Category: Formulation and Quality
Purpose: Phenylethyl resorcinol (PER) is a highly efficient whitening agent with clinically proven tyrosinase inhibition already at 0.5% active concentration. Its low chemical stability however leads to red discoloration of products even in dark and short storage time. This hinders the use of promising whitening agent PER in cosmetic products.
One approach to enable the use of PER for market products was the formulation of nanostructured lipid carriers (NLC, 2nd generation of solid lipid nanoparticles). Loaded at 20% in NLC and stabilized by polyethylene glycol (PEG), not only improved the chemical stability by 30% but also the tyrosinase inhibition by 60%. Hence, this approach is promising but still needs further improvements for successful market introduction: 1) PEG is not well accepted by consumers and should be replaced by a natural and “green” surfactant, 2) PER loading should be increased to obtain a dilution factor ≥ 10 for more favorable industrial production, and 3) even though the chemical stability is increased by 30% slight reddish discoloration was observed. Hence, further chemical stabilization is needed by PER protecting additives, e.g. antioxidants (AOX) or UV blocker.
To meet the expectations of consumers and the requirements from industry, PER with an AOX or an UV blocker were loaded into smartLipids, the next and improved generation of NLC.
Methods: PER smartLipid suspension consisted of Lipocire A (5.0%), PER (5.0%), AOX or UV blocker (1.0%), Lanette N (1.4%), and purified water (87.5%). Pre-emulsion was formed at 85 °C by rotor-stator-homogenization and subsequent high-pressure homogenization (Micron Lab 40, APV, Germany) at 500 bar for 3 cycles.
Particle size and polydispersity index were measured by photon correlation spectroscopy (PCS, Zetasizer Nano ZS, Malvern Instruments Ltd., UK) 1 day after production and 3 months after room temperature storage in dark. Light microscope was used to determine the presence of larger particles or aggregates outside PCS measuring range.
For investigation of discoloration every sample was divided into two glass vials and stored at dark conditions and under two lamps imitating the natural daylight imitating (Osram L58 W/25). Changes in color were compared to additive free formulation after 3 months in dark and 7 days in light.
Results: smartLipids are characterized by their complex lipid mixture of up to 10 solid lipids or solid and liquid lipids, allowing distinctly higher active loadings than for NLC. Staying solid at skin temperature, enhanced penetration and chemical stabilization already known from solid lipid nanoparticles also apply to smartLipids. Lipocire A is a blend of C10-18 triglycerides, hydrogenated mono- and di- palm kernel-oil, and hydrogenated mono-, di- and tri- palm-oil. This complex lipid mixture allowed a firm inclusion of PER at 50%.
Physically stable and additive free smartLipid suspension with 10% lipid phase was obtained with 1.4% Lanette N (ECOCERT). PCS mean particle size of 107 nm with polydispersity index (PdI) of 0.15 only negligible increased after 6 months at room temperature (109 nm and 0.16). Incorporating AOX (α-tocopherol, butylated hydroxytoluene (BHT), Tinogard TT) or UV blockers (octocrylene, oxybenzone, Oxynex ST liquid, Tinosorb S) resulted in particle sizes of 110-120 nm with PdIs of 0.14-0.20. After 3 months storage only very slight increase of particle size was measured (120-150 nm). No larger particles nor aggregates were observed under light microscope.
The intensity of discoloration varied strongly among samples and storage conditions. They were grouped in 1) whiter 2) similar and 3) redder than the reference formulation being additive free. In dark, the antioxidant BHT and UV blockers Oxynex ST liquid and Tinosorb S were whiter than the reference, where the UV blockers oxybenzone and octocrylene had the same color as reference. Adding the antioxidants Tinogard TT or α-tocopherol even led to redder samples than the reference. Interestingly, the group assignment changed for α-tocopherol and BHT samples under stress conditions (daylight lamps). α-tocopherol stayed completely white, while BHT turned similarly red as reference. This indicates a highly complex PER degradation process. For a product which will be stored in dark but also be exposed to light after skin application an additive being effective in both dark and light is needed. This only applied to the UV blockers Oxynex ST liquid and Tinosorb S.
Conclusion: By the chaotic lipid structure of smartLipids PER encapsulation was successfully increased to 50% with a total PER content of 5% in suspension. This allows an industry-friendly dilution factor of 10. Stabilizing the smartLipids with ECOCERT stabilizer Lanette N at 1.4% particles with sizes around 110-120 nm were obtained being storage stable for 3 months. The addition of the UV blockers Oxynex ST liquid and Tinosorb S suppressed discoloration in both dark and light. These PER smartLipids suspensions are commercially available and can be simply admixed to dermal vehicles.