Docetaxel/dimethyl-ß-cyclodextrin inclusion complexes: preparation, in vitro evaluation and physicochemical characterization.

Despite the development in novel drug delivery techniques and synthesis of multifunctional excipients, oral delivery of hydrophobic drug like docetaxel (DTX) is still challenging. The present work investigates the inclusion complexation of DTX, and dimethyl-ß-cyclodextrin (DM-ß-CD) to improve the solubility, dissolution and permeability of the drug. Amongst the native and modified ß-cyclodextrins, DM-ß-CD showed the highest solubility of DTX. Solid binary inclusion complex (IC) of DTX with DM-ß-CD was prepared by solvent evaporation technique and thoroughly characterized for solubility, dissolution, permeability, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance (1H NMR). The aqueous solubility and in vitro dissolution rate of DTX/DM-ß-CD IC were markedly increased by 76.04- and 3.55-fold compared to free DTX powder. The permeability of DTX/DM-ß-CD IC showed similar absorptive permeability but decreased efflux from the absorbed DTX, compared to pure DTX. Further, physicochemical studies of IC revealed the change of crystalline state DTX to its amorphous form. Moreover, FT-IR and 1H NMR results indicate the formation of true inclusion complex between DTX and DM-ß-CD at 1:1 molar ratio. Collectively, solid inclusion complexes prepared by spray drying method can be an effective strategy to enhance the biopharmaceutical performance of a highly hydrophobic drug DTX.

Revaprazan-loaded surface-modified solid dispersion: physicochemical characterization and in vivo evaluation.

The purpose of this research was to develop a novel revaprazan-loaded surface-modified solid dispersion (SMSD) with improved drug solubility and oral bioavailability. The impact of carriers on aqueous solubility of revaprazan was investigated. HPMC and Cremophor A25 were selected as an appropriate polymer and surfactant, respectively, due to their high drug solubility. Numerous SMSDs were prepared with various concentrations of carriers, using distilled water, and the drug solubility of each was assessed. Moreover, the physicochemical properties, dissolution and pharmacokinetics of selected SMSD in rats were assessed in comparison to revaprazan powder. Of the SMSDs assessed, the SMSD composed of revaprazan/HPMC/Cremophor A25 at the weight ratio of 1:0.28:1.12 had the most enhanced drug solubility (∼6000-fold). It was characterized by particles with a relatively rough surface, suggesting that the carriers were attached onto the surface of the unchanged crystalline revaprazan powder. It had a significantly higher dissolution rate, AUC and Cmax, and a faster Tmax value in comparison to revaprazan powder, with a 5.3-fold improvement in oral bioavailability of revaprazan. Therefore, from an environmental perspective, this SMSD system prepared with water, and without organic solvents, should be recommended as a revaprazan-loaded oral pharmaceutical alternative.

Formulation of novel dry powder inhalation for fluticasone propionate and salmeterol xinafoate with capsule-based device.

The aim of this study was to develop a novel fluticasone propionate (FP) and salmeterol xinafoate (SX)-loaded dry powder inhaler (DPI) system, which was composed of powder formulation and performance. The air flow resistances were determined with various types of DPI device, showing that the modified RS01 device gave the specific resistance similar to the commercial DPI device. The particle properties of FP, SX, and inhalation grade lactose particles, such as particle size, size distribution, and fine content, were assessed. Subsequently, the aerodynamic behaviors of the DPI powder formulations were evaluated by the in vitro deposition of drugs in the DPI products using Andersen cascade impactor. Amongst the DPI powder formulations tested, the formulation composed of FP, SX, Respitose® SV003, Respitose® SV010, and Respitose® ML006 at the weight ratio of 0.5/0.145/19/19/2 gave depositions, emitted dose, fine particle dose, fine particle fraction, and mass median aerodynamic diameter of drugs similar to the commercial product, suggesting that they had similar aerodynamic behaviors. Furthermore, it gave excellent content uniformity. Thus, this DPI using the modified RS01 device would be recommended as a candidate for FP and SX-loaded pharmaceutical DPI products.

Bioadhesive Drug Delivery System for Enhancing the Permeability of a BCS Class III Drug via Hot-Melt Extrusion Technology.

As the buccal route of administration has the ability to avoid the GI tract and first-pass effect by directing the absorption toward the cheek area, the bioavailability of BCS class III drugs can be increased through this route. Only a handful of studies have been conducted using oleic acid as a permeation enhancer in any transbuccal drug delivery system. Therefore, the objectives of this novel study were to develop a buccal tablet using two concentrations of oleic acid for a model BCS class III drug via hot-melt extrusion technology and to investigate the effects of oleic acid on the physicochemical properties of the tablet. The model drug selected was ondansetron hydrochloride. Formulations consisting of polymers (hydroxypropyl methylcellulose and polyethylene oxide) and two concentrations of oleic acid were prepared by hot-melt extrusion techniques. A melting point depression of the drug was obtained in the extruded granules as seen by the DSC thermograms. The ex vivo permeation studies showed a greater permeation of the drug in the formulation containing 10% oleic acid (F2) as compared to the formulation containing 20% oleic acid (F1), although not statistically significant. The in vitro bioadhesion studies, swelling studies, and surface pH measurements of the tablets were also conducted. In conclusion, permeation studies exhibited the potential of oleic acid as a buccal permeation enhancer as a significant permeation of the drug was obtained in the formulations. Hot-melt extrusion technology was successfully employed to formulate buccal tablets of ondansetron hydrochloride.

Influence of polyvinylpyrrolidone quantity on the solubility, crystallinity and oral bioavailability of fenofibrate in solvent-evaporated microspheres.

The objective of this study is to explore the influence of polyvinylpyrrolidone (PVP) quantity on the solubility, crystallinity and oral bioavailability of poorly water-soluble fenofibrate in solvent-evaporated microspheres. Numerous microspheres were prepared with fenofibrate, sodium lauryl sulphate (SLS) and PVP using the spray-drying technique. Their aqueous solubility, dissolution, physicochemical properties and pharmacokinetics in rats were assessed. The drug in the solvent-evaporated microspheres composed of fenofibrate, PVP and SLS at the weight ratio of 1:0.5:0.25 was not entirely changed to the amorphous form and partially in the microcrystalline state. However, the microspheres at the weight ratio of 1:4:0.25 provided the entire conversion to the amorphous form. The latter microspheres, with an improvement of about 115 000-fold in aqueous solubility and 5.6-fold improvement in oral bioavailability compared with the drug powder, gave higher aqueous solubility and oral bioavailability compared with the former. Thus, PVP quantity played an important role in these properties of fenofibrate in the solvent-evaporated microspheres.

Novel piroxicam-loaded nanospheres generated by the electrospraying technique: physicochemical characterisation and oral bioavailability evaluation.

To determine if a novel electrospraying technique could be applied to an oral drug delivery system for improving the solubility and oral bioavailability of poorly water-soluble piroxicam; the nanospheres were generated with drug and polyvinylpyrrolidone (PVP) using electrospraying technique; and their physicochemical properties, solubility, release and pharmacokinetics were evaluated in comparison with piroxicam powder. All nanospheres had significantly increased drug solubility and dissolution rates in comparison with the drug powder. In particular, the nanosphere composed of piroxicam and PVP at a weight ratio of 2:8 gave about 600-fold higher solubility, 15-fold higher release rate and 3-fold higher AUC in comparison to piroxicam powder, leading to significantly enhanced oral bioavailability in rats, due to the mingled effect of nanonisation along with transformation to the amorphous state. Thus, this electrospraying technique can be utilised to produce a novel oral nanosphere delivery system with enhanced solubility and oral bioavailability for poorly water-soluble piroxicam.

Clopidogrel Napadisilate Monohydrate Loaded Surface-Modified Solid Dispersion: Physicochemical Characterization and in Vivo Evaluation.

To develop a novel solid dispersion of clopidogrel napadisilate monohydrate (CNM) with improved stability and oral bioavailability, surface-modified solid dispersions were prepared by spray-drying using water as a solvent, Tween 80 as a surfactant, and hydroxypropylmethyl cellulose (HPMC) as a hydrophilic polymer, and optimized according to drug solubility. Its solid-state characterization was evaluated by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The stability study was performed at 50°C/75% RH over a period of 6 weeks. Its dissolution profiles and oral bioavailability in rats were also compared with that of CNM and clopidogrel bisulfate (CB). The solid dispersion, composed of CNM/HPMC/Tween80 at a weight ratio of 10/2.5/2.5, in which CNM was in the crystalline state, increased the drug solubility approximately 4.6-fold. It showed a significantly better dissolution profile than that of CNM in all the dissolution media, and gave either similar or higher dissolution compared to that of CB. This solubility and dissolution enhancement was attributed to improved wetting and solubilization of CNM crystals due to hydrophilic carriers attached on the drug surface. It had excellent stability, thereby addressing the stability problem of CB powder. Furthermore, it increased the area under curve (AUC) values by about 4-fold and 1.6-fold compared to CNM and CB, respectively, suggesting that it improved the oral bioavailability of the drug in rats. Thus, this solid dispersion system prepared with water, HPMC and Tween 80 can be used to enhance the bioavailability of CNM as well as to solve the stability problem of CB.

In vivo wound-healing effects of novel benzalkonium chloride-loaded hydrocolloid wound dressing.

The purpose of this study was to evaluate the wound-healing effects of a novel benzalkonium chloride (BC)-loaded hydrocolloid wound dressing (HCD). A BC-loaded HCD was prepared with various constituents using a hot melting method, and its mechanical properties and antimicrobial activities were assessed. The in vivo wound healings of the BC-loaded HCD in various would models were evaluated in rats compared with a commercial wound dressing, Duoderm™. This BC-loaded HCD gave better skin adhesion, swelling, mechanical strength, and flexibility compared with the commercial wound dressing. It showed excellent antimicrobial activity against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. In addition, as compared with the commercial wound dressing, it showed more improved wound healings and tissue restoration effect on the excision, infection, and abrasion wounds in rats. Thus, this novel BC-loaded HCD would be an excellent alternative to the commercial wound dressing for treatment of various wounds.

Solid self-nanoemulsifying drug delivery system (SNEDDS) for enhanced oral bioavailability of poorly water-soluble tacrolimus: physicochemical characterisation and pharmacokinetics.

To develop a novel self-nanoemulsifying drug delivery system (solid SNEDDS) with better oral bioavailability of tacrolimus, the solid SNEDDS was obtained by spray-drying the solutions containing the liquid SNEDDS and colloidal silica. Its reconstitution properties were determined and correlated to solid state characterisation of the powder. Moreover, the dissolution and pharmacokinetics in rats was done in comparison to the commercial product. Among the liquid SNEDDS formulations tested, the liquid SNEDDS comprised of Capryol PGMC, Transcutol HP and Labrasol (10:15:75, v/v/v) presented the highest dissolution rate. In the solid SNEDDS, this liquid SNEDDS was absorbed in the pores and attached onto the surface of the colloidal silica. Drug was present in the amorphous state in it. The solid SNEDDS with 5% w/v tacrolimus produced the nanoemulsions and improved the oral bioavailability of tacrolimus in rats. Therefore, this solid SNEDDS would be a potential candidate for enhancing the oral bioavailability of tacrolimus.

Development of flurbiprofen-loaded nanoparticles with a narrow size distribution using sucrose.

OBJECTIVE: A novel flurbiprofen-loaded nanoemulsion which gave uniform emulsion droplets with a narrow size distribution was previously reported to be prepared using membrane emulsification method. The purpose of this study is to develop a novel flurbiprofen-loaded nanoparticle with a narrow size distribution and improved bioavailability. METHOD: The nanoparticle was prepared by solidifying nanoemulsion using sucrose as a carrier via spray drying method. Its physicochemical properties were investigated using SEM, DSC and PXRD. Furthermore, dissolution and bioavailability in rats were evaluated compared to a flurbiprofen-loaded commercial product. RESULTS: The flurbiprofen-loaded nanoparticles with flurbiprofen/sucrose/surfactant mixture (1/20/2, weight ratio) gave good solidification and no stickiness. They associated with about 70,000-fold improved drug solubility and had a mean size of about 300 nm with a narrow size distribution. Flurbiprofen was present in a changed amorphous state in these nanoparticles. Moreover, the nanoparticles gave significantly shorter Tmax, and higher AUC and Cmax of the drug compared to the commercial product (p < 0.05). In particular, they showed about nine-fold higher AUC of the drug than did the commercial product. CONCLUSION: These flurbiprofen-loaded nanoparticles prepared with sucrose by the membrane emulsification and spray drying method would be a potential candidate for orally delivering poorly water-soluble flurbiprofen with enhanced bioavailability.

Amniotic membrane extract-loaded double-layered wound dressing: evaluation of gel properties and wound healing.

The conservative single-layered wound dressing system is decomposed when mixed in polyvinyl alcohol (PVA) solution, which means it cannot be used with a temperature-sensitive drug. The goal of this investigation was to make an amniotic membrane extract (AME)-loaded double-layered wound dressing with an improved healing result compared to the conservative single-layered wound dressing systems. The double-layered wound dressing was developed with PVA/sodium alginate using a freeze-melting technique; one layer was PVA layer and the other was the drug-loaded sodium alginate layer. Its gel properties were assessed compared to single-layered wound dressings. Moreover, in vivo wound-healing effects and histopathology were calculated compared to commercial products. The double-layered wound dressing gave a similar gel fraction and Young's module as single-layered wound bandages developed with only PVA, and a similar inflammation ability and WVTR as single-layered wound dressings developed with PVA and sodium alginate. Our data indicate that these double-layered wound bandages were just as swellable, but more elastic and stronger than single-layered wound dressings comprised of the same polymers and quantities, possibly giving an acceptable level of moisture and accumulation of exudates in the wound zone. Compared to the commercial product, the double-layered wound dressing comprising 6.7% PVA, 0.5% sodium alginate and 0.01% AME significantly enhanced the wound-healing effect in the wound-healing test. Histological investigations showed that superior full-thickness wound-healing effects compared to the commercial product. Therefore, the double-layered wound dressing would be an outstanding wound-dressing system with improved wound healing and good gel property.

A novel solid dispersion system for natural product-loaded medicine: silymarin-loaded solid dispersion with enhanced oral bioavailability and hepatoprotective activity.

A surface-attached silymarin-loaded solid dispersion with improved dissolution profile and enhanced oral bioavailability was formulated using silymarin, polyvinylpyrrolidone (PVP) and Tween 80 in water. In this solid dispersion, hydrophilic PVP was adhered onto the surface of crystalline drug rendering silymarin hydrophilic without changing its crystallinity. The drug solubility from the optimised solid dispersion prepared with silymarin/PVP/Tween 80 at the weight ratio of 5/2.5/2.5 increased by almost 650-fold compared to drug powder. The drug was physically and chemically stable in the solid dispersion for at least 6 months. Moreover, the solid dispersion enhanced the oral bioavailability of the drug in rats by almost 3-fold compared to the commercial product. The silymarin-loaded solid dispersion also exhibited advanced hepatoprotective bioactivity against CCl4-induced liver damage compared to silymarin or the commercial product. Thus, this silymarin-loaded solid dispersion would be useful for the enhancement of oral bioavailability and hepatoprotective activity of poorly water-soluble silymarin.

Development of a novel triamcinolone acetonide-loaded spray solution for the treatment of stomatitis.

To develop a novel triamcinolone acetonide (TAA)-loaded spray for the treatment of stomatitis, several spray solutions were prepared using various amounts of TAA, Eudragit L100 (Eudragit L) and PEG 400, and 100 ml ethanol. Their viscosity and spraying potential were investigated, with the result that the spraying threshold was 9.5 cP. The effect of PEG 400 on the properties of films formed after spraying was assessed. Its anti-inflammatory effect in mice was evaluated and compared to a commercial product. As the PEG 400 concentration increased, the film elongation and washability by the saliva solution increased, and tensile strength decreased. PEG 400 had little effect on mucoadhesive force and drug release. The TAA-loaded spray solution containing TAA, Eudragit L, PEG 400 and ethanol at the ratio of 1:6:3:100 (w/w/w/v) was easy to spray onto stomatitis lesions in the mouth via a spraying vessel incorporating a long straw. After spraying, the TAA-loaded spray formed a film with suitable elongation, tensile strength and washability that attached onto the mucosal membrane and released the drug. Moreover, it had excellent anti-inflammatory properties, similar to those of the commercial product. Thus, this novel TAA-loaded spray solution was easy to administer, had good film properties and excellent anti-inflammatory efficacy, and is therefore a potential candidate for the treatment of stomatitis.

Effectiveness of Shoe Rotation in Managing Plantar Fasciitis in Patients.

Background/Objectives: Plantar fasciitis (PF) is a common condition that causes heel pain. While various conservative treatment modalities for PF exist, no previous studies have investigated the effectiveness of shoe rotation (ShR) in patients with PF pain. This study aimed to compare the therapeutic effectiveness of ShR with that of two conventional treatments for PF-namely, foot orthosis (FO) and physical therapy (PT). Methods: Charts of 42 patients with heel pain were retrospectively reviewed. Participants were allocated to one of three treatment groups: the ShR group, the customized FO group, and the PT group. Pain and functional outcomes were assessed using the Visual Analog Scale (VAS), Digital Pain Scale (DPS), Foot Function Index (FFI), Foot Pain and Function Scale (FPFS), and American Orthopedic Foot and Ankle Society Ankle-Hindfoot Scale (AOFAS-AHS) at baseline and at 4 and 12 weeks after the intervention. Results: The ShR, FO, and PT groups all showed improvements, with statistically significant decreases in VAS, DPS, and FFI scores and significant increases in FPFS and AOFAS-AHS scores over time (p < 0.05). All three interventions resulted in significant improvements from baseline to 4 weeks and further to 12 weeks (p < 0.05). The ShR group exhibited a slightly larger effect on all measurements than the other groups. Conclusions: ShR, FO, and PT contributed to pain reduction and functional improvement, and alternating the shoes alleviated PF pain. These results suggest a new approach to managing PF and serve as a basis for providing convenient treatment for patients with PF.

Docetaxel-loaded thermosensitive and bioadhesive nanomicelles as a rectal drug delivery system for enhanced chemotherapeutic effect.

PURPOSE: To investigate the potential of thermosensitive and biadhesive nanomicelles in improving the bioavailability of docetaxel (DCT) and its chemotherapeutic effect. METHOD: DCT-loaded nanomicelles were prepared by emulsufication and characterized in terms of physico-chemical and visco-elastic parameters. The optimzed formulation was evaluated for in vivo localization, pharmacokinetic and anti-tumor efficacy. RESULTS: The hydrodynamic size of DCT-loaded nanomicelles was approximately 13 nm and the nanomicelles exhibited a sufficient gelation strength (9250 mPa·s) and bioadhesive force (2100 dyn/cm²) to be retained in the upper part of rectum. We observed a high rectal bioavailability of 29% DCT compared to that following oral administration in rats, as it successfully evaded the multidrug efflux transporters and hepatic first-pass metabolism. Plasma concentration around ∼50 ng/mL was maintained throughout the study period (12 h) while Taxotere® attained subtherapeutic range within 4 h of drug administration. Results also revealed that the rectally administered DCT-loaded nanomicelles exhibited a significant anti-tumor effect (200 mm³) with a reduced toxicity profile when compared to orally administered DCT (950 mm³). Furthermore, histological study showed that the rectal mucosa was completely intact with no signs of irritation upon treatment with DCT-loaded nanomicelles. CONCLUSIONS: Taken together, our novel thermosensitive and biadhesive nanomicelles demonstrated the ability to improve the bioavailability and chemotherapeutic potential of DCT in vivo. To the best of our knowledge, this is the first report describing the rectal delivery of DCT-loaded nanomicelles.

Physicochemical characterization and in vivo evaluation of solid self-nanoemulsifying drug delivery system for oral administration of docetaxel.

To formulate a self-nanoemulsifying drug delivery system (SNEDDS) for the oral administration of docetaxel as an alternative to commercial docetaxel-loaded injectable products, it was prepared by spray-drying an aqueous solution containing liquid SNEDDS and colloidal silica. Its physicochemical properties and oral bioavailability were investigated compared to a clear docetaxel solution administered intravenously or orally to rats. In the docetaxel-loaded solid SNEDDS prepared with colloidal silica, the liquid SNEDDS composed of Capryol 90, Cremophore EL and Transcutol HP (45/35/20, volume ratio) was absorbed inside the pores of carriers, and docetaxel was present in a changed amorphous state. The solid SNEDDS with 3.3% (w/v) docetaxel produced nanoemulsions, and showed about 12.5% absolute bioavailability in rats. Thus, this solid SNEDDS may be a potential candidate for oral pharmaceutical product with improved oral bioavailability of docetaxel.

Flurbiprofen-loaded nanoparticles prepared with polyvinylpyrrolidone using Shirasu porous glass membranes and a spray-drying technique: nano-sized formation and improved bioavailability.

A unique flurbiprofen-loaded nanoemulsion was listed earlier using a Shirasu porous glass (SPG) membrane emulsification technique, which gave constant emulsion droplets with a thin size distribution. In this study, a flurbiprofen-loaded nanoemulsion was developed further into a solid form using polyvinylpyrrolidone (PVP) as a carrier by a spray-drying technique. The flurbiprofen-loaded nanoparticles with a weight ratio of flurbiprofen/PVP/surfactant mixture of 1/8/2 were connected with about 130,000-fold enhanced drug solubility and had a mean size of about 70 nm. In these nanoparticles, flurbiprofen was found in an altered amorphous state. Additionally, the nanoparticles gave significantly shorter T(max), and greater AUC and C(max) compared to the commercially available product. Specially, the AUC of the drug from the nanoparticles was about 10-fold greater compared to the commercially available product. Therefore, these flurbiprofen-loaded nanoparticles can be convenient for distributing a poorly water-soluble flurbiprofen with improved bioavailability using uniform nano-sized particles.

Fabrication of Gastro-Floating Famotidine Tablets: Hydroxypropyl Methylcellulose-Based Semisolid Extrusion 3D Printing.

Semisolid extrusion (SSE) three-dimensional (3D) printing uses drug-loaded paste for the printing process, which is capable of constructing intricate 3D structures. This research presents a unique method for fabricating gastro-floating tablets (GFT) using SSE. Paste-loaded famotidine with a matrix made of hydroxypropyl methylcellulose (HPMC) were prepared. Nine 3D printed tablets were developed with different HPMC concentrations and infill percentages and evaluated to determine their physicochemical properties, content uniformity, dissolution, and floating duration. The crystallinity of the drug remained unchanged throughout the process. Dissolution profiles demonstrated the correlation between the HPMC concentration/infill percentage and drug release behavior over 10 h. All the fabricated GFTs could float for 10 h and the Korsmeyer-Peppas model described the dissolution kinetics as combination of non-Fickian or anomalous transport mechanisms. The results of this study provided insight into the predictability of SSE 3D printability, which uses hydro-alcoholic gel-API blend materials for GFTs by controlling traditional pharmaceutical excipients and infill percentages. SSE 3D printing could be an effective blueprint for producing controlled-release GFTs, with the additional benefits of simplicity and versatility over conventional methods.

Nitazoxanide and quercetin co-loaded nanotransfersomal gel for topical treatment of cutaneous leishmaniasis with macrophage targeting and enhanced anti-leishmanial effect.

Purpose: Anti-leishmanial medications administered by oral and parenteral routes are less effective for treatment of cutaneous leishmaniasis (CL) and cause toxicity, hence targeted drug delivery is an efficient way to improve drug availability for CL with reduced toxicity. This study aimed to develop, characterize and evaluate nitazoxanide and quercetin co-loaded nanotransfersomal gel (NTZ-QUR-NTG) for the treatment of CL. Methods: NTZ-QUR-NT were prepared by thin film hydration method and were statistically optimized using Box-Behnken design. To ease the topical delivery and enhance the retention time, the NTZ-QUR-NT were dispersed in 2 % chitosan gel. Moreover, in-vitro drug release, ex-vivo permeation, macrophage uptake, cytotoxicity and anti-leishmanial assays were performed. Results: The optimized formulation indicated mean particle size 210 nm, poly dispersity index (PDI) 0.16, zeta potential (ZP) -15.1 mV and entrapment efficiency (EE) of NTZ and QUR was 88 % and 85 %, respectively. NTZ-QUR-NT and NTZ-QUR-NTG showed sustained release of the incorporated drugs as compared to the drug dispersions. Skin permeation of NTZ and QUR in NTZ-QUR-NTG was 4 times higher in comparison to the plain gels. The NTZ-QUR-NT cell internalization was almost 10-folds higher than NTZ-QUR dispersion. The cytotoxicity potential (CC50) of NTZ-QUR-NT (71.95 ± 3.32 µg/mL) was reduced as compared to NTZ-QUR dispersion (49.77 ± 2.15 µg/mL. A synergistic interaction was found between NTZ and QUR. Moreover, in-vitro anti-leishmanial assay presented a lower IC50 value of NTZ-QUR-NT as compared to NTZ-QUR dispersion. Additionally, a significantly reduced lesion size was observed in NTZ-QUR-NTG treated BALB/c mice, indicating its antileishmanial potential. Conclusion: It can be concluded that nanotransfersomal gel has the capability to retain and permeate the incorporated drugs through stratum corneum and induce synergetic anti-leishmanial effect of NTZ and QUR against cutaneous leishmaniasis.

Postoperative Prognostic Predictors of Bile Duct Cancers: Clinical Analysis and Immunoassays of Tissue Microarrays.

Background/Aims: Cholangiocarcinoma frequently recurs even after curative resection. Expression levels of proteins such as epidermal growth factor receptor (EGFR), Snail, epithelial cadherin (E-cadherin), and interleukin-6 (IL-6) examined by immunohistochemistry have been studied as potential prognostic factors for cholangiocarcinoma. The aim of this study was to investigate significant factors affecting the prognosis of resectable cholangiocarcinoma. Methods: Ninety-one patients who underwent surgical resection at Samsung Medical Center for cholangiocarcinoma from 1995 to 2013 were included in this study. Expression levels of E-cadherin, Snail, IL-6, membranous EGFR, and cytoplasmic EGFR were analyzed by immunohistochemistry using tissue microarray blocks made from surgical specimens. Results: Patients with high levels of membranous EGFR in tissue microarrays had significantly shorter overall survival (OS) and disease-free survival (DFS): high membranous EGFR (score 0-2) 38.0 months versus low membranous EGFR (score 3) 14.4 months (p=0.008) and high membranous EGFR (score 0-2) 23.2 months versus low membranous EGFR (score 3) 6.1 months (p=0.004), respectively. On the other hand, E-cadherin, Snail, cytoplasmic EGFR, and IL-6 did not show significant association with OS or DFS. Patients with distant metastasis had significantly higher IL-6 levels than those with locoregional recurrence (p=0.01). Conclusions: This study showed that overexpression of membranous EGFR was significantly associated with shorter OS and DFS in surgically resected bile duct cancer patients. In addition, higher IL-6 expression was a predictive marker for recurrence in cholangiocarcinoma patients with distant organ metastasis after surgical resection.