Reportedly capable of demonstrating antioxidant activity, phloretin is a plant-derived dihydrochalcone polyphenol primarily found in various species of apple (J. Nutr. 2005;135:172-8).

This flavonoid exhibits potent antioxidant activity in peroxynitrite scavenging and in the suppression of lipid peroxidation (Biochem. Biophys. Res. Commun. 2002;295:9-13). Along with its glucoside phloridzin, phloretin is believed to be an important contributor to the health benefits of apples (J. Agric. Food Chem. 2003;51:6347-53).

Phloretin also has been identified in tomatoes, and is considered an important source of dietary flavonoids (J. Agric. Food Chem. 2008;56:2436-41). In addition, it was once used as a substitute for quinine.

Research on the potential cutaneous benefits of phloretin began more than 20 years ago, when two botanically derived flavonoids - phloretin and the structurally related compound nordihydroguaiaretic acid - were found to strongly inhibit keratinocyte growth. The investigators suggested that the compounds be considered antipsoriatic agents (Int. J. Dermatol. 1987;26:660-6).

Heightened Permeation
Nine years ago, phloretin was evaluated for its potential to enhance the transdermal penetration of lidocaine hydrochloride. Investigators treated excised human skin samples with a methanolic solution of phloretin 12 hours before lidocaine application, at pH 4.0 and 7.0. At a pH of 4.0, a 3.2-fold increase in total permeation was seen, compared with control samples after 24 hours.

In a subsequent test, unilamellar phosphatidylcholine liposomes were used as a vehicle for phloretin, and a 5.4-fold greater permeation of lidocaine was observed in pretreated skin, compared with control skin after 24 hours. The investigators concluded that phloretin indeed demonstrated potential as a transdermal penetration enhancer for lidocaine (J. Pharm. Sci. 2001;90:485-92).

In 2003, Auner et al. showed that permeation of porcine skin with phloretin and 6-ketocholestanol prior to treatment with 5-aminolevulinic acid increased acid diffusion (the permeation of which was enhanced by cetylpyridinium chloride and benzalkonium chloride) at pH 7.0 approximately 1.7-fold (Int. J. Pharm. 2003;255:109-16).

In an experiment also published in 2003, the same team studied the same compounds - phloretin and 6-ketocholestanol included in unilamellar liposomes - for their viability in enhancing the transport of sodium fluorescein across rat, porcine, and human skin. Phloretin was found to have a significant positive effect on sodium fluorescein diffusion in rat and porcine skin after 30 hours but no influence on human skin as compared to control, whereas 6-ketocholestanol exhibited a positive effect on all skin types (J. Control. Release 2003;89:321-8).

By using various methods to evaluate membrane interactions, some of the same investigators subsequently determined that phloretin and 6-ketocholestanol interact with the lipid layer and alter the structure, rendering a greater fluidity in the membrane (Eur. J. Pharm. Biopharm. 2004;57:329-36).

In the same issue of the European Journal of Pharmaceutics and Biopharmaceutics in which these findings were published, Auner and Valenta published a study on the effects of phloretin on the topical permeation of lidocaine using one hydrophilic and three lipophilic delivery systems. The researchers conducted standard diffusion experiments with Franz diffusion cells through porcine skin, and found that phloretin enhanced lidocaine permeation 1.39-fold in the hydrophilic formulation and 1.25- to 1.76-fold in the lipophilic formulations (Eur. J. Pharm. Biopharm. 2004;57:307-12).