Hairless Rat Skin Research Articles

Avocado ( Persea americana Mill.) Seed Extract Cream 10% Inhibited The Increase MMP-12 Enzyme Levels And Elastosis In UVA Exposed Hairless Male Wistar Rats Skin

Background: Skin is the main target of environmental influences, especially chronic exposure to the suns UVA rays which will result in wrinkling, decreased skin elasticity, the appearance of loose skin, and a rough clinical appearance. In the dermal tissue, not only affects collagen fibers but also degradation of elastin fibers occurs through an increase in the MMP-12 enzyme levels called photoaging and is characterized by the accumulation of dystrophic elastin fibers throughout the dermal tissue in a process called Elastosis. Avocado seed (Persea americana Mill.) is a part of the fruit that contains high concentrations of flavonoids, phenols, and tannins, it has the potential as a powerful antioxidant. The aim of the present study is to evaluate the effectiveness of avocado (Persea americana Mill.) seed extract cream 10% inhibiting the increase in MMP-12 enzyme levels and elastosis in hairless male Wistar rats (Rattus norvegicus) which were exposed to ultraviolet A rays. Methods: A Randomized post-test-only control group design was conducted among 30 male Wistar rats for 10 consecutive days. They were divided into 3 groups as follows: group (K) as the negative control without any intervention, group (P1) with UVA rays exposure, and group (P2) with application of avocado (Persea americana Mill.) seed extraxt cream 10% and UVA rays exposure. The UVA dosage used is 5J/cm2 twice a day among P1 and P2 groups. Avocado (Persea americana Mill.) seed extract 10% was applied to the hairless Wistar rats 4 hours after the exposure of UVA rays. MMP-12 was calculated with Rat MMP-12 ELISA Test. Elastin fiber density was calculated by Imageraster software. Statistical analysis was carried out using SPSS version 25 in measure means, normality test, homogeneity test, and comparative test. Results: The results showed that the average MMP-12 enzyme level in the 10% avocado seed cream (P2) group 18.138 ± 0.168% was significantly different from the (K) group 1.073 ± 0.1553% as the negative control and the (P1) group 33.454 ± 1.068%. The mean density of elastin fiber in the cream of avocado seed extract group (P2) 12.42 ± 3.672% was significantly different from the group (K) 20.08 ± 4.994% and group (P1) 26.30 ± 6.822%. Comparative analysis using the Kruskal Wallis test for MMP-12 and the One Way Annova test for elastin fibers showed a p-value of < 0.05, thus indicating a significant difference between groups after treatment. The Least Significance Difference (LSD) test showed that there was a significant difference between the cream of avocado seed extract (P2) group and the other groups (p<0.05). Conclusions: The administration of avocado seeds (Persea americana Mill.) extract cream 10% effectively inhibits the increase in MMP-12 enzyme levels and elastosis in hairless male Wistar rat skin which was exposed to ultraviolet A irradiation.

Formulation and Evaluation of Transdermal Gel Containing Tacrolimus-Loaded Spanlastics: In Vitro, Ex Vivo and In Vivo Studies.

Our goal was to prepare Span 60-based elastic nanovesicles (spanlastics (SPLs)) of tacrolimus (TCR) using the adapted ethanol injection method, characterize them, and evaluate their ability to improve the transdermal permeation of the active substance. The impact of two different concentrations of penetration enhancers, namely, propylene glycol and oleic acid, on the entrapment efficiency, vesicle size, and zeta potential was assessed. Moreover, in vitro release through a semipermeable membrane and ex vivo penetration through hairless rat skin were performed. Morphological examination and pharmacokinetics were performed for one selected formulation (F3OA1). TCR-loaded SPLs were effectively formulated with two different concentrations of permeation enhancers, and the effect of these enhancers on their physicochemical properties differed in accordance with the concentration and kind of enhancer used. The results of in vitro release displayed a considerable (p < 0.05) enhancement compared to the suspension of the pure drug, and there was a correlation between the in vitro and ex vivo results. The selected TCR-loaded nanovesicles incorporated into a gel base showed appreciable advantages over the oral drug suspension and the TCR-loaded gel. Additionally, the pharmacokinetic parameters were significantly (p < 0.05) improved based on our findings. Moreover, the AUC0–7 ng·h/mL form F3 OA1 was 3.36-fold higher than that after the administration of the TCR oral suspension.

Formulation development and evaluation of drug-in-adhesive-type transdermal patch of metoclopramide HCl

The objective was to design and develop a drug-in-adhesive-type transdermal patch formulation of metoclopramide HCl, which is used as an effective antiemetic, dopaminergic antagonist agent. In DIA patches, drug is directly embedded in the polymeric adhesive layer and permeates through the skin to provide systemic effect, avoiding gastrointestinal tract complications, including the first-pass metabolism. Six different patch formulations were prepared by a solvent evaporation method using varying metoclopramide HCl concentrations using acrylate polymer DURO-TAK® 387/2510 for adhesive support. In vitro permeation profiles and parameters were obtained by using the skin of hairless albino Wistar rats. The influence of drug content on the rate of permeation was investigated, and patch formulation was optimized based on Q12, flux, and lag time. The effect of permeation enhancers (EO and PG) on the permeation rate of metoclopramide HCl was also studied. The skin irritation study was performed to observe the hypersensitivity against the patch component. Stability studies of the optimized formulation of a transdermal patch for three months at three different temperatures were investigated. The transdermal patch formulation containing 10% w/w metoclopramide HCl was capable of effectively delivering metoclopramide HCl for systemic effect without any skin irritation. It has Q12 of 3.892 ± 0.0043 mg/cm2, flux rate of 0.2501 mg/cm2 h, and the coefficient of permeability of 6.25E−02 cm/h with a lag time of 0.442 h. The stability data revealed that the optimized patch formulation could be stored at 4 °C in the refrigerator with a shelf life of 3.53 months. This newly developed metoclopramide transdermal DIA patch is an effective alternative to oral delivery with desirable antiemetic activity.

Enhancement of Skin Permeation of a Hydrophilic Drug from Acryl-Based Pressure-Sensitive Adhesive Tape

Penetration enhancers are necessary to overcome a formidable barrier function of the stratum corneum in the development of topical formulations. Recently, non-lamella liquid crystal (NLLC)-forming lipids such as glycerol monooleate and phytantriol (PHY) are gaining increasing attention as a novel skin permeation enhancer. In the present study, fluorescein sodium (FL-Na) was used as a model hydrophilic drug, and acryl-base pressure-sensitive adhesive (PSA) tape containing NLLC forming lipids, mono-O-(5,9,13-trimethyl-4-tetradecenyl) glycerol ester (MGE) or PHY, was prepared to enhance drug permeation through the skin. A PSA patch containing FL-Na was prepared by mixing FL-Na entrapped in NLLC and acrylic polymer. FL permeation through excised hairless rat skin, and also human skin, was investigated. Changes in lipid structure, folding/unfolding state of keratin in the stratum corneum, and penetration of MGE into the stratum corneum were investigated using confocal Raman microscopy. Enhanced FL permeation was observed by the application of a PSA patch containing MGE and PHY. Especially, dramatically enhancement effect was confirmed by 15% of MGE contained formulation. Penetration of MGE provided diminished orthorhombic crystal structure and a peak shift of the aliphatic CH3 vibration of keratin chains toward lower wavenumbers. The present results suggested that the formulation development by adding MGE may be useful for improving the skin permeation of mal-permeable drugs such as hydrophilic drugs.

FORMULATION AND EVALUATION OF IVABRADINE HYDROCHLORIDE LOADED TRANSFERSOMAL GEL FOR TRANSDERMAL DELIVERY

Objective: Aim of this study was to develop the topical delivery containing ivabradine hydrochloride (IVH) loaded transpersonal gel for symptomatic treatment of chronic stable angina pectoris in coronary artery disease.&#x0D; Methods: Different hydrophilic-lipophilic balance (HLB) values of surfactants-tween-80, span-80 and sodium deoxycholate (SDC) were investigated to prepare transfersomes (TFs)respectively, with different concentration of soya phosphatidylcholine and 10% v/v ethanol in phosphate buffer solution (pH 6.8) by conventional rotary evaporation sonication method. The prepared formulations were evaluated for percentage entrapment efficiency (%EE), deformability index (DI), turbidity, vesicle shape and size, in vitro drug release study and stability. SEM was done on selected formulation F8 and liposome formulation (LF). Gel was prepared by using carbopol-940 as a gelling agent with propylene glycol, polyethylene glycol solution as permeation enhancer by 32 factorial design optimization methods. The developed gel was evaluated for pH, viscosity, drug content, ex-vivo permeation studies and stability studies of TFs-gel. This was compared with LF-gel prepared by same procedure.&#x0D; Results: Maximum % EE (78.4±0.94), suitable vesicular size (128.6 nm) and maximum DI (34.9±1.9) was found in TFs-TW-80 and selected for gel development. In vitro drug release data from TFs-TW-80, plain drug solution and liposomal formulation (LF) revealed that % cumulative drug released in TFs-TW-80 was found maximum (89.5±0.12 %) in 20 min than others. It was 2.1 times higher than LF and 3.3 times higher than the plain drug. SEM study showed spherical shape of vesicles. The drug contents in the TFs and LF gels were found to be 92 to 95%w/w. Partition coefficient for TFs-loaded gel was 1.04±0.03. Ex vivo permeation study from hairless rat skin showed that permeation of drug is described by firstly first-order kinetics than zero-order kinetics. The drug released from TFs-gel was found to be 1.7 times higher than LF-gel and about 1.9 times higher than plain drug. Flux from TFs-gel was 2.04 times greater than LF-gel and 3.28 times more than plan drug. Stability studies indicated that suitable storage condition for developed gel was temperature 25 °C or less, where the pH, potency and therapeutic efficacy of formulations remain constant.&#x0D; Conclusion: Thus, transdermal route has become one of the most successful and innovative focus for research in drug delivery of IVH loaded TFs-TW-80 to increase stability and bioavailability.

Evaluation of the Effect of Chronic 94 GHz Exposure on Gene Expression in the Skin of Hairless Rats In Vivo.

Millimeter waves (MMW) are broadband frequencies that have recently been used in several applications in wireless communications, medical devices and nonlethal weapons [i.e., the nonlethal weapon, Active Denial Systems, (ADS) operating at 94-95 GHz, CW]. However, little information is available on their potential effects on humans. These radio-frequencies are absorbed and stopped by the first layer of the skin. In this study, we evaluated the effects of 94 GHz on the gene expression of skin cells. Two rat populations consisting of 17 young animals and 14 adults were subjected to chronic long-term 94 GHz MMW exposure. Each group of animals was divided into exposed and sham subgroups. The two independent exposure experiments were conducted for 5 months with rats exposed 3 h per day for 3 days per week to an incident power density of 10 mW/cm2, which corresponded to twice the ICNIRP limit of occupational exposure for humans. At the end of the experiment, skin explants were collected and RNA was extracted. Then, the modifications to the whole gene expression profile were analyzed with a gene expression microarray. Without modification of the animal's temperature, long-term chronic 94 GHz-MMW exposure did not significantly modify the gene expression of the skin on either the young or adult rats.

Utility of hairless rats as a model for predicting transdermal pharmacokinetics in humans

This study investigated the use of HWY hairless rats to predict human plasma concentrations of drugs following dermal application.Utilizing a deconvolution method, pharmacokinetic parameters (e.g. in vivo absorption rates) were determined for six transdermal drugs in hairless rats. Obtained data were used to simulate the human plasma concentration-time profiles of transdermal drugs, which were then compared with clinical data in humans. Because hairless rats have lower hair follicle density than do humans, the impact of hair follicle density on skin permeability to hydrophilic compounds was also evaluated.Pharmacokinetic parameters showed low intra-individual variability in hairless rats. Simulated concentration profiles for compounds with logarithm of the octanol–water partition coefficient exceeding two were comparable to clinical data, but simulated concentration profiles for hydrophilic compounds (i.e. bisoprolol and nicotine) at maximum concentration differed from clinical data by more than two-fold. Finally, in vitro permeability to bisoprolol and nicotine was higher in human skin than in hairless rat skin, but hair follicle plugging reduced human skin permeability.In vivo skin absorption data from HWY hairless rats help to predict human concentration profiles for lipophilic compounds. However, the data underestimate human absorption of hydrophilic compounds.

Microneedle device samples fluid from skin

Applying a microneedle patch to the skin might one day replace the uncomfortable needle stick required to perform some blood tests. As a step toward that goal, researchers have demonstrated a prototype device that combines microneedles and plasmonic sensor paper to sample interstitial fluid from the skin and analyze it directly using surface-enhanced Raman spectroscopy (SERS) (ACS Sens. 2019, DOI: 10.1021/acssensors.9b00258). Mark R. Prausnitz of the Georgia Institute of Technology, Srikanth Singamaneni of Washington University in St. Louis, and colleagues demonstrated their device by detecting a positively charged fluorescent dye, rhodamine 6G, infused into rats. The researchers grew gold nanoparticles and coated them with negatively charged poly(4-styrenesulfonic acid). Then they concentrated the coated nanoparticles into an ink, wrote the ink onto a strip of filter paper, and attached the paper to a strip of 650 µm long steel microneedles. After applying the microneedles to the skin of hairless rats se...

Combined Use of N-Palmitoyl-Glycine-Histidine Gel and Several Penetration Enhancers on the Skin Permeation and Concentration of Metronidazole.

N-Palmitoyl-Glycine-Histidine (Pal-GH) is a novel low molecular weight gelator. In our previous report, ivermectin, a lipophilic drug, was effectively delivered to skin tissue after topical application with Pal-GH as a spray gel formulation, and a much higher skin concentration was confirmed than with the administration of a conventional oral formulation. The objective of this study was to increase the skin permeation of metronidazole (MTZ), a hydrophilic drug, after the topical application of Pal-GH gel. An evaluation of the combined effect of chemical penetration enhancers (CPEs), such as isopropyl myristate (IPM), propylene glycol (PG), ethanol, diethylene glycol monoethyl ether, and dimethyl sulfoxide (DMSO), on skin permeation was also conducted. We found that a 5% Pal-GH gel containing 1% MTZ (F5MTZ) exhibited a 2.7-fold higher MTZ permeation through excised hairless rat skin than its solution. Furthermore, F5PG-MTZ and F5IPM-MTZ further increased the skin permeation of MTZ when compared to F5MTZ. Interestingly, F5PG-MTZ enhanced the skin penetration of MTZ, although no enhancement effect was observed for an MTZ solution containing PG. Thus, a Pal-GH formulation containing PG and IPM may enhance the skin permeation of MTZ.

Formulation design and optimization of novel soft glycerosomes for enhanced topical delivery of celecoxib and cupferron by Box–Behnken statistical design

Background: The present study describes glycerosomes (vesicles composed of phospholipids, glycerol and water) as a novel drug delivery system for topical application of celecoxib (CLX) and cupferron (CUP) compound.Aim: The goal of this research was to design topical soft innovative vesicles loaded with CLX or CUP for enhancing the efficacy and avoiding systemic toxicity of CLX and CUP.Methods: CLX and CUP loaded glycerosomes were prepared by hydrating phospholipid-cholesterol films with glycerol aqueous solutions (20–40%, v/v). Box–Behnken design, using Design-Expert® software, was the optimum choice to statistically optimize formulation variables. Three independent variables were evaluated: phospholipid concentration (X1), glycerol percent (X2) and tween 80 concentration (X3). The glycerosomes particle size (Y1), encapsulation efficiency percent (Y2: EE %) and drug release (Y3) were selected as dependent variables. The anti-inflammatory effect of CLX and CUP glycerosomal gel was evaluated by carrageenan-induced rat paw edema method followed by histopathological studies.Results: The optimized formulations (CLX2* and CUP1*) showed spherical morphology under transmission electron microscopy, optimum particle size of 195.4 ± 3.67 nm, 301.2 ± 1.75 nm, high EE of 89.66 ± 1.73%, 93.56 ± 2.87%, high drug release of 47.08 ± 3.37%, 37.60 ± 1.89% and high cumulative amount of drug permeated in 8 h of 900.18 ± 50.24, 527.99 ± 34.90 µg.cm−2 through hairless rat skin, respectively. They also achieved significant remarkable paw edema inhibition in comparison with the control group (p < .05).Conclusion: Finally, the administration of CLX2* and CUP1* loaded glycerosomal gel onto the skin resulted in marked reduction of edema, congestive capillary and inflammatory cells and this approach may be of value in the treatment of different inflammatory disorders.

Iontophoresis-aided drug delivery into the eyeball via eyelid skin

Eyelid skin has gained attention as a drug delivery site for ophthalmic drugs as an alternative to conventional eye drops. Previously, it was found that the concentration of drugs administered via eyelid skin in the conjunctival sac is lower than with eye drop administration. In the present study, we investigated the necessity for utilizing physical approaches, such as iontophoresis (IP), to promote percutaneous absorption of pilocarpine and two fluorescent dyes delivered to the eyeball via the lower eyelid skin of hairless rats. In vitro diffusion cells were used to assess the skin permeability in order to provide key insights into the relationship between skin type and drug absorption. Moreover, in vivo skin permeation was conducted to determine drug distribution in the eyeball. Seven-fold higher permeation via eyelid skin was observed compared with that without IP, indicating the usefulness of IP application. In addition, significant differences were observed in the eyeball concentrations between treatment with or without IP at 0.5 h (p < 0.05) after administration of pilocarpine. The fluorescent dyes could be observed in the eyeball after topical administration onto eyelid skin with IP. These data suggested that a short application period of IP is effective for drug delivery into eyeballs.

Selection of phospholipids to design liposome preparations with high skin penetration-enhancing effects

This study attempted to identify a good selection method for phospholipids to design liposome preparations with high skin penetration-enhancing effects. Five kinds of phosphatidylcholines and phosphatidylglycerols each were selected. First, phospholipid aqueous dispersions and liposomes containing caffeine as a model drug were tested for their skin penetration-enhancing effects using excised hairless rat skin. Accordingly, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol, sodium salt (DPPG) dispersions showed high penetration-enhancing ratios (ERs), whereas DPPG, 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) liposomes showed high ERs, suggesting that liposomes had different skin penetration-enhancing mechanisms from phospholipid dispersions. Next, two experiments were done to clarify the possible mechanism of liposome penetration; excised skin was pretreated for 1 h with caffeine-free phospholipid dispersions and liposomes, and caffeine solution was added to determine its skin permeation. Separately, caffeine permeation experiments were done using physical mixtures of blank liposomes and caffeine solution (caffeine-spiked liposomes) and caffeine-entrapped liposomes (caffeine was entrapped only in liposomes). DPPG was found to be a promising phospholipid candidate for liposome formulations with high skin penetration-enhancing effects, because DPPG phospholipid and liposome vesicles had a combination effect of disrupting the SC lipid barrier to carry both free and entrapped caffeine in the formulation through the skin.

Betahistine dihydrochloride transdermal delivery via optimized thermosensitive gels: percutaneous absorption evaluation using rat growth as a biomarker.

The aim of this study was to develop and optimize a betahistine dihydrochloride (BH) thermoreversible bioadhesive gel intended for transdermal delivery. The gels were obtained via cold method. A full factorial design was employed to investigate the joint effect of Poloxamer 407 concentration (18 and 20%), adhesive polymer type (Polyvinyl pyrolidone, Hydroxypropyl methylcellulose, and Carbopol 934), and adhesive polymer concentration (0.5 and 1.5%) on gelling temperature, viscosity at 37°C, and adhesion strength. Data collected were analyzed using multiple linear regression. A desirability index approach with relative importance weight was used to choose the most desirable formulation. F4 (20% Poloxamer+1.5% Carbopol) was selected for further characterization. F4 released 96.97% drug in 12h across hairless rat skin. F4 gelation temperature and time were 36 ± 0.35°C, and 6 ± 0.7min, respectively. F4 adhesive force was 8835.68dyne/cm2. F4 was tested for its appetite suppressing effect in a rat model and it was evaluated histopathologically. Rats' chow intake and weight gain was significantly decreased with no signs of inflammation or lipolysis when the optimized BH gel formulation, F4, was compared with untreated animals and animals treated with BH free gel. The results suggest that BH is percutaneously absorbed from the gel base and that the BH gel is tolerable. The desirability index approach with relative importance weight of responses was effective in determination of the optimum formulation. BH is systemically effective and well-tolerated when applied topically in hydrogel-based systems. The Carbopol-Poloxamer gel is a promising modality for transdermal delivery of BH.

Cleansing technique using high-velocity steam–air micromist jet spray

Application of a high-velocity steam–air micromist jet spray (HVS-AMJS; micromist average diameter: 2.4 μm) for cleansing the skin is proposed. Low-pressure steam is mixed with compressed air (pH 6.5) in a nozzle, and then sprayed at a pressure of ≦0.25 MPa and a velocity of ≧0.34 m/s on the skin or surface of material located approximately 5–10 cm from the nozzle. The temperature on the sprayed surface and water flow rate could be controlled between 42 °C and 46 °C and at approximately 50 mL/min, respectively. Compared with ultrasonic cleansing with tap water and rubbing with only tap water, the HVS-AMJS successfully removed fluorescent lotion covering pieces of wood and significantly reduced both the number of coliforms and the total viable counts on pieces of wood and gauze. Furthermore, the HVS-AMJS effectively removed oily ink from the skin of hairless rats, and temporarily elevated the skin temperature and blood flow, indicating massage effects. The striking characteristics of this cleansing technique using HVS-AMJS are not only its ability to remove microbes and residue without using any chemicals or detergents but also its massage effects.

Safety evaluation of dermal exposure to phthalates: Metabolism-dependent percutaneous absorption

Phthalates, known as reproductive toxicants and endocrine disruptors, are widely used as plasticizers in polyvinyl chloride products. The present study was conducted for risk identification of dermal exposure to phthalates. When dibutyl phthalate was applied to the skin of hairless rats and humans, only monobutyl phthalate appeared through the skin, and the permeability of the skin was higher than that after the application of the monoester directly. The inhibition of skin esterases made the skin impermeable to the metabolite following dermal exposure to dibutyl ester, whereas removal of the stratum corneum from the skin did not change the skin permeation behavior. Similar phenomena were observed for benzyl butyl phthalate. The skin permeability of monobenzyl phthalate was higher than that of monobutyl phthalate in humans, although the reverse was observed in rats. Species difference in skin permeation profile corresponded to the esterase activity of the skin homogenate. Di(2-ethylhexyl) phthalate, which was not metabolized by esterases in the skin, was not transported across the skin. These results suggest that highly lipophilic phthalates may be transported easily across the stratum corneum lipids. The water-rich viable layer may become permeable to these phthalates by their metabolism into monoesters, which are relatively hydrophilic. Skin metabolism is essential to the percutaneous absorption of phthalates. Because esterase activity has large inter-individual differences, further study will be needed for individual risk identification of dermal exposure to phthalates.

Purification of isopropyl fatty acids markedly changed the skin permeation of a model hydrophilic chemical

We determined the difference in the skin-penetration enhancing effects of conventional (C-) and super-refined (SR-) isopropyl fatty acids (IPFAs) including isopropyl myristate (IPM), isopropyl palmitate (IPP), and isopropyl oleate (IPO). In vitro permeation experiments were performed with excised hairless rat skin using a model mal-absorbed chemical, calcein. As a result, SR-IPM pretreatment markedly increased the skin permeation of calcein from aqueous solution more than C-IPM pretreatment, in spite of a small difference in IPM purity (98.78 vs 99.96%). Similar phenomena were recorded even when using SR-IPM emulsion compared with C-IPM emulsion without pretreatment. In contrast, C-IPP pretreatment showed higher skin permeation than SR-IPP. In addition, no difference was observed in skin permeation between C-IPO and SR-IPO. Skin impedance was also determined as an index of skin barrier function. SR-IPM changed the skin barrier function more than C-IPM, which supported the penetration-enhancing order of C-IPM and SR-IPM shown above. It was unexpected to find such a big difference in the skin-penetration enhancing effect of C-IPM vs SR-IPM and C-IPP vs SR-IPP. The present results suggested that SR-IPM could be a promising ingredient in pharmaceutical and cosmetic products for topical use.

Topical Delivery of Fenoprofen Calcium via Elastic Nano-vesicular Spanlastics: Optimization Using Experimental Design and In Vivo Evaluation

The aim of this study was to investigate the potential of surfactant-based nanovesicular system (spanlastics) for topical delivery of fenoprofen calcium (FPCa) to eliminate its oral gastrointestinal adverse effects. FPCa-loaded spanlastics were prepared by thin film hydration (TFH) technique according to a full factorial design to investigate the influence of formulation variables on the drug entrapment efficiency (%EE), particle size (PS), deformability index (DI), and the % drug released after 24h through the cellulose membrane (Q24h) using Design-Expert® software. The optimized formula (composed of Span 60 and Tween 60 as an edge activator at weight ratio of 8: 2 in presence of Transcutol P as a cosolvent in the hydration media) exhibited the highest %EE (49.91±2.60%), PS of 536.1±17.14nm, DI of 5.07±0.06g, and Q24h of 61.11±2.70%; it was also characterized for morphology and physical stability. In vitro release study of FPCa-loaded spanlastic gel and conventional FPCa gel through a synthetic membrane and hairless rat skin were evaluated. The skin permeation study revealed that spanlastic gel exhibited both consistent and prolonged action. Finally, the % inhibition of carrageenan-induced rat paw edema of spanlastic gel was three times higher than the conventional FPCa gel after 24h. In conclusion, spanlastic-based gel could be a great approach for improving topical delivery of fenoprofen calcium, providing both prolonged and enhanced anti-inflammatory activity in the treatment of arthritis.

Enhancement of the bioavailability of an antihypertensive drug by transdermal protransfersomal system: formulation and in vivo study

Timolol Maleate (TiM), a nonselective β-adrenergic blocker, is a potent highly effective agent for management of hypertension. The drug suffers from poor oral bioavailability (50%) due to its first pass effect and a short elimination half-life of 4 h; resulting in its frequent administration. Transdermal formulation may circumvent these problems in the form of protransfersomes. The aim of this study is to develop and optimize transdermal protransfersomal system of Timolol Maleate by film deposition on carrier method where protransfersomes were converted to transfersomes upon skin hydration following transdermal application under occlusive conditions. Two 23 full factorial designs were employed to investigate the influence of three formulation variables which were; phosphatidyl choline: surfactant molar ratio, carrier: mixture and the type of SAA each on particle size, drug entrapment efficiency and release rate. The optimized formulation was evaluated regarding permeation through hairless rat skin and compared with oral administration of aqueous solution on male Wistar rats. Optimized protransfersomal system had excellent permeation rate through shaved rat skin (780.69 μg/cm2/h) and showed six times increase in relative bioavailability with prolonged plasma profile up to 72 h. A potential protransfresomal transdermal system was successfully developed and factorial design was found to be a smart tool in its optimization.

High-Throughput Screening of Potential Skin Penetration-Enhancers Using Stratum Corneum Lipid Liposomes: Preliminary Evaluation for Different Concentrations of Ethanol.

In this study, we developed a technique for high-throughput screening (HTS) of skin penetration-enhancers using stratum corneum lipid liposomes (SCLLs). A fluorescent marker, sodium fluorescein (FL), entrapped in SCLLs was prepared to provide a preliminary evaluation of the effect of different concentrations of ethanol on the disruption effect of SCLLs, which is an alternative for skin penetration-enhancing effects. In addition, SCLLs containing a fluorescent probe (DPH, TMA-DPH, or ANS) were also prepared and utilized to investigate SCLL fluidity. The results using SCLL-based techniques were compared with conventional skin permeation and skin impedance test using hairless rat skin. The obtained correlations were validated between FL leakage, SCLL fluidity with various probes, or skin impedance and increases in the skin permeation enhancement ratio (ER) of caffeine as a model penetrant. As a result, FL leakage and SCLL fluidity using ANS were considered to be good indices for the skin penetration-enhancing effect, suggesting that the action of ethanol on the SC lipid and penetration-enhancing is mainly on the polar head group of intercellular lipids. In addition, this screening method using SCLL could be utilized as an alternative HTS technique for conventional animal tests. Simultaneously, the method was found to be time-saving and sensitive compared with a direct assay using human and animal skins.

Microemulsion for topical delivery of fenoprofen calcium: in vitro and in vivo evaluation

The aim of this study was to investigate microemulsion (ME) based topical delivery system for fenoprofen calcium (FPCa) to eliminate its oral gastrointestinal adverse effects. ME was prepared by the water titration method using oleic acid as oil phase, tween 80 as a surfactant and propylene glycol as a cosurfactant. Oleic acid was selected as oil phase due to its good solubilizing capacity. ME existence region was determined using pseudo-ternary phase diagrams for preparing different formulations. Six different formulations were selected with various values of oil (25–68%), water (2–3%), and the mixture of surfactant and cosurfactant (1:1) (24–67%). The selected ME formulae were characterized for optical birefringence, transmission electron microscopy (TEM), pH, % transmittance, electronic conductivity, drug content, droplet size, rheological properties and stability evaluation. In vitro release study of FPCa from ME s through the synthetic membrane and hairless rat skin were evaluated. The optimized formula ME5 consisting of 5% w/w FPCa, 60% w/w oleic acid as oil phase, 3% w/w aqueous phase, and 32% w/w of surfactant phase containing Tween 80 and propylene glycol (1: 1) showed the highest transdermal flux and highest skin permeation rate. Finally, the % inhibition of carrageenan-induced rat paw edema of the optimized formula ME5 was highly significant (p < 0.001) as compared to plain gel of FPCa. In conclusion, ME is a promising technique for topical delivery of FPCa.