Abstract:
In dermal drug delivery studies, approaches and technologies have recently been advanced to enhance drug penetration through the skin, with chemical enhancers being the most widely used as the simplest strategy. Within their uses, polyoxyethylated (PEGylated) emulsifiers are focused on in this thesis as an interesting class of nonionic emulsifiers. It aims to determine their exact role in transporting drugs and their mechanism of action in skin layers to interact with the skin components. Herein, the disordered and loose state of stratum corneum (SC) lipids are used as indicators of emulsifiers’ penetration and lipids’ extraction during the washing process. The analyses were conducted with confocal Raman spectroscopy (CRS) as a label-free, non-invasive and time-efficient instrument to exploit multiple functions for the needs. Different instrumental configurations were evaluated to achieve optimal performance in skin analyses.
Characteristic CRS signals were determined to evaluate lipid properties and obtain the most selective and sensitive parameters for differentiating different samples applied to the skins. Analyses were performed between water and sodium lauryl sulfate (SLS)-treated skin samples regarding lipid content, SC thickness, and lipid molecular structure properties. It was found that the spectral signals in the fingerprint region were more sensitive than those in the high wavenumber (HWN) region. This initial study in this thesis filtered out more effective spectral features for skin analysis and formed the basis for subsequent studies (Chapter 3).
Suitable spectral signals were then selected to analyze the effects of PEGylated emulsifiers with different hydrophilic and lipophilic chain lengths and degrees of saturation on skin samples. The SC lipid content and organizational changes were examined to study the potential rules of disruptions of SC lipids by the studied emulsifiers. The results indicated that the hydrophilic chain lengths played an important role in governing the ability of applied emulsifiers to interact with the SC components. This led to a deeper investigation concerning PEGylated emulsifiers with a longer hydrophilic chain. The results could also help find suitable emulsifiers for formulation development (Chapter 4).
Another investigation was carried out to verify the effects of PEGylated emulsifiers on the skin. Heavy water (D2O) was used as a probe. The distribution of D2O was tracked using CRS. Simultaneously, the emulsifiers’ effects on skin lipid content, lipid organization, relative water content, and hydrogen bonding structure were monitored. The obtained results reflected the higher penetration ability of PEG-20 ethers in skin. The penetration of D2Owas also enhanced. This study verified the increased barrier disruption of PEGylated emulsifiers with longer hydrophilic chains. It demonstrated the possibility of using D2O as an appropriate probe to evaluate the skin barrier function (Chapter 5).
Following the study, the extended hydrophilic chain length of PEGylated emulsifiers was investigated. The SC thickness was used to reflect the reduced and loosened structure of SC components. In parallel, the configurations of CRS, including different objectives and pinhole sizes, were optimized. The results revealed the limit of oxyethylene groups of around 40 to cause lower interruptions of the SC lipids, which may help to reveal possible mechanisms that determine the interactions between emulsifiers and skin. Meanwhile, the combination of water immersion objective and 50 μm pinhole was the optimal CRS configuration for obtaining more precise data on SC thickness (Chapter 6).
To determine the role of PEGylated emulsifiers as penetration enhancers, fluorescein sodium salt (Fluo-Na) and procaine HCl were used separately as model drugs. The penetration enhancement efficacy was investigated using the conventional tape-stripping method and CRS. The results showed that the penetration performances were generally correlated, making CRS a powerful alternative for evaluating dermal drug delivery. Moreover, the penetration-enhancing effect of PEGylated emulsifiers has been associated with the disruption of SC components, suggesting the underlying mechanism of drug penetration (Chapter 7).
The final part of the thesis aims to gain a deeper insight into the interactions between emulsifiers and SC. Mixtures of PEGylated emulsifiers were investigated from the aspects of SC molecular properties and penetration enhancement. Simultaneously, different CRS laser wavelengths were used to evaluate their suitability and applicability in systematic SC analyses. The results showed that the mixed emulsifier systems had the potential to reduce their interaction with SC. This was also related to the CMC (critical micelle concentration) values, suggesting that the monomers present were the main cause of enhancing drug penetration and triggering skin disruption. Meanwhile, both 532 nm and 785 nm lasers were suitable for skin analyses. Benefits and pitfalls were addressed to allow selection based on different experimental needs (Chapter 8).
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