro release study and an in vitro permeation experiment in solution and hydrogels using porcine skin were performed.

We found that the Gla–CP hydrogel showed a higher drug release and skin retention amount than LicA–CP due to the higher solubility in medium and better miscibility with the skin of Gla than that of LicA. Enhancers with a higher molecular weight (MW) and lower polarizability showed a higher release enhancement effect (ER_release) for both LicA and Gla. The Van der Waals forces in the drug–enhancers–CP system were negatively correlated with the drug release percent. Moreover, enhancers with a higher log P and polarizability displayed a higher retention enhancement effect in solution (ER_{solution retention}) for LicA and Gla. Enhancers decreased the whole intermolecular forces indrug–enhancers-skin system, which had a linear inhibitory effect on the drug retention.

Moreover, C=O of ceramide acted asthe enhancement site for drug permeation. Consequently, Transcutol^® P (TP) and propylene glycol (PG), seven enhancers showed a higher retention enhancement effect in hydrogel (ER_{hydrogel retention}) for LicA and Gla. Taken together, the conclusions provide a strategy for reasonable utilization of enhancers and formulation optimization in topical hydrogel whitening.

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Material: Licochalcone A (LicA, purity >98%) and glabridin (Gla, purity >98%) were obtained from Nanjing Spring & Autumn Biological Engineering Co., Ltd. (Nanjing, China). Poly(acrylic acid) (commercial names: Carbomer 940 (CP)), isopropyl myristate (IPM, purity: 98%), diethylene glycol monoethyl ether (commercial names: Transcutol^® P (TP), purity: 99%), and 1-methyl-2-pyrrolidinone (NMP, purity >99%) were purchased from Shanghai Macklin Biochemical Co., Ltd. (Shanghai, China). Propylene glycol monocaprylate (commercial names: Capryol^TM 90 (CP 90)) and polyglyceryl-3dioleate (commercial names: Plurol^® Oleique CC 497 (POCC)) were supplied by Gattefossé (Lyon, France). Polyoxyethylenesorbitan monooleate (commercial names: Span 80 (SP)) and propylene glycol (PG, purity > 99%) were purchased from Damao Chemical Reagent Factory (Tianjin, China). Polyethylene glycol 400 (PEG 400) and cellophane membranes were purchased from Beijing Solarbio Technology Co., Ltd., Beijing, China. All other reagents were analytical grade.

Article information: Wang, Z.; Xue, Y.; Zhu, Z.; Hu, Y.; Zeng, Q.; Wu, Y.; Wang, Y.; Shen, C.; Jiang, C.; Liu, L.; Zhu, H.; Liu, Q. Quantitative Structure-Activity Relationship of Enhancers of Licochalcone A and Glabridin Release and Permeation Enhancement from Carbomer Hydrogel. Pharmaceutics 2022, 14, 262. https://doi.org/10.3390/pharmaceutics14020262