Magdalena Hoppel

Ultra-small NLC for improved dermal delivery of coenyzme Q10

Coenzyme Q10 (CoQ10) acts as an antioxidant in the skin and is frequently contained in anti-aging products. In previous studies, it could be shown that nano-structured lipid carriers (NLC) with a size of about 230 nm are beneficial for the dermal delivery of CoQ10. They increased Q10 skin penetration when compared to equally sized nanoemulsion. In this study, ultra-small NLC were prepared with even smaller mean particles sizes of around 80 nm. The influence of this decrease of particle size was investigated in terms of skin permeation and penetration as well as physicochemical stability of the NLC. Improved dermal delivery of CoQ10 by ultra-small NLC could be achieved.

Natural microemulsions: Formulation design and skin interaction

Microemulsions are thermodynamically stable, colloidal drug delivery systems. This study presents the first substantiated comparison of natural, skin-compatible and biodegradable surfactants in terms of their suitability to form isotropic microemulsions and their skin interaction. Pseudoternery phase diagrams were constructed for lecithin, sucrose laurate and alkylpolyglycoside as single surfactants. Moreover, also mixed surfactant films of lecithin and alkylpolyglycoside as well as lecithin and sucrose laurate were tested. Large isotropic areas could be identified for lecithin, sucrose laurate and lecithin-sucrose laurate. One defined composition was chosen from the pseudoternery phase diagram, prepared with all investigated surfactants and 1:1 surfactant mixtures, respectively, and analysed for their effect on the stratum corneum on a molecular level by ATR-FTIR. Significantly higher frequency values of the symmetric and asymmetric CH(2)-stretching bands compared to the control were recorded for all microemulsions, indicating a hexagonal arrangement of the lipid chains. A similar trend was observed for the lateral packing of the alkyl chains as suggested by the shift of the CH(2)-scissoring bands. Moreover, diffusion cell experiments using porcine skin were performed with the two model drugs flufenamic acid and fluconazole. In both cases, the lecithin-based microemulsions showed the highest permeation rates followed by the alkylpolyglycoside-lecithin microemulsions.

Validation of the combined ATR-FTIR/tape stripping technique for monitoring the distribution of surfactants in the stratum corneum

The physical presence of surfactants in the skin is linked to their skin irritation potential. Combined ATR-FTIR spectroscopy and tape stripping experiments in vitro on porcine ear skin were used to investigate the spatial distribution of sodium lauryl ether sulfate (SLES) in the stratum corneum and to assess its effects on conformational order of stratum corneum intercellular lipids, secondary structure of keratin and skin hydration. It was possible to monitor the spatial distribution of SLES in the stratum corneum for the first time by subtracting spectra of untreated from treated skin samples and without the need of a perdeuterated form. This method of analysis was evaluated by addressing potential error sources such as differences in removed amounts of corneocytes and intra-individual changes in stratum corneum composition as a function of depth. The obtained results indicate a penetration of SLES into deep layers of the stratum corneum. Furthermore, SLES treatment led to significantly decreased skin hydration levels, whereas the secondary structure of keratin remained nearly unaffected. The reliability of this semi-quantitative method of analysis was confirmed by receiving a coefficient of determination of 0.9963 after making a correlation of deep depended absorbances of two different characteristic bands with different absorption coefficients.

Natural polymer-stabilized multiple water-in-oil-in-water emulsions: a novel dermal drug delivery system for 5-fluorouracil.

The aim of this study was to create multiple water‐in‐oil‐in‐water (W/O/W) emulsions with an increased long‐term stability as skin delivery systems for the hydrophilic model drug 5‐fluorouracil.

Influence of the composition of monoacyl phosphatidylcholine based microemulsions on the dermal delivery of flufenamic acid

Although microemulsions are one of the most promising dermal carrier systems, their clinical use is limited due to their skin irritation potential. Therefore, microemulsions based on naturally derived monoacyl phosphatidylcholine (MAPL) were developed. The influence of the water, oil and surfactant content on dermal delivery of flufenamic acid was systematically investigated for the first time. A water-rich microemulsion led to significantly higher in vitro skin penetration of flufenamic acid compared to other microemulsions. The superiority of the water-rich microemulsion over a marketed flufenamic acid containing formulation was additionally confirmed. Differences in drug delivery could be explained by alterations of the microemulsions after application. Evaporation of isopropanol led to crystal-like structures of MAPL on the skin surface from the surfactant- or oleic acid-rich microemulsions. In contrast, the formation of this additional barrier was hindered in case of the water-rich microemulsion. The skin penetration of MAPL was additionally analyzed by combined ATR-FTIR and tape stripping experiments, where MAPL itself penetrated only into the initial layers of the stratum corneum, independent of the microemulsion composition. Since a surfactant must penetrate the skin to cause irritation, MAPL can be presumed as a skin-friendly emulsifier with the ability to stabilize pharmaceutically acceptable microemulsions.

Effect of monoacyl phosphatidylcholine content on the formation of microemulsions and the dermal delivery of flufenamic acid

The choice of appropriate excipients is crucial for the success of a dermal drug delivery system. Especially surfactants should be chosen carefully, because of their possible interactions with the skin or the applied drug. Since monoacyl phosphatidylcholine (MAPL) exhibits great emulsification properties and can be derived from natural sources, it is of great interest as surfactant in microemulsions. Therefore, the aim of the present study was to investigate the effect of the MAPL content on the formation of microemulsions. The great emulsification power of MAPL was confirmed by increased isotropic areas with increasing MAPL content. Moreover, a decrease in particle size, particle size distribution and viscosity with increasing MAPL content was determined. Besides its effects on microemulsion structure, MAPL exhibited a significant influence on the skin permeation of flufenamic acid. Interestingly, the higher the MAPL content, the lower was the skin permeation of flufenamic acid. A possible explanation might be that the hydrophilic MAPL could hinder the permeation of the lipophilic drug. In contrast, the skin permeation enhancing effects of the microemulsion with the lowest MAPL content might be attributed to formation of a patch-like structure and therefore better contact between the formulation and the skin.

Topical delivery of acetyl hexapeptide-8 from different emulsions: influence of emulsion composition and internal structure.

Acetyl hexapeptide-8 (AH-8) is a well-known component of anti-aging products and was recently explored as a promising topical treatment of blepharospasm. Although AH-8 appears in a variety of cosmetic products, its skin penetration is sparsely studied and controversially discussed. Therefore, the aim of the present study was to investigate the influence of the vehicle type on the AH-8 delivery to the skin. Besides skin permeation experiments with Franz type diffusion cells, the spatial distribution of AH-8 in the stratum corneum after a real in-use application was investigated by in vitro tape stripping on porcine ear skin. By applying LC-MS/MS for quantification of AH-8, we demonstrated that a multiple water-in-oil-in-water (W/O/W) emulsion can significantly increase penetration of AH-8 into porcine skin compared to simple O/W and W/O emulsions. The internal structure of the developed multiple emulsion was confirmed by electron microscopic investigations and NMR self diffusion studies. In general, a clear superiority of water-rich W/O/W and O/W emulsions over an oil-rich W/O emulsion in terms of dermal delivery of AH-8 was found. This enhanced delivery of AH-8 could be explained by an increased absorption of the water-rich emulsions into the skin, confirmed by combined ATR-FTIR and tape stripping experiments.

Corneocyte Quantification by NIR Densitometry and UV/Vis Spectroscopy for Human and Porcine Skin and the Role of Skin Cleaning Procedures

Optical methods of corneocyte quantification during tape stripping experiments on the skin are useful tools for the rapid evaluation of the skin penetration potential of dermally applied substances. However, a comparative investigation of the different methods proposed for this task, namely NIR densitometry and UV/Vis spectroscopy, is still missing. Thus, the aim of the present work was to employ these two techniques in comparative tape stripping experiments both in vivo on human forearm skin and in vitro on porcine ear skin. Standard tape stripping experiments were performed in the absence and presence of a marketed formulation containing flufenamic acid as a model drug. In the context of these methodological investigations, different methods of skin cleaning prior to the tape stripping procedure were evaluated to identify the most appropriate working protocol among the approaches proposed in the respective literature. The results showed that the investigated methods of NIR densitometry and UV/Vis spectroscopy deliver highly comparable results. Both optical methods are suitable to determine the skin penetration profiles of active substances during in vivo and in vitro tape stripping, especially if a simple working protocol without any cleaning procedures is maintained.

Application of Quantitative 19F Nuclear Magnetic Resonance Spectroscopy in Tape-Stripping Experiments with Natural Microemulsions

The skin penetration of flufenamic acid (Fluf) and fluconazole (Fluc) from innovative natural microemulsions was investigated in tape-stripping experiments on pig ears. The formulations were based on the eudermic surfactants lecithin, sucrose laurate, alkylpolyglycoside or a mixture thereof. The quantification of the penetrated drug amounts was executed by (19) F nuclear magnetic resonance (NMR) in comparison with high-performance liquid chromatography (HPLC). The data obtained by the (19) F NMR method were confirmed by additional quantitative studies using HPLC. An excellent linear correlation was found for Fluf as well as for Fluc between (19) F NMR and HPLC data. This work presents a strategy outlining the use of (19) F NMR to selectively monitor the skin penetration routes of fluorinated compounds. Fluc penetrated generally well into the stratum corneum with the significantly highest amounts from the sucrose laurate microemulsion on the tape strips 1-5. Similarly, the highest amounts of penetrated Fluf could be observed from the formulation based on sucrose laurate. In addition, NMR self-diffusion studies were conducted and revealed a bicontinuous microstructure of the investigated microemulsions. The skin penetration results are in good agreement with the obtained (19) F NMR self-diffusion coefficients of the active compounds in the microemulsion systems.

Monitoring the distribution of surfactants in the stratum corneum by combined ATR-FTIR and tape-stripping experiments.

Combined ATR-FTIR (attenuated total reflection-Fourier transform infrared) spectroscopy and tape-stripping experiments in vitro on porcine ear skin were used to investigate the spatial distribution of different surfactants in the stratum corneum (SC). To reveal a possible connection between the size of the formed micelles and skin penetration, dynamic light-scattering measurements of the aqueous surfactant solutions were also taken. Compared to an alkyl polyglycoside and sucrose laurate, a deeper skin penetration of the anionic surfactants sodium dodecyl sulfate (SDS) und sodium lauryl ether sulfate (SLES) could be related to a smaller size of the formed micelles. Beside the differences in spatial distribution, a link between the physical presence of anionic surfactants in the SC and a decrease of skin hydration was found. Furthermore, the incorporation of SDS and SLES into the SC, even after a brief, consumer-orientated washing procedure with commercially available hair shampoos, was confirmed.