[Aspects of sustainability of topical therapy]. / Aspekte der Nachhaltigkeit in der topischen Therapie.

BACKGROUND: Topical compounds are an important treatment option in dermatology. Many ingredients and packaging do not yet sufficiently fulfill sustainable criteria. OBJECTIVES: This article aims to provide a compact overview of sustainability criteria of topical compounds and packaging. MATERIALS AND METHODS: Based on a selective literature search and personal experience, common ingredients and packaging of topical preparations are summarized. RESULTS: Topical preparations often contain mineral oils, acrylates, silicones and polyethylene glycols (PEG), which show poor biodegradability and may accumulate in the environment. As an alternative to these non-renewable substances, plant-based fats, oils, and waxes can be used. Biopolymers such as plant-based gum, agar-agar, pectin, and biologically produced hyaluronic acid are an alternative to plastic polymers. The environmental footprint of glass as packaging material is overestimated. Currently, plastics and aluminum may be preferable when recycled correctly. CONCLUSION: The production of topical formulations without using mineral oils, silicones, acrylates, and PEGs is technically challenging. A sustainable packaging material that fulfills all relevant functionalities is not yet available. Packaging should meet high requirements regarding ecological, economic, and social factors. Better performance with respect to new opportunities in recycling and waste management should be incorporated. Overall, the legislative authorities should provide relevant incentives for more sustainable topical compounds and packaging.

The Anti-Inflammatory Effect of Humulus lupulus Extract In Vivo Depends on the Galenic System of the Topical Formulation.

We demonstrated the anti-inflammatory and anti-oxidative effects of Humulus lupulus (HL) extract on solar simulator-irradiated primary human keratinocytes (PHKs) by analyzing ERK and p38 MAPK phosphorylation and production of IL-6 and IL-8. The anti-inflammatory effect of topically applied HL was further tested in vivo on human skin. To this end, we developed an oil-in-water (O/W) and a water-in-oil (W/O) cream with a lipid content of 40%. The anti-inflammatory effect of 1% HL extract incorporated in these two vehicles was assessed in a randomized, prospective, placebo controlled, double-blind UVB erythema study with 40 healthy volunteers. Hydrocortisone acetate (HCA) in the corresponding vehicle served as positive control. Surprisingly, both HL and HCA were only effective in the O/W system but not in the W/O formulation. Release studies using vertical diffusion cells (Franz cells) revealed that HCA was released in much higher amounts from the O/W cream compared to the W/O formulation. In summary, we have shown that 1% HL extract exerts anti-inflammatory effects comparable to 1% HCA, but only when incorporated in our O/W cream. Our findings confirm the critical role of the vehicle in topical anti-inflammatory systems.

Anti-Inflammatory Effect of a Novel Topical Herbal Composition (VEL-091604) Consisting of Gentian Root, Licorice Root and Willow Bark Extract.

The anti-inflammatory properties of the topical herbal composition VEL-091604 with gentian root, licorice root, and willow bark extract were assessed in a randomized, prospective, placebo-controlled, double-blind ultraviolet (UV)-erythema test study with 42 healthy volunteers in comparison to 1% hydrocortisone acetate. The efficacy and tolerability of VEL-091604 cream 2 times daily over 2 wk was evaluated in an open-label, prospective proof of concept study in 10 subjects with atopic dermatitis using a lesional SCORAD severity score. In the UV-erythema test VEL-091604 cream significantly reduced inflammation compared to placebo and was as effective as 1% hydrocortisone acetate. The clinical study with atopic subjects revealed a significant and rapid reduction of the lesional SCORAD severity score in the test areas after 1 and 2 wk. No adverse events were recorded. It is concluded that the herbal cream VEL-091604 with licorice root, willow bark, and gentian root extract display anti-inflammatory properties in vivo. It is a promising new treatment option for atopic dermatitis that warrants further investigation in controlled studies.

Hop Extract Acts as an Antioxidant with Antimicrobial Effects against Propionibacterium Acnes and Staphylococcus Aureus.

Acne is associated with hyperkeratosis, elevated levels of skin sebum and growth of Propionibacterium acnes (P. acnes) and Staphylococcus aureus (S. aureus). Furthermore, P. acnes promotes inflammation by inducing IL-6 production and oxidative stress. The aim of this study was to assess the antioxidant, anti-inflammatory and antibacterial potential of a hop-CO2-extract with 50% humulone and lupulone. The susceptibility of P. acnes and S. aureus to the hop extract was tested by using the broth microdilution technique. The minimal inhibitory concentrations (MIC) for P. acnes and S. aureus were 3.1 and 9.4 µg/mL, respectively. In addition, the hop extract showed an antioxidative effect with a half maximal inhibitory concentration (IC50) of 29.43 µg/mL as well as additional anti-inflammatory effects by reducing the IL-6 expression (IC50: 0.8 µg/mL). In addition, a gel formulation with 0.3% hop extract (w/w) had antibacterial activity against P. acnes and S. aureus (inhibition zone value: 5.5 mm and 3 mm, respectively) which was significantly superior to the placebo gel. The positive control (a gel with the antibiotic clindamycin) showed an inhibition zone of 9 mm. Due to its antioxidant, anti-inflammatory and antibacterial effects hop extract might be a treatment option for acne-prone skin.

Effect of a botanical cleansing lotion on skin sebum and erythema of the face: A randomized controlled blinded half-side comparison.

BACKGROUND: Elevated levels of skin sebum are associated with the growth of Propionibacterium acnes. Intensive degreasing of the skin reduces Propionibacterium acnes but also may cause skin irritation. AIMS: We assessed the degreasing effect and skin tolerability of a botanical face cleanser with hops and willow bark extract and disodium cocoyl glutamate as mild cleansing agent compared to a standard face cleanser with sodium laureth sulfate (SLES). MATERIALS AND METHODS: A total of 21 healthy volunteers with normal to oily skin were enrolled in this study. Both cleansers were applied twice a day on the left or right side of the forehead for 15 days in a standardized manner. Bioengineering measurements were performed on day 8 and 15 and on day 17 after an application break of 48 hours. The sebum level was determined using a Sebumeter® , and skin redness was measured using a Mexameter® . RESULTS: The botanical face cleanser significantly reduced the sebum level (P < .01) in the test area on day 17. The SLES containing cleanser showed a statistically relevant degreasing effect already on day 15, but after the application break the sebum level increased again on day 17. None of the cleansers caused skin irritation as determined by skin redness measurements. CONCLUSIONS: In contrast to the SLES containing cleanser, the botanical skin cleanser with hops and willow bark extract had a continuous degreasing effect without reactive seborrhoe after the treatment break. Skin cleansing without SLES might be advantageous for sensitive skin.

The Herbal Bitter Drug Gentiana lutea Modulates Lipid Synthesis in Human Keratinocytes In Vitro and In Vivo.

Gentiana lutea is a herbal bitter drug that is used to enhance gastrointestinal motility and secretion. Recently we have shown that amarogentin, a characteristic bitter compound of Gentiana lutea extract (GE), binds to the bitter taste receptors TAS2R1 and TAS2R38 in human keratinocytes, and stimulates the synthesis of epidermal barrier proteins. Here, we wondered if GE also modulates lipid synthesis in human keratinocytes. To address this issue, human primary keratinocytes were incubated for 6 days with GE. Nile Red labeling revealed that GE significantly increased lipid synthesis in keratinocytes. Similarly, gas chromatography with flame ionization detector indicated that GE increases the amount of triglycerides in keratinocytes. GE induced the expression of epidermal ceramide synthase 3, but not sphingomyelinase. Lipid synthesis, as well as ceramide synthase 3 expression, could be specifically blocked by inhibitors of the p38 MAPK and PPARγ signaling pathway. To assess if GE also modulates lipid synthesis in vivo, we performed a proof of concept half side comparison on the volar forearms of 33 volunteers. In comparison to placebo, GE significantly increased the lipid content of the treated skin areas, as measured with a sebumeter. Thus, GE enhances lipid synthesis in human keratinocytes that is essential for building an intact epidermal barrier. Therefore, GE might be used to improve skin disorders with an impaired epidermal barrier, e.g., very dry skin and atopic eczema.

Inhibition of Osteoarthritis by Adipose-Derived Stromal Cells Overexpressing Fra-1 in Mice.

OBJECTIVE: To determine whether overexpression of the activator protein 1 (AP-1) transcription factor Fra-1 in adipose-derived stromal cells (ADSCs) is an effective treatment of collagenase-induced osteoarthritis (OA). METHODS: OA was induced by injection of collagenase into the knee joints of male C57BL/6 mice. ADSCs were isolated from the inguinal fat pads of 8-week-old wild-type or Fra-1-transgenic mice and injected into the knee joints of mice with collagenase-induced OA 7 days after OA induction. Histologic analyses of cartilage destruction and chondrocyte cell death were performed. Adipogenic differentiation capacity was evaluated, gene expression was analyzed, and cytokine profiling was performed in stromal vascular fractions (SVFs) and ADSCs. RESULTS: OA-related cartilage destruction and chondrocyte cell death were significantly reduced in mouse knee joints treated with ADSCs from Fra-1-transgenic mice compared to mouse knee joints treated with ADSCs from wild-type mice. This effect did not result from the higher number of adipogenic progenitors observed in SVFs from Fra-1-transgenic compared to wild-type mouse fat pads, since injection of wild-type mouse ADSCs enriched for adipogenic progenitors did not show any additional chondroprotective effects compared to nonsorted ADSCs. However, Fra-1-transgenic mouse ADSCs showed decreased adipogenic differentiation capacity. Moreover, Fra-1 significantly inhibited proinflammatory interleukin-6 and pentraxin 3 expression, while increasing the expression of extracellular matrix proteins, such as periostin and spondin 1. These findings suggest that Fra-1 overexpression leads to an increased chondroprotective effect of ADSCs in OA. CONCLUSION: ADSCs overexpressing Fra-1 effectively protect against OA. Our data indicate that genetic modifications of ADSCs, such as Fra-1 overexpression, may improve their potential to protect articular cartilage against OA-mediated damage.

Sclerostin inhibition reverses systemic, periarticular and local bone loss in arthritis.

OBJECTIVE: To test whether inhibition of sclerostin by a targeted monoclonal antibody (Scl-Ab) protects from bone and cartilage damage in inflammatory arthritis. Sclerostin is a potent inhibitor of bone formation and may be responsible for the low level of bone repair in patients with rheumatoid arthritis. METHODS: Human tumour necrosis factor transgenic mice (hTNFtg mice) developing inflammatory arthritis and local and bone loss were administered either vehicle, anti-TNF antibody, Scl-Ab, or a combination of both agents. Inflammation, systemic and periarticular bone loss, bone erosion and cartilage damage were evaluated at baseline (week 8) and after 3 weeks of treatment by clinical assessment, micro-CT and histology. RESULTS: Scl-Ab did not affect joint swelling or synovitis. Systemic bone loss in the spine and periarticular bone loss in the proximal tibia were completely blocked and partially reversed by inhibition of sclerostin but not by inhibition of TNF. Moreover, Scl-Ab completely arrested the progression of bone erosion in hTNFtg mice and in combination with TNF inhibition even led to significant regression of cortical bone erosions. Protective effects of Scl-Ab were also observed for the articular cartilage. CONCLUSIONS: These data suggest that sclerostin inhibition is a powerful tool to enhance bone repair in inflammatory arthritis.

Influence of nanostructured lipid carriers (NLC) on the physical properties of the Cutanova Nanorepair Q10 cream and the in vivo skin hydration effect.

Cutanvoa Nanorepair Q10 cream, the first NLC containing cosmetical product introduced to the market in October 2005, was compared to an identical o/w cream without NLC with regards to particle size, melting behaviour, rheological properties and the in vivo effect on skin hydration. The consistency, the spreadability on the skin and the subjective feeling of increase in skin hydration were evaluated using a standardized questionnaire, and compared to hydration data measured. Furthermore, it was shown by epicutaneous patch test that Cutanova Nanorepair Q10 cream has no irritating effects on the skin. By laser diffraction (LD) and differential scanning calorimetry (DSC) measurements it could be shown that NLC are physically stable in Cutanova Nanorepair Q10 cream. After 7 days application of Cutanova Nanorepair Q10 cream and NLC negative control cream an increase in skin hydration could be objectively confirmed by measurements in vivo. From day 28 on the skin hydration measured in the test areas of Cutanova Nanorepair Q10 cream was significantly higher than the skin hydration in the test areas of the NLC negative control cream (p=0.05). The subjective feeling of increase in skin hydration was also rated from the volunteers as superior for Cutanova Nanorepair Q10 cream. The rheological properties of Cutanova Nanorepair Q10 cream contributed to a better subjective impression of consistency and spreadability on the skin than found for NLC negative control cream.

Preservation of nanostructured lipid carriers (NLC).

Due to their positive features (e.g., increased penetration of actives, re-enforcement of the lipid barrier and increase in skin hydration), nanostructured lipid carriers (NLC) are used in many dermal formulations. These formulations require preservation, and preservatives can impair the physical stability of disperse systems. Therefore, in this study, the influence of preservatives on the physical stability of Q10-loaded NLC was investigated using 11 different preservative mixtures. Whereas for nanosuspensions, only a limited number of preservatives are known from the literature not affecting their physical stability, a surprisingly high number of seven preservatives could be identified to be suitable for the preservation of NLC dispersions. For Q10-loaded NLC, Hydrolite 5 proved to be the best preservative, as it was found surprisingly to stabilize the NLC dispersion. Based on the data, a preservative classification system is suggested and a mechanistic model describing six key parameters affecting the physical stability of NLC could be developed. As most suitable characterization method to screen for suitable preservatives, light microscopy was identified. By being a simple, fast and cost efficient method, even extensive preservative screening studies can be performed very efficiently.

Silver-nanolipid complex for application to atopic dermatitis skin: rheological characterization, in vivo efficiency and theory of action.

A skin care formulation was developed by incorporating microsilver, in combination with nanostructured lipid carriers (NLC) into an o/w cream and lotion. To increase skin adhesion of the NLC, and subsequent film formation and occlusion onto the skin, the NLC were produced with a size of about 200 nm. Production of NLC was performed by high-pressure homogenisation. Characterization was performed regarding size and charge (zeta potential), and for the cream and lotion also by rheology. Incorporation of NLC and/or microsilver into the cream or lotion led to pronounced changes in the thixotropic behaviour (shape of rheogram, yield point, viscosity). This was explained by specific interaction of the nanoparticles and/or the microsilver with the two formulations. In vivo studies revealed a high potential to remove not only symptoms of irritated sensitive skin, but also of light to medium atopic dermatitis. Based on zeta potential measurements, a silver ion-nanolipid complex seems to form which leads to a higher activity of the antimicrobial silver, e.g., increasing the silver ion concentration on skin and bacterial membranes. The antimicrobial effect in combination with restoration of normal skin condition (repair of stratum corneum lipid film by NLC) is obviously sufficient to replace in many cases medical therapy with glucocorticoids by a biological, natural skin care cosmetic nano formulation.