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Background: In the dose titration of transdermal fentanyl to prevent unrelieved pain, it is important to consider not only dose adjustment, but also the titration period, which is influenced by the time required to reach the steady state. Many patients with cancer pain experience comorbidities that might affect the skin properties and influence transdermal absorption. We hypothesized that skin changes due to diabetes mellitus (DM) would affect the titration period of transdermal fentanyl. We conducted a retrospective study and diabetic animal model study to test this hypothesis. Methods: In the retrospective study, the titration period was defined in terms of "dose change" and "number of rescue opioids" in patients initiated on transdermal fentanyl. Multiple logistic regression analysis was performed to analyze the relation between the titration period and comorbidities, including DM. In the diabetic animal model study, intercellular lipids of stratum corneum (SC) were analyzed in Goto-Kakizaki (GK) rats, a model of DM, and the pharmacokinetics of intravenously or transdermally administered fentanyl was examined. Results: In the retrospective study, the titration period ranged from 5 to 39 days (n = 387), and the patients taking a longer period (6 days or more) was significantly related to in patients with unspecified DM: AOR (95% confidence interval), 0.438 (0.217–0.884). In the diabetic animal model study, the ceramides (CERs) content in the SC was decreased by approximately 30% in GK rats compared to Wistar rats. The absorption rate constant (ka) of fentanyl administered transdermally was increased approximately 1.4-fold in GK rats, though there was no difference in transdermal bioavailability (F) or systemic clearance (CLtot). Conclusion: Our results suggest that the steady state of transdermally administered fentanyl is reached sooner in cancer patients with DM as a comorbidity. Earlier pain assessment and dose adjustment may be possible in these patients. [ABSTRACT FROM AUTHOR]

Background: Topical use of dexpanthenol presents well‐established moisturizing properties and maintenance and repair of the skin barrier function, however, its exact action mechanisms are not completely elucidated. In this context, Confocal Raman Microspectroscopy is an optical method that enables non‐invasive and non‐destructive in vivo analysis with the sensitive acquisition of molecular changes in different skin layers. Herein, the aim was to evaluate the effects of topical dexpanthenol on the components and physiological parameters of the stratum corneum (SC). Materials and methods: Ten healthy female subjects underwent skin evaluation by means of a Confocal Raman Spectrometer Skin Analyzer 3510. Spectral data were obtained from the skin of the anterior forearm region, before and 2 h after applying a cosmetic formulation containing or not containing 5% dexpanthenol. Results: Semiquantitative analysis of the natural moisturizing factor showed a significant decrease in content after 2 h of topical dexpanthenol application, while the analysis of the lamellar organization of intercellular lipids and the secondary structure of keratin showed a significant increase in hexagonal organization of lipids at the first half of the SC and a significant increase in β‐pleated sheet conformation of keratin. Conclusion: Effects of topical dexpanthenol on SC suggest a contribution in increasing fluidity of both lipidic and protein components of the SC and are compatible with dexpanthenol activity in maintaining adequate physiological conditions and preventing transepidermal water loss. This study also contributes to the elucidation of action mechanisms and other concurrent biochemical processes. [ABSTRACT FROM AUTHOR]

Imaging-based evaluation of lipids in the stratum corneum by label-free stimulated Raman scattering microscopy Keywords: barrier; intercellular lipids; label-free; noninvasive; stimulated Raman scattering microscopy; stratum corneum EN barrier intercellular lipids label-free noninvasive stimulated Raman scattering microscopy stratum corneum 1 5 5 06/28/23 20230601 NES 230601 B Dear Editor, b The stratum corneum (SC) plays an important role as a barrier against the external environment. White bars represent skin without acetone treatment, and black bars represent skin with acetone treatment. As we reported previously,[9] cell morphology in the SC could be visualized by using SRS microscopy, and polygonal cells were observed in the SC (dashed lines in Figure 1(B)). [Extracted from the article]

The physical barrier of the stratum corneum (SC) is provided by corneocytes and the lateral organization of intercellular lipids, which necessarily includes the orthorhombic organization phase. A review of methods used for in vivo non-invasive measurement of skin barrier function has been carried out and it has been shown that all currently used methods are indirect. The most popular method is the measurement of the transepidermal water loss (TEWL), which does not provide information on biophysical parameters responsible for the barrier function of the SC. It has been shown that confocal Raman microspectroscopy is the most suitable non-invasive method to determine the depth profile of the lateral organization of intercellular lipids, i.e. to study the skin barrier function in vivo.

Abstract Spectral signals of stratum corneum (SC) acquired from confocal Raman spectroscopy (CRS) are employed to track lipid variations and the most sensitive and efficient signals are of high interest. Herein, 1% of sodium lauryl sulfate treated SC was compared to water‐treated one to evaluate statistical difference of spectral signals concerning lipid content, SC thickness and lipid molecular structures. Results showed that peak ratio of 1425 to 1490 cm−1 and 1630 to 1710 cm−1 in fingerprint region and Gaussian‐function deconvoluted lipid‐keratin peak ratio in high wavenumber (HWN) region were both responsive for analyzing lipid content. SC thickness measurement using the full width of half‐maximum (FWHM) of 2920 to 2960 cm−1 signal presented good sensitivity. Nevertheless, the shift of peak 2850 cm−1 indicated less sensitivity compared to trans‐gauche peak signals and 1300 cm−1 peak position for lipid conformation analysis. Meanwhile, the ratio of peak 2880 and 2850 cm−1 indicating lipid lateral packing structure presented to be less responsive. More strikingly, FWHM of peak 2850 cm−1 appeared to be unable for lipid lateral packing order analysis in our study. In summary, this research can serve as a pilot study for further investigation of direct drug delivery and interaction between topical applied compounds and skin components.

Spectral signals of stratum corneum (SC) acquired from confocal Raman spectroscopy (CRS) are employed to track lipid variations and the most sensitive and efficient signals are of high interest. Herein, 1% of sodium lauryl sulfate treated SC was compared to water‐treated one to evaluate statistical difference of spectral signals concerning lipid content, SC thickness and lipid molecular structures. Results showed that peak ratio of 1425 to 1490 cm−1 and 1630 to 1710 cm−1 in fingerprint region and Gaussian‐function deconvoluted lipid‐keratin peak ratio in high wavenumber (HWN) region were both responsive for analyzing lipid content. SC thickness measurement using the full width of half‐maximum (FWHM) of 2920 to 2960 cm−1 signal presented good sensitivity. Nevertheless, the shift of peak 2850 cm−1 indicated less sensitivity compared to trans‐gauche peak signals and 1300 cm−1 peak position for lipid conformation analysis. Meanwhile, the ratio of peak 2880 and 2850 cm−1 indicating lipid lateral packing structure presented to be less responsive. More strikingly, FWHM of peak 2850 cm−1 appeared to be unable for lipid lateral packing order analysis in our study. In summary, this research can serve as a pilot study for further investigation of direct drug delivery and interaction between topical applied compounds and skin components. [ABSTRACT FROM AUTHOR]

Non-ionic emulsifiers are commonly found in existing pharmaceutical and cosmetic formulations and have been widely employed to enhance the penetration and permeation of active ingredients into the skin. With the potential of disrupting skin barrier function and increasing fluidity of stratum corneum (SC) lipids, we herein examined the effects of two kinds of non-ionic emulsifiers on intercellular lipids of skin, using confocal Raman spectroscopy (CRS) with lipid signals on skin CRS spectrum. Non-ionic emulsifiers of polyethylene glycol alkyl ethers and sorbitan fatty acid esters were studied to obtain a deep understanding of the mechanism between non-ionic emulsifiers and SC lipids. Emulsifier solutions and dispersions were prepared and applied onto excised porcine skin. Water and sodium laureth sulfate solution (SLS) served as controls. SC lipid signals were analysed by CRS regarding lipid content, conformation and lateral packing order. Polyethylene glycol (PEG) sorbitan esters revealed no alteration of intercellular lipid properties while PEG-20 ethers appeared to have the most significant effects on reducing lipid content and interrupting lipid organization. In general, the polyoxyethylene chain and alkyl chain of PEG derivative emulsifiers might indicate their ability of interaction with SC components. HLB values remained critical for complete explanation of emulsifier effects on skin lipids. With this study, it is possible to characterize the molecular effects of non-ionic emulsifiers on skin lipids and further deepen the understanding of enhancing substance penetration with reduced skin barrier properties and increased lipid fluidity.

Studies have shown that liquid crystals structurally resembling the intercellular lipids in the stratum corneum can beneficially affect the skin when applied topically by stimulating the skin’s natural regenerative functions and accelerating epidermal turnover. In the present study, the effects of applying low concentrations of a liquid crystal gel of our own creation were evaluated using epidermal thickening in mouse skin as an assay for effective stimulation of epidermal turnover. A liquid crystal gel was also applied topically to human facial skin, and analysis was conducted using before-and-after photographs of age spots, measurements of L* values that reflect degree of skin pigmentation, single-layer samples of the stratum corneum obtained via tape-stripping, and measurements of trans-epidermal water loss that reflect the status of the skin’s barrier function. The results suggested that cost-effective creams containing as low as 5% liquid crystal gel might be effective and safely sold as skin care products targeting age spots and other problems relating to uneven skin pigmentation.

Ethanol (EtOH) is one of the bases in topically applied medicines that promote the skin permeation of drugs. Although the effects of EtOH have been attributed to structural modifications in the stratum corneum, the underlying mechanisms, especially the influence of different concentrations of EtOH, have not been examined extensively. Structural modifications in the stratum corneum of hairless mouse due to the application of EtOH/water mixture were herein investigated at the molecular level using synchrotron X-ray diffraction. The results revealed that all EtOH concentrations examined greatly modified the short lamellar structures containing the aqueous layer in intercellular lipids and the structure of keratin fibrils in corneocytes, which can take up hydrophilic compounds. However, the long lamellar and the hydrocarbon-chain packing structures were unaffected by EtOH. Changes to the short lamellar structures were not proportional to the concentration of EtOH. However, the keratin fibril structures changed gradually with increasing EtOH concentration. The X-ray diffraction experiments enabled the effects of different EtOH concentrations on the morphology of the stratum corneum to be assessed by using a number of experimental samples to avoid variations due to individual differences. The results indicated that alterations to the short lamellar structures appeared to be related to the skin permeability of drugs with the application of EtOH/water mixture, and monotonous structural changes in the keratin fibrils with an increase in EtOH concentration may contribute to this permeation as supplement. These results will be useful for the development of new drug formulations containing EtOH. [ABSTRACT FROM AUTHOR]

Stratum corneum intercellular lipids play an important role in skin barrier function and are therefore considered useful in pharmaceutical and cosmetics products. In this study, we formulated cholesterol (Cho), the main component of intercellular lipids, into bicelles using a semi-spontaneous method, with the ultimate aim of extending the utility of bicelles in cosmetics. Bicelles are disk-shaped structures in which the planar part comprises long-chain phospholipids and the rims comprise short-chain phospholipids. We used soybean lecithin (SL) and nonionic surfactants (NS) to formulate Cho into bicelles using a semi-spontaneous method. Cho was successfully formulated into bicelles using poly(oxyethylene) cholesteryl ether (with an average of 10 ethylene oxide units, ChEO 10) as the NS. We identified the boundaries of the bicelle region in the SL-Cho-ChEO 10 system by measuring particle sizes. A bicelle region was formed up to around a maximum mixing ratio of 10wt% Cho, representing a mole fraction (mol%) of approximately 33. Phase changes in the system were observed. Comparison of poly(oxyethylene) cholesteryl ethers containing an average of 10 or 20 (ChEO 20) ethylene oxide units revealed that the size of the hydrophilic group affects both the bicelle formation region and the mixing ratio of Cho. We analyzed the state of the SL-Cho-ChEO 10 bicelles by differential scanning calorimetry and found that samples containing only phospholipid (SL/Ch/ChEO 10 = 1/0/0) provided an endothermic peak between 50 and 55 °C, corresponding to the gel-liquid crystal transition point of the phospholipid. In contrast, the bicelle regions (SL/Cho/ChEO 10 = 0.4/0/0.6 and 0.37/0.05/0.58) lacked a gel liquid crystal transition point and a liquid-ordered state was induced by Cho or ChEO 10. This indicates that these bicelles are highly stable towards thermal changes. [ABSTRACT FROM AUTHOR]