Exploring the Potent Combination of Quercetin-Boronic Acid, Epalrestat, and Urea Containing Nanoethosomal Keratolytic Gel for the Treatment of Diabetic Neuropathic Pain: In Vitro and In Vivo Studies.

Transdermal penetration of therapeutic moieties from topical dosage forms always remains a challenge due to the presence of permeation impeding keratin which should be addressed. The purpose of the study was to formulate quercetin and 4-formyl phenyl boronic acid (QB complex) used for the preparation of nanoethosomal keratolytic gel (EF3-G). The QB complex was confirmed by Fourier transform infrared spectroscopy while skin permeation, viscosity, and epalrestat entrapment efficiency were used for the optimization of nanoethosomal gel. The keratolytic effect of the proposed nanoethosomal gel with urea (QB + EPL + U) was calculated in rat and snake skin. The spherical shape of nanoethosomes was confirmed by scanning electron microscopy. According to the findings of stability studies, viscosity decreases as temperature increases, proving their thermal stability. The negative charge of optimized EF3 with 0.7 PDI proved narrow particle size distribution with homogeneity. Optimized EF3 showed two folds increase of epalrestat permeation in highly keratinized snake skin as compared to rats' skin after 24 h. Antioxidant behaviors of EF3 (QB) > QB complex > quercetin > ascorbic acid proved reduction of oxidative stress in DPPH reduction analysis. Interestingly, the hot plate and cold allodynia test in the diabetic neuropathic rat model reduced 3-fold pain as compared to the diabetic control group which was further confirmed by in vivo biochemical studies even after the eight week. Conclusively, ureal keratolysis, primary dermal irritation index reduction, and improved loading of epalrestat render the nanoethosomal gel (EF3-G) ideal for the treatment of diabetic neuropathic pain.

Cellular and Non-cellular Antioxidant Properties of Vitamin E-Loaded Metallic-Quercetin/Polycaprolactone Nanoparticles for the Treatment of Melanogenesis.

Inhibition of melanogenesis by quercetin and vitamin E is extensively reported in the literature, independently, with limitations in antioxidant potential owing to less permeation, solubility, decreased bioavailability, and reduced stability. Thus, the aim of the present study was to synthesize a novel complex of metal ions (copper and zinc) with quercetin to enhance antioxidant properties which were confirmed by docking studies. Polycaprolactone-based nanoparticles of the synthesized complex (PCL-NPs, Q-PCL-NPs, Zn-Q-PCL-NPs, Cu-Q-PCL-NPs) were made later loaded with vitamin E which made the study more interesting in enhancing antioxidant profile. Nanoparticles were characterized for zeta size, charge, and polydispersity index, while physiochemical analysis of nanoparticles was strengthened by FTIR. Cu-Q-PCL-NPs-E showed maximum in vitro release of vitamin E, i.e., 80 ± 0.54%. Non-cellular antioxidant effect by 2,2-diphenyl-1-picrylhydrazyl was observed at 93 ± 0.23% in Cu-Q-PCL-NPs-E which was twofold as compared to Zn-Q-PCL-NPs-E. Michigan Cancer Foundation-7 (MCF-7) cancer cell lines were used to investigate the anticancer and cellular antioxidant profile of loaded and unloaded nanoparticles. Results revealed reactive oxygen species activity of 90 ± 0.32% with the addition of 89 ± 0.64% of its anticancer behavior shown by Cu-Q-PCL-NPs-E after 6 and 24h. Similarly, 80 ± 0.53% inhibition of melanocyte cells and 95 ± 0.54% increase of keratinocyte cells were also shown by Cu-Q-PCL-NPs-E that confirmed the tyrosinase enzyme inhibitory effect. Conclusively, the use of zinc and copper complex in unloaded and vitamin E-loaded nanoparticles can provide enhanced antioxidant properties with inhibition of melanin, which can be used for treating diseases of melanogenesis.

Improved anti-inflammatory effect of curcumin by designing self-emulsifying drug delivery system.

The purpose of the present study was to prepare and evaluate self-emulsifying drug delivery system (SEDDS) of curcumin (Cur) to enhance its solubility and percentage release for the evaluation of anti-inflammatory effect. Curcumin loaded SEDDS formulation was prepared, and zones of self-emulsification were recognized by dilution method for the construction of phase diagram. Lauroglycol FCC, tween 80 (surfactant), and transcutol HP (co-surfactant) were selected based on their solubility and highest emulsion region in phase diagram. Thermodynamic stability of Cur-SEDDS was calculated through globule size, zeta potential, polydispersity index (PDI), viscosity, and pH. Cur-SEDDS were also characterized by encapsulation efficiency (EE %), FT-IR, in vitro release, and in vivo anti-inflammatory effect. Results revealed that droplet size of Cur-SEDDS was 19.77 ± 0.03 nm with their PDI 0.22 ± 0.19, zeta potential -19.33 ± 0.94 and viscosity 25.68 ± 0.86 cp. EE % of Cur-SEDDS was found to be 94.99 ± 0.38%, percentage release 65.83% compared with pure Cur powder. The designed formulation possesses significant anti-inflammatory activity in paw edema when compared with positive control in carrageenan induced rat paw edema assay. Newly developed Cur-SEDDS with enhanced Cur solubility, percentage release, and better anti-inflammatory action may be an alternative source of oral delivery of Cur.

A yeast-malic acid crosslinker/polyacrylic acid hydrogel containing doxycycline for the treatment of periodontitis.

Doxycycline (DX) is a drug of choice for the treatment of periodontitis, with the limitation of requiring a high dose, which may be overcome by the preparation of a targeted controlled-release hydrogel containing a newly synthesized yeast-malic acid crosslinker (YMC). YMC was synthesized via thermochemical modification of yeast with malic acid at 100-140 °C and compared with glutaraldehyde-saturated toluene (GST). Swelling capacity, acid and carboxyl content, scanning electron microscopy (SEM) imaging, Brunauer-Emmett-Teller (BET) analysis, viscosity, cross-linking density, DX loading and release behavior at pH 6.5, mucoadhesion, and antimicrobial and periodontal efficacy of the glutaraldehyde hydrogel (HGG) and YMC hydrogel (HGY) were compared. Changes from C-O (1421 cm-1) to C[double bond, length as m-dash]OOR (1702 cm-1) in the infrared spectroscopy, along with changes in the degree of substitution from 0 to 0.39, degree of esterification from 0 to 40 ± 1.5 and COOH content from 129 ± 0.5 to 290 ± 0.5 (meq. per 100 g), were found between yeast to YMC, respectively. The results revealed 1.5 times more dynamic swelling, 0.25-fold decrease in acid content, 2.3-fold increase in carboxyl content, and 1.2- and 2.1-fold increases in cross-linking density and viscosity of HGY as compared to HGG, respectively. The SEM and BET results revealed that HGY had a 2 times greater porous surface than HGG. HGY/DX was 35 ± 2% more effective in controlling periodontitis bacteria, decreased periodontal depth from 4 to 3.2 mm, and gingival index from 3 to 1 as compared to HGG/DX in patients suffering from periodontitis. HGY/DX not only serves as a tool for the controlled release of DX in periodontal pockets but also contributes to the treatment of gingival periodontitis.

Lipase-copper complex/chitosan microspheres; loaded with attapulgite used for the treatment of E. coli-induced diarrhea.

Diarrhea is a globally major problem especially Escherichia coli induced diarrhea becoming fatal nowadays in developing countries. Colon-targeted chitosan microspheres (Ms) comprising of lipase­zinc and lipase­copper complexes were prepared, loaded with Attapulgite (Cts-Li-Zn-ATG/Ms and Cts-Li-Cu-ATG/Ms) for the treatment of bacterial diarrhea. Thin layer chromatography (TLC) and Fourier-transform infrared spectroscopy (FTIR) studies were used for confirmation of proposed lipase-metal complexes. Ms showed particle size range 18 ± 0.24 to 23 ± 0.83 µm, zeta potential -13.7 ± 0.71 to -29.3 ± 1.34 mV, PDI 0.5 ± 0.04 to 1.0 ± 0.07 and hemolytic activity was found to be <5 ± 1.25 %. After coating with Eudragit S-100 for colon targeting, in-vitro % drug release of ATG at pH 7.4 was 80 ± 0.21 % for Eud-Cts-Li-Zn-ATG/Ms while it was increased to 83 ± 0.54 % for Eud-Cts-Li-Cu-ATG/Ms within 7 h, respectively. In-vivo anti-diarrheal activity of Eud-Cts-Li-Zn-ATG/Ms and Eud-Cts-Li-Cu-ATG/Ms was performed by oral challenge on albino mice having infectious diarrhea colonized with E. coli. Results revealed significant anti-diarrheal effect of proposed Eud-Cts-Li-Cu-ATG/Ms in terms of weight gain from 24 ± 0.12 g to 26.05 ± 0.31 g, which was 2-fold increase as compared to Eud-Cts-Li-Zn-ATG/Ms. Conclusively, Eud-Cts-Li-Cu-ATG/Ms provides an innovative alternate for the treatment of bacterial diarrhea with additional support of chitosan and lipase for nutritional support and immunity which was compromised in diarrheal patients.

Synthesis, characterization, computational assay and anti-inflammatory activity of thiosemicarbazone derivatives: Highly potent and efficacious for COX inhibitors.

Multiple studies in the literature have demonstrated that synthetic compounds containing heterocyclic rings possess a reparative potential against acute and chronic inflammation. In the present study, two novel thiosemicarbazone derivatives based on l-ethyl-6-(thiophen-2-yl)indoline-2,3-dione with different phenyl substituted thiosemicarbazides were synthesized by condensation reaction and the structures of proposed target compounds (KP-2 and KP-5) were confirmed by UV-VIS, FTIR, 1H-NMR and 13C-NMR. In-vitro anti-inflammatory behavior of KP-2 and KP-5 was confirmed by bovine serum albumin (BSA) and ovine serum albumin (OSA) analysis. Acute and chronic anti-inflammatory potential of synthesized compounds were evaluated by using carrageenan and complete Freund's adjuvant (CFA) as inflammation-inducing agents, respectively. Inhibition of pro-inflammatory mediators and prevention of protein denaturation owing to synchronization of more electronegative flouro-groups substituted on phenyl rings along with heterocyclic indoline ring provides anti-inflammatory effects and are corroborated by radiological, histopathological analysis. Additional support was provided through density functional theory (DFT) and molecular docking. KP-5 exhibited excellent lead-likeness based on its physicochemical parameters, making it a viable drug candidate. The synthesized compounds also showed promising ADMET properties, enhancing their potential as therapeutic agents. These findings emphasize the pivotal role of new compounds for drug design and development.

Quantitative analysis of loxoprofen sodium loaded microspheres comprising pectin and its thiolated conjugates: In-vivo evaluation of their sustained release behavior.

Continuous use of oral NSAIDs can damage mucosal membrane, which results in decreased bioavailability and non-compliance with the therapy. But the use of sustained release drug delivery systems might offer a solution. Objective was to synthesize mucoadhesive SR microspheres by using different combinations of pectin (PEC) and its thiolated derivative (T-PEC3100) for improved loxoprofen (LS) permeation. Thiolated pectin (T-PEC) was synthesized by the esterification method using thioglycolic acid. Thiolation was confirmed by thiol group quantification and charring point determination. Further characterization was done by Fourier Transform Infrared spectroscopy (FTIR), and Scanning electron microscopy (SEM). Ex-vivo mucoadhesion study was performed to confirm the improved characteristics. Microspheres (MS) were prepared using different ratios of PEC/T-PEC by solvent evaporation method and their particle size and surface morphology were evaluated. Mucus permeation study was carried out using the trans-well plate method. Sustained release behavior of prepared microspheres was investigated through the edema inhibition method in albino rats. T-PEC3100 was considered the optimum formulation for further evaluation and contained maximum thiol group content. FTIR spectra showed a characteristic peak of -SH and charring point was also changed considerably confirming the successful thiolation of PEC. SEM results showed spherical microspheres in the size range of 2-10 µm. Thiol-rich formulation of MS exhibited more than 80 % release after 12 h and maximum absorbable dose (MAD) was calculated as 400 µg % inhibition of edema in MS treated group was slowly attained initially but the reduction in inflammation was detected even after 24 h as compared to control group. Promising results from In-vivo edema inhibition study suggest the possible use of these thiolated MS in formulating sustained release formulation for arthritis.

An insight into anticancer, antioxidant, antimicrobial, antidiabetic and anti-inflammatory effects of quercetin: a review.

Flavonoids are present naturally in many fruits and vegetables including onions, apples, tea, cabbage, cauliflower, berries and nuts which provide us with quercetin, a powerful natural antioxidant and cytotoxic compound. Due to antioxidant property, many nutraceuticals and cosmeceuticals products contain quercetin as a major ingredient nowadays. Current review enlightened sources and quercetin's role as an antioxidant, antimicrobial, antidiabetic, anticancerous and anti-inflammatory agent in medical field during last 5 to 6 years. Literature search was systematically done using scientific for the published articles of quercetin. A total of 345 articles were reviewed, and it was observed that more than 40% of articles were about quercetin's use as an antioxidant agent, more than 25% of studies were about its use as an anticancer agent, and articles on antimicrobial activity were more than 15%. 10% of the articles showed anti-inflamamatory effects of quercetin. Literature search also revealed that quercetin alone and its complexes with chitosan, metal ions and polymers possessed good antidiabetic properties. Thus, the review focuses on new therapeutic interventions and drug delivery system of quercetin in medical field for the benefit of mankind.

Chitosan-coated halloysite nanotube magnetic microspheres for carcinogenic colorectal hemorrhage and liver laceration in albino rats.

Carcinogenic colorectal hemorrhage can cause severe blood loss and longitudinal ulcer, which ultimately become fatal if left untreated. The present study was aimed to formulate targeted release gemcitabine (GC)-containing magnetic microspheres (MM) of halloysite nanotubes (MHMG), chitosan (MCMG), and their combination (MHCMG). The preparation of MM by magnetism was confirmed by vibrating sample magnetometry (VSM), the molecular arrangement of NH2, alumina, and silica groups was studied by X-ray diffraction (XRD) and energy-dispersive spectroscopy (EDS), the hollow spherical nature of the proposed MM was observed by scanning electron microscopy (SEM), functional groups were characterized by Fourier transform infrared (FTIR) spectroscopy and thermochemical modification was studied by thermogravimetric analysis (TGA). In vitro thrombus formation showed a decreasing trend of hemostatic time for MMs in the order of MHMG3 < MCMG3 < MHCMG7, which was confirmed by whole blood clotting kinetics. Interestingly, rat tail amputation and liver laceration showed 3 folds increased clotting efficiency of optimized MHCMG7 compared to that of control. In vivo histopathological studies and cell viability assays confirmed the regeneration of epithelial cells. The negligible systemic toxicity of MHCMG7, more than 90% entrapment of GC and high % release in alkaline medium made the proposed MM an excellent candidate for the control of hemorrhage in colorectal cancer. Conclusively, the healing of muscularis and improved recovery of the colon from granulomas ultimately improved the therapeutic effects of GC-containing MMs. The combination of both HNT and CTS microspheres made them more targeted.

Design, synthesis, spectroscopic characterization, in-vitro antibacterial evaluation and in-silico analysis of polycaprolactone containing chitosan-quercetin microspheres.

Aim of present study was to synthesize a novel chitosan-quercetin (CTS-QT) complex by making a carbodiimide linkage using maleic anhydride as cross-linker and to investigate its enhanced antibacterial and antioxidant activities as compare to pure CTS and QT. Equimolar concentration of QT and maleic anhydride were used to react with 100 mg CTS to form CTS-QT complex. For this purpose, three bacterial strains namely E. Coli, S. Aureus and P. Aeruginosa were used for in-vitro antibacterial analysis (ZOI, MIC, MBC, checker board and time kill assay). Later molecular docking studies were performed on protein structure of E. Coli to assess binding affinity of pure QT and CTS-QT complex. MD simulations with accelerated settings were used to explore the protein-ligand complex's binding interactions and stability. Antioxidant profile was determined by performing DPPH• radical scavenging assay, total antioxidant capacity (TAC) and total reducing power (TRP) assays. Delivery mechanism to CTS-QT complex was improved by synthesizing polycaprolactone containing microspheres (CTS-QT-PCL-Levo-Ms) using Levofloxacin as model drug to enhance their antibacterial profile. Resulted microspheres were evaluated by particle size, charge, surface morphology, in-vitro drug release and hemolytic profile and are all were found within limits. Antibacterial assay revealed that CTS-QT-PCL-Levo-Ms showed more than two folds increased bactericidal activity against E. Coli and P. Aeruginosa, while 1.5 folds against S. Aureus. Green colored formation of phosphate molybdate complexes with highest 85 ± 1.32% TAC confirmed its antioxidant properties. Furthermore, molecular docking and dynamics studies revealed that CTS-QT was embedded nicely within the active pocket of UPPS with binding energy greater than QT with RSMD value of below 1.5. Conclusively, use of maleic acid, in-vitro and in-silico antimicrobial studies confirm the emergence of CTS-QT complex containing microspheres as novel treatment strategy for all types of bacterial infections.Communicated by Ramaswamy H. Sarma.

Chitosan/halloysite nanotubes microcomposites: A double header approach for sustained release of ciprofloxacin and its hemostatic effects.

Clotting time of lower gastro intestinal bleeding (LGIB) can be reduced by using simple, cost-effective, and naturally occurring halloysite nanotubes (HNTs). The present study aimed to decrease the clotting time by the application of chitosan (CHT) and its microcomposites (MCs) prepared by suspension emulsification technique with HNTs (CHT/HNTs MC). Physicochemical properties, X-Ray diffraction (XRD), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and percentage release of ciprofloxacin from CHT/HNTs MCs was evaluated. In-vitro procoagulant activity of CHT, HNTs and their complexes CHT/HNTs MCs was performed on rabbit blood which was confirmed by a rat tail amputation. Direct relation of HNTs was observed for the whole-blood clotting kinetics i.e., 2% HNTs showed a maximum 66.0% increase in the clotting ability as compared with pure CHT. Interestingly, rat-tail amputation studies showed comparative results of CHT, HNTs, and CHT/HNTs MCs. A total of 75% permeation of ciprofloxacin of CHT/HNTs MCs on rat intestinal membrane was observed within 3 h, confirming their SR behavior. Furthermore, improved hemostatic and clotting properties were CHT/HNTs MC1 > CHT/HNTs MC2 > CHT/HNTs MC3 > CHT > HNTs, respectively. Thus, it provided the control of bleeding disorders in LGIB with any antibacterial agents, particularly ciprofloxacin.

Improved solubility and corneal permeation of PEGylated curcumin complex used for the treatment of ophthalmic bacterial infections.

Naturally occurring curcumin can be used for the treatment of corneal bacterial infections with its limitation of poor solubility. Aim of the present study was to enhance solubility and permeation of curcumin for the treatment of corneal bacterial infections. For increasing solubility, curcumin and polyethylene glycol (PEG 6000) complex (1:3) was prepared by fusion melting method. Phase solubility studies were used for the calculation of Gibbs free energy of curcumin. Central composite rotatable design (CCRD) was applied for optimization of Curcumin (CUR), PEGylated Curcumin (PEG-CUR), penetration enhancer cremophore (CR). Optimized ointments were further evaluated by mucous permeation, membrane permeability and cell toxicity studies by Transwell cell, ussing chamber and Caco-2 cells respectively. Antibacterial test was also performed by agar well diffusion method. Solubility of PEG-CUR was increased up to 93±3.2% as compared to pure curcumin and content uniformity was in the range of 95-110%. Curcumin permeation from PEG-CUR ointment was increased up to 12 folds. No toxicity of Caco-2 cells for PEG-CUR even after 24h was observed. Activity index of pure CUR, PEG-CUR ointment with or without CR against S. aureus and P. aeruginosa was 97±2.3, 96±1.6, 95±2.5% respectively. Ointment with solubility enhanced PEG-CUR and cremophore can be used as a promising tool for the treatment of corneal bacterial infections.

Thiolated sodium alginate conjugates for mucoadhesive and controlled release behavior of metformin microspheres.

The absorption of BCS III drugs can be improved by inhibiting the P-glycoprotein (P-gp) efflux and by increasing the mucoadhesion of natural polymers. In the present study, an esterification of sodium alginate (SA) with thioglycolic acid (TGA) was applied for the preparation of thiolated sodium alginate (TSA). The Ellman's test was applied to quantify the thiol group and a di-sulphide bond test was performed to confirm any SS linkages. The FTIR, DSC, XRD, 1H NMR and charring point determinations were confirmed the thiol group of TSA. The gel like rheological properties with porcine mucous was confirmed by viscoelasticity properties and the mucoadhesion with the rabbit intestine was carried out after compression of 30 mg tablets of TSA. The content of thiol group was in the range of 320-730 µmoL/g of the polymer. The FTIR spectrum showed a characteristic peak of sulfhydryl group at 2557 cm-1 in TSA and the reduction of the charring point from 220 °C to 178 °C was confirmed the thiolation of TSA. A direct relationship of mucoadhesion and swelling was observed with the concentration of TGA and SA, respectively. The prepared microspheres were 2-7 µm in size, excellent rheological properties and non-fickian drug release behavior was observed.