Combining protection with skin health: In vivo studies of an innovative gelatin/tannic acid-based hydrogel patch to prevent PPE-related skin lesions.

The prolonged use of Personal Protective Equipment (PPE) can lead to skin problems due to persistent pressure, friction, and tension. This issue has prompted the exploration of solutions to protect the skin while maintaining the effectiveness of the PPE. This study aimed to evaluate the in vivo effectiveness of a gelatin/tannic acid-based hydrogel patch positioned beneath a mask to alleviate skin damage resulting from mask-wearing. To understand the pressure exerted by PPE, in vitro tests were conducted to measure the tensile strength of three types of facial masks. The FFP2 masks exhibited the highest tensile strength and were selected for subsequent in vivo biometric investigations. Biometric parameters were evaluated using the Flir E50bx® thermographic camera, Corneometer®, MoistureMap®, Sebumeter®, Tewameter®, and VISIA® systems. The results showed that when the hydrogel patch was used under the mask, there were no significant differences in facial skin temperature, sebum levels, or TEWL values (p > 0.05). However, a statistically significant increase in skin hydration and a decrease in frontal redness (p < 0.05) were observed. Consumer acceptance was assessed through sensory analysis questionnaires. In summary, the observed attenuation of physiological changes in the facial area and the positive consumer feedback suggest that this polymeric film-forming system is a simple yet effective solution to prevent PPE use-related skin issues.

Prevention of skin lesions caused by the use of protective face masks by an innovative gelatin-based hydrogel patch: Design and in vitro studies.

The recent Covid-19 pandemics led to the increased use of facial masks, which can cause skin lesions due to continuous pressure, tension and friction forces on the skin. A preventive approach is the inclusion of dressings between the face and the mask. However, there are still uncertainties about the protective effect of dressings and whether their use compromises the efficiency of masks. The current study aimed to develop and test the efficacy of a gelatin-based hydrogel patch to be placed between the mask and the facial area. Design of Experiment with a Quality by Design approach tools were used in the patch development and in vitro characterization was performed through rheological evaluation, ATR-FTIR and molecular docking studies. Furthermore, tribology studies were performed to test the patch performance. The results showed that the addition of excipients enhanced gelation temperature, elasticity and adhesiveness parameters. The interactions between excipients were confirmed by ATR-FTIR and molecular docking. The tribology assay revealed similar friction values at room and physiological temperature, and when testing different skin types. In conclusion, the physical properties and the performance evaluation reported in this study indicate that this innovative film-forming system can be used to prevent skin lesions caused by the continuous use of protective masks.

Towards the personalization of gelatin-based 3D patches: a tunable porous carrier for topical applications.

Cell-free based therapies, for example, the use of the cell secretome, have emerged as a promising alternative to conventional skin therapies using bioactive and, when combined with 3D printing technologies, allow the development of personalized dosage forms. This research work aimed to develop gelatin-based patches with controlled network topology via extrusion 3D printing, loaded with cell culture medium as a model of the secretome, and applicable as vehicles for topical delivery. Inks were optimized through rheological and printing assays, and the incorporation of medium had minor effects in printability. Regarding network topology, grid infills rendered more defined structures than the triangular layout, depicting clearer pores and pore area consistency. Release studies showed that filament spacing and infill pattern influenced the release of rhodamine B (model bioactive) and bovine serum albumin (model protein). Moreover, the grid patches (G-0.7/1/0.7), despite having around a seven-fold higher mean pore area than 0.7-mm triangular ones (T-0.7), showed a similar release profile, which can be linked to the network topology of the printed structures This work provided insight on employing (bio)printing in the production of carriers with reproducible and controlled pore area, able to incorporate cell-derived secretome and to be quickly tailored to the patient's lesions.

The regulatory challenges of innovative customized combination products.

Background/aims: Combination products are therapeutic and/or diagnostic products that can combine drugs and medical devices and which increasing complexity has raised new regulatory framework challenges. To reach the market, a combination product must be classified based on the principal mode of action (PMOA). However, research and technological progress has been leading to the development of novel combination products with no clearly defined PMOA, emphasizing the lack of a systematization process, thus challenging the correct classification of these products. To illustrate the regulatory challenge, two case studies are discussed: innovative combination products with PMOA that can change due to an external stimulus, specifically custom-made 3D-printed scaffolds with incorporated medicinal substances. Methods: Data was collected through computational search engines, regulatory agencies and equally relevant associations. The analysis of the data resulted on this state-of-the-art review, a description of the decision-making process by the regulatory authorities, and case studies analysis that culminated in the proposal of a decision-tree scheme. Findings: Current regulations do not fully address complex combination products namely personalized 3D-printed scaffolds. Two merged regulatory approaches are suggested along with the schematization of the rational assisted by a decision-tree tool. Conclusion: Combination products have become increasingly sophisticated, which has furthered the need to develop multidisciplinary collaborations within the health sector to adapt to these innovative healthcare solutions as well as with regulators to overcome the challenges posed for their classification.

Correction: Martins et al. Cannabis-Based Products for the Treatment of Skin Inflammatory Diseases: A Timely Review. Pharmaceuticals 2022, 15, 210.

The authors would like to make the following corrections about the published paper [...].

Chemical Characterization and Bioactivity of Commercial Essential Oils and Hydrolates Obtained from Portuguese Forest Logging and Thinning.

Essential oils (EOs) and hydrolates (Hds) are natural sources of biologically active ingredients with broad applications in the cosmetic industry. In this study, nationally produced (mainland Portugal and Azores archipelago) EOs (11) and Hds (7) obtained from forest logging and thinning of Eucalyptus globulus, Pinus pinaster, Pinus pinea and Cryptomeria japonica, were chemically evaluated, and their bioactivity and sensorial properties were assessed. EOs and Hd volatiles (HdVs) were analyzed by GC-FID and GC-MS. 1,8-Cineole was dominant in E. globulus EOs and HdVs, and α- and ß-pinene in P. pinaster EOs. Limonene and α-pinene led in P. pinea and C. japonica EOs, respectively. P. pinaster and C. japonica HVs were dominated by α-terpineol and terpinen-4-ol, respectively. The antioxidant activity was determined by DPPH, ORAC and ROS. C. japonica EO showed the highest antioxidant activity, whereas one of the E. globulus EOs showed the lowest. Antimicrobial activity results revealed different levels of efficacy for Eucalyptus and Pinus EOs while C. japonica EO showed no antimicrobial activity against the selected strains. The perception and applicability of emulsions with 0.5% of EOs were evaluated through an in vivo sensory study. C. japonica emulsion, which has a fresh and earthy odour, was chosen as the most pleasant fragrance (60%), followed by P. pinea emulsion (53%). In summary, some of the studied EOs and Hds showed antioxidant and antimicrobial activities and they are possible candidates to address the consumers demand for more sustainable and responsibly sourced ingredients.

Cannabis-Based Products for the Treatment of Skin Inflammatory Diseases: A Timely Review.

The use of natural products in dermatology is increasingly being pursued due to sustainability and ecological issues, and as a possible way to improve the therapeutic outcome of chronic skin diseases, relieving the burden for both patients and healthcare systems. The legalization of cannabis by a growing number of countries has opened the way for researching the use of cannabinoids in therapeutic topical formulations. Cannabinoids are a diverse class of pharmacologically active compounds produced by Cannabis sativa (phytocannabinoids) and similar molecules (endocannabinoids, synthetic cannabinoids). Humans possess an endocannabinoid system involved in the regulation of several physiological processes, which includes naturally-produced endocannabinoids, and proteins involved in their transport, synthesis and degradation. The modulation of the endocannabinoid system is a promising therapeutic target for multiple diseases, including vascular, mental and neurodegenerative disorders. However, due to the complex nature of this system and its crosstalk with other biological systems, the development of novel target drugs is an ongoing challenging task. The discovery of a skin endocannabinoid system and its role in maintaining skin homeostasis, alongside the anti-inflammatory actions of cannabinoids, has raised interest in their use for the treatment of skin inflammatory diseases, which is the focus of this review. Oral treatments are only effective at high doses, having considerable adverse effects; thus, research into plant-based or synthetic cannabinoids that can be incorporated into high-quality, safe topical products for the treatment of inflammatory skin conditions is timely. Previous studies revealed that such products are usually well tolerated and showed promising results for example in the treatment of atopic dermatitis, psoriasis, and contact dermatitis. However, further controlled human clinical trials are needed to fully unravel the potential of these compounds, and the possible side effects associated with their topical use.

On the progress of hydrogel-based 3D printing: Correlating rheological properties with printing behaviour.

One of the exciting future directions in the 3D printing field is the development of innovative personalized smart constructions for bio-applications, including drug delivery, namely high-throughput drug screening and customized topical/oral administration of pharmaceuticals, as well as tissue engineering. In this context, hydrogels have emerged as a promising material that, when combined with extrusion 3D printing, allow the creation of soft-material structures with defined spatial locations, that can be printed at room temperature and customized by tuning the geometric design and/or the formulation components. Thus, the efficacy and quality of such vehicles is dependent on formulation, design, and printing process parameters. However, hydrogel inks are often designed and characterized using different methods and this lack of uniformity impairs. Characterization techniques are usually arbitrary and differ among research groups, challenging the inference of possible conclusions on hydrogel behaviour and potential applications. Therefore, to properly analyse the potential of a particular hydrogel ink formulation, we review, for the first time, the most frequently employed characterization procedures, from rheological approaches to printing parameters and settings, and discuss their relevance, limitations and drawbacks, and highlight future perspectives. Overall, to accelerate the development of high-quality 3D constructs, comprehensive characterization protocols for both pre-printing and printing assays should be adopted. Furthermore, their transversal adoption could serve as a boost in terms of quality requirements and regulatory aspects.

Diving into 3D (bio)printing: A revolutionary tool to customize the production of drug and cell-based systems for skin delivery.

The incorporation of 3D printing technologies in the pharmaceutical industry can revolutionize its R&D, by providing a simple and rapid method to produce tailored one-off batches, each with customized dosages, different compounds, shapes, sizes, and adjusted release rates. Particularly, this type of technology can be advantageous for the development of topical and transdermal drug delivery systems, including patches and microneedles. The use of both systems as drug carriers offers advantages over the oral administration, but the possibility of skin irritation and sensitization, and the high production costs, may hinder the expansion of this market. In this context, 3D printing, a high-resolution technique, allows the design of high quality, personalized, complex and sophisticated structures, thus reducing the production costs and improving the patient compliance. This review covers the 3D printing concept and discusses the relevance of this technology to the pharmaceutical industry, with a special focus on the development of topical and transdermal products - patches and microneedles. The potential of 3D bioprinting for skin applications is also presented, highlighting the development of patch-like skin constructs for wound and burn treatment, and skin equivalents for in vitro research and drug development. Several recent studies were selected to support the relevance of the subjects addressed herein. Additionally, the limitations of these printing technologies are discussed, including regulatory, quality and safety issues.

Effects of Starch Incorporation on the Physicochemical Properties and Release Kinetics of Alginate-Based 3D Hydrogel Patches for Topical Delivery.

The development of printable hydrogel inks for extrusion-based 3D printing is opening new possibilities to the production of new and/or improved pharmaceutical forms, specifically for topical application. Alginate and starch are natural polysaccharides that have been extensively exploited due to their biocompatibility, biodegradability, viscosity properties, low toxicity, and relatively low cost. This research work aimed to study the physicochemical and release kinetic effects of starch incorporation in alginate-based 3D hydrogel patches for topical delivery using a quality by design approach. The incorporation of a pregelatinized starch is also proposed as a way to improve the properties of the drug delivery system while maintaining the desired quality characteristics. Critical material attributes and process parameters were identified, and the sensitivity and adequacy of each parameter were statistically analyzed. The impact of alginate, starch, and CaCl2·2H2O amounts on relevant quality attributes was estimated crosswise. The amount of starch revealed a synergetic impact on porosity (p = 0.0021). An evident increase in the size and quantity of open pores were detected in the as printed patches as well as after crosslinking (15.6 ± 5.2 µm). In vitro drug release studies from the optimized alginate-starch 3D hydrogel patch, using the probe Rhodamine B, showed an initial high burst release, followed by a controlled release mechanism. The results obtained also showed that the viscoelastic properties, printing accuracy, gelation time, microstructure, and release rates can be modulated by varying the amount of starch added to the system. Furthermore, these results can be considered an excellent baseline for future drug release modulation strategies.

The Brain-Skin Connection and the Pathogenesis of Psoriasis: A Review with a Focus on the Serotonergic System.

Psoriasis is a common non-communicable chronic immune-mediated skin disease, affecting approximately 125 million people in the world. Its pathogenesis results from a combination of genetic and environmental factors. The pathogenesis of psoriasis seems to be driven by the interaction between innate immune cells, adaptive immune cells and keratinocytes, in a process mediated by cytokines (including interleukins (IL)-6, IL-17 and IL-22, interferon and tumor necrosis factor) and other signaling molecules. This leads to an inflammatory process with increased proliferation of epidermal cells, neo-angiogenesis and infiltration of dendritic cells in the skin. Dysfunctional de novo glucocorticoid synthesis in psoriatic keratinocytes and the skin microbiome have also been suggested as mediators in the pathogenesis of this disease. To understand psoriasis, it is essential to comprehend the processes underlying the skin immunity and neuroendocrinology. This review paper focuses on the skin as a neuroendocrine organ and summarizes what is known about the skin immune system, the brain-skin connection and the role played by the serotonergic system in skin. Subsequently, the alterations of neuroimmune processes and of the serotonergic system in psoriatic skin are discussed, as well as, briefly, the genetic basis of psoriasis.

Improved Morphine-Loaded Hydrogels for Wound-Related Pain Relief.

The use of morphine applied topically to painful wounds has potential advantages, such as dose reduction, fewer side effects and compound formulations, have been proposed for this purpose. Given the potential high impact of drug product quality on a patient's health, the aim of the present study was to develop two stable sterile hydrogels containing morphine hydrochloride, intended for topical application on painful wounds. Two carboxymethylcellulose sodium-based hydrogels were prepared containing 0.125% w/w (F1-MH semi-solid formulation) and 1.0% w/w (F2-MH fluid formulation) morphine hydrochloride (MH), respectively. Studies included a risk assessment approach for definition of the quality target product profile (QTPP) and assessment of critical quality attributes (CQA) of the hydrogels to support product quality and safety. Safe, odourless, yellowish, translucent and homogeneous gels were obtained, with suitable microbiological and pharmaceutical characteristics. The active substance concentration was adapted according to the characteristics of the dose-metering device. Release profiles were investigated using Franz diffusion cells, and characterised by different kinetic models. Increasing gel viscosity prolonged drug release, with rates of 17.9 ± 2.2 µg·cm-2·h-1 (F1-MH) and 258.0 ± 30.4 µg·cm-2·h-1 (F2-MH), allowing for the reduction of the number of applications and improving patient compliance. The gels proved to be stable for up to 60 days at room temperature. The semi-solid and fluid MH-containing hydrogel formulations are safe, stable and suitable for use in hospital settings, which is rather important for wound-related pain management in cancer palliative care or burn patients.

Synthesis and Characterization of Isosorbide-Based Polyurethanes Exhibiting Low Cytotoxicity Towards HaCaT Human Skin Cells.

The synthesis of four samples of new polyurethanes was evaluated by changing the ratio of the diol monomers used, poly(propylene glycol) (PPG) and D-isosorbide, in the presence of aliphatic isocyanates such as the isophorone diisocyanate (IPDI) and 4,4'-methylenebis(cyclohexyl isocyanate) (HMDI). The thermal properties of the four polymers obtained were determined by DSC, exhibiting Tg values in the range 55⁻70 °C, and their molecular structure characterized by FTIR, ¹H, and 13C NMR spectroscopies. The diffusion coefficients of these polymers in solution were measured by the Pulse Gradient Spin Echo (PGSE) NMR method, enabling the calculation of the corresponding hydrodynamic radii in diluted solution (1.62⁻2.65 nm). The molecular weights were determined by GPC/SEC and compared with the values determined by a quantitative 13C NMR analysis. Finally, the biocompatibility of the polyurethanes was assessed using the HaCaT keratinocyte cell line by the MTT reduction assay method showing values superior to 70% cell viability.

Pickering emulsions: challenges and opportunities in topical delivery.

INTRODUCTION: Topical drug delivery is a challenging area with many advantages such as avoidance of first passage effect, stabilization of blood concentrations and attainment of local therapeutic effect with fewer side effects. Despite all these advantages, topical drug delivery remains limited to few molecules, since skin acts as a barrier to the delivery of many therapeutic molecules. To overcome this obstacle, a favored strategy relies on selecting suitable vehicles for dermatologic therapy, such as emulsions, gels and, more recently, nanoparticulate systems. AREAS COVERED: Particle-stabilized emulsions, also known as Pickering emulsions, have garnered interest in recent years. Although most of the investigation on Pickering emulsions has been based on model systems with inorganic or organic solid particles, recent advances have been made regarding the application of nanocarriers, protein-based particles or cyclodextrins for this purpose. This review reports the latest advances in Pickering emulsions technical challenges, and discusses the potential benefits and drawbacks of using these formulations for topical pharmaceutical and cosmetic applications as an alternative to conventional surfactant-based systems. EXPERT OPINION: Pickering emulsions appear as a multifunctional dosage form with endless advantages. A great deal of progress is expected in this area, which might represent a renewed vision for the pharmaceutical and cosmetic industry.

Melatonin-based pickering emulsion for skin's photoprotection.

CONTEXT: Based on its antioxidant activity, melatonin was recently found to have a protection effect against photocarcinogenesis. OBJECTIVE: This work aimed to develop an innovative sunscreen formulation based on the Pickering emulsions concept, stabilized by physical UV filters, modified starch and natural oils associated to melatonin as a key strategy for prevention against UV-induced skin damage. MATERIALS AND METHODS: For this purpose, melatonin was incorporated in Pickering emulsions that were characterized using physicochemical, in vitro and in vivo testing. Physicochemical studies included physical and chemical stability by a thorough pharmaceutical control. The possible protective effects of melatonin against UV-induced cell damage in HaCaT cell lines were investigated in vitro. The safety assessment and the in vivo biological properties of the final formulations, including Human Repeat Insult Patch Test and sunscreen water resistance tests were also evaluated. RESULTS AND DISCUSSION: These studies demonstrated that melatonin sunscreen Pickering emulsion was beneficial and presented a powerful protection against UVB-induced damage in HaCat cells, including inhibition of apoptosis. The inclusion of zinc oxide, titanium dioxide, green coffee oil and starch ensured a high SPF (50+) against UVA and UVB. CONCLUSION: The combination of melatonin, multifunctional solid particles and green coffee oil, contributed to achieve a stable, effective and innovative sunscreen with a meaningful synergistic protection against oxidative stress.

Mometasone furoate-loaded cold processed oil-in-water emulsions: in vitro and in vivo studies.

Over the years, research has focused on strategies to increase benefit/risk ratio of corticoids. However, vehicles intended for topical glucocorticoids delivery with an improved benefit/risk ratio are still on demand. The aim of this work was the in vitro and in vivo characterization of cold processed oil-in-water (o/w) emulsions intended for mometasone furoate (MF) delivery to induce drug targeting to upper skin strata, decreasing adverse effects. Two o/w emulsions, containing 0.1% of MF, were developed differing in the glycol used (2-methyl-2,4-pentanediol - PT and ethoxydiglycol - TC emulsions). In vitro permeation studies revealed that these emulsions are suitable vehicles for the delivery of MF containing ingredients which are responsible for a drastically increased on the permeability coefficients of MF from a theoretical value of 1.18 × 10(-4 )cm/h to 5.20 × 10(-4) ± 2.05 × 10(-4 )cm/h and 6.30 × 10(-4) ± 2.94 × 10(-4 )cm/h, for PT and TC, respectively. The tape stripping results showed that the amount of drug that reached the viable skin layers was very low (1.99 %) and the amount that remained in the stratum corneum (SC) was 10.61%. The in vivo studies showed that the developed formulations decreased the edema and erythema in mice skin in more that 90%, assuring, at least, the same anti-inflammatory effect compared with the commercial cream. PT placebo demonstrated to contribute to restore the skin barrier by increasing the amount of lipids within the human skin.

Cold processed oil-in-water emulsions for dermatological purpose: formulation design and structure analysis.

The aim of this work is to develop, optimize and characterize cold process emulsions that are stable at acidic pH. The main surfactant was selected according to the hydrophilic lipophilic balance (HLB) concept and surface tension, whereas polymers were selected by viscoelastic measurements and analytical centrifugation. It was showed that the inclusion of methyl vinyl ether/maleic anhydride copolymer crosslinked with decadiene (PVM/MA) increased the storage modulus (G') of the gels (23.9-42.1 Pa) two-fold and the droplet migration decreased from 3.66% to 0.95%/h. Cetrimide was selected as a preservative based on its microbiological results and additional contribution to the stability of the emulsions. Four emulsions were developed that differed by the co-emulsifier used (PEG-20 glyceril laurate and polyglyceryl-4-isostearate) and the glycol (2-methyl-2,4-pentanediol and ethoxydiglycol). Viscoelastic measurements and droplet size/microscopic analysis showed that the structure of PEG-20 glyceril laurate emulsion (η' = 76.0 Pa.s at 0.01 Hz and 32.9 ± 3.7 µm, respectively) was stronger compared to polyglyceryl-4-isostearate (η' = 37.4 Pa.s at 0.01 Hz and 37.8 ± 15.7 µm, respectively). Differential scanning calorimetry (DSC) results were in accordance with the latter and showed that PEG-20 glyceril laurate with 2-methyl-2,4-pentanediol corresponded to the strongest structure (|224.4| W °C g(-1)). This cold process allowed a total production savings of more than 17% when compared to the traditional hot process.

Mometasone furoate hydrogel for scalp use: in vitro and in vivo evaluation.

Dermatological inflammatory diseases often affect the scalp and the eyebrows. Common dosage forms available on the market for those situations are lotions; however, the presence of hair limits their use. Gels, for their consistency and adhesiveness, are a suitable alternative to the lotions in these situations. The aim of this study was to develop a new stable gel containing mometasone furoate (MF), with anti-inflammatory activity and a controlled delivery, to improve topical treatment of scalp dermatitis. Pharmaceutical development, physical and chemical characterization, stability, in vitro release and permeation studies and in vivo anti-inflammatory activity were performed. The gel presented an acidic pH and an apparent viscosity of 35 Pa.s. The microbiological analysis showed that the results were within the established specification limits. The release and the permeation profiles suggest that the drug is mainly retained in the upper skin layers. MF gel was tested in an animal model of cutaneous inflammation and presented similar anti-inflammatory activity compared to a commercially available MF dosage form. The gel was chemically, physically and microbiologically stable. The results suggest that the developed hydrogel formulation containing MF can be of actual value for improving the clinical effectiveness in the treatment of scalp dermatitis.

Safety assessment and biological effects of a new cold processed SilEmulsion for dermatological purpose.

It is of crucial importance to evaluate the safety profile of the ingredients used in dermatological emulsions. A suitable equilibrium between safety and efficacy is a pivotal concern before the marketing of a dermatological product. The aim was to assess the safety and biological effects of a new cold processed silicone-based emulsion (SilEmulsion). The hazard, exposure, and dose-response assessment were used to characterize the risk for each ingredient. EpiSkin assay and human repeat insult patch tests were performed to compare the theoretical safety assessment to in vitro and in vivo data. The efficacy of the SilEmulsion was studied using biophysical measurements in human volunteers during 21 days. According to the safety assessment of the ingredients, 1,5-pentanediol was an ingredient of special concern since its margin of safety was below the threshold of 100 (36.53). EpiSkin assay showed that the tissue viability after the application of the SilEmulsion was 92 ± 6% and, thus considered nonirritant to the skin. The human studies confirmed that the SilEmulsion was not a skin irritant and did not induce any sensitization on the volunteers, being safe for human use. Moreover, biological effects demonstrated that the SilEmulsion increased both the skin hydration and skin surface lipids.