Search Results (14)

Background/Objective: This study provided a comparison of the influence of each component of the microemulsion formulation and investigated the impact of varying concentrations of the microemulsion components on curcumin’s ability to penetrate the skin using an ex vivo porcine ear model. Methods: Curcumin microemulsions with different compositions were prepared and analyzed for their physicochemical properties. The dermal penetration efficacy of curcumin was evaluated from the different formulations and compared with non-microemulsion formulations. Results: Findings proved that microemulsion formulations improve the dermal penetration efficacy for curcumin when compared with non-microemulsion formulations. The composition of the microemulsion affects the penetration efficacy of curcumin and increases with decreasing oil content and increasing surfactant and water content. The best penetration for curcumin is achieved with a microemulsion that contained 7.7 g of medium-chain triglycerides as the oil phase, 6.92 g of Tween^® 80 and 62.28 g of ethanol as the surfactant mixture, and 23.1 g water. Conclusions: The present study provides a foundational basis for further development of different microemulsion formulations for enhancing the dermal penetration of poorly water-soluble active compounds. Full article

(1) Background: Ethanol is a multifunctional excipient often used as a preservative in topical formulations. Due to its known ability to impair skin barrier function, this study investigated the effect of ethanol (EtOH) as a preservative in creams on the dermal penetration of active compounds. (2) Methods: A hydrophilic and a lipophilic fluorescent dye were used as active ingredient surrogates that were incorporated into creams with and without ethanol. The dermal penetration efficacy was assessed by epifluorescence microscopy on an ex vivo porcine ear model with intact and irritated skin. (3) Results: Ethanol reduced the dermal penetration by about 40% for the hydrophilic and about 20% for the lipophilic surrogates on intact skin, but had minimal impact on irritated skin. The bio-physical skin properties were also altered by the addition of ethanol to the cream. On intact skin, it increased transepidermal water loss (TEWL) and decreased skin hydration, whereas on irritated skin, it decreased TEWL and increased skin hydration. The results indicate that skin impairment can be considered to have different stages, while in an early stage of skin impairment, the formation of a “Pudding skin” is proposed. A “Pudding skin” is the formation of a thin layer of dried skin on top of the skin that “seals” the lower parts of the skin and reduces dermal penetration and water loss from inside the skin and reduces the dermal penetration of chemical compounds from outside the skin. (4) Conclusions: Overall, the findings emphasize the need to carefully consider the use of ethanol in formulations, balancing its preservative benefits with its potential to impair the efficacy of active ingredients, particularly in varying skin conditions. Full article

Dermal drug delivery presents a significant challenge for poorly soluble active compounds like curcumin, which often struggle to penetrate the skin barrier effectively. In this study, the dermal penetration efficacy of curcumin nanocrystals and bulk suspensions when applied to skin using microneedles of varying lengths—0.25 mm, 0.5 mm, and 1.0 mm—was investigated in an ex vivo porcine ear model. The findings revealed that all formulations, in conjunction with microneedle application, facilitated transepidermal penetration; however, the combination of microneedles and curcumin nanocrystals demonstrated the highest efficacy. Notably, the 1.0 mm microneedle length provided optimal penetration, significantly enhancing curcumin delivery compared with bulk suspensions alone. Additionally, even the use of 0.25 mm microneedles resulted in a high level of efficiency, indicating that shorter microneedles can still effectively facilitate drug delivery. Overall, this study underscores the potential of microneedle technology in improving the transepidermal absorption of poorly soluble actives like curcumin, suggesting that the integration of nanocrystals with microneedles could enhance the therapeutic effects of topical curcumin applications. Full article

The limited water solubility of active compounds remains a significant challenge for efficient dermal drug delivery, particularly for BCS class IV drugs such as curcumin. This study aimed to enhance curcumin’s dermal penetration using two strategies: extracellular vesicles (EVs) and plantCrystals derived from soybeans. EVs were isolated using classical methods. However, plantCrystals containing extracellular vesicles (PCEVs) were formed during the preparation of plantCrystals through bead milling. Curcumin was either added after PCEVs were formed, resulting in curcumin-added PCEVs, or added to the soybean dispersion before bead milling, forming curcumin-loaded PCEVs. The formulations were characterized for their physicochemical properties and assessed for dermal penetration efficacy using quantitative dermatokinetic and semi-quantitative ex vivo porcine ear models. The results indicated that curcumin-loaded PCEVs achieved higher penetration efficacy compared to curcumin-added PCEVs and curcumin-loaded EVs, with approximately 1.5-fold and 2.7-fold increases in penetration efficacy, respectively. Additionally, curcumin-loaded PCEVs showed superior penetration depth, while curcumin from the curcumin-loaded EVs remained in the stratum corneum. These findings suggest that the plantCrystals strategy via bead milling offers a more effective approach than the classical EVs strategy for improving the topical delivery of class IV drugs like curcumin. Full article

Objective: This study aimed to investigate the feasibility of using the digital image processing technique, developed to semi-quantitatively study dermal penetration, to study corneal penetration in an ex vivo porcine eye model. Here, we investigated various formulation strategies intended to enhance dermal and corneal bioavailability of the model hydrophobic drug, curcumin. Methods: Several formulation principles were explored, including oily solutions, oily suspensions, aqueous nanosuspension, micelles, liposomes and cyclodextrins. The dermal penetration efficacy was tested using an ex vivo porcine ear model previously developed at Philipps-Universität Marburg with subsequent digital image processing. This image analysis method was further applied to study corneal penetration using an ex vivo porcine whole-eye model. Results: For dermal penetration, oily solutions, oily suspensions and nanosuspensions exhibited the least penetration, whereas liposomes and cyclodextrins showed enhanced penetration. Corneal curcumin penetration correlated with dermal penetration, with curcumin loaded into cyclodextrins penetrating the deepest. Conclusions: Overall, our study suggests that the image analysis method previously developed for ex vivo skin penetration can easily be repurposed to study corneal penetration of hydrophobic drugs. Full article

In this study, a functional nanostructured lipid carriers (NLCs)-based hydrogel was developed to repair the damaged epidermal skin barrier. NLCs were prepared via a high-energy approach, using argan oil and beeswax as liquid and solid lipids, respectively, and were loaded with ceramides and cholesterol at a physiologically relevant ratio, acting as structural and functional compounds. Employing a series of surfactants and optimizing the preparation conditions, NLCs of 215.5 ± 0.9 nm in size and a negative zeta potential of −42.7 ± 0.9 were obtained, showing acceptable physical and microbial stability. Solid state characterization by differential scanning calorimetry and X-ray powder diffraction revealed the formation of imperfect crystal NLC-type. The optimized NLC dispersion was loaded into the gel based on sodium hyaluronate and xanthan gum. The gels obtained presented a shear thinning and thixotropic behavior, which is suitable for dermal application. Incorporating NLCs enhanced the rheological, viscoelastic, and textural properties of the gel formed while retaining the suitable spreadability required for comfortable application and patient compliance. The NLC-loaded gel presented a noticeable occlusion effect in vitro. It provided 2.8-fold higher skin hydration levels on the ex vivo porcine ear model than the NLC-free gel, showing a potential to repair the damaged epidermal barrier and nourish the skin actively. Full article

The influence of size, particle concentration and applied dose (finite vs. infinite dose) on the dermal penetration efficacy of curcumin was investigated in this study. For this, curcumin suspensions with different particle sizes (approx. 20 µm and approx. 250 nm) were produced in different concentrations (0.625–5% (w/w)). The dermal penetration efficacy was determined semi-quantitatively on the ex vivo porcine ear model. The results demonstrated that the presence of particles increases the dermal penetration efficacy of the active compounds being dissolved in the water phase of the formulation. The reason for this is the formation of an aqueous meniscus that develops between particles and skin due to the partial evaporation of water from the vehicle after topical application. The aqueous meniscus contains dissolved active ingredients, and therefore creates a small local spot with a locally high concentration gradient that leads to improved dermal penetration. The increase in penetration efficacy depends on the number of particles in the vehicle, i.e., higher numbers of particles and longer contact times lead to higher penetration efficacy. Therefore, nanocrystals with a high particle concentration were found to be the most suitable formulation principle for efficient and deep dermal penetration of poorly water-soluble active ingredients. Full article

Hair follicles constitute important drug delivery targets for skin antisepsis since they contain ≈25% of the skin microbiome. Nanoparticles are known to penetrate deeply into hair follicles. By massaging the skin, the follicular penetration process is enhanced based on a ratchet effect. Subsequently, an intrafollicular drug release can be initiated by various trigger mechanisms. Here, we present novel ultraviolet A (UVA)-responsive nanocapsules (NCs) with a size between 400 and 600 nm containing hydroxyethyl starch (HES) functionalized by an o-nitrobenzyl linker. A phase transfer into phosphate-buffered saline (PBS) and ethanol was carried out, during which an aggregation of the particles was observed by means of dynamic light scattering (DLS). The highest stabilization for the target medium ethanol as well as UVA-dependent release of ethanol from the HES-NCs was achieved by adding 0.1% betaine monohydrate. Furthermore, sufficient cytocompatibility of the HES-NCs was demonstrated. On ex vivo porcine ear skin, a strong UVA-induced release of the model drug sulforhodamine 101 (SR101) could be demonstrated after application of the NCs in cyclohexane using laser scanning microscopy. In a final experiment, a microbial reduction comparable to that of an ethanol control was demonstrated on ex vivo porcine ear skin using a novel UVA-LED lamp for triggering the release of ethanol from HES-NCs. Our study provides first indications that an advanced skin antisepsis based on the eradication of intrafollicular microorganisms could be achieved by the topical application of UVA-responsive NCs. Full article

The effective dermal penetration of active ingredients (AI) is a major task in the formulation of topical products. Besides the vehicle, the mechanical skin treatments are also considered to impact the penetration efficacy of AI. In particular, professional skin treatments, i.e., professional cosmetic skin treatments, are considered to be optimal for the dermal delivery of AI. However, a systematic study that proves these theories is not yet available and was therefore performed in this study while utilizing an ex vivo porcine ear model with subsequent digital image analysis. Hydrophilic and lipophilic fluorescent dyes were used as AI surrogates and were applied onto the skin without and with professional skin treatments. The skin hydration and the penetration efficacy were determined, respectively. Results showed that professional skin treatments with massage were able to increase the skin hydration, whereas a professional skin treatment without massage could not increase the skin hydration when compared to skin without professional skin treatment. Regarding the penetration efficacy, it was found that all parameters tested, i.e., type of professional skin treatment, lipophilicity of the AI, and the time point at which the AI are applied onto the skin, can have a tremendous impact on the penetration efficacy of the AI. The most effective penetration and the most effective skin hydration is achieved with a professional skin treatment that includes a professional skin massage. This kind of skin treatment can therefore be used to improve dermal drug delivery. Full article

(1) Background: The study systematically investigated the influence of dispersed particles within a topical formulation on the dermal penetration efficacy of active compounds that are dissolved in the water phase of this formulation. The aim was to prove or disprove if particle-assisted dermal penetration can be used for improved dermal drug delivery. (2) Methods: Fluorescein was used as a surrogate for a hydrophilic active ingredient (AI). It was dissolved in the water phase of different formulations with and without particles. Two different types of particles (titanium dioxide and nanostructured lipid carriers (NLC)) were used. The influence of particle size and number of particles and the influence of skin hydrating excipients was also investigated. (3) Results demonstrate that the addition of particles can strongly increase the dermal penetration efficacy of AI. The effect depends on the size of the particles and the number of particles in the formulation, where smaller sizes and higher numbers resulted in higher penetration parameters. Formulations with NLC that contained 20% w/w or 40% w/w particles resulted in an about 2-fold higher amount of penetrated AI and increased the penetration depth about 2.5-fold. The penetration-enhancing effect was highly significant (p < 0.001) and allowed for an efficient delivery of the AI in the viable dermis. In contrast, the penetration-enhancing effect of excipients that increase the skin hydration was found to be very limited and not significant (≤5%, p > 0.05). (4) Conclusions: Based on the results, it can be concluded that particle-assisted dermal penetration can be considered to be a simple but highly efficient and industrially feasible formulation principle for improved and tailor-made dermal drug delivery of active compounds. Full article

(1) Background: The ex vivo porcine ear model is often used for the determination of the dermal penetration efficacy of chemical compounds. This study investigated the influence of the post-slaughter storage time of porcine ears on the dermal penetration efficacy of chemical compounds. (2) Methods: Six different formulations (curcumin and different fluorescent dyes in different vehicles and/or nanocarriers) were tested on ears that were (i) freshly obtained, (ii) stored for 24 or 48 h at 4 °C after slaughter before use and (iii) freshly frozen and defrosted 12 h before use. (3) Results: Results showed that porcine ears undergo post-mortem changes. The changes can be linked to rigor mortis and all other well-described phenomena that occur with carcasses after slaughter. The post-mortem changes modify the skin properties of the ears and affect the penetration efficacy. The onset of rigor mortis causes a decrease in the water-holding capacity of the ears, which leads to reduced penetration of chemical compounds. The water-holding capacity increases once the rigor is released and results in an increased penetration efficacy for chemical compounds. Despite different absolute penetration values, no differences in the ranking of penetration efficacies between the different formulations were observed between the differently aged ears. (4) Conclusions: All different types of ears can be regarded to be suitable for dermal penetration testing of chemical compounds. The transepidermal water loss (TEWL) and/or skin hydration of the ears were not correlated with the ex vivo penetration efficacy because both an impaired skin barrier and rigor mortis cause elevated skin hydration and TEWL values but an opposite penetration efficacy. Other additional values (for example, pH and/or autofluorescence of the skin) should, therefore, be used to select suitable and non-suitable skin areas for ex vivo penetration testing. Finally, data from this study confirmed that smartFilms and nanostructured lipid carriers (NLC) represent superior formulation strategies for efficient dermal and transdermal delivery of curcumin. Full article

Enterotoxigenic Escherichia coli (ETEC) infections have been identified as a major cause of acute diarrhoea in children in developing countries, associated with substantial morbidity and mortality rates. Additionally, ETEC remains the most common cause of acute diarrhea of international travellers to endemic areas. The heat-labile toxin (LT) is a major virulence factor of ETEC, with a significant correlation between the presence of antibodies against LT and protection in infected patients. In the present work, we constructed a recombinant LTB unit (rLTB) and studied the capacity of this toxoid incorporated in microneedles (rLTB-MN) to induce a specific immune response in mice. MN were prepared from aqueous blends of the polymer Gantrez AN^® [poly (methyl vinyl ether-co-maleic anhydride)], which is not cytotoxic and has been shown to possess immunoadjuvant properties. The mechanical and dissolution properties of rLTB-MNs were evaluated in an in vitro Parafilm M^® model and in mice and pig skin ex vivo models. The needle insertion ranged between 378 µm and 504 µm in Parafilm layers, and MNs fully dissolved within 15 min of application inside porcine skin. Moreover, female and male BALB/c mice were immunized through ear skin with one single dose of 5 μg·rLTB in MNs, eliciting significant fecal anti-LT IgA antibodies, higher in female than in male mice. Moreover, we observed an enhanced production of IL-17A by spleen cells in the immunized female mice, indicating a mucosal non-inflammatory and neutralizing mediated response. Further experiments will now be required to validate the protective capacity of this new rLTB-MN formulation against this deadly non-vaccine-preventable disease. Full article

During the last decade, many studies have been reported on the design and formulation of novel drug delivery systems proposed for dermal or transdermal administration. The efforts focus on the development of biocompatible nanodispersions that can be delivered to the skin and treat severe skin disorders, including cancer. In this context, oil-in-water (O/W) microemulsions have been developed to encapsulate and deliver lipophilic bioactive molecules for dermal application. An O/W biocompatible microemulsion composed of PBS buffer, Tween 80, and triacetin was assessed for its efficacy as a drug carrier of DPS-2, a lead compound, initially designed in-house to inhibit BRAF^V600E oncogenic kinase. The system was evaluated through both in vitro and ex vivo approaches. The cytotoxic effect, in the presence and absence of DPS-2, was examined through the thiazolyl blue tetrazolium bromide (MTT) cell proliferation assay using various cell lines. Further investigation through Western blotting revealed that cells died of necrosis. Porcine ear skin was used as a skin model to evaluate the degree of permeation of DPS-2 through skin and assess its retention. Through the ex vivo experiments, it was clarified that encapsulated DPS-2 was distributed within the full thickness of the stratum corneum (SC) and had a high affinity to hair follicles. Full article

Anthocyanins are natural colorants with antioxidant properties, shown to inhibit photoaging reactions and reduce symptoms of some skin diseases. However, little is known about their penetration through the stratum corneum, a prerequisite for bioactivity. The aim was to investigate anthocyanin penetration from lipophilic cosmetic formulations through the skin using a porcine ear model and human volunteers. ATR-FTIR/PLS regression and HPLC-PDA-MS were used to analyze anthocyanin permeation through the stratum corneum. Penetration of all anthocyanins was evident and correlated with molecular weight and hydrophilicity. Lower-molecular-weight (MW) anthocyanins from elderberry (449–581 Da) were more permeable within the skin in both ex vivo and in vivo models (K_p = 2.3–2.4 × 10⁻⁴ cm h⁻¹) than the larger anthocyanins (933-1019 Da) from red radish (K_p = 2.0–2.1 × 10⁻⁴ cm h⁻¹). Elderberry and red radish anthocyanins were found at all levels of the stratum corneum and at depths for activity as bioactive ingredients for skin health. Full article