Article

Oleic acid, a skin penetration enhancer, affects Langerhans cells and corneocytes

Authors:
  • Houston Methodist Research Institute, Institute of Academic Medicine
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Abstract

Permeation enhancers (PE) are frequently used in the field of dermal research and for the development of transdermal delivery products. However, their influence on skin epidermal Langerhans cells (LC) has not yet been investigated. In this work we studied the effect of four PE, oleic acid (OA), propylene glycol (PG), ethanol, and diethylene glycol monoethyl ether (DGME), and an iontophoretic treatment on the morphometric parameters of epidermal Langerhans cells (LC). Retinoic acid (RA) was used as a positive control. Test solutions were applied to the footpad of Sabra mice. The area, perimeter, density and shape factor (SF) were the morphometric parameters evaluated following ATPase staining of LC. Application of RA led to a large decrease in cell density (-50.2%, P<0.01) and dendritic shape (19.8%, P<0.01). Treatment with 10% OA in ethanolic solution caused a severe decrease in LC density (-69.0%, P<0.01), accompanied by a decrease in dendricity as measured by the changes in SF. Ethanol had no statistically significant effect on the LC morphologic parameters tested. All other PE had a mild, if any, effect on LC morphology. SEM micrographs of the skin of IOPS hairless rats demonstrated that 24 h in vivo treatment with 10% OA in ethanolic solution resulted in the generation of pores on the surface of epidermal corneocytes.

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... Accordingly different approaches were investigated to facilitate the macromolecules traversing into epidermal layer. It was reported that the delivery of compounds with high molecular weight through stratum corneum requires either chemical permeation enhancers or physical techniques such as iontophoresis [20][21][22]. Among different chemical permeation enhancers, oleic acid found to be a good modifier for the dermal biochemical environment, and thus considered for delivering the drug moieties into/through the skin layers [18,[23][24][25]. ...
... Many studies reported on the advantages of employing oleic acid in transdermal therapy. It was found that oleic acid acts as an effective medium to increase the drug diffusivity by reducing the barrier properties of skin layers particularly the stratum corneum [20,21,26]. Besides, oleic acid has the capability to modify the intercellular and structural arrangements of lipids lamellae of the stratum corneum [23], and/or the intracellular proteins (collagen type I) [27]. ...
... Stage-2: Using the optimal nanoemulsion achieved in stage-1, the influence of loading of different amounts of b-D-glucan on the physical characteristics of generated nanoemulsion, i.e., droplet diameter, size distribution and viscosity was studied. Stability study involved subjecting the obtained optimal b-Dglucan-loaded nanoemulsions to different storage temperatures (4°C, 25°C) and duration (1,7,21,30,60, 90 days) with monitoring their droplet diameter, size distribution and viscosity. Antioxidant activity study involved two assays: DPPH radical scavenging activity and ferric reducing antioxidant power activity. ...
Article
Polysaccharides of β-d-glucan configuration have well-known antioxidant activity against reactive free radicals generated from the oxidation of metabolic processes. In this study, β-d-glucan-polysaccharides extracted from Ganoderma lucidum were incorporated in palm olein based nanoemulsions which act as carrier systems to enhance the delivery and bioactivity of these polysaccharides and could be potentially useful for skin care applications. Initially response surface statistical design (Central Composite Design – CCD) was subjected to optimize the formulation variables of oil-in-water (O/W) nanoemulsions induced by ultrasound. The optimal formulation variables as predicted by CCD resulted in considerably improving the physical characteristics of ultrasonically formulated nanoemulsions by minimizing their droplet size, polydispersity index and viscosity. Moreover, the β-d-glucan-loaded nanoemulsions exhibited good stability over 90 days under different storage conditions (4 °C and 25 °C). The studies using palm olein based β-d-glucan-loaded nanoemulsion generated using ultrasound confirm higher antioxidant activity as compared to free β-d-glucan.
... To get insight into the IMQ partitioning between the SC and viable epidermis, we tape-stripped Aldara-treated skin and found approximately equal IMQ amounts in the SC and viable epidermis; this better performance of ME 5.2 over Aldara may be attributed to the high OA concentration (61.6%) in ME 5.2 . OA is a potent permeation enhancer widely used for transdermal drug delivery [26,43,44]. OA can increase skin permeability by disordering the highly packed SC intercellular lipids or forming separate fluid pools in the barrier lipids (which provide a more permeable shortcut for drugs) [45][46][47]. ...
... To get insight into the IM partitioning between the SC and viable epidermis, we tape-stripped Aldara-treated sk and found approximately equal IMQ amounts in the SC and viable epidermis; this bet performance of ME5.2 over Aldara may be attributed to the high OA concentration (61.6 in ME5.2. OA is a potent permeation enhancer widely used for transdermal drug delive [26,43,44]. OA can increase skin permeability by disordering the highly packed SC int cellular lipids or forming separate fluid pools in the barrier lipids (which provide a mo permeable shortcut for drugs) [45][46][47]. ...
Article
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Imiquimod (IMQ) is a potent immune response modifier with antiviral and antitumor properties. IMQ’s low aqueous solubility and unsatisfactory cutaneous permeability limit its formulation into effective dosage forms. This work aimed to develop IMQ-loaded microemulsions (MEs) based on phospholipids and oleic acid to improve IMQ penetration into the epidermis. A pseudo-ternary phase diagram was constructed, and the microstructure of the formulations was examined by measuring the conductivity values. Selected MEs were characterized and studied for their ability to deliver IMQ into and through ex vivo human skin. ME1 with 1% IMQ (bicontinuous ME with Bingham rheology) delivered similar IMQ quantities to the human epidermis ex vivo as the commercial product while having a 5-fold lower IMQ dose. IMQ was not detected in the acceptor phase after the permeation experiment, suggesting a lower systemic absorption risk than the established product. Infrared spectroscopy of the stratum corneum revealed less ordered and less tightly packed lipids after ME1 application. The ME1-induced barrier disruption recovered within less than 5 h after the formulation removal, as detected by transepidermal water loss measurements. In conclusion, our findings demonstrate that phospholipid and oleic acid-based MEs could become a promising alternative for topical IMQ administration.
... The ability of OA to enhance skin penetration has been widely recognized in various in vitro studies [45]. It disrupts highly stacked intercellular domain lipids in the cuticle [46]. Azone was the first compound specifically designed as a skin penetration enhancer, and its penetration-enhancing properties reflected the molecule's ability to reduce skin diffusion resistance [47,48]. ...
Article
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We developed a sustained-release transdermal drug delivery system (TDDS) containing simvastatin (SIM) and captopril (CAP) to treat hypertension and hyperlipidemia and overcome treatment drawbacks, including significant liver first-pass effects, low bioavailability, and the short half-life of SIM and CAP oral tablets. We used a transdermal diffusion meter to preselect the formula of the SIM-CAP TDDS. Based on in vitro permeation experiments, we optimized the formula of the SIM-CAP TDDS to include 24% SIM, 24% CAP, 34% polyvinyl alcohol (PVA), 16% oleic acid (OA)–azone, and 2% polyacrylic acid resin II. We evaluated the optimized SIM-CAP TDDS formula by its appearance, stability, stickiness, drug content, in vivo pharmacokinetics, and skin irritation tests. The results indicated that the patch had good stability and stickiness. The SIM and CAP contents were 5.02 ± 0.41 mg/cm2 in the 1 cm2 SIM-CAP TDDS. The pharmacokinetic results indicated that the system continuously released SIM and CAP for 24 h and significantly enhanced their bioavailability, with a higher area under the curve. The SIM-CAP TDDS exhibits a sustained-release effect with good characteristics and pharmacokinetics. And it is safe and has no irritating effects on the skin; therefore, it is an ideal formulation.
... 1,2 The natural barrier for topical distribution is skin 3,4 which makes drug delivery problematic. Taking this into account, microemulsions are formed that have low skin irritation a high drug loading capacity, and may minimise the diffusion barrier of the Stratum corneum and boosting drug absorption 5,6 . ...
Article
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The present research work was to develop ketoconazole loaded microemulgel formulation. The main objective was to enhance the penetration capability of ketoconazole by incorporating penetration boosters and to administer the drug in a sustained release fashion. Currently available dermal creams refuse to provide intended action as needed. Screening of oils, surfactants, and co-surfactants was done by the construction of pseudo ternary phase diagrams with 2% ketoconazole. Compatibility studies like FT-IR, DSC were performed to determine incompatibilities. The microemulsion was characterized for droplet size, zeta potential, viscosity , thermodynamic stability. Moreover for enhancement of patient compliance the optimized microemulsion was modified into microemulsion based gel. Ex-vivo studies were carried out for microemulgel using Franz diffusion cell by help of porcine skin membrane. The antifungal activity of microemulgel was evaluated using cup plate method incorporating Candida albicans (MTCC Code: 3018).The optimized microemulsion had a composition of 20% Oleic acid: coconut oil (2:1), 34.06% Tween 80: Propylene glycol (2:1), and 43.94% water and was later incorporated into polymeric gel base. The microemulgel exhibited 10hr sustained release profile when compared to the Kz cream®. In-vivo investigation i.e; skin irritation test on albino mice was done by grouping into standard[Kz cream®],control[placebo], test[microemulgel] and it was identified that no irritation caused by microemulgel as well as standard Kz cream. The control showed signs of irritation as it does not possess active moiety. The optimized microemulsion showed 99.02% Formulation and Evaluation of Ketoconazole Microemulgel with Mixture of Penetration Enhancers Section A-Research paper 895 Eur. Chem. Bull. 2023,12(12), 894-912 drug loading and 98.07% transmittance.The thermodynamic stability, sustained drug release with greater penetration and enhanced activity due to the presence of oleic acid in microemulgel warrant its application as an excellent formulation for treating opportunistic fungal infections.
... The solubility of TQ in various excipients was investigated, and the findings are presented in Figure 1. Amongst the different experimental oils, the highest solubility (268.18 ± 0.20 mg/mL) of TQ was observed in the kalonji oil [25], making it a suitable oil phase for the purported formulation. Tween 80 and Transcutol-P were selected as the surfactant and co-surfactant, respectively, as they showed the maximum drug solubility, i.e., 83.23 ± 02.57 ...
Article
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Thymoquinone has a multitude of pharmacological effects and has been researched for a wide variety of indications, but with limited clinical success. It is associated with pharmaco-technical caveats such as hydrophobicity, high degradation, and a low oral bioavailability. A prudent approach warrants its usage through an alternative dermal route in combination with functional excipients to harness its potential for treating dermal afflictions, such as psoriasis. Henceforth, the present study explores a nanoformulation approach for designing a fulvic acid (peat-sourced)-based thymoquinone nanoemulsion gel (FTQ-NEG) for an enhanced solubility and improved absorption. The excipients, surfactant/co-surfactant, and oil selected for the o/w nanoemulsion (FTQ-NE) are Tween 80/Transcutol-P and kalonji oil. The formulation methodology includes high-energy ultrasonication complemented with a three-dimensional/factorial Box–Behnken design for guided optimization. The surface morphology assessment through scanning/transmission electron microscopy and fluorescence microscopy revealed a 100 nm spherical, globule-like structure of the prepared nanoemulsion. Furthermore, the optimized FTQ-NE had a zeta potential of −2.83 ± 0.14 Mv, refractive index of 1.415 ± 0.036, viscosity of 138.5 ± 3.08 mp, and pH of 5.8 ± 0.16, respectively. The optimized FTQ-NE was then formulated as a gel using Carbopol 971® (1%). The in vitro release analysis of the optimized FTQ-NEG showed a diffusion-dominant drug release (Higuchi model) for 48 h. The drug permeation flux observed for FTQ-NEG (3.64 μg/cm2/h) was much higher compared to that of the pure drug (1.77 mg/cm2/h). The results were further confirmed by confocal microscopy studies, which proved the improved penetration of thymoquinone through mice skin. Long-term stability studies of the purported formulation were also conducted and yielded satisfactory results.
... The aim of this investigation was to obtain effective new nanocarriers made up of naturally derived components. Oleic acid was chosen as the main component of the proposed oleoethosomes due to its documented properties as a penetration enhancer [37][38][39]. In order to emphasize these features, the oleic acid was associated with ethanol in the composition of the oleoethosomes, in the attempt to exploit the synergistic effect between the two components on the stratum corneum [40,41]. ...
Article
The topical administration of a drug compound remains the first choice for the treatment of many local skin ailments. Many skin diseases can be treated by applying the active formulation directly to the skin, but unfortunately some drugs are unable to overcome the stratum corneum and exert their pharmacological action. An example is thymoquinone, a naturally derived drug obtained from Nigella sativa L. and potentially effective in the treatment of inflammatory and oxidative skin conditions. Since its physico-chemical properties are not suitable for overcoming the stratum corneum, we wanted to circumvent the problem by proposing new lipid-based nanovesicles called "oleoethosomes", made up of naturally derived ingredients, for its delivery. Among several formulations of oleoethosomes, the sample made up of 2% (w/w) oleic acid:PL90G 1:1 (molar ratio), and ethanol 15% showed the best physico-chemical characteristics and above all it showed the capacity to contain a suitable amount of thymoquinone (2 mg/ml). The formulation was tested in vitro on stratum corneum and viable epidermis membranes confirming its ability to induce the passage of thymoquinone through the human stratum corneum and to act as a permeation enhancer. In fact, it showed thymoquinone permeation values of 22.63 ± 1.49% regarding the applied drug amount. Oleoethosomes were compared with oleosomes, another kind of naturally derived nanosystems but free of ethanol. The experimental data confirmed that ethanol was an important component that enhanced the activity of the oleoethosomes when tested on the skin of healthy volunteers. The thymoquinone-loaded oleoethosome treatment demonstrated a significantly greater extent of anti-inflammatory activity than the treatment with thymoquinone-loaded oleosomes or the conventional dosage form of the drug. These in vivo results confirmed the synergic effect between oleic acid and ethanol on the lipid and protein compartments of the outermost skin layer, thus promoting a greater penetration capacity.
... Oleic and linoleic acid vesicles, instead, have demonstrated their ability to improve the passage of entrapped compound through stratum corneum, thanks to their lipid composition. In fact, some unsaturated fatty acids are well known as penetration enhancers in pharmaceutical products [25,57]. In particular, the increased skin permeability induced by oleic and linoleic acid seems to be related to a perturbation of the lipid structures of the stratum corneum, inducing a disorder in the highly packed stratum corneum intercellular domain lipids [58]. ...
Article
Full-text available
Linoleic and oleic acids are natural unsaturated fatty acids involved in several biological processes and recently studied as structural components of innovative nanovesicles. The use of natural components in the pharmaceutical field is receiving growing attention from the scientific world. The aim of this research work is to design, to perform physico-chemical characterization and in vitro/in vivo studies of unsaturated fatty acids vesicles containing ammonium glycyrrhizinate, obtaining a new topical drug delivery system. The chosen active substance is well known as an anti-inflammatory compound, but its antioxidant activity is also noteworthy. In this way, the obtained nanocarriers are totally natural vesicles and they have shown to have suitable physico-chemical features for topical administration. Moreover, the proposed nanocarriers have proven their ability to improve the in vitro percutaneous permeation and antioxidant activity of ammonium glycyrrhizinate on human keratinocytes (NCTC 2544 cells). In vivo studies, carried out on human volunteers, have demonstrated the biocompatibility of unsaturated fatty acid vesicles toward skin tissue, indicating a possible clinical application of unsaturated fatty acid vesicles for the treatment of topical diseases.
... Fig. 1 shows the molecular structures of VH, OA and PA. OA enhances the skin permeation of small molecules by causing transient disruption of the ordered orientation of the lipid region of stratum corneum (Touitou et al., 2002). PA has not been widely used as a skin permeation enhancer attributed to its saturated hydrocarbon tail. ...
Article
Topical and transdermal delivery of vancomycin hydrochloride (VH), a broad-spectrum peptide antibiotic, is a challenge because of its high molecular weight (1485.7 Da) and hydrophilicity (log P -3.1). The objective of this study was to investigate the feasibility of delivering VH into and across the skin using permeation enhancement techniques. Skin permeation studies were performed using Franz diffusion cell apparatus in the excised porcine skin model. The influence of co-treatment and pre-treatment of chemical permeation enhancers (oleic acid and palmitic acid) on permeation of VH across intact and tape-stripped skin was evaluated. In addition, continuous anodal iontophoresis was applied to enhance the skin permeation of VH. The mechanism of skin permeation enhancement by palmitic acid was investigated using FTIR spectroscopy, impedance spectroscopy, and thermal analysis techniques. Pharmacokinetic analysis was performed after the topical application of VH formulations in Sprague Dawley rats. Results from permeation studies showed that VH did not passively permeate across the intact skin after 48 h, whereas the cumulative amount of VH permeated across the tape-stripped skin was found to be 854±67 µg/cm². A combination of tape-stripping and chemical enhancers resulted in enhancing the cumulative amount of VH permeated across the skin by 2- and 10-fold with oleic acid and palmitic acid application, respectively. Similarly, 2 and 12 h pre-treatment of tape-stripped skin with palmitic acid enhanced the flux of VH across the skin by 1.7- and 5-fold, respectively. It was found that tape-stripping and the palmitic acid application would provide greater VH permeation compared with 0.31 mA/cm² iontophoresis application. Thermal analysis and impedance spectroscopic analysis showed that palmitic acid interacts with epidermal lipids to enhance VH permeation. Pharmacokinetic analysis after topical application showed that the Cmax and mean residence time increased by 3-fold with the application of VH and palmitic acid on tape-stripped skin compared with free VH on intact skin. Taken together, VH can be delivered through the topical route using a combination of chemical enhancer and tape-stripping to treat local and systemic bacterial infections.
... In recent research, the coenzyme Q10 NLCs were developed using myristic acid as a solid lipid, whereas oleic acid, isopropyl myristate, and isopropyl palmitate were used as liquid lipids. The previous studies revealed that myristic acid, oleic acid, isopropyl myristate, and isopropyl palmitate capable of penetration enhancers in transdermal delivery systems (Touitou et al., 2002;Guo et al., 2006;Ibrahim and Li, 2010;Eichner et al., 2017). Moreover, the liquid lipids used in this study have different lipophilicity. ...
Article
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Context: Nanostructured lipid carriers can enhance skin penetration of active substances. Coenzyme Q10 is a lipophilic antioxidant, that has poor skin penetration. This limitation is overcome by nanostructured lipid carriers. Aims: To developed coenzyme Q10 nanostructured lipid carriers using myristic acid with various liquid lipids as lipid matrix by in vitro studies and in silico approach for explaining the interaction of coenzyme Q10-lipid at the molecular level. Methods: The coenzyme Q10 nanostructured lipid carriers were prepared using myristic acid as solid lipid with oleic acid, isopropyl myristate, and isopropyl palmitate as liquid lipids using the high shear homogenization method. Then, they were evaluated in physicochemical characteristics by dynamic light scattering, differential scanning calorimetry, Fourier transforms infrared, scanning electron microscopy, spectrophotometry ultraviolet-visible, and pH meter. Furthermore, the in silico studies were conducted using AutoDock 4.2. Results: The coenzyme Q10 nanostructured lipid carriers using myristic acid-oleic acid, myristic acid-isopropyl myristate, and myristic acid-isopropyl palmitate as lipid matrix had the mean particle size, polydispersity index, entrapment efficiency, drug loading, and pH value were less than 300 nm, less than 0.3, more than 80%, about 10%, and about 5.0, respectively. Moreover, molecular docking of coenzyme Q10 and lipid showed hydrogen and hydrophobic bonds. These results supported differential scanning calorimetry and Fourier transforms infrared results. Conclusions: The coenzyme Q10 nanostructured lipid carriers were successfully prepared using myristic acid-oleic acid, myristic acid-isopropyl myristate, and myristic acid-isopropyl palmitate as lipid matrix as well as in silico study could be used for explaining of coenzyme Q10-lipid interaction.
... They are extra-occlusive and seal in moisture really well. Oleic acid is absorbed well by the skin, has anti-inflammatory and skin softening properties [24]. ...
Article
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Bilberry represents a valuable source of antioxidant substances responsible for its application for the treatment of different conditions (such as inflammation, cardiovascular disease, cancer, diabetes, and different age-related diseases) associated with increased oxidative stress. As oxidative stress might cause skin impairments, we aim to evaluate a topical preparation containing bilberry leaves extract and bilberry seeds oil, obtained as a byproduct of the food industry. To obtain the extracts, the conventional maceration technique for leaves, and supercritical carbon dioxide extraction for seeds were employed. The chemical profile of both actives was achieved by HPLC and GC methods, revealing the presence of phenolic acids (chlorogenic being the most abundant), flavonoids (isoquercetin in the highest amount), and resveratrol in leaves extract, while in seeds oil the essential ω-3 and ω-6 fatty acids were determined in favorable ratio, almost being 1. Antioxidant potential of the wild bilberry extract and seed oil was evaluated using in vitro DPPH and FRAP assays. Finally, effects of the oil-in-water creams with mentioned wild bilberry isolates on the skin were investigated in an in vivo study conducted on healthy human volunteers, revealing the significant beneficial effects when topically applied.
... Oleic acid was used as a model to enhance permeation of piroxicam [38] and naloxone [39]. It seems that oleic acid acts through interaction with the lipid content in the SC causing lipid fluidization and phase separation [40,41] also it seems to generate holes in the corneocytes [42]. ...
... Moreover, oleic acid is the most abundant free fatty acid in SLS and is known to reduce the barrier function of the skin and increase the diffusibility of the entire stratum corneum by causing phase separation in the lipid domains of the stratum corneum. 28,29) Touitou et al. found that patches containing oleic acid formed pores on the surface of epidermal keratinocytes in rats, 30) and Larrucea et al. also reports that oleic acid applied to mouse skin increases the transdermal absorption of tenoxicam. 31) These results suggested that high SLS concentrations enhanced FEN uptake from the patch and the corresponding accumulation of FEN in the skin tissue. ...
Article
The percutaneous absorption of a fentanyl (FEN)-patch is affected by various external factors including the volume of sebum secretion, which causes changes in the skin surface environment. In this study, we prepared a lard-based sebum-like secretion (SLS), and applied it to investigate the effect of different skin surface conditions on the drug penetration of a FEN-patch. In vitro work to test drug release using the Franz diffusion cell indicated that drug release was significantly suppressed by treatment with 5% SLS, which is equivalent to the amount of daily human sebum secretion. Conversely, in ex vivo experiments using rat skin, the amount of FEN that accumulated in the skin tissue of the 5% SLS-treated rats was higher in comparison with the non-SLS treated group. Furthermore, in vivo experiments indicated that the plasma FEN concentration in rats treated with the FEN-patch was significantly increased by treatment with 5% SLS. These results suggest that the sebum affected the release, accumulation, and absorption of FEN from the FEN-patch, and the FEN concentration in the blood was reflected by the balance of the suppression of drug release and the enhancement of drug accumulation in the skin with SLS. Graphical Abstract Fullsize Image
... Microemulsions are also able to reduce the diffusion barrier and increase hydration of the epidermal stratum corneum. This is possible by dissolving lipids in the stratum corneum, which contributes significantly to increased drug penetration [85,86]. Therefore, they are seen as potential topical drug delivery systems that can further increase the bioavailability of poorly water-soluble active pharmaceutical ingredients [87]. ...
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Hydrogels are playing an increasingly important role in medicine and pharmacy. Due to their favorable physicochemical properties, biocompatibility, and designed interaction with living surroundings, they seem to be one of the most promising groups of biomaterials. Hydrogel formulations from natural, semi, or synthetic polymeric materials have gained great attention in recent years for treating various dermatology maladies and for cosmetology procedures. The purpose of this review is to present a brief review on the basic concept of hydrogels, synthesis methods, relevant mechanisms, and applications in dermatology or cosmetology. This review discusses transdermal therapies and the recent advances that have occurred in the field.
... It also acts by decreasing the viscosity of lipids of superficial layer (Naik et al. 1995). Touitou et al. studied the effect of various penetration enhancers on morphology of epidermal Langerhans cell and concluded that oleic acid has prominent effect on skin morphology hence improves permeation across skin (Touitou et al. 2002). The fraction rate controlled by device is found between 0.252 and 0.713 indicating that the rate is not controlled by device and influence of permeation parameters is involved (Kalia and Guy 2001). ...
Article
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The drug-in-adhesive (DIA)-type matrix patches of lamotrigine are developed using variable permeation enhancers (oleic acid, PG, lemon oil and aloe vera), and drug in vitro release and its permeation are evaluated. Lamotrigine has been long used as an anti-epileptic, mood stabilizer, to treat bipolar disorder in adults and off label as an antidepressant. lamotrigine matrix patches comprising of Eudragit®RS100 (rate-controlling polymer) and DuroTak® 387-2510 (adhesive) were prepared by pouring the solution on backing membrane (3M-9720). The thickness of 120 µm was adjusted through micrometer film applicator. USP Apparatus V was used for the evaluation of release profile, which was fitted into various mathematical models. Quality characteristics of patches were determined through weight variation, moisture content, moisture uptake and drug content evaluation. FTIR studies were performed for drug-excipient compatibility; Franz diffusion cell was employed for studying in vitro permeation parameters such as flux, lag time, and ER. Skin sensitivity study of optimized patch was also performed. The release from patches comprising of PG and oleic acid was maximum, i.e., 96.24 ± 1.15% and 91.12 ± 1.11%, respectively. Formulations (A1–A5) exhibited Makoid–Banakar release profile. Formulation A3 consisting of oleic acid was optimized due to enhanced permeation of drug across skin compared to other enhancers with enhancement ratio of 3.55. Skin sensitivity study revealed patch as safe and non-allergenic. The study demonstrates that oleic acid can be used as a suitable permeation enhancer for transdermal delivery of lamotrigine from matrix-type patches.
... Oleic acid is a biocompatible, unsaturated fatty acid that finds wide application in drug delivery (Srisuk et al., 2012). It has been used as a penetration enhancer in transdermal delivery systems (Touitou et al., 2002), a stabilizer in liposomes (Bergstrand et al., 2003;Drummond et al., 2000) and magnetic nanoparticles (Darwish, 2017;Soares et al., 2016) and a liquid lipid in nanostructured lipid carriers (Zhao et al., 2016). It also has antibacterial activity, which may enable the fabrication of nanocarriers that can synergize antimicrobial activity of the encapsulated drugs (Huang et al., 2011). ...
Article
Stimuli-responsive nano-drug delivery systems can optimize antibiotic delivery to infection sites. Identifying novel lipids for pH responsive delivery to acidic conditions of infection sites will enhance the performance of nano-drug delivery systems. The aim of the present investigation was to synthesize and characterize a biosafe novel pH-responsive lipid for vancomycin delivery to acidic conditions of infection sites. A pH-responsive solid lipid, N-(2-morpholinoethyl) oleamide (NMEO) was synthesized and used to prepare vancomycin (VCM)-loaded solid lipid nanoparticles (VCM_NMEO SLNs). The particle size (PS), polydispersity index (PDI), zeta potential (ZP) and entrapment efficiency (EE) of the formulation were 302.8 ± 0.12 nm, 0.23 ± 0.03, -6.27 ± 0.017 mV and 81.18 ± 0.57 % respectively. The study revealed that drug release and antibacterial activity were significantly greater at pH 6.0 than at pH 7.4, while the in silico studies exposed the molecular mechanisms for improved stability and drug release. Moreover, the reduction of MRSA load was 4.14 times greater (p <0.05) in the skin of VCM_NMEO SLNs treated mice than that of bare VCM treated specimens. Thus, this study confirmed that NMEO can successfully be used to formulate pH-responsive SLNs with potential to enhance the treatment of bacterial infections.
... Another possible mechanism for the action of OA is lamellar solid fluid phase separation. When applied together with ethanol, OA is also believed to cause stratum corneum lipid extraction (Touitou et al., 2002). Alteration of the percentage of oleic acid resulted in no significant difference in the accumulated drug amount (Figure 7(B) and Table 3). ...
Article
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The film forming gel, adhered to skin surfaces upon application and formed a film, has an advantage onto skin to provide protection and continuous drug release to the application site. This study aimed to prepare a chitosan-based film forming gel containing ketoprofen (CbFG) and to evaluate the CbFG and film from CbFG (CbFG-film). CbFG were prepared with chitosan, lactic acid and various skin permeation enhancers. The physicochemical characteristics were evaluated by texture analysis, viscometry, SEM, DSC, XRD and FT-IR. To identify the mechanism of skin permeation, in vitro skin permeation study was conducted with a Franz diffusion cell and excised SD-rat and hairless mouse dorsal skin. In vivo efficacy assessment in mono-iodoacetate (MIA)-induced rheumatoid arthritis animal model was also conducted. CbFG was successfully prepared and, after applying CbFG to the excised rat dorsal skin, the CbFG-film was also formed well. The physicochemical characteristics of CbFG and CbFG-film could be explained by the grafting of oleic acid onto chitosan in the absence of catalysts. In addition, CbFG containing oleic acid had a higher skin permeation rate in comparison with any other candidate enhancers. The in vivo efficacy study also confirmed significant anti-inflammatory and analgesic effects. Consequently, we report the successful preparation of chitosan-based film forming gel containing ketoprofen with excellent mechanical properties, skin permeation and anti-inflammatory and analgesic effects.
... Studies on UFFAs, i.e., OA and palmitoleic acid, were shown to induce calcium influx and abnormal keratinocyte differentiation in hairless mice [17]. When OA was applied topically, it either induced ultrastructural changes on rabbit ears similar to those seen in human comedones [25] or it caused a decrease in Langerhans cells density and generation of pores on the surface of epidermal corneocytes [45]. In addition, inflammatory acne may be triggered by UFFAs to produce multiple proinflammatory cytokines such as IL-1a, tumor-necrosis factor (TNF)-a, and chemokines (e.g., IL-8) stimulating keratinocytes, sebocytes, and immune cells, which, in turn, attract neutrophils and mononuclear cells to the pilosebaceous unit [10,21,30,31,37,38,[46][47][48][49]. ...
Article
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Acne vulgaris is a disease of pilosebaceous units with multifactorial pathogenesis, including hyperkeratinization, increased sebum secretion, and inflammation. Recently, it was suggested that acne subjects may have also impaired skin barrier. We hypothesized that excess unsaturated free fatty acids (UFFA) present in the sebum may cause barrier impairment associated with increased follicular stratum corneum (SC) thickening and inflammation seen in acne. Therefore, epidermal and sebaceous lipid profiles from acne and healthy subjects were analyzed and an in vitro epidermal tissue model was developed to validate this hypothesis. Significantly increased levels of free fatty acids (p < 0.05) were observed in skin lipids of human acne vs. healthy subjects. Exposure of human epidermal equivalents (HEEs) to the UFFA oleic acid (OA), also present in sebum, led to barrier impairment associated with increased SC lipid disorder, increased secretion of interleukin-1α (IL-1α), and excessive SC thickening. Furthermore, the expression of genes encoding for inflammatory cytokines and epidermal differentiation proteins was also increased both in acne lesions and in OA-treated HEEs. Taken together, these data are in agreement with the hypothesis that excess UFFAs in sebum of acne subjects may contribute to impaired skin barrier associated with the increased follicular SC thickness and inflammation seen in acne. Moreover, OA induces similar molecular and phenotypic changes in HEEs as those seen in acne lesions and suggests that an UFFA-treated epidermal tissue model can be used to study the UFFA-mediated pathways involved in the pathogenesis of inflammatory acne and for the development of appropriate therapies.
... Furthermore, TO contains the highest amount of oleic acid, which is known as skin penetration enhancer [18]. Oleic acid can reduce the diffusional resistance of the skin by reacting with the lipid matrix in stratum corneum increasing lipid fluidity [18,19]. The extract was also found to have the highest solubility in TO. ...
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The aim of this study was to enhance the solubility and stability of Acacia concinna extract by loading in a microemulsion for topical application. Both physical appearance and biological activitie of the extract-loaded microemulsion were determined in comparison with the extract solution. Pseudoternary phase diagrams of three oil types including tea seed oil, grape seed oil, and sesame oil, together with polysorbate 85 or the mixture of polysorbate 85 and sorbitan oleate as surfactants, and absolute ethanol as a co-surfactant were constructed to optimize the microemulsion area. The selected microemulsion was then characterized for droplets size, polydispersity index, and viscosity. Tea seed oil exhibited the highest microemulsion area in the phase diagram because it had the highest unsaturated fatty acid content. The microemulsion composed of tea seed oil (5%), polysorbate 85 (40%), ethanol (20%), and water (35%) exhibited Newtonian flow behavior with the droplet size and polydispersity index of 68.03 ± 1.09 nm and 0.44 ± 0.04, respectively. After 4% w/w of the extract was incorporated into the microemulsion, larger droplets size was observed (239.77 ± 12.69 nm) with a lower polydispersity index (0.37 ± 0.02). After storage in various conditions, both physical appearances and the stability of biological activity of the extract-loaded microemulsion were improved compared to the solution. Therefore, the A. concinna loaded microemulsion may be a promising carrier for further development into a topical formulation and clinical trials for pharmaceutical and cosmeceutical applications are also suggested.
... Azone acted through destroying the ordered arrangement of lipid layers and increasing the liquidity of membrane, and thus promoted drug permeation (Xu and Zhu, 2007). Oleic acid would change the oil-water partition coefficients of drug and influence the permeation procedure (Touitou et al., 2002). The 5-HMT hydrogels with 10% NMP as enhancer displayed the maximum Q and permeated significantly. ...
Article
development, single-factor experiments were employed to evaluate the effect of adding different matrix, enhancers, 5-HMT, ethanol and glycerol on drug skin development, single-factor experiments were employed to evaluate the effect of adding different matrix, enhancers, 5-HMT, ethanol and glycerol on drug skin permeation. Finally, Carbopol 940 was selected as the gel matrix with N-methyl pyrrolidone (NMP) chosen as the enhancer. The relationship between time and the steady accumulative percutaneous amount (Q, μg cm− 2) of optimized 5-HMT hydrogels was Q4–12 h = 1290.8 t1/2 − 1227.7. The absolute bioavailability of 5-HMT hydrogels was 20.7% showed in pharmacokinetic study. No skin irritation was observed in 5-HMT hydrogels skin irritation study. In the pharmacodynamic study, the overactive bladder model was induced by 150 μg/kg of pilocarpine in rats. The significant effects of 5-HMT hydrogels on the inhibition of urine output on rat model were last to 12 h. The optimized 5-HMT hydrogels displayed prolonged pharmacological responses. 5-HMT hydrogels effectively avoided the metabolism difference of enzyme in bodies compared with tolterodine tablets, provided one single active compound in plasma to reduce the variability of having two active compounds. To further elucidate the transdermal mechanism, fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and activation energy measurements were used to study the transdermal routes and changes of stratum corneum during drug release.
... The trials where the breakage occurred at the jaw were invalid and the result was repeated on another strip. The Tensile strength was calculated by the formula, Tensile strength = Break force [1 + change in length] / (width) (breadth) [initial length of the film].The percent elongation was determined by noting the length just before the break point and substituting the formula % Elongation = [Final length -Initial length] /Initial length * 100 [15][16][17] . ...
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To treat allergic disorders on long term therapy needs plasma concentration of drug in better manner. This was achieved by formulating the drug in controlled release pattern. Fexofenadine hydrochloride is almost completely absorbed from the gastro-intestinal tract following oral administration,but bioavailability is reported to be only about 45% due to hepatic first-pass metabolism. The present study aims to prepare Transdermal patch of Fexofenadine hydrochloride.Preparation of transdermal patches of Fexofenadine hydrochloride using polymers: Hydroxypropyl methyl cellulose, Ethyl cellulose plasticized with Glycerol. The patches were evaluated for various parameters like Thickness, Water-Vapor Permeability, Tensile Strength, Drug Content,Diffusion and Dissolution studies. Prepared patches exhibited Zero Order Kinetics and the permeation profile was matrix diffusion type.In-vitrorelease study of Fexofenadine hydrochloride transdermal patch shown release of drug 79 % at 24 h and also follows zero order kinetics release pattern. Keywords: Fexofenadine Hydrochloride, Ethyl cellulose, Hydroxypropyl methyl cellulose, In-vitro.
... This effect may be attributed to the fact that OA can improve the fluidity of lipid and expand the cell gap. Thus, the drug distribution in this group was more uniform, and more drugs could pass from the cell gap 38 . Oleic acid was a good penetration enhancer for the skin penetration of piroxicam. ...
Article
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This study aims to investigate the solid lipid nanoparticle (SLN) as a novel vehicle for the sustained release and transdermal delivery of piroxicam, as well as to determine the anti-inflammation effect of piroxicam loaded SLN. SLN formulation was optimized and the particle size, polydispersity index, zeta potential (ZP), encapsulation efficiency, drug release, and morphological properties were characterized. The transdermal efficiency and mechanism of the piroxicam loaded SLNs were investigated in vitro. With the inflammation induced edema model in rat, the anti-inflammatory efficiency of piroxicam-enriched SLNs (Pir-SLNs) was evaluated. The SLN formulation was optimized as: lecithin 100mg, Glycerin monostearate 200mg and Tween (1%, w/w). The particle size is around 102±5.2 nm with a PDI of 0.262. The ZP is 30.21±2.05 mV. The prepared SLNs showed high entrapment efficiency of 87.5% for piroxicam. There is no interaction between piroxicam and the vehicle components. The presence of polymorphic form of lipid with higher drug content in the optimized Pir-SLNs enables the Pir-SLNs to release the drug with a sustained manner. Pir-SLNs with OA as enhancer can radically diffuse into both the stratum corneum and dermal layer, as well as penetrate through the hair follicles and sebaceous glands with significantly higher density than the other control groups. Pir-SLNs promptly inhibited the inflammation since the 3(rd) hour after the treatment by decreasing the PGE2 level. SLN was demonstrated to be a promising carrier for encapsulation and sustained release of piroxicam. Pir-SLN is a novel topical preparation with great potential for anti-inflammation application.
... Measurements were repeated three times. In this study, the TEWL results were expressed as percent change compared to data obtained from basal TEWL values [35,36]. % change=([(value after treatment)-(basal value)]×100)/ (basal value) ...
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Objectives: Nitrofurantoin is widely used in the prophylaxis of urinary-tract infections. The aim of this study was to develop and characterize innovative transdermal formulations of nitrofurantoin, to increase the patient compliance and decrease the adverse effects such as nausea and vomiting which limit the drug use in long-term. Methods: Nitrofurantoin loaded microemulsion, gel (hydrogel, lipogel and DMSO gel) and film formulations were prepared and characterized via several parameters. Ex-vivo drug permeation studies were performed to determine the amount of drug permeated through the rat skin. In in-vivo studies, in order to detect nitrofurantoin in urine, the selected formulations were applied to male Wistar rats transdermally. Also, skin irritation tests (transepidermal water loss and erythema) were performed. Results: All nitrofurantoin loaded formulations were prepared successfully and were stable at +4oC for 3 months. 13%, 16%, 32.5%, 36.5% and 39% of drug permeated through the rat skin in the 168th hour for hydrogel, lipogel, film, microemulsion and DMSO gel, respectively. Only with film and DMSO gel formulations, nitrofurantoin was detected in urine. Transepidermal water loss was increased compared to basal level in film type formulations (p<0.05). However, in erythema experiments there was no difference (p>0.05). Conclusion: There is no approved transdermal formulation of nitrofurantion on the market. Therefore, the prepared film formulations could be an alternative due to their high penetration through the rat skin, the presence of nitrofurantoin in urine and because they cause no irritation on the skin.
... When applied together with ethanol, OA is also believed to cause SC lipid extraction. [37,38] ...
... One possible explanation for the high uptake efficiency of MO:OA:PEI is the more elastic character of these nanoparticles due to their OA content. 31 Furthermore, OA has been shown to be a potent penetration enhancer, 32 and PEI polymer is considered the 'gold standard' for non-viral gene delivery due to its high transfection potential and high endosomolytic activity. 33 It is important to mention the fusogenic effect of the structural lipid of the nanodispersion provided by MO, which can improve the cellular uptake of nanoparticles. ...
Article
Short-interfering RNAs (siRNAs) are a potential strategy for the treatment of cutaneous diseases. In this context, liquid crystalline nanoparticles functionalized with specific proteins and peptide-transduction domains (PTDs), which act as penetration enhancers, are a promising carrier for siRNA delivery through the skin. Herein, hexagonal phase liquid crystal nanoparticles based on monoolein (MO) and/or oleic acid (OA) containing (or lacking) the cationic polymer polyethylenimine (PEI) and the cationic lipid oleylamine (OAM) were functionalized with the membrane transduction peptides transcriptional activator (TAT) or penetratin (PNT). These nanoparticles were complexed with siRNA and characterized by particle size, polydispersity, zeta potential, complexation efficiency and siRNA release. The formulations containing cationic agents presented positive zeta potentials, sizes on the nanometer scale, and complexed siRNAs at concentrations of 10 μM; these agents were successfully released in a heparin competition assay. Cell culture studies demonstrated that nanoparticles composed of MO:OA:PEI functionalized with TAT were the most efficient at transfecting L929 cells, and the uptake efficiency was enhanced by TAT peptide functionalization. Thereafter, the selected formulations were evaluated for in vivo skin irritation, penetration and in vivo efficacy using a chemically induced inflammatory animal model. These nanoparticles did not irritate the skin and provided higher siRNA penetration and delivery into the skin than control formulations. Additionally, efficacy studies in the animal model showed that the association of TAT with the nanodispersion provided higher suppression of tumor necrosis factor (TNF)-α. Thus, the development of liquid crystalline nanodispersions containing TAT may lead to improved topical siRNA delivery for the treatment of inflammatory skin diseases.
... Measurements were repeated three times. In this study, the TEWL results were expressed as percent change compared to data obtained from basal TEWL values [35,36]. ...
... Pseudoternary phase diagram of HO and oleic acid (1:1)/Triton X-114 and propan-2-ol (2:1)/water is shown in fig. 2. The microemulsion region in the phase diagram was 45.25%. Oleic acid was mixed with HO and used as an oil phase in the system since oleic acid has been reported to act as a penetration enhancer by lipid fluidization and phase separation [34][35]. Six formulations in the microemulsion region (ME1 -ME6) were formulated and characterized for their particle size and size distribution as the results shown in fig. 3. The particle size was in the range of 26 to 32 nm which were in the microemulsion range [36]. ...
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Objective: The present study aims to develop and characterize microemulsion from herbal infused oil of Zingiber cassumunar (HO) and microemulsion-based hydrogel (MBH) containing indomethacin. The release patterns of indomethacin from MBH were also investigated. Methods: HO was produced by hot extraction of Z. cassumunar rhizome in coconut oil, and characterized for acid value, iodine value, and saponification value. The cytotoxicity of HO on human peripheral blood mononucleared cells Results: HO exhibited an acid value of 0.203 ± 0.004 mg of KOH/g, iodine value of 7.39 ± 0.15 g of I (PBMCs) was also investigated. Pseudoternary phase diagram was constructed to study suitable compositions of microemulsion containing HO, oleic acid, Triton X-114, propan-2-ol, and water. Indomethacin was then incorporated into the microemulsion and finally blended with gel base (2% Carbopol 940 or 3% sodium carboxymethylcellulose) to produce MBH. The indomethacin MBH was characterized for appearance, pH, viscosity, and in vitro release characteristics. 2/100 g, and saponification value of 265.4 ± 7.3 mg of KOH/g with no cytotoxic effect on human PBMCs. The microemulsion region in the pseudoternary phase diagram of HO, oleic acid, Triton X-114, propan-2-ol, and water was 45.25%. Six microemulsions (ME1– ME6) containing 10% of HO and oleic acid mixture (1:1) as the oil phase and Triton X-114 and propan-2-ol (3:2) as surfactant mixture were formulated and characterized. The droplet size was in the range of 26 to 32 nm with polydispersity index less than 0.3. They showed a Newtonian flow behavior with the viscosity ranging from 15.12 ± 0.15 to 16.78 ± 0.12 Pas. The microemulsion was incorporated into hydrogel using 3% sodium carboxymethylcellulose or 2% Carbopol 940. Only ME1 – ME3 gave clear MBH; therefore, they were studied in the in vitro Conclusion: The topical MBH, containing microemulsion of HO, oleic acid, Triton X-114, propan-2-ol and water, might be a promising approach for sustained transdermal delivery of poor water-soluble compounds, including indomethacin. release of indomethacin, and the results indicated the sustained-release characteristic fitted the Higuchi model.
... OA was reported to increase the permeation of 5fluorouracil (Yamane et al. 1995), fluconazole (Zakir et al. 2010) and methotrexate (Srisuk et al. 2012). It has also been reported that OA dramatically change the morphology and the density of epidermal Langerhans cells and generates pores on the surface of epidermal corneocytes at a concentration of 10% (Touitou et al. 2002). The concentration used in our study was well below this irritant concentration and ceramide-2 in vesicle composition counterbalances its effects since it is a skin protectant. ...
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Context: Vesicular transdermal delivery can enhance the bioavailability of a drug especially affected by first-pass metabolism, e.g. nitrendipine. However effective transdermal delivery employs permeation enhancer, e.g oleic acid (OA) with ceramide 2, stearic acid, behenic acid, and cholesteryl sulfate lipid complex. Objective: This study investigated the preparation, characterization of physicochemical properties, ex vivo permeation using human skin, pharmacokinetic parameters and antihypertensive potential in rats, of nitrendipine-loaded nanovesicles of ceramide 2, stearic acid, behenic acid and cholesteryl sulfate containing oleic acid gel (NOVG). Materials and methods: The nanovesicles were made using film hydration method and characterized for physicochemical properties, ex vivo permeation using human skin, pharmacokinetic parameters and antihypertensive potential. Results: Nitrendipine-loaded nanovesicles of ceramide-2 containing oleic acid (NOV-5) have shown fluxes in the range of 4.88-24.72 μg/cm(2)/h nitrendipine oral suspension (NOS) at equal dose. NOVG-5 has shown almost 33% reduction in blood pressure in the first hour and a further decrease of 25% in the second hour to restore the normal pressure. Discussion: The permeation increases with increase in OA content. OA gets integrated in vesicle wall and enhances its permeability, whereas ceramide content makes sure that skin does not become damaged even after permeation. Conclusion: NOVG-5 has shown the most favorable physicochemical properties and good permeation through skin providing good management of hypertension during crucial initial hours.
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The dermal delivery of peptide therapeutics that are of high molecular weight is a challenge. Cyclosporine A (CsA) is a cyclic undecapeptide with poor aqueous solubility and high molecular weight (1202 Da) indicated for psoriasis. The objective of the study was to evaluate the effect of ionic liquids mixed with the Pluronic F127 matrix in skin permeation of CsA and its efficacy in psoriasis treatment. Choline and geranic acid (CAGE) ionic liquids in a 1:2 molar ratio were mixed with Pluronic F127 (22.7%) and PEG 400 (45%) to prepare an organogel formulation. The CsA-loaded CAGE (CsA-CAGE) and CAGE-Pluronic F127 gels (CsA-CAGE-P gel) were characterized for physical and rheological characteristics. The skin transport studies showed that free CsA did not permeate across the excised porcine skin after 48 h. The amount of CsA permeated across the oleic acid (0.25% v/v) and palmitic acid (0.25% w/v) cotreated skin was found to be 244 ± 4 and 1236 ± 17 μg/cm², respectively. The application of CsA-CAGE and CsA-CAGE-P gel enhanced CsA flux by 110- and 135-fold, respectively, compared with the control. The thermal analysis and biophysical studies changed the barrier property of the skin significantly (p < 0.05) after incubation with CAGE and CAGE-P gel. The pharmacokinetic studies in the rat model showed that topical application of CsA-CAGE-P gel provided 2.6- and 1.9-fold greater Cmax and AUC0–t, respectively, compared to the control group. In vitro–in vivo level A correlations were established with R² values of 0.991 and 0.992 for both linear and polynomial equations for the CsA-CAGE-P gel formulation using the Wagner–Nelson method. The topical application of CsA-CAGE-P gel (10 mg/kg) on an imiquimod-induced plaque psoriatic model reduced the area of the psoriasis and severity index (PASI) score significantly for erythema and scaling, reversing the changes to skin thickness, blood flow rate, and transepidermal water loss. Together, CAGE-Pluronic F127 organogel was developed as an effective topical formulation for the local and systemic delivery of CsA for the treatment of psoriasis.
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Vaccination is one of the most successful measures in modern medicine to combat diseases, especially infectious diseases, and saves millions of lives every year. Vaccine design and development remains critical and involves many aspects, including the choice of platform, antigen, adjuvant, and route of administration. Topical vaccination, defined herein as the introduction of a vaccine to any of the three layers of the human skin, has attracted interest in recent years as an alternative vaccination approach to the conventional intramuscular administration because of its potential to be needle-free and induce a superior immune response against pathogens. In this review, we describe recent progress in developing topical vaccines, highlight progress in the development of delivery technologies for topical vaccines, discuss potential factors that might impact the topical vaccine efficacy, and provide an overview of the current clinical landscape of topical vaccines.
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Diabetes mellitus is a complex chronic metabolic disease that has a negative impact on patient health as well as creates a significant financial strain on healthcare systems worldwide. An unregulated molecular and cellular wound microenvironment and persistent inflammation are characteristics of chronic diabetic ulcers. Films, antimicrobial dressings, hydrogels, foams, and other biomaterials have all found uses in wound treatment. Despite many studies, there is still no “perfect” therapy for chronic wound healing, and complexities have been addressed. In this paper, we discuss the present difficulties associated with the production of biomaterials for the management and treatment of chronic wounds. Which includes a wide range of important biomaterials and their composites that accelerate angiogenesis, inhibit bacterial infection, collagen matrix deposition, and wound closure. This review also highlights other factors like oxygenation, hormones, obesity, medications, smoking, and nutrition. Finally, the future directions of biomaterials for chronic wound healing are discussed.
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A painless and non-invasive method to deliver drugs using dermal and transdermal administration routes has been expanding for more than 30 years as it reduces the risk of drug overdoses that can be associated with oral administrations or injections. To understand the particularities of this drug delivery pathway, we will present a rapid review of the skin, including its structure and the parameters that influence drug diffusion into it, and then discuss the strategies that improve dermal drug delivery. Of the multitude of existing systems used for topical dermal and transdermal applications, this review will focus on the breakthroughs in drug delivery systems made of hydrogels. Specifically, we will firstly present the use of hydrogels as innovative drug delivery vehicles to carry the active ingredient and penetrate the skin barrier. We will discuss the structure of hydrogels and the physicochemical parameters to master for improving drug delivery, as well as the drug encapsulation and release processes from hydrogels. In the last part, we will review the use of hydrogels as pharmaceutical forms associated with other vehicles - as emulsions, lipid nanoparticles, vesicles, capsules and polymeric or inorganic nanoparticles - suitable for skin penetration enhancement and drug protection, as well as side effects that may limit their use.
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Neglected Tropical Diseases, such as schistosomiasis, still affect thousands of people, presenting high morbidity rates. Currently, praziquantel is the only drug available for the treatment, disclosing the urgency of developing new treatment alternatives. Oleic acid is commonly used as a permeation promoter, inducing the disruption of the membrane's lipid structure. It is an exciting characteristic for the oleic acid to act on the Schistosoma mansoni worm tegument as a therapeutic target. However, it possesses low aqueous solubility and oral bioavailability. Thus, the oleic acid encapsulation in a nanostructured system, such as polymeric nanocapsules, can improve its properties and efficacy. This study aimed to develop, characterize, and evaluate the in vitro cytotoxicity and antischistosomal effect of oleic acid-loaded nanocapsules. We employed the interfacial deposition method for the oleic acid-loaded polymeric nanocapsules preparation. We performed physicochemical characterization, in vitro cytotoxicity, and antischistosomal effect studies for the designed nanocapsules. The oleic acid-loaded nanocapsules are spherical, with a smooth surface, average size around 200 nm, low polydispersity index (<0.3), and zeta potential higher than (-) 30 mV. All oleic acid was encapsulated in the nanocapsules. The cell viability was greater than 70 % for all treatments with oleic acid-loaded nanocapsules, except for samples diluted 1:10 (v/v), and greater than 100 % for some dilutions. Sub-lethal concentrations (12.5 and 25 μg/mL) of nanocapsules reduce egg production and worms' motor activity. The oleic acid-loaded polymeric nanocapsules cause death in a concentration-dependent manner, showing 100 % of worms mortality from 200 μg/mL in 4 hours of incubation and 50 μg/mL in 24 hours. Besides, optical microscopy revealed that oleic acid-loaded polymeric nanocapsules caused moderate to intense damage of the tegument dorsal surface, which is essential to cause the worm killing. Finally, the developed oleic acid-loaded polymeric nanocapsules show considerable in vitro activity against S. mansoni, promising a new treatment option.
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Human basic fibroblast growth factor (hFGF2) is widely recognized for accelerating skin wound healing in both animal models and randomized clinical trials. However, the low skin permeation and bioavailability of hFGF2 remain the most limiting factors in the pharmacological application. For the first time, Camelina Lipid Droplets (CLD) delivery system was displayed important virtue, by promoting the skin absorption of hFGF2, which is a key factor that accelerates the skin wound repair , and provide a new alternative for skin therapy. In this study, we used the CLD as a safer material to prepare the nanoparticles, which were characterized by size and morphology. Our data revealed that particle sizes of Camelina Lipid Droplets linked to hFGF2 (CLD-hFGF2) were around 133.5 nm; it also displayed that the complex of CLD-hFGF2 penetrates the skin barrier in deeper than an individual hFGF2. This suggests that once the hFGF2 is fixed onto the surface of CLD, it can cross the stratum corneum and play a therapeutic role into the dermis . Furthermore, we demonstrated that CLD-hFGF2 enhances fibroblast migration, and significantly improves skin regeneration for accelerating wound healing without any significant toxicity. This paper highlights the importance of CLD as an emerging delivery system; it is also providing a new and applicable therapeutic research direction through enhancing the skin permeation of hFGF2 to accelerate wound healing.
Chapter
This book provides a critical overview of the advances being made towards overcoming biological barriers through the contribution of nanosciences and nanotechnologies. Overcoming these barriers is of primary importance for solving the problems of many current drugs and vaccines and it is also especially relevant for the commercial exploitation of new therapeutic strategies i.e. gene and cellular therapies. Despite important information that has been covered in recently published books related to nanomedicine (mainly oriented to technologies and applications), there is still an important gap related to the relationship between the chemical properties of nanobiomaterials and their interaction with the biological environment. Thus, this comprehensive new book that is presented with a clear and organised structure dedicated to the different biological barriers relevant for drug delivery applications will focus on (i) mechanistic issues related to the interaction between drug delivery systems and biological barriers and (ii) the analysis of the critical factors determining the efficacy of nanobiomaterials for specific applications. Moreover, this field has become highly multidisciplinary over the last decade, leading to the development of new products, as well as to significant advances from the regulatory point of view. Moreover, this book will also provide an up-to-date view on the clinical relevance of nanomedicine and on its possible impact on global health.
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Introduction In the past, mathematical modelling of the transport of transdermal drugs has been primarily focused on the stratum corneum. However, the development of pharmaceutical technologies, such as chemical enhancers, iontophoresis, and microneedles, has led to two outcomes; an increase in permeability in the stratum corneum or the ability to negate the layer entirely. As a result, these outcomes have made the transport of a solute in the viable skin far more critical when studying transdermal drug delivery. Areas covered The review will explicitly show the various attempts to model drug transport within the viable skin. Furthermore, a brief review will be conducted on the different models that explain stratum corneum transport, microneedle dynamics and estimation of the diffusion coefficient. Expert opinion Future development of mathematical models requires the focus to be changed from traditional diffusion-based tissue models to more sophisticated three-dimensional models that incorporate the physiology of the skin.
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Curcumin, resveratrol, and thymoquinone are the potential natural bio-actives reported with good anti-psoriatic activity. However, poor aqueous solubility and limited skin permeation of these natural bio-actives hinder their effective delivery and potential therapeutic outcome. In this regard, current research work focuses on the design and optimization of nanoemulsion (NE) gel formulation for the concurrent delivery of these three drugs. The NE system is consisting of oleic acid as oil phase, Tween 20 as surfactant, and PEG 200 as co-surfactant. The optimized formulation exhibited the droplet size 76.20 ± 1.67 nm, PDI of 0.12 ± 0.05, RI of 1.403 ± 0.007, and viscosity of 137.9 ± 4.07 mp. Carbopol 940 (0.5% w/v) was used as the gelling agent to prepare the NE gel which exhibited a good texture profile. The optimized formulation exhibited a higher % of growth inhibition on A-431 cells and demonstrated good anti-angiogenic activity in the HET-CAM test. Finally, in vivo studies in Balb/c mice model showed improved anti-psoriatic conditions which indicated that the triple natural bio-actives combination in nanoemulgel formulation is effective in the management of psoriasis.
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Cryptotanshinone (CPT) is an efficacious acne treatment, while niosomal hydrogel is a known effective topical drug delivery system that produces a minimal amount of irritation. Three-dimensional (3D) printing technologies have the potential to improve the field of personalized acne treatment. Therefore, this study endeavored to develop a 3D-printed niosomal hydrogel (3DP-NH) containing CPT as a topical delivery system for acne therapy. Specifically, CPT-loaded niosomes were prepared using a reverse phase evaporation method, and the formulation was optimized using a response surface methodology. In vitro characterization showed that optimized CPT-loaded niosomes were below 150 nm in size with an entrapment efficiency of between 67 and 71%. The CPT-loaded niosomes were added in a dropwise manner into the hydrogel to formulate CPT-loaded niosomal hydrogel (CPT-NH), which was then printed as 3DP-CPT-NH with specific drug dose, shape, and size using an extrusion-based 3D printer. The in vitro release behavior of 3DP-CPT-NH was found to follow the Korsmeyer-Peppas model. Permeation and deposition experiments showed significantly higher rates of transdermal flux, Q24, and CPT deposition (p < 0.05) compared with 3D-printed CPT-loaded conventional hydrogel (3DP-CPT-CH), which did not contain niosomes. In vivo anti-acne activity evaluated through an acne rat model revealed that 3DP-CPT-NH exhibited a greater anti-acne effect with no skin irritation. Enhanced skin hydration, wide inter-corneocyte gaps in the stratum corneum and a disturbed lipid arrangement may contribute towards the enhanced penetration properties of CPT. Collectively, this study demonstrated that 3DP-CPT-NH is a promising topical drug delivery system for personalized acne treatments.
Article
The aim of this work was the preparation of solid lipid nanoparticles, based on trehalose monooleate, loaded with cyclosporin-A for potential treatment of psoriasis. Trehalose was esterified with oleic acid in order to obtain a more lipophilic compound suitable as a lipid matrix for the formulation of a new type of solid lipid nanoparticles. The ester formation was confirmed by FT-IR and ¹HNMR. The solid lipid nanoparticles, based on trehalose monooleate, were successfully prepared with and without cyclosporin-A, using the microemulsion technique. Further characterizations were performed by differential scanning calorimetry (DSC). The drug release from the SLNs was then evaluated through the Franz diffusion cells, using both dialysis membranes and rabbit ear skin. With the aim to verify the localization of SLNs in the skin layers, additional investigations using confocal microscope and stripping tape test were carried out. Finally, a dermatological formulation, based of SLNs loaded with cyclosporin-A, was prepared and tested through Franz diffusion cells. The obtained results indicate the possibility of using these nanoparticles as vehicle of cyclosporin-A for topical treatment of psoriasis, reducing the side effects due to systemic absorption of cyclosporin-A and, at the same time, increasing its concentration at skin injury level.
Article
The traditional Chinese medicine Kushen (Radix Sophorae flavescentis) is medicinally used for the subterraneous root leaving the stems, leaves and seeds as a major industrial waste. The application value of the Sophora flavescens seed is worth of attention. Herein, it was intended to characterize the mature S. flavescens seed for their phytochemicals composition in alkaloids, fatty acids, polysaccharide, protein, nucleosides and nucleobases. In addition, their bioactivities such as antioxidant and antimicrobial activity were also evaluated through different in vitro biochemical assays. The mature S. flavescens seed is rich in alkaloids, linoleic acid and crude protein, which exhibit excellent antibacterial, antioxidant activity and nutritional value. The phytochemical profiles and the bioactivities of S. flavescens seed endorse it a promising resource, which could be utilized in pharmaceutical, cosmetics and food industry as the raw material.
Chapter
Most widely used approach to enhance drug permeation across skin is the use of chemical penetration enhancers that reversibly and transiently compromise skin barrier function. Ideally, penetration enhancers or any pharmaceutical excipients are expected to be pharmacologically inert and devoid of any clinical and/or histopathological side effects. Despite their wide spread use in topical preparations and high interest in transdermal research and generally regarded as safe (GRAS) status, most penetration enhancers are associated with high incidence of dose-dependent side effects ranging from local irritation to systemic reactions upon acute or chronic use. This chapter attempts to summarize and describe the reported toxicological aspects of some of the commonly used skin penetration enhancer classes such as terpenes, fatty acids, fatty alcohols, alcohols, glycols, laurocapram (Azone®), sulfoxides, pyrrolidones, and surfactants.
Chapter
Fatty alcohols, fatty acids (saturated and unsaturated), and fatty acid esters have been extensively utilized as skin penetration enhancers in many research studies over the past 3 decades. Some of these compounds, for example, oleic acid, stearic acid, isopropyl palmitate, ethyl oleate, have been approved by the US Food and Drug Administration for their use in topical and transdermal products. It is generally believed that these agents increase skin permeation by disrupting the lipid organization in skin layers, forming solvated complexes, increasing the diffusivity and partitioning of drugs in/through the skin barrier. This chapter summarizes the utility of fatty alcohols, fatty acids, and their esters as promising percutaneous penetration enhancers for topical and transdermal delivery of drugs. The role of vehicle or other ingredients from the formulation on the enhancement effects of the topical or transdermal formulation and their skin irritation potential has also been presented.
Article
Thermal mud (peloids), which are frequently used for thermal therapy purposes consist of organic and inorganic (minerals) compounds in general. Organic structure is formed after a variety of chemical processes occurring in decades and comprise of a very complex structure. Stagnant water environment, herbal diversity, microorganism multiplicity and time are crucial players to form the structure. Data regarding description of organic compounds are very limited. Nowadays, it was clearly understood that a variety of compounds those are neglected in daily practice are found in thermal mud after GC-MS and similar methods are being frequently used. Those compounds which are biologically active are humic compounds, carboxylic acids, terpenoids, steroids and fatty acids. By comprising the thermal mud, these different compound groups which are related to divers areas from cosmetology to inflammation, make the thermal mud very meaningful in the treatment of human disease. In this review, it was tried to put forward the effects of several molecule groups those consisting of the thermal mud structure.
Chapter
Both film-forming and heated system approaches have shown great potential for improving drug delivery across the skin and have been able to show good patient acceptability, key attributes required for the development of products that improve patient treatment. One of the major advantages of using film-forming systems is that they can use supersaturation or at least generate high drug thermodynamic activity in the formulation to improve drug permeation across the skin. Two main methods are most commonly cited in the literature to produce supersaturated systems on the skin: the co-solvent technique and solvent evaporation. Both ethanol and isopropanol, the most common volatile solvents in film-forming systems, can act as penetration enhancers. Synergism has been observed with drugs such as nicardipine, clonazepam, tenoxicam, diclofenac sodium and nifedipine when using various combinations of penetration enhancing chemicals, in particular with propylene glycol since it is one of the most commonly studied penetration enhancers.
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The aim of the present research was to develop and evaluate transdermal patch formulations of Sumatriptan Succinate (SUS). Matrix type transdermal patches of SUS were prepared by solvent evaporation technique. The enhancing effects of the permeation enhancers Tween 80 (0.25, 0.5,1, 1.5 and 2% w/w), olive oil (2, 4, 6, 8 and 10% w/w) and Isopropyl myristate (2, 4, 6, 8 and 10%w/w IPM) were evaluated using Franz diffusion cell and rabbit skin membrane. All the formulations were subjected to physical (rheological) and in vitro permeation studies. IPM (10%) showed 2-fold enhancement in permeation compared to the control formulation (without enhancer) and also greater permeability was noticed compared to Tween 80 and olive oil. In conclusion, the present data confirm the feasibility of developing SUS transdermal patches.
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Transcutaneous immunization (TCI) is a new technique that uses the application of vaccine antigens in a solution on the skin to induce potent antibody responses without systemic or local toxicity. We have previously shown that cholera toxin (CT), a potent adjuvant for oral and nasal immunization, can induce both serum and mucosal immunoglobulin G (IgG) and IgA and protect against toxin-mediated mucosal disease when administered by the transcutaneous route. Additionally, CT acts as an adjuvant for coadministered antigens such as tetanus and diphtheria toxoids when applied to the skin. CT, a member of the bacterial ADP-ribosylating exotoxin (bARE) family, is most potent as an adjuvant when the A-B subunits are present and functional. We now show that TCI induces secondary antibody responses to coadministered antigens as well as to CT in response to boosting immunizations. IgG antibodies to coadministered antigens were also found in the stools and lung washes of immunized mice, suggesting that TCI may target mucosal pathogens. Mice immunized by the transcutaneous route with tetanus fragment C and CT developed anti-tetanus toxoid antibodies and were protected against systemic tetanus toxin challenge. We also show that bAREs, similarly organized as A-B subunits, as well as the B subunit of CT alone, induced antibody responses to themselves when given via TCI. Thus, TCI appears to induce potent, protective immune responses to both systemic and mucosal challenge and offers significant potential practical advantages for vaccine delivery.
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Retinoic acid (0.5% in acetone) was applied topically to the back skin of five juvenile rhesus monkeys once a day for 7 successive days. Two control animals were given vehicle alone. Skin specimens were taken from each animal at 0, 1, 2, and 4 weeks. The tissues were prepared for both histology (1-[mu]m plastic sections) and split epidermal sheets (after incubation with EDTA solution, 17 mM). The split epidermal sheets were stained with ATPase and anti-Ia. antibody, and the number of Langerhans cells was counted. The activity of [beta]-glucuronidase in the split epidermis was assayed by Fishman's method. After one week of treatment, the epidermis showed marked acanthosis and hyperkeratosis. The Langerhans cells showed severe degeneration, and the number of cells had dropped to approximately one-third of the number in the control skins. Concomitantly, the activity of [beta]-glucuronidase in the epidermis had also decreased to one-third of the control levels. After withdrawal, the number of Langerhans cells and activity of [beta]-glucuronidase showed gradual recovery, and by the fourth week they were back to the ranges of pretreatment or control skins, but acanthotic change remained. The results suggest that retinoid applied topically to normal primate skin induces reversible degeneration and desquamation of the Langerhans cells, while the epidermis shows prolonged proliferative change.
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The aim of this study was to assess the effects of chemical and electrical modes of percutaneous penetration enhancement on the intercellular lipid lamellae of the stratum corneum. Hairless mice were treated with either oleic acid/propylene glycol and iontophoresis separately or together. Permeability barrier function was evaluated by measuring transepidermal water loss and correlated with the structure of stratum corneum intercellular lamellae, as evaluated by electron microscopy, using ruthenium tetroxide postfixation. Transepidermal water loss levels did not change following 1 h iontophoresis alone. In contrast, topical applications of 0.3 M oleic acid in propylene glycol for 1 h increased transepidermal water loss significantly. Moreover, the combined use of iontophoresis plus 0.3 M oleic acid for 1 h further increased transepidermal water loss at equivalent time points. Ultrastructural observations demonstrated both marked disorganization of the intercellular lipid lamellae, as well as the presence of distended lacunae within the stratum corneum in oleic acid/propylene glycol plus or minus iontophoresis-treated stratum corneum. This study provides direct evidence that the oleic acid/propylene glycol system can disrupt the stratum corneum lipid lamellar structures, and that coapplications of oleic acid with iontophoresis further enhance the effects of oleic acid. The synergy between chemical and physical enhancement may afford a new approach to promote transdermal drug delivery.Keywords: barrier function, intercellular lipid lamellae, transdermal drug delivery
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The effect of propylene glycol (PG), azone (LDA) and n-decylmethyl sulfoxide (LDB) on the permeation course of fluorouracil through the hairless mouse skin was studied. Steady-state fluxes and permeability coefficients were measured in buffer solutions and in systems containing the enhancing agents. The permeation rates of fluorouracil have been shown to be highly pH dependent in the pH range of 5–9, the rate decreases with an increase in pH. The solubility of fluorouracil in pure propylene glycol at equilibrium measured by the solubility method was found to be 2.2 mg · ml−1 at 25°C which is a relatively low value as compared to the solubility in water. The effect of various concentrations of propylene glycol in aqueous donor solutions on the drug permeation rate was examined at pH's 5.7 and 9.0. It was found that propylene glycol decreases the permeation flux when increasing concentrations are added to the aqueous pH 5.7 system; however, at pH 9, a strong enhancement effect was shown. PG was also found to decrease the drug reservoir in the hairless mouse skin e.g. 8.4 and 2.8 mg · (mg skin)−1 for buffer pH 9 and PG/aqueous solution pH 9 systems, respectively. The concentration dependent enhancement effects of azone and n-decylmethyl sulfoxide have been measured. Both have been found to be potent enhancing agents. However, at relatively low concentrations such as 5%, Azone induced a 50-fold and n-decylmethyl sulfoxide only a two-fold enhancement of the drug steady-state flux. At high concentrations as much as 40%, n-decylmethyl sulfoxide appears to be more effective than Azone. The fluxes measured with these systems were 0.21, 0.17 and 0.003 mg · cm−2 · h−1 for the n-decylmethyl sulphoxide, Azone and PG/H2O systems, respectively.
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The skin permeation behavior of a tetrahydrocannabinol (THC) is described for the first time. In the design of transdermal delivery systems, Δ8-THC was chosen over Δ9-THC due to the former's better stability and its lower psychotropic potency. Sk permeation kinetic parameters were established through rat and human skin in vitro. The rat skin was found to be about 13-fold more permeable to Δ8-THC than the human skin. Autoradiographs showed that 24 h after application the drug was concentrated in the stratum corneum, in the upper epidermis, and around the hair follicles, indicating that THC penetrates the skin through the lipophilic pathways. A transdermal formulation containing oleic acid as a permeation enhancer was tested in rats. A serum level of about 50 ng/ml cross-reacting cannabinoids (THC + metabolites) was maintained for about 24 h, indicating a sustained delivery of THC to the bloodstream. The transdermal preparation presented in this study is designed for future clinical studies.
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Sheets of epidermis for incubation to demonstrate ATPase activity were obtained from specimens of mouse footpad using EDTA as the separation medium. The use of EDTA in place of the NaBr method previously described, resulted in a greatly reduced incubation time, precise localization of reaction product and preservation of ultrastructural detail. A population of closely and regularly spaced ATPase-positive dendritic cells was demonstrated by light microscopy. Electron microscopy demonstrated that, with short incubation times, reaction product was found only in the extracellular space adjacent to dendritic cells, the majority of which possessed the typical ultrastructural features of Langerhans cells.
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Free Putty acids of human skin surface Lipids have previously been implicated in The pathogenesis of acne vulgaris because of their apparent irritant and comedogenic properties. Prior studies on the relative irritancy of free fatty acids revealed the saturated C8 to C14 fatty acids and a C18 dienotic unsaturated fatty acid to he most irritating. Saturated free fatty acids from C3 to C18, and unsaturated C18 free fatly acids were applied daily under occlusive patch tests to human skin until detectable erythema appeared. The most irritating fatty acids were C8 through C12. Of the unsaturated fatty acids tested, only linoleic acid produced irritation.
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Langerhans' cells could have an important role in the immune surveillance for the malignant transformation associated with certain viral infections. A planimetric study of Langerhans' cells was performed on epithelial sheets obtained from male and female patients who presented with human papillomavirus-induced condylomata. Preliminary epidemiological studies have indicated that after a human papillomavirus infection the risk of malignant transformation is higher in the cervix than in the penis. Our study was designed in such a way that the Langerhans' cell density observed in condylomata could be compared to that detected in adjacent normal areas from the same patients. The results showed that a highly significant decrease in Langerhans' cells occurred in male and female human papillomavirus infected genital tracts. In the penis the local treatment with 5-fluorouracil restored the normal Langerhans' cell density. The significance of these findings in relationship with malignant transformation is discussed.
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We investigated the density and morphology of Langerhans cells in epidermal sheets of basal cell carcinomas in chronically sun-exposed skin (face) and less exposed skin (trunk) of 65 patients. Langerhans cells in perilesional and control skin at the same anatomical sites as the tumours were also examined. Two markers (ATPase and OKT6) were used in a parallel fashion to identify Langerhans cells. The density of the cells was reduced, and their morphology was changed in epidermis overlying tumours of both the face and trunk. These alterations were confined to tumour areas, as Langerhans cells in perilesional skin were normal when compared with control skin at both anatomical sites. Results with both markers were the same.
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The irritation of transdermal devices delivering levonorgestrel and the permeation enhancer ethyl acetate with or without ethanol was evaluated in rabbits. Erythema and oedema were assessed 24, 48 and 72 hr and 7 days after application of the 24-hr delivery system. The devices were found to be mild to moderately irritating, with erythema the primary manifestation. No differences were observed between devices using pure ethyl acetate or ethyl acetate-ethanol (7:3, v/v) as enhancers. Devices using pure ethanol as an enhancer gave levels of irritation similar to those using ethyl acetate-ethanol (7:3) or pure ethyl acetate. Control devices containing only water (no drug) were also found to be mildly irritating to rabbits following a 24-hr exposure period. A histological evaluation of the application sites of two of the formulations confirmed the visual observations of mild subacute irritation. The changes produced by transdermal levonorgestrel were reversible. The problems of skin irritation of transdermal devices is discussed with particular reference to the use of ethyl acetate and ethanol as skin penetration enhancers.
Article
Retinoic acid (0.5% in acetone) was applied topically to the back skin of five juvenile rhesus monkeys once a day for 7 successive days. Two control animals were given vehicle alone. Skin specimens were taken from each animal at 0, 1, 2, and 4 weeks. The tissues were prepared for both histology (1-micron plastic sections) and split epidermal sheets (after incubation with EDTA solution, 17 mM). The split epidermal sheets were stained with ATPase and anti-Ia antibody, and the number of Langerhans cells was counted. The activity of beta-glucuronidase in the split epidermis was assayed by Fishman's method. After one week of treatment, the epidermis showed marked acanthosis and hyperkeratosis. The Langerhans cells showed severe degeneration, and the number of cells had dropped to approximately one-third of the number in the control skins. Concomitantly, the activity of beta-glucuronidase in the epidermis had also decreased to one-third of the control levels. After withdrawal, the number of Langerhans cells and activity of beta-glucuronidase showed gradual recovery, and by the fourth week they were back to the ranges of pretreatment or control skins, but acanthotic change remained. The results suggest that retinoid applied topically to normal primate skin induces reversible degeneration and desquamation of the Langerhans cells, while the epidermis shows prolonged proliferative change.
Article
The epidermal Langerhans cell (LC) plays an important role in contact hypersensitivity reactions by presenting the antigens to T lymphocytes. LCs may also play a role in defence mechanisms against neo-antigens in skin tumours. Some studies have indicated that the LC population declines with age. Ultraviolet radiation induces a significant reduction in the number of epidermal LCs and most immunosuppressive drugs decrease the number and function of LCs as well. Such alterations in LCs might predispose to the development of skin tumours. To evaluate the importance of LCs in immunosurveillance of skin tumours, the number and the morphology of LCs was investigated in unaffected skin of patients with cutaneous tumours and in immunosuppressed patients. LCs within basal cell carcinoma (BCC) were examined as well. ATPase and CD1a staining was used to visualise LCs. The inflammatory response around BCC was estimated by the expression of HLA-DR+, CD3+ and ICAM-1+ cells. The prevalence of skin tumours was studied in renal transplant recipients on different immunosuppressive treatments such as azathioprine (Aza) and prednisolone (P), cyclosporin (CyA), azathioprine and prednisolone or cyclosporin and prednisolone. We found no difference in LC populations in patients treated with PUVA (psoralen and UVA-radiation) or in patients with skin tumours as compared with controls and no age-related reduction in LC numbers. However, immunosuppressed patients showed a reduced number of LCs, especially those who had received triple drug therapy (CyA+Aza+P). Patients treated with azathioprine and prednisolone (10-25 years) had a high prevalence of multiple warts (40%) and skin tumours (29%). In contrast, warts and skin tumours were not common in patients treated for 5 years with CyA+Aza+P or with CyA+P. Thus, the duration of immunosuppressive treatment seems crucial for the development of warts and skin tumours. However, the reduction in LC numbers was not more pronounced with time or in patients with skin lesions as compared with those without lesions. In the epidermis overlying basal cell carcinoma (BCC) the number of LCs was decreased and their morphology changed as compared with LCs in perilesional skin. These alterations were documented in horizontal sheets as well as in vertical sections of the epidermis analysed by light microscopy and with confocal laser scanning microscopy (CLSM). The latter technique permits a quantitative and morphological analysis of LCs in the same tissue volume. In vertical sections, numerous LCs were observed in the dermis surrounding BCC nests.(ABSTRACT TRUNCATED AT 400 WORDS)
Article
Langerhans cells are part of a vast system of potent antigen-presenting cells known under the name of dendritic cells. During the last decade, much has been learned on dendritic cell involvement in the immune response to infectious diseases. This review briefly summarizes our current understanding of the role played by Langerhans cells and other dendritic cells in the pathogenesis of DNA and RNA virus infections. These data may form the basis for the development of innovative approaches in the diagnosis, prevention, and treatment of viral diseases.
Article
The present study explores the effect of chemical penetration enhancers and iontophoresis on the in vitro permeability of cholecystokinin-8 (CCK-8) through porcine epidermis and on the ultrastructural changes in stratum corneum as observed by transmission electron microscopy (TEM). Enhancer [i.e., ethanol (EtOH), and 10% oleic acid in combination with ethanol (OA/EtOH)] pretreatment significantly increased (p < 0.01) the permeability coefficient of CCK-8 in comparison with the control (pretreated epidermis without enhancer). Iontophoresis further increased the permeability of CCK-8 (p < 0.01) through the enhancer-pretreated epidermis in comparison with the control. These results showed the synergistic effect of iontophoresis and enhancers such as OA/EtOH that provides an additional driving force to maintain and control the target flux of CCK-8. The ultrastructure of stratum corneum treated with ethanol demonstrated a loss of structural components in the superficial stratum corneum cell layers. OA/EtOH transformed the highly compact cells of stratum corneum into a looser network of filaments, creating an increased free volume and greater intracellular surface area. Treatment of stratum corneum with OA/EtOH followed by iontophoresis resulted in further swelling of stratum corneum cell layers. In conclusion, OA/EtOH in combination with iontophoresis increased the permeability of CCK-8 by loosening and swelling of stratum corneum cell layers.
Article
The outermost layer of the skin, stratum corneum (SC), provides an outstanding barrier against the external environment and is also responsible for skin impermeability toward most solutes. The barrier function is related to the unique composition of the SC lipids and their complex structural arrangement. The lipoidal matrix of the SC, therefore, is a target of penetration enhancer action. The literature on the skin barrier structure and function and on the mechanisms of action of some well established permeation promoters, with a focus on their impact on SC structural alterations, is reviewed. Data obtained from infrared, thermal, and fluorescence spectroscopic examinations of the SC and its components imply enhancer improved permeation of solutes through the SC is associated with alterations involving the hydrocarbon chains of the SC lipid components. Data obtained from electron microscopy and X-ray diffraction reveals that the disordering of the lamellar packing is also an important mechanism for increased permeation of drugs induced by penetration enhancers.
Article
Activation of mast cells, the key cells of allergic inflammation, causes typical morphological changes associated with an increase in volume, that is a function of area and perimeter. The purpose of this study was to evaluate the effect of mast cell activation to degranulate, carried out by the secretagogue Compound 48/80, and of inhibition of this activation carried out by Nedocromil sodium, a mast cell stabilizing drug, on mast cell area, perimeter and shape factor by a computerized image analyzer. Mast cells were isolated and purified by peritoneal lavage of rats (purity >98%) and co-cultured with mouse 3T3 fibroblasts to which they adhere. Cultures were incubated for 10 min at 37 degrees C with culture medium alone (Enriched Medium) or Enriched Medium containing either Nedocromil (10(-4) M) or Compound 48/80 (0.3 microg/ml) or Compound 48/80 and Nedocromil (0.3 microg/ml and 10(-4) M respectively). Supernatants were then assessed for histamine release, as a marker of mast cell activation and the cell monolayers were fixed and stained with an alcoholic-acidic toluidine blue solution and examined with a computerized image analyzer connected with a light microscope. Mast cells incubated in Enriched Medium or Nedocromil possessed similar morphometric parameters. Mast cells activated with Compound 48/80 (70% histamine release) had a significant increase in area and perimeter and a decrease in shape factor in comparison to mast cells in Enriched Medium alone. Simultaneous incubation of mast cells with Compound 48/80 and Nedocromil significantly inhibited their histamine release (36% histamine release) and the increase in area and perimeter, but did not affect significantly their shape factor, in comparison with mast cells incubated with Compound 48/80 alone. These data clearly show that there is a relationship between mast cell activation, consequent histamine release and changes in cell area, perimeter and shape factor and that Nedocromil not only inhibits mast cell histamine release but also the activation induced morphometric changes in mast cells.
Article
Transdermal drug delivery has been intensively studied over the last two decades because of the many advantages offered by this route of administration. However, the number of drugs used in transdermal drug delivery systems has been somewhat limited, in part resulting from the formidable barrier to drug permeation presented by the upper layer of the skin, the stratum corneum. In order to overcome this, different strategies have been implemented to render the skin more permeable to drugs. These strategies include both chemical and physical approaches. In this review, we outline the enhancing activities and mechanisms of action of some of the more extensively studied chemical penetration enhancers (oxazolidinones, propylene glycol, and epidermal enzymes). In addition, we discuss novel physical strategies, such as the use of microneedles or electroporation.
Iontophoresis Maibach gy following OA treatment are shown in Fig Percutaneous Penetration Enhancers
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