Rat Abdominal Skin Research Articles

FEASIBILITY OF PALIPERIDONE FOR TRANSDERMAL THERAPEUTIC SYSTEMS: EX VIVO PERMEATION KINETIC STUDIES OF DRUG THROUGH RAT ABDOMINAL SKIN

Objective: The main objective of the current research study was to investigate the effect of various permeation enhancers on the skin permeation of paliperidone for transdermal therapeutic systems (TTS).
 Methods: A part of pre-formulation studies was performed to authentication of the drug by determining the melting point, solubility, partition coefficient (PC), attenuated total reflection-Fourier transform infrared, differential scanning calorimetry, and its purity by reversed-phase high-performance liquid chromatography. Ex vivo permeation kinetic study for paliperidone alone and with 5% concentration of permeation enhancers hyaluronidase, dimethylsulfoxide (DMSO), groundnut oil, and tween 80 was conducted in modified Franz diffusion cell through rat abdominal skin as a barrier. The receptor phase containing 20% polyethylene glycol 400 in normal saline was maintained at 37°C. The steady-state flux was obtained to calculate permeability coefficient, enhancement ratio (ER), and the cumulative amount of drug permeated at 12 h.
 Results: The pre-formulation study results indicated that the received pure drug was authentified as paliperidone and its purity at par with official pharmacopeia. The PC of the drug was found to be 1.916±1.07, indicated that the drug to be lipophilic. The ex vivo permeation study results showed that the enhancement effect of some permeation enhancers on paliperidone was as follows: Hyaluronidase>DMSO>groundnut oil>tween 80. Hyaluronidase has high permeation enhancing activity with the highest permeation flux of 12.038 μg/cm2/h, and the cumulative amount of drug permeated was 212.760 μg/cm2. The ER of hyaluronidase was 3.69 folds higher than control.
 Conclusion: The results of the present research study attributed that hyaluronidase was a potential permeation enhancer which would be included in the TTS of paliperidone.

Formulation of transdermal nanoemulsion gel drug delivery system of lovastatin and its in vivo characterization in glucocorticoid induced osteoporosis rat model

Lovastatin possess bone formation capabilities but due to first pass effect could not provide significant results. Thus the aim of present investigation was to formulate a transdermal nanoemulsion (NE) gel drug delivery system to overcome its drawbacks and evaluate its potential on glucocorticoid induced osteoporosis (GIOP) in rats. NEs of size range 11–123 nm were prepared with labrafac PG, tween 80 and transcutol using pseudo-ternary phase diagrams. NEs were formulated into gel using carbopol 940 and evaluated for ex vivo permeation testing using rat abdominal skin. Finally, lovastatin NE gel preparations were tested against normal and GIOP induced rats. Femurs of rats were collected and tested for microarchitecture and biomechanical strength testing. Lovastatin NE gel preparations (LNG5 and LNG10) showed significant improvements in the microarchitecture of trabeculae near the growing plates and the strength of femurs as compared to the GIOP group. Bone resorption biomarkers (CTx and TrAcP) were reduced significantly while bone formation biomarkers (b-ALP, OC and PINP) were significantly improved in the LNG5 (p < 0.05) and LNG10 (p < 0.05) treated groups when compared to GIOP. The results suggested that LNG formulations showed promising results for improving bone microstructure and strength after osteoporosis induction.

Design and Evaluation of Chitosan films for Transdermal delivery of Glimepiride

Glimepiride is a third generation oral antidiabetic sulphonylurea drug frequently prescribed to patients of type 2 diabetes. However, its oral therapy is encountered with bioavailability problems due to its poor solubility leading to irreproducible clinical response, in addition to adverse effects like dizziness and gastric disturbances. As a potential for convenient, safe and effective antidiabetic therapy, the rationale of this study was to develop a transdermal delivery system for glimepiride. Chitosan polymer was utilized in developing transdermal films for glimepiride. Chitosan has film forming ability, bioadhesive and absorption enhancing properties. Aiming at optimizing the drug delivery and circumventing the skin barrier function, inclusion complexation of glimepiride with beta-cyclodextrin (β-CyD) as well as the use of several conventional penetration enhancers were monitored for augmenting the drug flux. The physical and mechanical properties of the prepared films were investigated using tensile testing, IR spectroscopy and X-ray diffractometry. Release studies revealed adequate release rates from chitosan films. Permeation studies through full thickness rat abdominal skin were conducted. High flux values were obtained from films comprising a combination of the drug with limonene and ethanol as well as from films containing glimepiride-β-CyD complex. In vivo studies on diabetic rats for selected formulae revealed a marked therapeutic efficacy sustained for about 48 hours. The above-mentioned results shed light on feasibility of utilizing chitosan as an effective, safe transdermal delivery system for glimepiride characterized by increased patient compliance and better control of the disease.

Necrostatin-1 protects against ischemia/reperfusion injury by inhibiting receptor-interacting protein 1 in a rat flap model

The failure of reconstructive surgeries remains a challenge for plastic surgeons. Ischemia reperfusion (I/R) injury is considered to be one of the major problems in flap surgery. Necroptosis is a recently discovered and caspase-3-independent programed necrosis. Necrostatin-1 (Nec-1) is a specific inhibitor of necroptosis. Reports indicate that Nec-1 provides protection in ischemic models, such as brain, kidney, and heart. The aim of this study is to investigate the influence of Nec-1 on the I/R process in rat abdominal skin flaps. Twenty male Sprague-Dawley rats, weighing 280-320 g, were randomly divided into three groups. The extended epigastric skin flap (6 cm × 9 cm) of rats was used. Three hours of complete ischemia was performed using a clamp, and the clamp was then removed to reperfusion the flap. Twenty-four hours after the onset of the reperfusion, the rats were assessed for flap survival and perfusion analysis. One sample (1 cm × 1 cm) was taken for H&E, TUNEL, electron microscopy, IHC staining for RIP-1, and ELISA analysis for caspase-3 activity. Compared to the CTL group, the flap in the Nec-1 group showed a higher survival rate and better blood perfusion. In histological observation, skin flap in the Nec-1 group showed less inflammatory infiltration than the CTL group. The AI in the CTL group was higher than that in the Nec-1 group and showed typical morphological changes of apoptotic cells. In IHC study, RIP-1 expression was higher in the CTL group. But there was no significant difference between the two groups in caspase-3 activity detection. Nec-1 has a protective effect against I/R injury through the inhibition of RIP-1 on the skin flap model; this makes it a promising novel strategy in clinical setting.

Development and evaluation of transdermal gel of acyclovir using Nerolidol as penetration enhancer

The aim of this study was to investigate the effect of Nerolidol on the penetration of Acyclovir in the form of transdermal gel formulation. Different formulations were prepared containing different concentrations of Nerolidol (0-5%) using Aloe vera gel as a base. Formulations evaluated for pH, Viscosity, Percent drug content, Spreadability, Diffusion study and In-vitro permeation study. Rheological study showed that viscosity is inversely proportional to the rate of shear and thus the system shows pseudoplastic behaviour. pH of all the formulations was found to be around 6 which is skin compatible. The percent drug content was found to be within the range of 98 to 101% for all the formulations. Spreadability of formulations is found to be in the range of 11.25 to 12.66 gm.cm/sec. Stability studies showed that the formulation is stable at 40oC at 75% RH for a period of one month. It was evident that the permeation of Acyclovir was enhanced, across freshly excised hairless rat abdominal skin, in presence of Nerolidol which can be attributed toincreased lipid disruption in the stratum corneum. Comparison of F5with marketed formulation (Acivir, Cipla) for permeation of Acyclovir across hairless rat abdominal skin, showed greater flux 12.89 mg/cm2. as compared to flux 4.74 mg/cm2.hr of marketed formulation. F0 (without Nerolidol) showed better flux of 6.59 mg/cm2.hr than the marketed product, this can be attributed to the use of Aloe vera gel as an absorption base which consists of lignins, that intensify penetrative properties.

Effect of hydrophilic and hydrophobic polymer on the release of ketoprofen and allopurinol from bilayer matrix transdermal patch

AbstractThe aim of this study was to design a matrix transdermal patch of ketoprofen and allopurinol for the possible treatment of arthritis with reduced side effects. For this purpose, a bilayer matrix transdermal patch was prepared with an immediate release layer of Methocel containing ketoprofen while secondary sustained layer composed of allopurinol with combinations of Eudragit RL100 and Methocel. The patch was studied for swelling index in distilled water and was found to increase with an increase in concentration of hydrophilic polymer. The in vitro dissolution was conducted in USP dissolution apparatus II using phosphate buffer saline (pH 7.4) as dissolution medium at 37 ± 2°C. Based on in vitro dissolution studies, KA1BL (99.65% release in 10 hr) was selected for ex vivo permeation studies through Franz diffusion cell using excised abdominal skin of albino rats, and using clove oil and menthol as permeation enhancers. The optimized formulation KA1BL‐M3 released 69.37% drug over 12 hr and followed zero‐order kinetics with anomalous release mechanism. The patch had uniform distribution of components as per digital microscopic analysis.

DEVELOPMENT AND OPTIMIZATION OF RIZATRIPTAN BENZOATE ETHOSOMES

Objective: The objective of this study was to assess the development of ethosomal drug delivery system for site-specific topical delivery of rizatriptan benzoate (RBZ) for sustained action.Methods: In the present study ethosomes were prepared using the cold method. The formulation was optimized using 33 full factorial designs. The lipid concentration (X1), ethanol concentration (X2) and stirring speed (X3) were selected as independent factors and the vesicle size (Y1) and % entrapment efficiency (Y2) were selected as dependent variables.Results: The equation of multiple regression revealed that there was no significant interaction among factors. The lipid concentration had a positive effect on vesicle size while ethanol concentration and stirring speed had a negative effect. For entrapment efficiency, all factors showed a positive effect while lipid concentrative found to be the main influencing factor. The formulation F4E459 (4% SPC, 45% v/v ethanol 900 RPM), which was characterized by optimum vesicle size (5.5 µm) and high entrapment efficiency (93.32%), was considered to be an optimal formulation. The scanning electron microscopy (SEM) results showed that RBZ ethosome have a smooth surface. The polydispersity index (PI) and zeta potential of the optimized formulation were found to be 0.493±0.021and–21.3 mV respectively. In vitro permeation through rat abdominal skin from the ethosomal gel followed Higuchi diffusion model over a period of 8 h.Conclusion: The results obtained in this research work clearly indicated a promising potential of ethosomal carrier system of RBZ for migraine treatment with a topical approach for sustained action.

Preparation and transdermal permeation of triptolide and ferulic acid ethosomes gel in vitro

The aim of this study was to prepare triptolide and ferulic acid ethosomes gel, investigate its transdermal permeation, and compare the results with ordinary gel and cream. Improved Franz diffusion cell method was used in the transdermal delivery experiment with rat abdominal skin as in vitro model. The receptor fluid at different time points was collected; ferulic acid concentration was determined by high performance liquid chromatography (HPLC) and triptolide concentration was determined by liquid chromatography-electrospray ionization mass spectrometry (LC-MS/MS). Then the penetration rate, transdermal volume and skin reserve of three dosage forms (hydroplasy gel, ordinary gel, and cream) to investigate the transdermal properties of ferulic acid and triptolide in vitro of triptolide and ferulic acid ethosomes gel. The results showed that the steady penetration rate of ferulic acid was 5.268 5, 8.990 9, 12.042 0 μg·cm⁻² ·h⁻¹ respectively in triptolide and ferulic acid ethosomes gel, ordinary gel and cream; the skin retention was (30.234 8±1.525 4), (20.402 6±0.402 6), (7.635 3±1.094 2) μg·cm⁻² . The steady-state permeation rate of triptolide was 67.238 0, 67.238 0 ng·cm⁻² ·h⁻¹ in triptolide and ferulic acid ethosomes gel, about 1.24 times of cream and 3.28 times of ordinary gel; the skin retention was (371.351 4±35.317 1) ng·cm⁻², about 3.35 times of cream and 5.25 times of ordinary gel. Therefore, the ethosomes gel showed good transdermal absorption property and it may be good for clinical safety administration.

NGF/FAK signal pathway is implicated in angiogenesis after acute cerebral ischemia in rats

Neurogenesis in the cerebral infarction after an ischemic event is important to the rehabilitation of patients. However, the mechanism of angiogenesis around cerebral ischemia is not clear. Our study designed to test whether the nerve growth factor (NGF)-P-focal adhesion kinase (FAK) signaling pathway for associations with angiogenesis plays a key role in post-acute cerebral ischemia of rats. Firstly, we implanted the Matrigel, a carrier of basement membrane matrix, into the abdominal skin of rats to identify the relevant components of the NGF-P-FAK signaling pathway related to angiogenesis. Secondly, we used a model established by ligation of the middle cerebral artery (MCA) to observe the effect of the same signal pathway on angiogenesis in the subventricular and subgranular zones of the dentate gyrus(SVG and SGZ). The results showed that the tissue scores was significantly increased by NGF. However, the tissue scores was signifcaintly decreased by FAK inhibitor TAE226. Furthermore, CD31 and α-SMA were significantly increased by NGF and were decreased by anti-NGF and TAE226 in Matrigel. The P-FAK protein expression in Matrigel was markedly increased by NGF and decreased by TAE226. In the SVZ and SVG of cerebral ischemia, the numbers of BrdU-positive cells were significantly increased by NGF and decreased by TAE226, respectively. Our findings suggest that the therapy targeting the NGF-P-FAK signaling pathway may be an option for patients suffering from cerebral ischemia.

Development and Evaluation of Terbinafine Hydrochloride Polymeric Microsponges for Topical Drug Delivery

The objective of the present study was to develop and evaluate sustained delivery of terbinafine hydrochloride from topical polymeric microsponges. Microsponges of ethyl cellulose containing terbinafine hydrochloride were prepared by quasi emulsion solvent diffusion method. Effect of drug polymer ratio on active drug content, particle size and entrapment efficiency were studied. Drug polymer ratio greatly affects properties (entrapment efficiency, active drug content, particle size) of microsponges. Terbinafine hydrochloride microsponges showed highest actual drug content, entrapment efficiency and smaller particle size, so 1.5:1 ratio of drug and polymer was selected for optimization study. Optimization study was carried out by taking internal phase volume, stirring rate, emulsifier concentration as independent variables and their effects on entrapment efficiency, particle size were studied. It was found that as stirring speed increases, the particle size decreases and entrapment efficiency increases, while as volume of dichloromethane increases, particle size decreases. Morphology of obtained microsponges was revealed by scanning electron microscope and was found to be porous and spherical. Optimized formulation of microsponge was dispersed in Carbopol gel and evaluated for drug content, pH, viscosity and in vitro drug release. Release of drug was found to be sustained through microsponge gel as compared to marketed product and pure drug gel. Ex vivo drug deposition study was carried using rat abdominal skin. Drug deposition was found to be satisfactory. Prepared polymeric microsponges could be a potential topical drug delivery system in antifungal therapy.

Design of antihistaminic transdermal films based on alginate–chitosan polyelectrolyte complexes: characterization and permeation studies

The purpose of this study was to develop suitable matrix-type transdermal drug delivery systems of Ketotifen fumarate (KF) as antiasthmatic drugs. Chitosan–alginate polyelectrolyte complex (PEC) films were used as drug release regulators for KF. Antihistaminic films with variable PEC compositions were prepared using different ratios of chitosan (CTS) to sodium alginate (ALG). Propylene glycol (PG) was used as plasticizer; Tween 80 (T80) and Span 20 (S20) were used as permeability enhancers. Nine formulations were obtained by film casting method and characterized in terms of weight uniformity, thickness, folding endurance, moisture lost, and moisture absorption. In addition, drug release and permeation through rat abdominal skin mounted in Franz cell were investigated. All formulations were found to be suitable in terms of physicochemical characteristics, and there was no significant interaction between the used drug and polymers. It was noticed that when T20 is used as permeation enhancer, a satisfactory drug release pattern was found where 99.88% of drug was released and an amount of 2.121 mg/cm2 of KF was permeated after 24 h. For the optimal formulation, a permeability coefficient of 14.00 ± 0.001 cm h−1 and a latency time of 0.35 ± 0.02 h were found. The in-vitro analysis showed controlled release profile which was fitted by Korsmeyer–Peppas model (R2 = 0.998). The obtained results suggested that new controlled release transdermal formulations of asthmatic drugs could be suitably designed as an alternative to the common forms.

Iontophoretic transdermal delivery using chitosan-coated PLGA nanoparticles for positively charged drugs

Recently, poly(dl-lactide-co-glycolide) (PLGA) nanoparticles prepared using a combination of an antisolvent diffusion method with preferential solvation was shown to be beneficial for the iontophoretic transdermal delivery of therapeutic agents. Also, this preparation method can contain a hydrophilic drug. However, since PLGA nanoparticles were negatively charged, it was difficult to apply iontophoresis for positively charged hydrophilic drugs. In this study, we prepared positively charged PLGA nanoparticles containing donepezil hydrochloride (DP). DP was used as a positively charged hydrophilic drug model. The PLGA nanoparticles were coated with chitosan hydroxypropyltrimonium chloride. The average particle diameter of the nanoparticles was 117.7±60.6nm and the surface charge number density changed from negative to positive. Ex vivo skin accumulation study was carried out using abdominal rat skin and a Franz-type diffusion cell with/without iontophoresis. When iontophoresis was applied, the DP concentration in the rat skin of chitosan-coated PLGA nanoparticles was 2.2 times higher than that of non-coated PLGA nanoparticles. This indicated that chitosan-coated PLGA nanoparticles were suitable for iontophoresis. To investigate the transdermal delivery route of the nanoparticles, we prepared chitosan-coated PLGA nanoparticles containing DP, coumarin-6, and rhodamine 6G. Coumarin-6 and rhodamine 6G were used as a trace marker of the PLGA nanoparticles and positively charged hydrophilic drug model, respectively. From the results of ex vivo accumulation test of this fluorescent nanoparticles, it was suggested that positively charged hydrophilic drugs reached the hair follicles as a nanoparticle, and then they were released from the nanoparticles.

The abdominal skin of female Sprague-Dawley rats is more sensitive than the back skin to drug-induced phototoxicity

In vivo phototoxicity studies are important to predict drug-induced phototoxicity in humans; however, a standard methodology has not established. To determine differences in sensitivity to drug-induced phototoxicity among various skin sites, we evaluated phototoxic reactions in the back and abdominal skin of female Sprague-Dawley rats orally dosed with phototoxic drugs (pirfenidone, 8-methoxysoraren, doxycycline, and lomefloxacin) or a non-phototoxic drug (gatifloxacin) followed by solar-simulated light irradiation comprising 18J/cm2 ultraviolet A. Tissue reactions were evaluated by macroscopic and microscopic examination and immunohistochemistry for γ-H2AX, and tissue concentrations of pirfenidone, doxycycline, and lomefloxacin were measured by tandem mass spectrometry. In addition, the thicknesses of the skin layers at both sites were measured in drug-naïve rats. The abdominal skin showed more severe reactions to all phototoxic drugs than the back skin, whereas the minimal erythema dose in drug-naïve rats and skin concentrations of each drug were comparable between the sites. Furthermore, histopathological lesions and γ-H2AX-positive cells in the abdominal skin were detected in deeper layers than in the back skin. The stratum corneum and dermis in the abdominal skin were significantly thinner than in the back skin, indicating a difference in the depth of light penetration and potentially contributing to the site differences observed in sensitivity to phototoxicity. Gatifloxacin did not induce any phototoxic reactions at either site. In conclusion, the abdominal skin is more sensitive to drug-induced phototoxicity than the back skin and may represent a preferable site for irradiation in this rat phototoxicity model.

A pH-independent instantaneous release of flurbiprofen: a study of the preparation of complexes, their characterization and in vitro/in vivo evaluation

In this study, furbiprofen/hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complexes were prepared to improve the drug dissolution and facilitate its application in hydrophilic gels. Inclusion complexes were prepared using a supercritical fluid processing and a conventional optimized co-lypholization method was employed as a reference. The entrapment efficacy and drug loading of both methods were investigated. Evaluation of drug dissolution enhancement was conducted in deionized water as well as buffer solutions of different pH. Carbopol 940 gels of both flurbiprofen and flurbiprofen/HPβCD inclusion complexes, with or without penetration enhancers, were prepared and percutaneous permeation studies were performed using rat abdominal skin samples. Formation of flurbiprofen/HPβCD inclusion complexes was confirmed by Fourier transform-infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. The results obtained showed that SCF processing produced a higher EE (81.91 ± 1.54%) and DL (6.96 ± 0.17%) compared with OCL with values of 69.11 ± 2.23% and 4.00 ± 1.01%, respectively. A marked instantaneous release of flurbiprofen/HPβCD inclusion complexes prepared by SCF processing (103.04 ± 2.66% cumulative release within 5 min, a 10-fold increase in comparison with flurbiprofen alone) was observed. In addition, this improvement in dissolution was shown to be pH-independent (the percentage cumulative release at pH 1.2, 4.5, 6.8 and 7.4 at 5 min was 95.19 ± 1.71, 101.75 ± 1.44, 105.37 ± 4.58 and 96.84 ± 0.56, respectively). Percutaneous permeability of flurbiprofen-in-HPβCD-in-gels could be significantly accelerated by turpentine oil and was related to the water content in the system. An in vivo pharmacokinetic study showed a 2-fold increase in Cmax and a shortened Tmax as well as a comparable relative bioavailability when compared with the commercial flurbiprofen Cataplasms (Zepolas®). With their superior dissolution, these flurbiprofen/HPβCD inclusion complexes prepared by SCF processing could provide improved applications for flurbiprofen.

Transdermal potential and anti-gout efficacy of Febuxostat from niosomal gel

Gout is a metabolic disorder which causes inflammation of the joints. The pain can be relieved by taking anti-inflammatory or pain-relieving medication. Febuxostat, a xanthine oxidase inhibitor is also used in the treatment of gout. It is a weak acid (pKa = 3.08) and is therefore, practically insoluble in water. Due to its limited solubility in water and susceptibility to enzymatic degradation in intestine and liver, its oral bioavailability is affected. The presence of food also decreases its maximum plasma concentration (Cmax) by 38–39%. Hence, transdermal route is preferred for its administration. In the present research, niosomal vesicles were selected for Febuxostat delivery because of their penetration enhancing ability. Niosomes containing Febuxostat were prepared using thin film hydration method. A 23 factorial design (DOE analysis) was carried out to reduce the number of experiments. Parameters contribution was determined using a 3-D response curve. Prepared optimized batch (F4) exhibited entrapment efficiency of 73.93 ± 0.75% and percent cumulative drug release of 83.03 ± 0.07%. Transmission Electron Microscopy (TEM) revealed vesicular, spherical particles with a smooth surface in the nano range. Niosomal gel of optimized batch (F4) was prepared incorporating 2% w/w carbopol 934. The ex-vivo permeation study was performed in the Franz diffusion apparatus using excised rat abdominal skin in phosphate buffer pH 7.4, which showed prolonged drug permeation of 80.37 ± 0.02%. In-vivo study of optimized Febuxostat niosomal gel NG (F4) on rabbits revealed better results than the standard (pure) Febuxostat. NG (F4) exhibited good stability throughout 90 days at different temperature and humidity.

Hydrophilic drug-loaded PLGA nanoparticles for transdermal delivery

Transdermal delivery has been widely studied since it can avoid the effect of first-pass hepatic metabolism and deliver therapeutic agents as systemic or local administration for long period of time. In this study, procaine hydrochloride-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles for transdermal delivery were prepared using a combination of an antisolvent diffusion method with preferential solvation. The physicochemical characteristics and skin permeability were studied. Mean volume diameter of prepared nanoparticles was 99.4 ± 0.8 nm. They were “soft particles” and have negatively charged polyelectrolyte layer on the surface. Ex vivo experiment was carried out using the skin of male Sprague–Dawley rat with Franz diffusion cells. Compared to procaine hydrochloride free molecules, a higher amount of procaine hydrochloride was delivered through rat skin when procaine hydrochloride was loaded in nanoparticles. Moreover, a solution mixture of ethanol and isopropyl myristate, which were used as transdermal enhancers, improved skin permeability of the nanoparticles. In vivo experiment was carried out using male Sprague–Dawley rats aging 8 weeks. Samples were administered on rat abdominal skin (2.5 cm × 2.5 cm). After 9 h, drug concentrations of the skin and muscle under the area of sample administration were measured by using HPLC. Skin accumulation of the drug was increased when drug was included into PLGA nanoparticles, and muscle accumulation was increased by using transdermal enhancer. These results indicate that the nanoparticles that were prepared using a combination of an antisolvent diffusion method with preferential solvation were useful for transdermal delivery.

Diclofenac transdermal patch versus the sustained release tablet: A randomized clinical trial in rheumatoid arthritic patients

Purpose : To prepare and characterize transdermal films of diclofenac diethanolamine as a safer and more effective alternative than the sustained release (SR) tablet equivalent for prolonged relief from pain and inflammation in arthritis. Methods: Transdermal films of diclofenac were prepared using sodium carboxymethyl cellulose and polyvinyl pyrrolidone K30, with turpentine oil and sesame oil as penetration enhancers. The films were characterized for physicochemical properties and for ex vivo permeation in a randomized clinical trial (RCT) for analgesic activities in arthritic patients. Results: The transdermal films were uniform in weight and thickness, flat, with high drug content (94.40 ± 1.04 to 98.62 ± 1.08 %) and with high folding endurance (149 ± 9.09 to 192 ± 10.12). Drug permeation through excised rat abdominal skin was prolonged. Films containing penetration enhancers showed higher ex vivo drug permeation than those without the enhancer; furthermore, drug permeation increased with increase in the concentration of enhancer. The films were non-irritating to the skin. In RCT, F3 (containing turpentine oil, 1 %v/w) decreased the pain score from 9.87 ± 1.14 to 4.94 ± 0.78 units, compared with the SR tablet (once daily) which decreased pain from 9.59 ± 0.42 to 6.49 ± 1.20 units, 48 h post-administration. Turpentine oil showed better permeation enhancement than sesame oil in the transdermal films. Conclusion: Transdermal films of diclofenac, formulated with permeation enhancers, may have greater therapeutic advantages over conventional oral tablets in terms of prolonged release and improvement of patient compliance in rheumatoid arthritis. Keywords : Analgesic activity, Diclofenac, Permeation enhancer, Rheumatoid arthritis, Transdermal films

Novel Injury Site Targeted Fusion Protein Comprising Annexin V and Kunitz Inhibitor Domains Ameliorates Ischemia-Reperfusion Injury and Promotes Survival of Ischemic Rat Abdominal Skin Flaps

The effects of ANV-6L15 on survival of rat abdominal fasciocutaneous flaps subjected to 10 hours of critical ischemia were assessed on day 5. Near-IR imaging was applied to evaluate the distribution of ANV-6L15 and flap perfusion. The rat cremaster muscle island flap was used to evaluate the effect of ANV-6L15 on IRI-induced leukocyte-endothelial interactions via intravital microscopy. 2,3,5 triphenyl-tetrazolium chloride assay was used to determine the ratio between live-versus-dead tissue. ANV-6L15 significantly increased the ratio of viable tissue (68.5 ± 9.79% vs 84.8 ± 5.14%, P < 0.05), and promoted survival of rat pedicled abdominal flaps (59.3 ± 6.86 vs. 47.0 ± 8.67, P < 0.05). Intravital microscopy demonstrated a significant decrease in the number of adhesive leukocytes (1.8 ± 1.64 vs. 10.0 ± 6.32, P < 0.05), and the percentage change of functional capillaries (16.4 ± 15.1 vs. 47.3 ± 18.3, P < 0.05) in ANV-6L15-treatment group. ANV-6L15 promoted survival of ischemic rat cremaster muscle and abdominal fasciocutaneous flaps and ameliorated leukocyte-related IRI. Future evaluation of potential clinical application of ANV-6L15 is warranted as a flap treatment adjunct.

EFFECTIVITY AND PHYSICOCHEMICAL STABILITY OF NANOSTRUCTURED LIPID CARRIER COENZYME Q10 IN DIFFERENT RATIO of LIPID ALFA CETYL PALMITATE AND ALPHA TOCOPHERYL ACETATE AS CARRIER

Objective: The aim of this study was to investigate physical characteristics of nanostructured lipid carriers (NLCs) mixture of alpha tocopheryl acetate, cetyl palmitate, Tween 80 and propylene glycol using high shear homogenization technique on NLC preparation to predict the optimum ratio of alpha tocopheryl acetate-cetyl palmitate to produce good characteristics of NLC loaded coenzyme, higher % EE, good penetration, controlled release, and stable.Methods: Lipid characterizations were conducted by diffraction scanning calorimetry, X-ray diffraction, and Fourier transforms infrared spectrophotometry. Coenzyme Q10 concentration was measured by spectrophotometer at 275 nm. NLC characteristics based on their morphology was determined using transmission electron microscope, particle size, and its polydispersity index which were measured with Delsa Nano™ particle size analyzer. Percentage of coenzyme Q10 entrapped in NLC was determined by dialysis bag method. Coenzyme Q10 release profile was measured using with Franz cell for 12 hrs. The penetration depth of NLC coenzyme Q10 in abdominal skin of Wistar rat was determined with fluorescence microscopy using rhodamine B as marker. NLC physical stability based on minimum of particle size variation, pH and viscosity during 90 days storage.Results: The result showed that formula with ratio of cetyl palmitate-alpha tocopheryl acetate 70:30 (% w/w) produce good characteristics of NLCloaded coenzyme, higher % EE, good penetration, controlled release, and stable in 90 days storage.Conclusion: The coenzyme Q10 NLC system with cetyl palmitate and alpha tocopherol acetate as lipid matrixare characterized by small particle size, low crystallinity, spherical morphology of particle and high coenzyme Q10 entrapment efficiency. Crystal modification led to the formation of a more amorphous thereby increasing the drug entrapmentKeywords: Coenzyme Q10, Nanostructured lipid carrier, Cetyl palmitate, Alpha tocopheryl acetate, High shear homogenization.

Development of essential oils as skin permeation enhancers: penetration enhancement effect and mechanism of action

Context: Essential oils (EOs) have shown the potential to reversibly overcome the stratum corneum (SC) barrier to enhance the skin permeation of drugs. Objective: The effectiveness of turpentine, Angelica, chuanxiong, Cyperus, cinnamon, and clove oils were investigated for the capacity and mechanism to promote skin penetration of ibuprofen. Materials and methods: Skin permeation studies of ibuprofen across rat abdominal skin with the presence of 3% w/v EOs were carried out; samples were withdrawn from the receptor compartment at 8, 10, 22, 24, 26, 28, 32, 36, and 48 h and analyzed for ibuprofen content by the HPLC method. The mechanisms of penetration enhancement of EOs were further evaluated by attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) analysis and determination of the properties of EOs. Moreover, the toxicities of EOs on skin cells were also measured. Results: The enhancement ratio (ER) values of turpentine, Angelica, chuanxiong, Cyperus, cinnamon, clove oils and azone were determined to be 2.23, 1.83, 2.60, 2.49, 2.63 and 1.97, respectively. Revealed by ATR-FTIR analysis, a linear relationship (r = 0.9045) was found between the ER values and the total of the shift of peak position of SC lipids. Furthermore, the results of HaCaT skin cell toxicity evaluation revealed that the natural EOs possessed relatively lower skin irritation potential. Conclusion: Compared with azone, the investigated EOs possess significantly higher penetration enhancement effect and lower skin toxicity. EOs can promote the skin permeation of ibuprofen mainly by disturbing rather than extracting the SC lipids.