smartOX - Smarte Antioxidantien zur Pflege und Regeneration sensitiver Haut
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Philipps-Universität Marburg
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The first part of the thesis describes a method to track the dermal penetration of substances with low or no fluorescence. Utilizing this technique combined with the ex-vivo pig ear model, the evaluation of pharmaceutical ingredients and antioxidants such as carotenes or flavonoids was possible. Furthermore, the detection of APIs in formulations at a semi-quantitative level, with sensitivities in the range of 1-2 mg/cm², in a finite-dose study was achieved. The model allowed to assess the penetration of these substances in a location- and time-dependent manner. The application of pressure on the pig ear skin had a significant impact on the penetration efficacy of APIs. The high sensitivity of the method is highly beneficial in estimating the effects that these substances may have on living organisms. Furthermore, we developed an ex-vivo model for testing damaged skin, which may play an important role in the development of potential therapeutic agents.
In the second part of this thesis, the ex-vivo model was utilized to investigate how particle size affects drug penetration in both intact and damaged skin. The study specifically focused on particle suspensions of active ingredients with low solubility, such as rutin and β-carotene. The results indicated that small particle formulations had a higher significant effect on healthy skin compared to larger particles. However, when mechanical damage was exerted on the skin, a water barrier built up, hindering the sedimentation of small API particles and impeding contact with the skin. As a result, the penetration capacity of nanoscale formulations was negatively impacted.
The third part of the work studied the penetration behavior of preservatives through intact and irritated skin using the ex-vivo model. The results showed penetration of all preservatives into skin. Whereas sorbic acid and parabens reduced the SCT due to dehydration, Euxyl and Verstatil TBG MB led to a swelling of the SC. The effects were more pronounced for irritated skin compared to intact skin. Ethanol caused skin drying but also improved the SC structure. It is believed that ethanol may have a sealing effect. Ethanol-containing formulations loaded with hydrophilic, amphiphilic or lipophilic API was tested on skin to understand the comprehensive dermal effect of ethanol-containing formulations. Compared with ethanol-free formulations, ethanol-containing formulations let to a significant decrease in API’s penetration amount and depth through intact and irritated skin.
In the fourth section of this work, detailed research on preservative-free formulations and how they interacted with various sterilization methods such as autoclave (AK), ultra-high temperature (UHT) and high-pressure homogenization (HPH) was conducted. The investigation focused on how these methods affected the physico-chemical properties, microbial stability, and drug penetration of the formulations. The results demonstrated that all the sterilization methods were effective in producing sterile formulations. However, the use of temperature and pressure caused an instability and a negative impact on the physical properties and additionally led to chemical decomposition of the incorporated antioxidants. The data indicate that hydrophilic antioxidants were more susceptible to pressure and temperature treatment, while the effect on amphiphilic and lipophilic antioxidant mixtures was less pronounced. This suggested that one antioxidant may protect the others by decomposing. AK and UHT displayed similar effects, which were observed through the decreased amounts of antioxidants during biopharmaceutical testing. High-pressure homogenization, on the other hand, caused the least damage to the formulation and even improved its penetration properties. Therefore, it is recommended as a sterilization method for preservative-free dermal formulations.
The fifth part of this thesis focused on developing a dermal formulation for damaged skin. Hence, the influence of various ingredients (preservatives, fragrance) and drug delivery systems (emulsion, cream, nanoscale lipid particles (LNP)) on the penetration of API in intact and irritated skin was investigated. Two natural cosmetic bases, that showed barrier strengthening and nourishing properties for intact and irritated SC were selected. The addition of the antioxidant mixture led to an unpleasant odor. Therefore lemongrass oil was tested as an odor-masking agent. The API dissolved in a carrier showed an excellent penetration caused by solvent-drag mechanism, nevertheless a slight irritation of the SC was observed. Hence, oil was incorporated into LNP. Sodium stearyl glutamate and sodium cocoamphoacetate were selected and tested as cosmos certified emulsifiers regarding their skin compatibility. Sodium stearyl glutamate showed lower effects and less negative changes in skin studies in comparison to sodium cocoamphoacetate. The penetration of the two emulsifiers demonstrated a micelle-assisted penetration mechanism. It was also observed that an API dissolved in a carrier was superior to LNP in terms of penetration efficiency. This implies that the solvent-drag mechanism is superior to the micelle-assisted-penetration mechanism in terms of penetration.
The final formulations were prepared with and without lemongrass oil or with lemongrass oil-LNP. Both bases were subsequently prepared with and without ethanol. The penetration studies on healthy skin showed a change in penetration mechanisms for the formulation when a single substance, or a combination of substances, was added. However, the addition of ethanol to the formulations had little to no effect due to the intact skin barrier. The same combination of formulations were tested on irritated skin. The influence of the components of the formulation and the addition of ingredients on the changes in penetration mechanisms was more obvious. Ethanol showed further damage to the barrier membrane. The skin appeared dehydrated after irritation and showed additional damage caused by ethanol, resulting in the formation of a barrier similar to a pudding skin.
In conclusion, it was determined that the ideal formulation for sensitive skin must be preservative-free. A firmer texture of the formulation had positive effects on the penetration efficacy of the APIs. The addition of lipid nanoparticles for the possible formation of an invisible layer and the utilization of the advanced corneotherapy principles may be added as a supportive treatment.
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