Dermal Application Research Articles

Scoping review of polycyclic aromatic hydrocarbons (PAH) human and experimental animal cancer studies

Background: The carcinogenicity of some PAHs has not been evaluated. To gauge feasibility of a potential systematic review of PAH cancer hazard, we conducted a scoping review on PAH cancer studies.Methods: We searched PubMed for human cancer studies and mapped them by exposure source and cancer type. For animal studies, we searched three databases for PAHs in general and 35 specific PAHs, excluding PAH listed in the Report on Carcinogens; studies were mapped by PAH, exposure route, and cancer sites.Results: Human cancer studies assessed exposure to PAH mixtures or surrogates from (1) the workplace using expert assessment or job exposure matrices, (2) the environment by measuring or modeling indoor or outdoor PAH exposure, or (3) all sources by measuring PAH biomarkers. Occupational studies reported lung and urinary bladder cancers most often, but also head and neck, pancreas, and other cancers. Environmental studies reported breast cancer, childhood leukemia, and others. Biomonitoring studies using PAH urinary biomarkers reported lung and breast cancers. Biomonitoring studies using PAH adducts, some including gene-environment interaction, reported lung, breast, and liver cancers.We selected animal studies using physiologically relevant exposures (oral, dermal, inhalation, intratracheal instillation, or IP injection). Laboratory animals were tested with individual PAHs. Most were mouse studies with dermal applications, and many reported skin cancer. The similar study of different PAHs could facilitate PAH comparisons. IP studies in mice reported lung and liver cancer. Anthracene, benzo[ghi]perylene, chrysene, cyclopenta[cd]pyrene, fluoranthene, and pyrene had increased cancer at two or more sites. Anthracene, chrysene, and benzo[c]fluorene has increased cancer via two exposure routes. No cancer sites were reported from the three rat studies with relevant exposures.Discussion: Both human and animal cancer literature are sufficient for systematic review of PAH cancer hazard. Integrating human cancer evidence across exposure scenarios will inform future assessments.

Repeated dermal application of the common preservative methylisothiazolinone triggers local inflammation, T cell influx, and prolonged mast cell-dependent tactile sensitivity in mice.

Occupational exposure to toxic chemicals increases the risk of developing localized provoked vulvodynia-a prevalent, yet poorly understood, chronic condition characterized by sensitivity to touch and pressure, and accumulation of mast cells in painful tissues. Here, we topically sensitized female ND4 Swiss mice to the common household and industrial preservative methylisothiazolinone (MI) and subsequently challenged them daily with MI or acetone and olive oil vehicle on the labiar skin. MI-challenged mice developed significant, persistent tactile sensitivity and long-lasting local accumulation of mast cells alongside early, transient increases in CD4+ and CD8+ T cells, eosinophils, neutrophils, and increases in pro-inflammatory cytokines. Therapeutic administration of imatinib, a c-Kit inhibitor known to inhibit mast cell survival, led to reduced mast cell accumulation and alleviated tactile genital pain. We provide the first pre-clinical evidence of dermal MI-induced mast-cell dependent pain and lay the groundwork for detailed understanding of these intersections between MI-driven immunomodulation and chronic pain.

Natural Lipids as Structural Components of Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for Topical Delivery.

Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) are useful drug delivery systems for dermal application. Thanks to their biocompatible and biodegradable profile, these carriers offer many advantages such as enhanced bioavailability, low toxicity, viable drug targeting and controlled release. SLN and NLC are composed of well-tolerated lipids, including natural fats and oils that are successfully used in the pharmaceutical and cosmetic dermal formulation. This article presents an overview of the benefits of selecting natural fats and oils as structural components of SLN and NLC for topical application. This review is based on data published over the past 20 years about the development of stable and nontoxic lipid nanoparticles with natural lipids. We shed light on the role of natural fats in skin restoration, as well as on the contributed penetration and occlusive properties of SLN and NLC. The deliberate selection of excipients (type and lipid ratio) influences the quality of the final dermal formulation. Natural lipids show good compatibility with different active molecules and are able to create stable lipid matrices that facilitate the biopharmaceutical properties of lipid nanoparticles. Patents involving natural fats and oils in SLN and NLC composition are listed, yet it is important to note that the approved marketed formulations are mainly cosmetic, not pharmaceutical, products. Natural lipids can enhance topical drug delivery by adding their ability of improving skin penetration and hydration to the permeation and occlusion properties of SLN and NLC.

Structural characterization of plant glucosylceramides and the corresponding ceramides by UHPLC-LTQ-Orbitrap mass spectrometry

Ceramides (CERs) play a major role in skin barrier function and direct replacement of depleted skin CERs, due to skin disorder or aging, has beneficial effects in improving skin barrier function and skin hydration. Though, plants are reliable source of CERs, absence of economical and effective method of hydrolysis to convert the dominant plant sphingolipid, glucosylceramides (GlcCERs), into CERs remains a challenge. This study aims at exploring alternative GlcCERs sources and chemical method of hydrolysis into CERs for dermal application. GlcCERs isolated from lupin bean (Lupinus albus), mung bean (Vigna radiate) and naked barley (Hordium vulgare) were identified using ultra high performance liquid chromatography hyphenated with atmospheric pressure chemical ionization - high resolution tandem mass spectrometer (UHPLC/APCI-HRMS/MS) and quantified with validated automated multiple development-high performance thin layer chromatography (AMD-HPTLC) method. Plant GlcCERs were hydrolyzed into CERs with mild acid hydrolysis (0.1 N HCl) after treating them with oxidizing agent, NaIO4, and reducing agent, NaBH4. GlcCERs with 4,8-sphingadienine, 8-sphingenine and 4-hydroxy-8-sphingenine sphingoid bases linked with C14 to C26 α-hydroxylated fatty acids (FAs) were identified. Single GlcCER (m/z 714.5520) was dominant in lupin and mung beans while five major GlcCERs species (m/z 714.5520, m/z 742.5829, m/z 770.6144, m/z 842.6719 and m/z 844.56875) were obtained from naked barley. The GlcCERs contents of the three plants were comparable. However, lupin bean contains predominantly (> 98 %) a single GlcCER (m/z 714.5520). Considering the affordability, GlcCER content and yield, lupin bean would be the preferred alternative commercial source of GlcCERs. CER species bearing 4,8-sphingadienine and 8-sphingenine sphingoid bases attached to C14 to 24 FAs were found after mild acid hydrolysis. CER species with m/z 552.4992 was the main component in the beans while CER with m/z 608.5613 was dominant in the naked barley. However, CERs with 4-hydroxy-8-sphingenine sphingoid base were not detected in UHPLC-HRMS/MS study suggesting that the method works for mainly GlcCERs carrying dihydroxy sphingoid bases. The method is economical and effective which potentiates the commercialization of plant CERs for dermal application.

Part 1. Evaluation of Epigallocatechin Gallate or Tannic Acid Formulations of Hydrophobic Drugs for Enhanced Dermal and Bladder Uptake or for Local Anesthesia Effects.

Epigallocatechin gallate (EGCG) and tannic acid (TA) are known to increase the aqueous solubility and cellular uptake of the hydrophobic drugs docetaxel, paclitaxel, amphotericin B, and curcumin. In this study the practical application of gallate-based solubilization phenomena for the uptake of these drugs into dermal and bladder tissue and of lidocaine for wound healing application was studied. The penetration of all these drugs into pig skin or docetaxel into pig bladder using EGCG or TA formulations was measured. Overall, EGCG and TA particulate or propylene glycol paste formulations of drugs allowed for greatly increased levels of drug uptake into skin as compared to control formulations. EGCG/propylene glycol pastes allowed for rapid lidocaine uptake into skin. EGCG and TA formulations of docetaxel allowed for approximately 10 fold increases in bladder tissue uptake of docetaxel over tween based solutions. Morphologically, both EGCG and TA caused a mild, dose dependent exfoliation of the bladder wall. Both EGCG and TA formed injectable viscous pastes with propylene glycol which solidified in water and degraded and released lidocaine over 2-35 days. These data support the use of EGCG and TA based formulations of certain drugs for improved dermal, bladder and wound applications.

Voriconazole-natural latex dressings for treating infected Candida spp. skin ulcers.

Aim: This work aimed to develop a membrane based on voriconazole (VCZ)-loaded natural rubber latex (NRL) for treating infected ulcers with Candida spp. and study their interaction, drug release, antifungal activity against Candida parapsilosis and biological characterization. Materials & methods: VCZ-loaded NRL membrane was produced by casting method. Results: Infrared spectrum showed that the incorporation of VCZ into the NRL membrane maintained its characteristics. Its mechanical properties were considered suitable for dermal application. The VCZ was able to release from NRL membrane, maintaining its antifungal activity against C. parapsilosis, besidesdidnot present hemolytic effects. Conclusion: The VCZ-NRL membrane showed good results in mechanical, antifungal and biological assays, representing an interesting alternative to treatment of infected wound with Candida spp.

Preparation and in vitro / in vivo evaluation of flurbiprofen nanosuspension-based gel for dermal application

Flurbiprofen (FB) is an analgesic and anti-inflammatory drug, but its low water solubility (BCS Class II) limits its dermal bioavailability. The aim of this study is to develop a FB nanosuspension (NS) based gel and to evaluate its analgesic and anti-inflammatory activities in rats. FB-NS was produced by the wet milling method with Plantacare 2000Ⓡ, as stabilizer. The FB-NS was then incorporated in different carrier gels such as hydroxypropyl methyl cellulose (HPMC), polycarbophil, oleogel, and chitosan. To select the optimum gel type, visual examinations, pH and rheological property measurements, texture profile analysis, in vitro release and ex vivo permeation studies were performed. Following these tests, the analgesic and anti-inflammatory activities of the optimum NS based gel were evaluated using the tail flick and carrageenan-induced paw edema methods consecutively. The NS was successfully prepared with the wet milling method, and the PS, PDI and ZP values were found to be 237.7 ± 6.8 nm, 0.133±0.030, and -30.4 ± 0.7 mV; respectively. Among the NS-based gels, HPMC gel showed more suitable rheological and mechanical properties, also the percentage of permeated FB and the flux value observed for HPMC gel were higher for HPMC than for the other gels. Thus, HPMC gel was selected as a carrier gel for in vivo pharmacodynamics studies. The anti-inflammatory activity of FB-NS HPMC gel was higher than that of the physical mixture gel and that of the coarse suspension gel. Results of our analgesic activity studies showed that, in the 180th min of FB nanosuspension treatment, the latency time was significantly prolonged compared to that of the control group (p<0.05). As a conclusion, while nanosuspensions increased the in vivo pharmacodynamics effect of FB by means of nanosized particles and a large surface area, the HPMC gel as a carrier prolonged the contact time of NSs with skin and eased the dermal application.

Preparation and Characterization of Electrospun Collagen Based Composites for Biomedical Applications.

Electrospinning is a widely used technology for obtaining nanofibers from synthetic and natural polymers. In this study, electrospun mats from collagen (C), polyethylene terephthalate (PET) and a blend of the two (C-PET) were prepared and stabilized through a cross-linking process. The aim of this research was to prepare and characterize the nanofiber structure by Fourier-transform infrared with attenuated total reflectance spectroscopy (FTIR-ATR) in close correlation with dynamic vapor sorption (DVS). The studies indicated that C-PET nanofibrous mats shows improved mechanical properties compared to collagen samples. A correlation between morphological, structural and cytotoxic proprieties of the studied samples were emphasized and the results suggest that the prepared nanofiber mats could be a promising candidate for tissue-engineering applications, especially dermal applications.

Breast Implants for Mammaplasty: An Umbrella Review of Meta-analyses of Multiple Complications.

The association of breast implants and complications after mammaplasty has been extensively researched. The aim of this study isto summarize all available results in meta-analysis investigating the association between implants and the incidence of various complications. An umbrella review for breast implants and associated complications was performed by searching related reviews from electronic databases including Pubmed, Ovid and CINAHL. We collected and reviewed evidence across meta-analyses of observational and interventional studies of implants and any health outcome. The quality of the reviews was assessed using the AMSTAR tool (A measurement tool to assess systematic reviews). The research included 92 meta-analyses of 609 studies concerning various areas. Capsular contracture was the most investigated outcome. Radiotherapy, human acellular dermal matrix application, direct-to-implant reconstruction, smooth implant, silicone-filled implant and periareolar incision were significantly associated with higher rates of some of the complications. This umbrella review provides surgeons with summarized evidence of the association between the complications and implant-related factors in mammaplasty surgery to help surgeons make informed choices in the future. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Duloxetine hydrochloride loaded film forming dermal gel enriched with methylcobalamin and geranium oil attenuates paclitaxel-induced peripheral neuropathy in rats

ObjectiveIn attempt to conquer the major concerns of oral duloxetine hydrochloride (like low bioavailability, intolerable side-effects and no regeneration of demyelinated nerve fibres) for the management of chemotherapy-induced peripheral neuropathy (CIPN), an alternative delivery of duloxetine hydrochloride was aimed for in-vivo optimization. MethodsA film forming dermal gel consisting of duloxetine hydrochloride was formulated and enriched with methylcobalamin and geranium oil. The formulated gel successfully qualified the various pharmaceutical characteristics of gel. Administration of paclitaxel (8 mg/kg/i.p. in four divided doses) for 4 alternate days induced the symptoms of peripheral neuropathy in rats. On 14th day, the responses to noxious stimulus (mechanical hyperalgesia, cold allodynia, and heat hyperalgesia) were increased and reached to its maximum. Thereafter, drug treatment with formulated dermal gel and oral duloxetine hydrochloride (30 mg/kg, once daily) was initiated for 2 weeks in different group of animals. On the 28th day animals were sacrificed to isolate sciatic nerve, to assess biochemical changes (TBARS, reduced GSH, total protein, TNF-α, IL-6) and for histopathological examinations of nerve sections using Hematoxylin-Eosin and Toludine blue staining methods. ResultsApplication of formulated dermal gel to paclitaxel-treated rats significantly improved paw-withdrawal latency responses during noxious stimulus testing, reduced the levels of TBARS, TNF-α, IL-6 and elevated the levels of reduced GSH as compared to paclitaxel treated rats. Histographs also indicated marked regeneration of the damaged nerve fibers. Topical delivery of duloxetine hydrochloride produced similar results in disparity to oral route. However, no significant disparity in responses was obtained with twice application of formulated dermal gel when compared to once daily application. ConclusionTremendous recovery from nociception, oxidation and inflammation in addition to nerve degeneration was achieved through dermal application of duloxetine hydrochloride in peripheral neuropathy.

Disposition and metabolism of antibacterial agent, triclocarban, in rodents; a species and route comparison

Triclocarban is a residue-producing antibacterial agent used in a variety of consumer products. These studies investigated the disposition and metabolism of [14C]triclocarban. In male rats following a single gavage administration of 50, 150, and 500 mg/kg, excretion was primarily via feces (feces, 85–86%; urine, 3–6%) with no apparent dose-related effect. In male rats, 29% of the administered dose was excreted in bile suggesting some of the fecal excretion is from the absorbed dose which was excreted to the intestine via bile. The tissue retention of radioactivity was low in male rats (24 h, 3.9%; 72 h, 0.1%). Disposition pattern following gavage administration of 50 mg/kg in female rats and male and female mice were similar to male rats. Plasma elimination half-life of triclocarban in rats following gavage administration was shorter (∼2 h) compared to that based on total radioactivity (≥9 h) which included all products of triclocarban. Absorption following a single dermal application of 1.5 or 3% was low (≤3%) in rodents. Hydroxylated and conjugated metabolites of triclocarban predominated in bile. In hepatocytes, clearance of triclocarban in mouse and human was similar and was faster than in rat.

Disposition and metabolism of 2,2′-dimorpholinodiethyl ether in sprague dawley rats and B6C3F1/N mice after oral, intravenous administration, and dermal application

The specialty amine catalyst 2,2′-dimorpholinodiethyl ether (DMDEE) is a high-production volume chemical used in the production of flexible foam, high-resilient molded foam, and in coatings and adhesives. The disposition and metabolism of [14C]DMDEE (20 or 200 mg/kg) were determined in male ane female rats and mice after oral and intravenous administration and dermal application. In male and female rats, following a single oral administration, [14C]DMDEE was well-absorbed and excreted rapidly and extensively via urine (75–93%) and some in feces (∼4–8%). The total radioactivity in tissues at 24 h and 72 h (males only) following oral administration was 8–10% and ∼4%, respectively, suggesting considerable tissue distribution. A moderate amount of the total tissue radioactivity in kidney and liver were unextractable suggesting covalent binding of [14C]DMDEE-derived products in tissue macromolecules. Absorption following a single dermal application in rats was significant (∼64%) with a similar disposition pattern to oral. The oral and dermal disposition of [14C]DMDEE in male and female mice was similar to rats. Urinary products of DMDEE identified were oxidative metabolism of the morpholine ring. Coadministration of DMDEE with nitrite in rats didn’t produce the rodent carcinogen, N-nitrosomorpholine.

Favorable effect of creams with skimmed donkey milk encapsulated in nanoliposomes on skin physiology.

The use of donkey milk has a long history in external dermal application for cosmetic and medical purposes. The encapsulation of different drugs into nanoliposomes and nutrients may have many benefits for the delivery of the targeted substance. The aim of the present study is to test creams with nanoliposomes encapsulated with skimmed donkey milk, reported in our registered patent, compared with effect of the placebo cream and the untreated skin. To investigate the effect of formulated cream, we have measured the electrical capacitance, transepidermal water loss and the skin pH value. The study included 15 healthy volunteers (11 women and 4 men). The patented creams exhibited satisfactory moisturizing properties very soon after application, while hydration was reached earlier in the spots treated with night cream. Transepidermal water loss slightly decreased only after 4 weeks of treatment in each of the spots assessed. The pH value was similar after each of the treatments. Tested creams may enhance the moisture of skin very soon after application, in this way potentially enable deeper permeation of phospholipids and essential proteins, without changing the pH. It may also contribute to additional anti-aging effects.

Development of textile-based sodium alginate and chitosan hydrogel dressings

Wound healing is a dynamic and complex mechanism. The healing process is affected by many factors, which can be local factors such as wound type, depth of the damaged tissue and bacterial contamination or systemic factors such as patient’s age, diet, and diseases. Prior goals should be shortening the wound healing time, ease the pain of the patient and limiting the scar formation. Therefore, the wound should be evaluated profoundly, and the wound care process decided carefully. In this study, textile-hydrogel hybrids were designed to use in mild to moderate exudate wounds. Hydrogels were formed using natural based sodium alginate and chitosan polymers in different cross-linker (PEGDGE) concentrations. To identify the optimum formulation the mechanical properties (hardness, compressibility, adhesiveness, cohesiveness, and elasticity) was examined by texture profile analysis. The gel flow properties were determined by rheological analysis. The suitable formulations for dermal applications were formed on viscose and Tencel nonwovens. Physical features (mass and thickness), pH, absorbency characteristics, transfer properties (air and water vapor permeability), morphologic features (SEM), chemical properties (FT-IR) of textile-based hydrogel dressings were examined.

Nanocrystals for Improved Drug Delivery of Dexamethasone in Skin Investigated by EPR Spectroscopy.

Nanocrystals represent an improvement over the traditional nanocarriers for dermal application, providing the advantages of 100% drug loading, a large surface area, increased adhesion, and the potential for hair follicle targeting. To investigate their advantage for drug delivery, compared to a base cream formulation, dexamethasone (Dx), a synthetic glucocorticoid frequently used for the treatment of inflammatory skin diseases, was covalently linked with the paramagnetic probe 3-(carboxy)-2,2,5,5-tetramethyl-1-pyrrolidinyloxy (PCA) to DxPCA. To investigate the penetration efficiency between these two vehicles, electron paramagnetic resonance (EPR) spectroscopy was used, which allows the quantification of a spin-labeled drug in different skin layers and the monitoring of the drug release. The penetration behavior in excised healthy and barrier-disrupted porcine skin was monitored by EPR, and subsequently analyzed using a numerical diffusion model. As a result, diffusion constants and free energy values in the different layers of the skin were identified for both formulations. Dx-nanocrystals showed a significantly increased drug amount that penetrated into viable epidermis and dermis of intact (factor 3) and barrier-disrupted skin (factor 2.1) compared to the base cream formulation. Furthermore, the observed fast delivery of the spin-labeled drug into the skin (80% DxPCA within 30 min) and a successive release from the aggregate unit into the viable tissue makes these nanocrystals very attractive for clinical applications.

Topical Application of the Antimicrobial Agent Triclosan Induces NLRP3 Inflammasome Activation and Mitochondrial Dysfunction.

5-Chloro-2-(2,4-dichlorophenoxy)phenol (triclosan) is an antimicrobial chemical widely used in consumer household and clinical healthcare products. Human and animal studies have associated triclosan exposure with allergic disease. Mechanistic studies have identified triclosan as a mitochondrial uncoupler; recent studies suggest that mitochondria play an important role in immune cell function and are involved in activation of the NLRP3 inflammasome. In this study, early immunological effects were evaluated via NLRP3 activation following dermal triclosan application in a BALB/c murine model. These investigations revealed rapid caspase-1 activation and mature IL-1β secretion in the skin and draining lymph nodes (dLNs) after 1.5% and 3% triclosan exposure. Correspondingly, pro-Il-1b and S100a8 gene expression increased along with extracellular ATP in the skin. Peak gene expression of chemokines associated with caspase-1 activation occurred after 2 days of exposure in both skin tissue and dLNs. Phenotypic analysis showed an increase in neutrophils and macrophages in the dLN and myeloid and inflammatory monocytes in the skin tissue. Triclosan also caused mitochondrial dysfunction shown through effects on mitochondrial reactive oxygen species, mass, mitochondrial membrane potential, and mitochondrial morphology. These results indicate that following triclosan exposure, activation of the NLRP3 inflammasome occurs in both the skin tissue and dLNs, providing a possible mechanism for triclosan's effects on allergic disease and further support a connection between mitochondrial involvements in immunological responses.

Evaluation of a Peptide-Based Coassembled Nanofibrous and Thixotropic Hydrogel for Dermal Wound Healing.

The development of a peptide-based coassembled thixotropic hydrogel is a promising biomaterial, which could be used for dermal wound healing application. Cyclodextrins are widely used as biocompatible cyclic oligosaccharides that have hydrophilic exterior and hydrophobic interior for the formation of functional biomaterials. The current work presents a paradigm of a coassembled hydrogel with suitable mechanical strength that exhibits in vivo wound healing efficacy. In this report, we have designed and synthesized an Amoc (9-anthracenemethoxycarbonyl)-capped dipeptide, which self-assembles into a tough and robust hydrogel owing to participation of various noncovalent interactions. The mechanical strength of the self-assembling peptide-based hydrogel is tuned by incorporation of equimolar β-cyclodextrin (CD), which leads to the formation of a coassembled hydrogel suitable for wound healing application. The coassembled hydrogel exhibits simple syringe injectability and is thixotropic in nature. The nanostructural morphology of the coassembled hydrogel reveals a highly cross-linked and entangled nanofibrillar network. Several spectroscopic data elucidate the presence of noncovalent interactions between CD and peptide, which could be the driving force for the formation of ordered nanostructures. The coassembled hydrogel shows potent antibacterial activity against Gram-positive pathogenic bacteria. In vitro biocompatibility of the coassembled hydrogel has been investigated with the human embryonic kidney (HEK293) and MCF-7 cell lines. Additionally, confocal laser scanning microscopic data show cellular uptake of the coassembled hydrogel with blue fluorescence. Moreover, the in vivo wound healing activity of the coassembled hydrogel has been investigated by the histopathology study. The biochemical parameters such as nitric oxide and collagen contents have been evaluated by Griess and hydroxy proline assays. All the results corroborate the wound healing efficacy of a nanofibrillar antibacterial coassembled hydrogel.

Permeation kinetics of active drugs through lanolin-based artificial membranes

Skin-penetration studies play an essential role in the selection of drugs for dermal or transdermal application. In vivo experiments in humans are not always possible for ethical, practical, or economic reasons, especially in the first part of the drug development. It is necessary to develop alternative methods using accessible and reproducible surrogates for in vivo human skin. The in vitro methodologies using biological membranes (human and animal skin) are recognized and well accepted as an alternative but present high inter- and intra-individual variability. Therefore, the formation of synthetic membranes has been studied to obtain skin- mimicking models for permeation studies. The aim of this work is to create lanolin-based artificial membranes that can mimic the absorption through the skin of compounds applied topically.A series of synthetic membranes using two different types of lanolin (water-extracted (WE) and solvent-extracted (SE)) were prepared. Next, the in vitro release test of three drugs (diclofenac sodium, ibuprofen and lidocaine) was performed on artificial membranes and on porcine skin placed on Franz cells. The percentage of release, flux, permeability coefficient, lag time, area under the curve, maximal concentration and time were determined for each compound in the different types of membrane.The results showed that lanolin membranes presented a strong diminution of permeability compared to most artificial membranes, leading to a very similar permeability to that of skin. The SE and WE membranes showed a diminution of transepidermal water loss and permeability of compounds compared with membranes alone. The results from WE membranes were similar to those found for the skin. The lanolin membranes were not capable of perfectly mimicking permeation through the skin, but they did have the same rank order of drug penetration as the skin. It may be deduced from these tests that these systems provide more reliable results for compounds with low to medium lipophilicity. The results demonstrated that new lanolin-based artificial membranes have the potential to be exploited as screening models for determining the permeability of a compound destined to be topically delivered.

Bioactive and biostable hyaluronic acid-pullulan dermal hydrogels incorporated with biomimetic hydroxyapatite spheres.

In this study, hyaluronic acid-pullulan injectable hydrogels were incorporated with biomimetic hydroxyapatite spheres and were modified using silane coupling agents in order to improve the physicochemical, mechanical, and biological performance of hydrogels. So the biomimetic hydroxyapatite spheres were synthesized through immersion of gelatin-siloxane microspheres in the simulated body fluid. The results of field emission scanning electron microscopy, energy dispersive X-ray spectroscopy, and X-ray diffraction spectra confirmed the formation of hydroxyapatite on the surface of hybrid spheres. The morphology observation of the prepared hydrogels confirmed the uniform distribution of hydroxyapatite spheres in gel structure. The chemical characterization proved the possible interactions between the polymers and the created complex with a silane coupling agent to provide more durability. Improvement of storage modulus and viscosity indicated the positive role of hydroxyapatite spheres on the stability and long-lasting durability of hydrogels. A slight reduction was observed in the absorption capacity and water retention in hybrid hydrogels; even though, the great resistance to enzymatic biodegradation led to higher durability of hydroxyapatite-contained gels. Improvement in L-929 fibroblast cell adhesion and spreading especially around the biomimetic hydroxyapatite spheres along with higher cell viability demonstrated the initial potential of hydrogels for further pre-clinical and clinical studies in order to recommend the gels for dermal rejuvenation applications.

Metal alginates for polyphenol delivery systems: Studies on crosslinking ions and easy-to-use patches for release of protective flavonoids in skin

Incorporation of bioactive natural compounds like polyphenols is an attractive approach for enhanced functionalities of biomaterials. In particular flavonoids have important pharmacological activities, and controlled release systems may be instrumental to realize the full potential of these phytochemicals.Alginate presents interesting attributes for dermal and other biomaterial applications, and studies were carried here to support the development of polyphenol-loaded alginate systems. Studies of capillary viscosity indicated that ionic medium is an effective strategy to modulate the polyelectrolyte effect and viscosity properties of alginates. On gelation, considerable differences were observed between alginate gels produced with Ca2+, Ba2+, Cu2+, Fe2+, Fe3+ and Zn2+ as crosslinkers, especially concerning shrinkage and morphological regularity. Stability assays with different polyphenols in the presence of alginate-gelling cations pointed to the choice of calcium, barium and zinc as safer crosslinkers. Alginate-based films loaded with epicatechin were prepared and the kinetics of release of the flavonoid investigated. The results with calcium, barium and zinc alginate matrices indicated that the release dynamics is dependent on film thicknesses, but also on the crosslinking metal used.On these grounds, an alginate-based system of convenient use was devised, so that flavonoids can be easily loaded at simple point-of-care conditions before dermal application. This epicatechin-loaded patch was tested on an ex-vivo skin model and demonstrated capacity to deliver therapeutically relevant concentrations on skin surface. Moreover, the flavonoid released was not modified and retained full antioxidant bioactivity. The alginate-based system proposed offers a multifunctional approach for flavonoid controllable delivery and protection of skin injured or under risk.