Hairless Rat Research Articles

A novel method to assess the severity and prognosis in crush syndrome by assessment of skin damage in hairless rats.

Crush syndrome (CS), a serious medical condition characterised by damage to the muscle cells due to pressure, is associated with high mortality, even when patients receive fluid therapy during transit to the hospital or admission to the hospital. There is no standard triage approach for earthquake victims with crush injuries due to the scarcity of epidemiologic and quantitative data. We examined whether mortality can be predicted based on the severity of skin damage so that assess the severity and prognosis in crush syndrome by assessment of skin damage in hairless rats because we have previously observed that CS results in oedema and redness of the skin in rats. Anaesthetised rats were subjected to bilateral hind limb compression [1kg (mild) and 2kg (severe) loads] with a rubber tourniquet for 5h. The rats were then randomly divided into three groups: sham, mild CS, and severe CS. The mild and severe CS groups had mortality rates of 20 and 90%, respectively. The severe CS group demonstrated higher rates of hyperkalaemia, hypovolemic shock, acidosis, and inflammation. Skin damage was significantly worse in the severe CS group compared to the mild CS group. Skin damage showed good correlation with pathological severity. Skin damage is a valid measure of transepidermal water loss and severity of CS. We suggest that these models may be useful to professionals who are not experienced in disaster management to identify earthquake victims at high risk of severe CS.

A Novel Small-Animal Model of Irradiated, Implant-Based Breast Reconstruction.

There is currently a need for a clinically relevant small-animal model for irradiated, implant-based breast reconstruction. Present models are inadequate in terms of suboptimal location of expander placement and mode of radiation delivery, correlating poorly with the human clinical scenario. The authors hypothesized that by delivering fractionated radiation and placing an expander under the scalp of the animal, they would achieve soft-tissue changes histologically analogous to those seen in human irradiated, implant-based breast reconstruction. This study consisted of 11 immunocompetent, hairless rats divided into three groups as follows: untreated control (n = 3), tissue-expanded scalps (n = 4), and fractionated irradiation plus tissue expansion of the scalp (n = 4). At the completion of the experiment for each group, skin tissue samples were analyzed histologically for vascularity, epidermal and dermal thickness, and collagen fiber alignment or scar formation. Expanded rat epidermis was significantly thicker and dermis was more vascular than nonexpanded skin. The authors observed a greater degree of collagen fiber alignment in the expanded group compared with nonexpanded skin. The combination of irradiation and expansion resulted in significant dermal thinning, vascular depletion, and increased scar formation compared with expanded skin alone. The authors describe a novel small-animal model for irradiated, implant-based breast reconstruction where histologic analysis shows structural changes in the skin consistent with known effects of radiation therapy and expansion in human skin. This model represents a significant improvement from previous ones and, as such, holds the potential to be used to test new therapeutic agents to improve clinical outcomes.

Alternative Administration Routes of a Biopolymer‐Stabilized VEGF Chimera to Optimize Therapeutic Efficacy in Treating a Rodent Model of Placental Ischemia

Preeclampsia is a form of gestational hypertension that complicates 5–8% of pregnancies in the United States. The unknown etiology originates from abnormal remodeling of the maternal spiral arteries, creating an ischemic placenta that releases factors that drive the pathophysiology. One of these pathogenic factors, soluble fms‐like tyrosine kinase‐1 (sFlt‐1), causes angiogenic imbalance by sequestering vascular endothelial growth factor (VEGF), leading to endothelial dysfunction and hypertension. Apart from delivery of the ischemic placenta, no effective therapy exists to treat preeclampsia. Innovative treatments are needed not only to reduce the morbidity and mortality rates during the preeclamptic index pregnancy, but also to decrease the incidence of later life cardiovascular‐renal and metabolic risk factors that are associated with the systemic endothelial dysfunction.In order to develop treatments that are safe for both the mother and fetus, we are testing novel therapies that target sFlt‐1 and other pathogenic factors in a preclinical model of placental ischemia, the reduced uterine perfusion pressure (RUPP) surgery. Previously, we demonstrated in timed pregnant Sprague‐Dawley rats that the biopolymer drug carrier elastin‐like polypeptide (ELP) fused to human VEGF‐A121 (ELP‐VEGF) prevents VEGF from crossing the placental barrier and thus ameliorates the risk of fetal exposure. Furthermore, in pregnant rats that had undergone the RUPP surgery, chronic administration of ELP‐VEGF at 5 mg/kg/day via intraperitoneal minipump blocked hypertension, significantly enhanced renal nitric oxide signaling, and had no deleterious effect on fetal weight or placental efficiency. However, dams also experienced dose‐dependent adverse events likely attributed to the continuous intraperitoneal infusion method, including ascites production, neovascular tissue encapsulation around the minipump, and, at the 10 mg/kg/day dose, fetal loss.With the aim of minimizing dose‐dependent side effects while retaining the therapeutic efficacy of ELP‐VEGF, chronic biodistribution studies were conducted in non‐pregnant female hairless Sprague‐Dawley rats. ELP‐VEGF was fluorescently labeled with Alexa Fluor 633 succinimidyl ester. In a repeated intravenous dosing cohort, a 5 mg/kg IV bolus of fluorescent labeled ELP‐VEGF was delivered via jugular catheter once daily for 5 days. In a parallel controlled‐release dosing study, rats received a single 5 mg/kg bolus subcutaneously between the scapulae. In vivo imaging and blood draws were conducted at specific time points in order to assess ELP‐VEGF biodistribution and plasma clearance rates, respectively. Mean fluorescence radiant efficiency was averaged, levels were corrected for autofluorescence, and data were fit to the standard curve of the injected protein. We report that whereas a single subcutaneous bolus yields a slow absorption and release of ELP‐VEGF, repeated intravenous dosing can replicate tissue levels comparable to the therapeutic levels achieved by the intraperitoneal osmotic pumps, and free of any peritoneal ascites. Plasma clearance rates and terminal half‐life of ELP‐VEGF determined from these studies are being employed in ongoing experiments to test the therapeutic efficacy of these administration routes in the RUPP model of placental ischemia.Support or Funding InformationSupported by NIH NHLBI grant R01HL121527 (GLB), NIH grant T32HL105324 (OCL) and AHA fellowship 17POST3346012 (OCL).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Effects of Donepezil, an Acetylcholinesterase Inhibitor, on Impaired Learning and Memory in Rodents.

A previous study in humans demonstrated the sustained inhibitory effects of donepezil on acetylcholinesterase (AChE) activity; however, the effective concentration of donepezil in humans and animals is unclear. This study aimed to characterize the effective concentration of donepezil on AChE inhibition and impaired learning and memory in rodents. A pharmacokinetic study of donepezil showed a mean peak plasma concentration of donepezil after oral treatment (3 and 10 mg/kg) of approximately 1.2 ± 0.4 h and 1.4 ± 0.5 h, respectively; absolute bioavailability was calculated as 3.6%. Further, AChE activity was inhibited by increasing plasma concentrations of donepezil, and a maximum inhibition of 31.5 ± 5.7% was observed after donepezil treatment in hairless rats. Plasma AChE activity was negatively correlated with plasma donepezil concentration. The pharmacological effects of donepezil are dependent upon its concentration and AChE activity; therefore, we assessed the effects of donepezil on learning and memory using a Y-maze in mice. Donepezil treatment (3 mg/kg) significantly prevented the progression of scopolamine-induced memory impairment in mice. As the concentration of donepezil in the brain increased, the recovery of spontaneous alternations also improved; maximal improvement was observed at 46.5 ± 3.5 ng/g in the brain. In conclusion, our findings suggest that the AChE inhibitory activity and pharmacological effects of donepezil can be predicted by the concentration of donepezil. Further, 46.5 ± 3.5 ng/g donepezil is an efficacious target concentration in the brain for treating learning and memory impairment in rodents.

Design of a Topically Applied Gel Spray Formulation with Ivermectin Using a Novel Low Molecular Weight Gelling Agent, Palmitoyl-Glycine-Histidine, to Treat Scabies.

Palmitoyl-glycine-histidine (Pal-GH) is a new low molecular weight gelling agent. It exhibits thixotropic behavior, low viscosity, and high dissolving properties for a wide range of hydrophilic to lipophilic drugs. Orally administered ivermectin (IVM) is used to treat scabies. However, this treatment is associated with well-known side effects, thus a study is awaited to search for alternative routes of administration. Although a topical formulation of IVM could be a candidate, it requires whole body application except the head and face for several hours on a daily basis. Therefore, in this study, we prepared a gel spray formulation containing IVM as an approach for application to large skin areas with a single spray application without further contact with the applied formulation. Pal-GH gel spray formulations were prepared from its aqueous solution by a heating and cooling method. Rheological behavior and physical appearance (spraying, spreading ability, volume of spraying, and homogeneity) of the prepared formulations were evaluated. Pal-GH gel with propylene glycol demonstrated impressive rheological properties (typical thixotropic behavior) with high hysteresis area among all the tested Pal-GH gels and spreading ability. The obtained IVM concentration in the skin after topical application of 0.1% IVM-containing Pal-GH formulation onto hairless rats was much higher than the reported therapeutic concentration obtained from oral administration in humans. These results suggested that topical application of IVM using a Pal-GH gel spray formulation could be an alternative to the conventional oral forms for the scabies treatment.

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.

Efficacy of subcutaneous injection of platelet-rich plasma in alopecia: A clinical and histological pilot study on a rat model with a six-month long-term follow-up experience.

To assess the potential of platelet-rich plasma (PRP) subcutaneous injection of to treat alopecia and to evaluate local toxicity. Twelve Hairless rats were used. At D0, we performed systematic clinical examination and divided the rat back into four quadrants (Q). We initiated subcutaneous injection using either PRP in PRPQ+, platelet-poor plasma (PPP) in PPPQ+, physiological serum (PS) in PSQ+, or no treatment (Q4). At D7, D14, D21, and D28 but also second month (M2), M3, M4, M5, rats had exactly the same injection procedure. Follow-up with PRP efficacy and toxicity at D28 and M6 using clinical and histological evaluation was performed. Hair density was significantly improved at D28 and at M6 for PRPQ+ vs PSQ+ (respectively, P = .0156 and P = .0313), PPPQ+ (respectively, P = .042 and P = .046). Significant histological improvement was observed between D28 and M6, for PRPQ+ vs PPPQ+ and PSQ+ for vessels (respectively, P = .0160 and P = .021), collagen (respectively, P = .0036 and P = .032), and epithelium (respectively, P = .0138 and P = .022) with no local toxicity. Our study suggests that subcutaneous PRP injections using controlled concentration of platelets and leukocytes improve hair growth.

Dihydroergotamine mesylate-loaded dissolving microneedle patch made of polyvinylpyrrolidone for management of acute migraine therapy

Migraine is a widespread neurological disease with negative effects on quality of life and productivity. Moderate to severe acute migraine attacks can be treated with dihydroergotamine mesylate (DHE), an ergot derivative that is especially effective in non-responders to triptan derivatives. To overcome limitations of current DHE formulations in subcutaneous injection and nasal spray such as pain, adverse side effects and poor bioavailability, a new approach is needed for DHE delivery enabling painless self-administration, quick onset of action, and high bioavailability. In this study, we developed a dissolving microneedle patch (MNP) made of polyvinylpyrrolidone, due to its high aqueous solubility and solubility enhancement properties, using a MNP design previously shown to be painless and simple to administer. DHE-loaded MNPs were shown to have a content uniformity of 108±9% with sufficient mechanical strength for insertion to pig skin ex vivo and dissolution within 2min. In vivo pharmacokinetic studies were carried out on hairless rats, and DHE plasma levels were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The area under curve (AUC) value after DHE delivery by MNP (1259±917ng/mL min) was not significantly different (p>0.05) as compared to subcutaneous injection, with a relative bioavailability of 97%. Also, appreciable plasma levels of DHE were seen within 5min for both delivery methods and tmax value of MNPs (38±23min) showed no significant difference (p>0.05) compared to subcutaneous injection (24±13min). These results suggest that DHE-loaded MNPs have promise as an alternative DHE delivery method that can be painlessly self-administered with rapid onset and high bioavailability.

Eyelid skin as a potential site for drug delivery to conjunctiva and ocular tissues

The feasibility of topical application onto the (lower) eyelid skin to deliver hydrophilic and lipophilic compounds into the conjunctiva and ocular tissues was evaluated by comparing with conventional eye drop application. Skin permeation and the concentration of several model compounds, and skin impedance were determined utilizing eyelid skin from hairless rats, as well as abdominal skin in the same animals for comparison. In vitro static diffusion cells were used to assess the skin permeation in order to provide key insights into the relationship between the skin sites and drugs. The obtained results revealed that drug permeation through the eyelid skin was much higher than that through abdominal skin regardless of the drug lipophilicity. Specifically, diclofenac sodium salt and tranilast exhibited approximately 6-fold and 11-fold higher permeability coefficients, respectively, through eyelid skin compared with abdominal skin. Histomorphological evaluation and in vivo distribution of model fluorescent dyes were also examined in the conjunctiva and skin after eyelid administration by conventional microscope and confocal laser scanning microscope analyses. The result revealed that eyelid skin has a thinner stratum corneum, thereby showing lower impedance, which could be the reason for the higher drug permeation through eyelid skin. Comparative evaluation of lipophilic and hydrophilic model compounds administered via the eyelid skin over 8h revealed stronger fluorescence intensity in the skin and surrounding tissues compared with eye drop administration. These results suggested that the (lower) eyelid skin is valuable as a prospective site for ophthalmic medicines.

Transdermal Permeation of Drugs in Various Animal Species.

Excised human skin is utilized for in vitro permeation experiments to evaluate the safety and effect of topically-applied drugs by measuring its skin permeation and concentration. However, ethical considerations are the major problem for using human skin to evaluate percutaneous absorption. Moreover, large variations have been found among human skin specimens as a result of differences in age, race, and anatomical donor site. Animal skins are used to predict the in vivo human penetration/permeation of topically-applied chemicals. In the present review, skin characteristics, such as thickness of skin, lipid content, hair follicle density, and enzyme activity in each model are compared to human skin. In addition, intra- and inter-individual variation in animal models, permeation parameter correlation between animal models and human skin, and utilization of cultured human skin models are also descried. Pig, guinea pig, and hairless rat are generally selected for this purpose. Each animal model has advantages and weaknesses for utilization in in vitro skin permeation experiments. Understanding of skin permeation characteristics such as permeability coefficient (P), diffusivity (D), and partition coefficient (K) for each skin model would be necessary to obtain better correlations for animal models to human skin permeation.

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.

Effects of cocoa‐enriched diet on orofacial pain in a murine model

To investigate and discuss the effects of cocoa on orofacial pain. The Department of Orthodontics at the University of Florida (UF). Male and female hairless rats (N=20/group) were tested. Rats were tested using the Orofacial Pain Assessment Device (OPAD) before and after changing their food from the standard chow to a cocoa-enriched or control-equivalent diet. Male rats fed the cocoa diet had a significantly higher operant pain index when tested at 37°C as compared to control diet-fed animals. Female rats on the cocoa diet had a significantly higher pain index when tested at 18°C and 44°C, as compared to animals fed the control diet. Capsaicin-induced pain was inhibited, with cocoa-diet male rats having a significantly higher pain index than control-diet male rats and cocoa-diet female rats at both 37°C and 44°C. Cocoa-diet female rats had a significantly higher pain index at 44°C than control-diet females. Mechanical sensitivity was affected following capsaicin cream, with a significantly decreased tolerated bottle distance in both cocoa- and control-diet animals, but there was no difference between cocoa- and control-diet groups. Using the OPAD operant system, we demonstrated that a diet rich in cocoa was effective in inhibiting neurogenic inflammatory pain in rats. This has implications for the use of novel alternative therapies such as diet modification for pain control.

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.

Effect of Topical Aplication of Gel Aloe Vera Extract on The UVB-Induced Skin Photoaging in Hairless Rats

UVB generates the production of Reactive Oxygen Species (ROS) and decrease antioxidants enzymatic excessively. Both of these biological effects caused photo-aging. Excessive ROS production afforded overexpression of AP-1 as a major regulator of photoaging. This paper figured out the potential of Aloe vera extract as topical gel treatment on the UVB-induced skin photo-aging in twenty male wistar hairless rats (Rattus novergicus) divided into 2 groups. First group was induced by UVB and the second was induced by UVB and topical gel extract Aloe vera treatment. Each group was given treatment for 4 weeks. The expression of MDA and SOD were measured with immunohistochemistry. The result showed that the topical gel therapy decreased the MDA expression and increased SOD expression significantly (p < 0.01). The conclusion from this study was Aloe vera extract had potentially as an alternative topical treatment of photoaging.

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.