Mechanism insight on licorice flavonoids release from Carbopol hydrogels: Role of “release steric hindrance” and drug solubility in the release medium

The present study was to systematically evaluate different licorice flavonoids (LFs) compounds release behaviors from the single payload hydrogel and LFs extracts hydrogels based on the drug solubility in the release medium (DSRM), intermolecular strength of the hydrogel and the "release steric hindrance" (RSH). Two kinds of LFs (LFs 1: LFs 2 = 5:1, W/W) hydrogels were prepared with Carbopol 940 (CBP) as the thickener, and ten LFs single payload hydrogels were prepared according to the actual content in the LFs 1 extracts. The drug release mechanisms were confirmed by in vitro release experiments and molecular dynamic simulation analysis, and evaluated using novel indicators of ERLFs 1/Sin (the enhancement ratio (ER) of drug release percent of LFs 1-CBP hydrogel to the single payload hydrogel), ERLFs 2/ LFs 1 (ER of drug release percent of LFs 2-CBP hydrogel to LFs 1-CBP hydrogel) and ERrelease medium (ER of drug release percent in different release medium). We found that LFs 1-CBP possessed a significantly higher intermolecular strength and RSH than LFs 2-CBP, resulting in a higher viscosity, which had a positive correlation with the payload content and a negative correlation with the drug release percent. Therefore, the ERLFs 2/ LFs 1 values of ten LFs compounds were all higher than 1. For liquiritigenin and retrochalcone with higher DSRM, they displayed similar ERLFs 1/ Sin, ERLFs 2/ LFs 1 and ERrelease medium values (≈1). For formononetin, licoflavone A and licochalcone A with low DSRM, they exhibited ERLFs 1/Sin values >1. The low DSRM was the decisive factor to restrict their release from the single payload hydrogel. The presence of glycyrrhizin acid (GA) in the LFs could facilitate their release from the LFs extracts hydrogel. For isoliquiritin, isoliquiritigenin and glabridin with a lower content in the LFs extracts, they exhibited ERLFs 1/Sin values <1. The RSH predominantly restricted its release. The study provided guidelines for the reasonable design of LFs extracts hydrogel in pharmaceutical topical formulations.