Liposomes, lipid nanocapsules and smartCrystals®: A comparative study for an effective quercetin delivery to the skin.

Quercetin is a flavonoid with strong antioxidant and antiinflammatory activities considered as a potential drug candidate for skin exogenous supplementation. Nevertheless, crude quercetin suffers from poor water solubility and consequently topical inactivity. Therefore, quercetin formulation within a suitable system that overcomes its solubility limitation is a matter of investigation. Three approaches were tested to improve quercetin delivery to skin: liposomes, lipid nanocapsules (LNC) and smartCrystals®. These nanoformulations were compared in terms of average particle size, homogeneity (PDI), quercetin loading and cellular interactions with HaCaT (keratinocytes) and TPH-1 (monocytes) cell lines. Finally, two formulations were selected for testing quercetin delivery to human skin in vivo using stripping test. Different size distribution was obtained with each strategy starting from 26 nm with quercetin LNC, 179 nm with liposomes to 295 nm with quercetin smartCrystals®. The drug loading varied with each formulation from 0.56 mg/ml with liposomes, 10.8 mg/ml with LNC to 14.4 mg/ml with smartCrystals®. No toxicity was observed in HaCaT cells with quercetin and free radical scavenging ability was established at 5 µg/ml. The safety of quercetin at 5 µg/ml was further confirmed on THP-1 cells with efficient free radical scavenging ability. Finally, skin penetration evidenced different behavior between the two selected forms (LNC and SmartCrystals®), which could lead to different promising strategies for skin protection. On one side, quercetin smartCrystals® seems to enable the superficial deposition of quercetin on top of the skin, which presents a good strategy for a quercetin-based sunscreen product. On the other side, LNC seems to allow quercetin delivery to viable epidermis that holds the promise for skin inflammatory disorders such as psoriasis.

Quercetin topical application, from conventional dosage forms to nanodosage forms.

Skin is a multifunctional organ with activities in protection, metabolism and regulation. Skin is in a continuous exposure to oxidizing agents and inflammogens from the sun and from the contact with the environment. These agents may overload the skin auto-defense capacity. To strengthen skin defense mechanisms against oxidation and inflammation, supplementation of exogenous antioxidants is a promising strategy. Quercetin is a flavonoid with very pronounced effective antioxidant and antiinflammatory activities, and thus a candidate of first choice for such skin supplementation. Quercetin showed interesting actions in cellular and animal based models, ranging from protecting cells from UV irradiation to support skin regeneration in wound healing. However, due to its poor solubility, quercetin has limited skin penetration ability, and various formulation approaches were taken to increase its dermal penetration. In this article, the quercetin antioxidant and antiinflammatory activities in wound healing and supporting skin against aging are discussed in detail. In addition, quercetin topical formulations from conventional emulsions to novel nanoformulations in terms of skin penetration enhancement are also presented. This article gives a comprehensive review of quercetin for topical application from biological effects to pharmaceutical formulation design for the last 25 years of research.

Dermal quercetin smartCrystals®: Formulation development, antioxidant activity and cellular safety.

Flavonoids are natural plant pigments, which possess high antioxidative and antiradical activities. However, their poor water solubility led to a limited bioavailability. To overcome this major hurdle, quercetin nanocrystals were produced implementing smartCrystals® technology. This process combines bead milling and subsequent high-pressure homogenization at relatively low pressure (300bar). To test the possibility to develop a dermal formulation from quercetin smartCrystals®, quercetin nanosuspensions were admixed to Lutrol® F127 and hydroxythylcellulose nonionic gels. The physicochemical properties (morphology, size and charge), saturation solubility, dissolution velocity and the antioxidant properties (DPPH assay) as well as the cellular interaction of the produced quercetin smartCrystals® were studied and compared to crude quercetin powder. Quercetin smartCrystals® showed a strong increase in the saturation solubility and the dissolution velocity (7.6 fold). SmartCrystals® loaded or not into gels proved to be physically stable over a period of three months at 25°C. Interestingly, in vitro DPPH assay confirmed the preservation of quercetin antioxidative properties after nanonization. In parallel, the nanocrystalline form did not display cellular toxicity, even at high concentration (50µg/ml), as assayed on an epithelial cell line (VERO cells). In addition, the nanocrystalline form confirmed a protective activity for VERO cells against hydrogen peroxide induced toxicity in vitro. This new formulation presents a promising approach to deliver quercetin efficiently to skin in well-tolerated formulations.

Preservative system development for argan oil-loaded nanostructured lipid carriers.

Nanostructured lipid carriers (NLC) are used in many dermal cosmetic formulations. To prevent microbiological spoilage of NLC suspensions preservative systems must be used. Preservatives can impair the physical stability of NLC suspensions. Therefore, a systematic screening of preservative systems should be performed and the compatibility of these preservative systems with each NLC formulation has to be investigated. In this study three Argan oil-loaded NLC formulations were developed. Ethanol, propylene glycol and pentylene glycol were admixed to these formulations as preservative systems. The physical stability of the non-preserved and preserved formulations has been investigated. Upon admixing 20% w/w ethanol to the selected formulations, immediate particle aggregation could be detected using laser diffractometry and after 24 hours gelling occurred. This was accompanied with a lowering of Zeta potential value. Samples preserved with 10% w/w propylene glycol did not show any change in particle size or in Zeta potential, in comparison to the non-preserved formulation, when measured after one day and 120 days. Samples preserved with 5% pentylene glycol proved also to be stable after 120 days and did not show any change in particle size or Zeta potential.

Nanostructured lipid carriers (NLC) in cosmetic dermal products.

The first generation of lipid nanoparticles was introduced as solid lipid nanoparticles (SLN), the second, improved generation as nanostructured lipid carriers (NLC). Identical to the liposomes, the lipid nanoparticles (NLC) appeared as products first on the cosmetic market. The article gives an overview of the cosmetic benefits of lipid nanoparticles, that means enhancement of chemical stability of actives, film formation, controlled occlusion, skin hydration, enhanced skin bioavailability and physical stability of the lipid nanoparticles as topical formulations. NLC are on the market as concentrates to be used as cosmetic excipients, special formulation challenges for these products are discussed. NLC appeared also in a number of finished cosmetic products world-wide. An overview of these products is provided including their special effects due to the lipid nanoparticles, lipids used for their production and incorporated cosmetic actives.