Development and evaluation of topical formulations for a novel skin whitening agent (AP736) using Hansen solubility parameters and PEG-PCL polymers.

AP736 itself is a novel skin whitening agent reported to exhibit anti-melanogenic and tyrosinase inhibitory activity. However, formulating a topical product has been difficult because AP736 is insoluble in water as well as in many oils. In this study, we aimed to develop a new topical delivery system in which AP736 is not only physically stable, but also suitably delivered to the skin. By calculating each HSP (Hansen Solubility Parameters), ethylenedioxy moiety-containing compounds could be easily selected for the formulation ingredients of AP736. Although diethylene glycol monoethyl ether with the highest solubility of AP736 enalbes to make AP736-incorporated water-in-oil emulsions well, the recrystallization of AP736 was observed in oil-in-water emulsions. Therefore, we fabricated polymeric nanoparticles (PNPs) in order to encapsulate AP736 to prevent its recrystallization. We used three different PEG-PCL polymers with various chain lengths and ethylenedioxy moiety-containing surfactants (i.e. Choleth) for fabricating PNPs. The prepared PNPs had a mean particle size from 50 nm to 200 nm. Most of PNPs showed the good encapsulation efficiency up to 90%. In particular, Choleth-24 had a significant role in encapsulating AP736 in PNPs. After encapsulation of AP736, no significant changes were observed in the sizes of tested PNPs within 4 weeks. Further, the recrystallization of AP736 was not observed in oil-in-water emulsions after 24 weeks of storage at 40 °C. In vitro permeation study using Strat-M showed that PNPs containing Choleth-24 has the faster release pattern compared to PNPs using Tween 80 and saturated in D.I. water. These results are demonstrating that PNPs might be an effective vehicle for stabilization in oil-in-water emulsions and topical application of AP736.

Glutathione as a skin whitening agent: Facts, myths, evidence and controversies.

Glutathione is a low molecular weight thiol-tripeptide that plays a prominent role in maintaining intracellular redox balance. In addition to its remarkable antioxidant properties, the discovery of its antimelanogenic properties has led to its promotion as a skin-lightening agent. It is widely used for this indication in some ethnic populations. However, there is a dichotomy between evidence to support its efficacy and safety. The hype around its depigmentary properties may be a marketing gimmick of pharma-cosmeceutical companies. This review focuses on the various aspects of glutathione: its metabolism, mechanism of action and the scientific evidence to evaluate its efficacy as a systemic skin-lightening agent. Glutathione is present intracellularly in its reduced form and plays an important role in various physiological functions. Its skin-lightening effects result from direct as well as indirect inhibition of the tyrosinase enzyme and switching from eumelanin to phaeomelanin production. It is available in oral, parenteral and topical forms. Although the use of intravenous glutathione injections is popular, there is no evidence to prove its efficacy. In fact, the adverse effects caused by intravenous glutathione have led the Food and Drug Administration of Philippines to issue a public warning condemning its use for off-label indications such as skin lightening. Currently, there are three randomized controlled trials that support the skin-lightening effect and good safety profile of topical and oral glutathione. However, key questions such as the duration of treatment, longevity of skin-lightening effect and maintenance protocols remain unanswered. More randomized, double-blind, placebo-controlled trials with larger sample size, long-term follow-up and well-defined efficacy outcomes are warranted to establish the relevance of this molecule in disorders of hyperpigmentation and skin lightening.