Drug-impregnated contact lenses via supercritical carbon dioxide: A viable solution for the treatment of bacterial and fungal keratitis.

Keratitis is a corneal infection caused by various bacteria and fungi. Eye drop treatment of keratitis involves significant challenges due to difficulties in administration, inefficiencies in therapeutic dosage, and frequency of drug applications. All these are troublesome and result in unsuccessful treatment, high cost, time loss, development of drug resistance by microorganisms, and a massive burden on human health and the healthcare system. Most of the antibacterial and antifungal medications are non-water-soluble and/or include toxic drug formulations. Here, the aim was to develop drug-loaded contact lenses with therapeutic dosage formulations and extended drug release capability as an alternative to eye drops, by employing supercritical carbon dioxide (ScCO2) as a drug impregnation solvent to overcome inefficient ophthalmic drug use. ScCO2, known as a green solvent, has very low viscosity which provides high mass transfer power and could enhance drug penetration into contact lenses much better with respect to drug loading using other solvents. Here, moxifloxacin (MOX) antibiotic and amphotericin B (AMB) antifungal medicines were separately loaded into commercially available silicone hydrogel contact lenses through 1) drug adsorption from the aqueous solutions and 2) impregnation techniques via ScCO2 and their efficacies were compared. Drug impregnation parameters, i.e., 8-25 MPa pressure, 310-320 K temperature, 2-16-hour impregnation times, and the presence of ethanol as polar co-solvent were investigated for the optimization of the ScCO2 drug impregnation process. The highest drug loading and long-term release kinetic from the contact lenses were obtained at 25 MPa and 313 K with 2.5 h impregnation time by using 1 % ethanol (by volume). Furthermore, antibacterial/antifungal activities of the MOX- and AMB-impregnated contact lenses were effective against in vitro Pseudomonas aeruginosa (ATCC 10145) bacteria and Fusarium solani (ATCC 36031) fungus for up to one week. Consequently, the ScCO2 method can be effectively used to impregnate commercial contact lenses with drugs, and these can then be safely used for the treatment of keratitis. This offers a sustainable delivery system at effective dosage formulations with complete bacterial/fungal inhibition and termination, making it viable for real animal/human applications.

Dual Drug-Loaded Coaxial Nanofiber Dressings for the Treatment of Diabetic Foot Ulcer.

Introduction: Diabetes mellitus is frequently associated with foot ulcers, which pose significant health risks and complications. Impaired wound healing in diabetic patients is attributed to multiple factors, including hyperglycemia, neuropathy, chronic inflammation, oxidative damage, and decreased vascularization. Rationale: To address these challenges, this project aims to develop bioactive, fast-dissolving nanofiber dressings composed of polyvinylpyrrolidone loaded with a combination of an antibiotic (moxifloxacin or fusidic acid) and anti-inflammatory drug (pirfenidone) using electrospinning technique to prevent the bacterial growth, reduce inflammation, and expedite wound healing in diabetic wounds. Results: The fabricated drug-loaded fibers exhibited diameters of 443 ± 67 nm for moxifloxacin/pirfenidone nanofibers and 488 ± 92 nm for fusidic acid/pirfenidone nanofibers. The encapsulation efficiency, drug loading and drug release studies for the moxifloxacin/pirfenidone nanofibers were found to be 70 ± 3% and 20 ± 1 µg/mg, respectively, for moxifloxacin, and 96 ± 6% and 28 ± 2 µg/mg, respectively, for pirfenidone, with a complete release of both drugs within 24 hours, whereas the fusidic acid/pirfenidone nanofibers were found to be 95 ± 6% and 28 ± 2 µg/mg, respectively, for fusidic acid and 102 ± 5% and 30 ± 2 µg/mg, respectively, for pirfenidone, with a release rate of 66% for fusidic acid and 80%, for pirfenidone after 24 hours. The efficacy of the prepared nanofiber formulations in accelerating wound healing was evaluated using an induced diabetic rat model. All tested formulations showed an earlier complete closure of the wound compared to the controls, which was also supported by the histopathological assessment. Notably, the combination of fusidic acid and pirfenidone nanofibers demonstrated wound healing acceleration on day 8, earlier than all tested groups. Conclusion: These findings highlight the potential of the drug-loaded nanofibrous system as a promising medicated wound dressing for diabetic foot applications.

Nanocrystalline cellulose as a reinforcing agent for poly (vinyl alcohol)/ gellan-gum-based composite film for moxifloxacin ocular delivery.

Nanocrystalline cellulose (NCC) is a star material in drug delivery applications due to its good biocompatibility, large specific surface area, high tensile strength (TS), and high hydrophilicity. Poly(Vinyl Alcohol)/Gellan-gum-based innovative composite film has been prepared using nanocrystalline cellulose (PVA/GG/NCC) as a strengthening agent for ocular delivery of moxifloxacin (MOX) via solvent casting method. Impedance analysis was studied using the capacitive sensing technique for examining new capacitance nature of the nanocomposite MOX film. Antimicrobial properties of films were evaluated using Pseudomonas aeruginosa and Staphylococcus aureus as gram-negative and gram-positive bacteria respectively by disc diffusion technique. XRD revealed the characteristic peak of NCC and the amorphous form of the drug. Sustained in vitro release and enhanced corneal permeation of drug were noticed in the presence of NCC. Polymer matrix enhanced the mechanical properties (tensile strength 22.05 to 28.41 MPa) and impedance behavior (resistance 59.23 to 213.23 Ω) in the film due to the presence of NCC rather than its absence (16.78 MPa and 39.03 Ω respectively). Occurrence of NCC brought about good antimicrobial behavior (both gram-positive and gram-negative) of the film. NCC incorporated poly(vinyl alcohol)/gellan-gum-based composite film exhibited increased mechanical properties and impedance behavior for improved ocular delivery of moxifloxacin.

Moxifloxacin-loaded nanoparticles of thiolated xyloglucan for ocular drug delivery: Permeation, mucoadhesion and pharmacokinetic evaluation.

The current study goal was to improve mucoadhesive potential and ocular pharmacokinetics of nanoparticles of thiolated xyloglucan (TXGN) containing moxifloxacin (MXF). Thiolation of xyloglucan (XGN) was achieved with esterification with 3-mercaptopropionic acid. TXGN was characterized by NMR and FTIR analysis. The nanoparticles of TXGN were prepared using ionic-gelation method and evaluate the antibacterial properties. TXGN and nanoparticles were determined to possess 0.06 and 0.08 mmol of thiol groups/mg of polymer by Ellman's method. The ex-vivo bioadhesion time of TXGN and nanoparticles was higher than XGN in a comparative assessment of their mucoadhesive properties. The creation of a disulfide link between mucus and TXGN is responsible for the enhanced mucoadhesive properties of TXGN (1-fold) and nanoparticles (2-fold) over XGN. Improved MXF penetration in nanoparticulate formulation (80 %) based on TXGN was demonstrated in an ex-vivo permeation research utilizing rabbit cornea. Dissolution study showed 95 % release of MXF from nanoparticles. SEM images of nanoparticles showed spherical shape and cell viability assay showed nontoxic behavior when tested on RPE cell line. Antibacterial analysis revealed a zone of inhibition of 31.5 ± 0.5 mm for MXF, while NXM3 exhibited an expanded zone of 35.5 ± 0.4 mm (p < 0.001). In conclusion, thiolation of XGN improves its bioadhesion, permeation, ocular-retention and pharmacokinetics of MXF.

Triple combination dry powder formulation of pretomanid, moxifloxacin, and pyrazinamide for treatment of multidrug-resistant tuberculosis.

Both latent and multidrug-resistant tuberculosis (TB) have been causing significant concern worldwide. A novel drug, pretomanid (PA-824), has shown a potent bactericidal effect against both active and latent forms of Mycobacterium tuberculosis (MTb) and a synergistic effect when combined with pyrazinamide and moxifloxacin. This study aimed to develop triple combination spray dried inhalable formulations composed of antitubercular drugs, pretomanid, moxifloxacin, and pyrazinamide (1:2:8 w/w/w), alone (PaMP) and in combination with an aerosolization enhancer, L-leucine (20 % w/w, PaMPL). The formulation PaMPL consisted of hollow, spherical, dimpled particles (<5 µm) and showed good aerosolization behaviour with a fine particle fraction of 70 %. Solid-state characterization of formulations with and without L-leucine confirmed the amorphous nature of moxifloxacin and pretomanid and the crystalline nature of pyrazinamide with polymorphic transformation after the spray drying process. Further, the X-ray photoelectron spectroscopic analysis revealed the predominant surface composition of L-leucine on PaMPL dry powder particles. The dose-response cytotoxicity results showed pyrazinamide and moxifloxacin were non-toxic in both A549 and Calu-3 cell lines up to 150 µg/mL. However, the cell viability gradually decreased to 50 % when the pretomanid concentration increased to 150 µg/mL. The in vitro efficacy studies demonstrated that the triple combination formulation had more prominent antibacterial activity with a minimum inhibitory concentration (MIC) of 1 µg/mL against the MTb H37Rv strain as compared to individual drugs. In conclusion, the triple combination of pretomanid, moxifloxacin, and pyrazinamide as an inhalable dry powder formulation will potentially improve treatment efficacy with fewer systemic side effects in patients suffering from latent and multidrug-resistant TB.

A Periosteum-Bioinspired Electrospun Janus Membrane with Antibacterial and Osteogenic Dual Function.

For a guided bone regeneration membrane, it is critical to possess osteogenic capability while inhibiting infection caused by bacteria. Inspired by the bilayer structure of the native periosteum, an electrospun Janus membrane with osteogenic and antibacterial dual-function is fabricated for guided bone regeneration. Hydrophilic moxifloxacin (MXF) and hydrophobic icariin (ICA) are loaded in the nanofibers made of a mixture of polycaprolactone and gelatin at the top and bottom layers, respectively, leading to the opposing hydrophilic/hydrophobic properties of the bilayer Janus membranes. The as-obtained Janus membrane exhibits excellent physical properties (tensile strength > 6.0 MPa) and robust biocompatibility, indicating the immense potential as a suitable replacement for the native periosteum. The membrane has a superior surface morphology and outstanding degradation performance in vitro. Besides, the rapid release of MXF and the slow release of ICA can meet the different needs of drug release rates. Only ≈30% ICA is released from the as-obtained Janus membrane after 21 d while almost 80% MXF is released. Mimicking the bilayer structure of the native periosteum, the electrospun Janus membrane containing ICA and MXF exhibits excellent comprehensive properties, which provides a promising strategy for preparing multifunctional scaffolds for tissue engineering.

Cationic Chitosan/Pectin Polyelectrolyte Nanocapsules of Moxifloxacin as Novel Topical Management System for Bacterial Keratitis.

PURPOSE: Moxifloxacin (MOX) is a fourth-generation fluoroquinolone and a broad spectrum antibiotic used in the management of bacterial keratitis (BK). This investigation aimed to formulate MOX-loaded chitosan/pectin cationic polyelectrolyte nanocapsules (CPNCs) for the effective topical treatment of BK. METHODS: Physicochemical properties like nanocapsule size, charge, drug entrapment efficiency (EE), viscosity, pH, and in-vitro release profile of CPNCs were evaluated. The in-vitro antibacterial activity of CPNCs and marketed formulations (MFs) was studied against Staphylococcus aureus. Ex-vivo corneal permeation studies of CPNCs were evaluated with the help of a modified diffusion apparatus, which was used with goat cornea. The pharmacodynamic study was performed with optimized CPNCs on a BK-induced rabbit eye model and compared with MF. RESULTS: The optimized nanocapsules appeared as positive charge (+19.91 ± 0.66) with a nano size (242.0 ± 0.30 nm) as calculated by the dynamic light scattering method. The in-vitro release profile of CPNCs exhibited sustained release properties. The ex-vivo permeation pattern also supported the improved drug permeation through the cornea from CPNCs as compared with MF. Draize irritation studies confirmed that the prepared formulation is compatible with the corneal tissue. The in-vivo study concluded that the antibacterial activity of CPNCs was improved when evaluated with MF. CONCLUSION: The obtained results showed that CPNCs were the better choice for the management of BK therapy due to its capability to improve the corneal adhesion of CPNCs through direct interaction with the mucous membrane of the corneal tissue.

The Biochemical and Molecular Analysis of Changes in Melanogenesis Induced by UVA-Activated Fluoroquinolones-In Vitro Study on Human Normal Melanocytes.

Fluoroquinolones cause phototoxic reactions, manifested as different types of skin lesions, including hyperpigmentation. The disturbances of melanogenesis indicate that fluoroquinolones may affect cellular processes in melanocytes. It has been reported that these antibiotics may bind with melanin and accumulate in pigmented cells. The study aimed to examine the changes in melanogenesis in human normal melanocytes exposed to UVA radiation and treated with lomefloxacin and moxifloxacin, the most and the least fluoroquinolone, respectively. The obtained results demonstrated that both tested fluoroquinolones inhibited melanogenesis through a decrease in tyrosinase activity and down-regulation of tyrosinase and microphthalmia-associated transcription factor production. Only lomefloxacin potentiated UVA-induced melanogenesis. Under UVA irradiation lomefloxacin significantly enhanced melanin content and tyrosinase activity in melanocytes, although the drug did not cause an increased expression of tyrosinase or microphthalmia-associated transcription factor. The current studies revealed that phototoxic activity of fluoroquinolones is associated with alterations in the melanogenesis process. The difference in phototoxic potential of fluoroquinolones derivatives may be connected with various effects on UVA-induced events at a cellular level.

Gellan Gum-Based Bilayer Mucoadhesive Films Loaded with Moxifloxacin Hydrochloride and Clove Oil for Possible Treatment of Periodontitis.

BACKGROUND/OBJECTIVE: Periodontitis is a widely spread oral infection and various antibiotics are utilized for its treatment, but high oral doses and development of antibiotic resistance limit their use. This study was aimed at development of natural polymer-based mucoadhesive bilayer films loaded with moxifloxacin hydrochloride (Mox) and clove essential oil (CEO) to potentially combat bacterial infection associated with periodontitis. METHODS: Films were synthesized by double solvent casting technique having an antibiotic in the gellan gum-based primary layer with clove oil in a hydroxyethyl cellulose-based secondary layer. RESULTS: Prepared films were transparent, flexible, and showed high antibacterial response against both gram-positive and gram-negative bacteria. The films showed excellent pharmaceutical attributes in terms of drug content, folding endurance, swelling index, and mucoadhesive strength. Solid state characterization of formulation showed successful incorporation of drug and oil in separate layers of hydrogel structure. An in-vitro release study showed an initial burst release of drug followed by sustained release for up to 48 hours. CONCLUSION: The prepared mucoadhesive bilayer buccal films could be used as a potential therapeutic option for the management of periodontitis.

Intracellular Accumulation of Novel and Clinically Used TB Drugs Potentiates Intracellular Synergy.

The therapeutic repertoire for tuberculosis (TB) remains limited despite the existence of many TB drugs that are highly active in in vitro models and possess clinical utility. Underlying the lack of efficacy in vivo is the inability of TB drugs to penetrate microenvironments inhabited by the causative agent, Mycobacterium tuberculosis, including host alveolar macrophages. Here, we determined the ability of the phenoxazine PhX1 previously shown to be active against M. tuberculosis in vitro to differentially penetrate murine compartments, including plasma, epithelial lining fluid, and isolated epithelial lining fluid cells. We also investigated the extent of permeation into uninfected and M. tuberculosis-infected human macrophage-like Tamm-Horsfall protein 1 (THP-1) cells directly and by comparing to results obtained in vitro in synergy assays. Our data indicate that PhX1 (4,750 ± 127.2 ng/ml) penetrates more effectively into THP-1 cells than do the clinically used anti-TB agents, rifampin (3,050 ± 62.9 ng/ml), moxifloxacin (3,374 ± 48.7 ng/ml), bedaquiline (4,410 ± 190.9 ng/ml), and linezolid (770 ± 14.1 ng/ml). Compound efficacy in infected cells correlated with intracellular accumulation, reinforcing the perceived importance of intracellular penetration as a key drug property. Moreover, we detected synergies deriving from redox-stimulatory combinations of PhX1 or clofazimine with the novel prenylated amino-artemisinin WHN296. Finally, we used compound synergies to elucidate the relationship between compound intracellular accumulation and efficacy, with PhX1/WHN296 synergy levels shown to predict drug efficacy. Collectively, our data support the utility of the applied assays in identifying in vitro active compounds with the potential for clinical development. IMPORTANCE This study addresses the development of novel therapeutic compounds for the eventual treatment of drug-resistant tuberculosis. Tuberculosis continues to progress, with cases of Mycobacterium tuberculosis (M. tuberculosis) resistance to first-line medications increasing. We assess new combinations of drugs with both oxidant and redox properties coupled with a third partner drug, with the focus here being on the potentiation of M. tuberculosis-active combinations of compounds in the intracellular macrophage environment. Thus, we determined the ability of the phenoxazine PhX1, previously shown to be active against M. tuberculosis in vitro, to differentially penetrate murine compartments, including plasma, epithelial lining fluid, and isolated epithelial lining fluid cells. In addition, the extent of permeation into human macrophage-like THP-1 cells and H37Rv-infected THP-1 cells was measured via mass spectrometry and compared to in vitro two-dimensional synergy and subsequent intracellular efficacy. Collectively, our data indicate that development of new drugs will be facilitated using the methods described herein.

A rapid RP-HPLC stability-indicating method development and validation of moxifloxacin hydrochloride-related substances in finished dosage forms.

A reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated for the identification and quantification of moxifloxacin hydrochloride-related substances in finished dosage forms. Chromatographic separation was achieved on an Agilent C18 column (150 × 4.6 mm, 5 µm) with the mobile phase (0.01 M potassium dihydrogen orthophosphate as buffer and methanol in the ratio of 70:30) eluted in isocratic mode. The HPLC flow rate was 1.0 mL min-1 , and peaks were monitored at 230 nm using a photodiode array (PDA) detector. The column temperature was kept constant at 30°C, and the injection volume was 10 µL. The run time of the method was 16 min. The method was validated as per the International Conference on Harmonization (ICH) guidelines. Linearity was recorded at various concentrations ranging from 0.25 to 1.5 µg mL-1 for all the moxifloxacin impurities. Linearity, regression value, recovery, %relative standard deviation (RSD) of method precision values were found within the acceptance limits. The method for related substances (RS) in moxifloxacin was found to be specific, linear, accurate, precise, rugged, and robust. The validated method was suitable for the quantification of the RSs in moxifloxacin drug products. The method was applied in quality control lab for the analysis of moxifloxacin impurities in stability analysis.

Synthesis and Characterization of Mesoporous Mg- and Sr-Doped Nanoparticles for Moxifloxacin Drug Delivery in Promising Tissue Engineering Applications.

Mesoporous silica-based nanoparticles (MSNs) are considered promising drug carriers because of their ordered pore structure, which permits high drug loading and release capacity. The dissolution of Si and Ca from MSNs can trigger osteogenic differentiation of stem cells towards extracellular matrix calcification, while Mg and Sr constitute key elements of bone biology and metabolism. The aim of this study was the synthesis and characterization of sol-gel-derived MSNs co-doped with Ca, Mg and Sr. Their physico-chemical properties were investigated by X-ray diffraction (XRD), scanning electron microscopy with energy dispersive X-ray analysis (SEM/EDX), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), X-ray fluorescence spectroscopy (XRF), Brunauer Emmett Teller and Brunauer Joyner Halenda (BET/BJH), dynamic light scattering (DLS) and ζ-potential measurements. Moxifloxacin loading and release profiles were assessed with high performance liquid chromatography (HPLC) cell viability on human periodontal ligament fibroblasts and their hemolytic activity in contact with human red blood cells (RBCs) at various concentrations were also investigated. Doped MSNs generally retained their textural characteristics, while different compositions affected particle size, hemolytic activity and moxifloxacin loading/release profiles. All co-doped MSNs revealed the formation of hydroxycarbonate apatite on their surface after immersion in simulated body fluid (SBF) and promoted mitochondrial activity and cell proliferation.

Moxifloxacin Hydrochloride-Loaded Eudragit® RL 100 and Kollidon® SR Based Nanoparticles: Formulation, In vitro Characterization and Cytotoxicity.

BACKGROUND: Considering the low ocular bioavailability of conventional formulations used for ocular bacterial infection treatment, there is a need to design efficient novel drug delivery systems that may enhance precorneal retention time and corneal permeability. AIM AND OBJECTIVE: The current research focuses on developing nanosized and non-toxic Eudragit® RL 100 and Kollidon® SR nanoparticles loaded with moxifloxacin hydrochloride (MOX) for its prolonged release to be promising for effective ocular delivery. METHODS: In this study, MOX incorporation was carried out by spray drying method aiming ocular delivery. In vitro characteristics were evaluated in detail with different methods. RESULTS: MOX was successfully incorporated into Eudragit® RL 100 and Kollidon® SR polymeric nanoparticles by a spray-drying process. Particle size, zeta potential, entrapment efficiency, particle morphology, thermal, FTIR, NMR analyses and MOX quantification using HPLC method were carried out to evaluate the nanoparticles prepared. MOX loaded nanoparticles demonstrated nanosized and spherical shape while in vitro release studies demonstrated modified-release pattern, which followed the Korsmeyer-Peppas kinetic model. Following the successful incorporation of MOX into the nanoparticles, the formulation (MOX: Eudragit® RL 100, 1:5) (ERL-MOX 2) was selected for further studies because of its better characteristics like cationic zeta potential, smaller particle size, narrow size distribution and more uniform prolonged release pattern. Moreover, ERLMOX 2 formulation remained stable for 3 months and demonstrated higher cell viability values for MOX. CONCLUSION: In vitro characterization analyses showed that non-toxic, nano-sized and cationic ERL-MOX 2 formulation has the potential of enhancing ocular bioavailability.

Thermochromic Hydrogel-Functionalized Textiles for Synchronous Visual Monitoring of On-Demand In Vitro Drug Release.

In vitro drug release systems have recently received tremendous attention because they allow noninvasive, convenient, and prolonged administration of pharmacological agents. On-demand epidermal drug release systems can improve treatment efficiency, prevent multidrug resistance, and minimize drug toxicity to healthy cells. In addition, real-time monitoring of drug content is also essential for guiding the determination of drug dosage and replacing drug carriers in time. Therefore, it is important to integrate the above properties in one ideal epidermal patch. Herein, photonic crystals (PCs) based on Fe3O4@C nanoparticles were introduced into drug-loaded poly(N-isopropylacrylamide-co-acrylic acid) (P(NIPAM-AAc)) hydrogel-functionalized textiles. Drug loading and release depended on the expansion and contraction of the hydrogels. The lower critical solution temperature (LCST) of the hydrogels was adjusted to 40 °C, which is higher than the skin temperature, by varying the content of hydrophilic comonomer acrylic acid (AAc) to store the drug at room temperature, and on-demand release was achieved by mild thermal stimulation. Moreover, the lattice spacing (d) of PCs varied with the expansion and contraction of the hydrogels, which can cause the color of P(NIPAM-AAc) hydrogel-functionalized textiles to change. These synchronous thermoresponsive chromic drug uptake and release behaviors provided an effective method for visual and real-time monitoring of drug content. Furthermore, in view of the poor mechanical properties of hydrogel wound dressings, textile matrices were composited to prevent holistic breaking during the stretching process. Biological experiments proved that the drug-loaded P(NIPAM-AAc) hydrogel-functionalized textiles had good antibacterial properties and wound-healing effects.

Effect of cross-linking on the inclusion complex formation of derivatized ß-cyclodextrins with small-molecule drug moxifloxacin.

Derivatized ß-cyclodextrins (CDs), cyclic oligomers of glucose with inner cavity, are able to form the inclusion complex with many poorly soluble lipophilic organic molecules, including drugs, thus improving their solubility in aqueous solutions and drug bioavailability. Here, we have studied the effect of cross-linking of derivatized CDs with different substituent nature, on their binding with antibacterial drug moxifloxacin (MF) which served as a model small molecule drug. Cross-linking of derivatized CDs with 1,6-hexamethylene diisocyanate (HMD) yielded 100-200 nm nanoparticles with distinct binding properties, strongly depending on the nature of the CD substituent, degree of oligomerization, and the nanoparticle's charge. Interestingly, substituent that improved MF binding to monomeric CDs the most (methyl moiety), had reverse effect in the case of cross-linked CD. Whereas the substituent that had only limited effect on the monomeric CD (sulfobutyl ether moiety), improved binding of cross-linked CD by almost two orders of magnitude. Further, we show that the cross-linked CD complexes with MF perform better in vitro antibacterial assay on E.coli, compared to both free MF and monomeric CD-MF. Overall, this data indicates the potential utility of CD cross-linking and derivatization to develop small molecule drug formulations with improved pharmacological properties.

Eudragit RL100 Based Moxifloxacin Hydrochloride and Ketorolac Tromethamine Combination Nanoparticulate System for Ocular Drug Delivery.

BACKGROUND: Bacterial conjunctivitis is a serious ocular infection if left untreated. It is caused by several species of bacteria like Pseudomonas, Staphylococcus and Mycobacterium. OBJECTIVE: The present investigation explores the development and characterization of moxifloxacin hydrochloride and ketorolac tromethamine combination loaded Eudragit RL 100 nanosuspension for ocular drug delivery in order to overcome the problems associated with conventional dosage forms. METHODS: The nanosuspension prepared by nanoprecipitation technique showed successful entrapment of both water-soluble drugs in the polymer matrix indicated by their % entrapment efficiencies. RESULTS: Formulations showed a mean particle size <200 nm with narrow size distribution and positive surface charge due to the presence of quaternary ammonium groups of Eudragit RL100. FTIR study revealed compatibility among the components, while a reduction in the crystallinity of formulation was observed in the PXRD study. The release of both the drugs was found to be sustained in nanosuspension as compared to commercial eyedrops. Ex vivo studies showed increased transcorneal permeation of drugs from nanosuspension, where approximately 2.5-fold and 2-fold increase in the permeation was observed for moxifloxacin hydrochloride and ketorolac tromethamine, respectively. The formulation was stable at 4°C and room temperature. CONCLUSION: Due to their sustained release, positive surface charge and higher transcorneal permeation, this will be a promising ocular drug delivery.

A Computational Pipeline to Predict Cardiotoxicity: From the Atom to the Rhythm.

RATIONALE: Drug-induced proarrhythmia is so tightly associated with prolongation of the QT interval that QT prolongation is an accepted surrogate marker for arrhythmia. But QT interval is too sensitive a marker and not selective, resulting in many useful drugs eliminated in drug discovery. OBJECTIVE: To predict the impact of a drug from the drug chemistry on the cardiac rhythm. METHODS AND RESULTS: In a new linkage, we connected atomistic scale information to protein, cell, and tissue scales by predicting drug-binding affinities and rates from simulation of ion channel and drug structure interactions and then used these values to model drug effects on the hERG channel. Model components were integrated into predictive models at the cell and tissue scales to expose fundamental arrhythmia vulnerability mechanisms and complex interactions underlying emergent behaviors. Human clinical data were used for model framework validation and showed excellent agreement, demonstrating feasibility of a new approach for cardiotoxicity prediction. CONCLUSIONS: We present a multiscale model framework to predict electrotoxicity in the heart from the atom to the rhythm. Novel mechanistic insights emerged at all scales of the system, from the specific nature of proarrhythmic drug interaction with the hERG channel, to the fundamental cellular and tissue-level arrhythmia mechanisms. Applications of machine learning indicate necessary and sufficient parameters that predict arrhythmia vulnerability. We expect that the model framework may be expanded to make an impact in drug discovery, drug safety screening for a variety of compounds and targets, and in a variety of regulatory processes.

Moxifloxacin-isatin Hybrids Tethered by 1,2,3-triazole and their Anticancer Activities.

AIMS: To explore more active fluoroquinolone anticancer candidates. BACKGROUND: Cancer which can affect almost any part of the body, is most striking and deadliest disease. It is estimated that around one in five people globally develop cancer during their lifetime, and approximately 10% people eventually die from this disease, and 18.1 million new cancer cases with 9.6 million deaths occurred in 2018. The anticancer agents play an intriguingly role in fighting against cancer, and above 100 drugs have already been marketed for this purpose. However, the major drawback of current accessible anticancer agents is the low specificity which results in many side effects. Moreover, cancer cells have already generated resistance to almost all available drugs, creating an urgent need to novel anticancer agents with high specificity and great efficiency especially towards drug-resistant cancers. Quinolone and isatin derivatives were reported to possess promising anticancer activity, high specificity, and relatively few side effects. Currently, several quinolone and isatin derivatives such as Voreloxin, Quarfloxin, AT-3639, Semaxanib, Sunitinib and Nintedanib have already been introduced in clinical practice or under evaluations for the treatment of cancer including drug-resistant cancers, revealing their potential as novel anticancer agents. Hybrid molecules have the potential to increase the specificity, improve the efficiency, and overcome the drug resistance, so hybridization is a promising strategy in the drug discovery. Some of the moxifloxacin-isatin hybrids exhibited considerable activity against various cancer cells even drug-resistant cells, so it is conceivable that hybridization of quinolone and isatin moieties may provide novel anticancer candidates. The structure-activity relationships (SARs) demonstrated that the linkers between quinolone and isatin skeletons were critical for the biological activity, and 1,2,3-triazole could exert various noncovalent interactions with biological targets, so introduction of 1,2,3-triazole as the linker between the two moieties may provide more efficient anticancer candidates. OBJECTIVE: To explore more active fluoroquinolone anticancer candidates and enrich the structureactivity relationships of fluoroquinolone-isatin hybrids. METHODS: The synthesized moxifloxacin-isatin hybrids 5a-c, 6a-g and 13a-d were assessed for their anticancer activities against liver cancer cells HepG2, breast cancer cells MCF-7, MCF-7/DOX, prostate cancer cells DU-145 and MDR DU-145 by MTT assay. Hybrid 5b was selected for further evaluation of its tubulin polymerization inhibitory activity with combretastatin A-4 as comparison. RESULT: Most of the synthesized hybrids were active against the tested cancer cell lines, and the most active hybrid 5b (IC50: 31.3-76.8 µM) was more potent than vorinostat (IC50: 96.7->100 µM), demonstrating moxifloxacin-isatin hybrids are potential anticancer candidates. CONCLUSION: The mechanism study revealed that inhibition of tubulin polymerization is at least one of the mechanisms of action for this kind of hybrids. Other: The structure-activity relationship was summarized for further rational design of more efficient anticancer candidates.

Development of Chitosan-Based Hydrogel Containing Antibiofilm Agents for the Treatment of Staphylococcus aureus-Infected Burn Wound in Mice.

Methicillin-resistant Staphylococcus aureus (MRSA) is considered a common colonizer of burn wound and accounts for high morbidity and mortality all across the globe. Systemic antibiotic therapy which is generally prescribed for these patients has a number of limitations. These include high drug dose, toxicity, and chances of development of drug resistance. However, local delivery of drug not only addresses these limitations but also provides better efficacy at the site of infection. In the present study, hydrogel preparations were developed for the topical delivery of moxifloxacin for the treatment of S. aureus-infected burn wound. Moxifloxacin was characterized by UV, FTIR, DSC, hot-stage microscopy, NMR, and HPLC and loaded into conventional and Boswellia-containing novel gels. Gels were characterized by visual examination, pH, UV spectroscopy, and release assays. In vivo studies showed that both gels were effective in eradicating the bacteria completely from the wound site when treatment was started during the early stage of infection. On the contrary, delayed treatment of planktonic and biofilm cells with novel gel showed better efficacy as compared with conventional gel in S. aureus-infected burn wound. Histopathological analysis also showed better skin healing efficacy of novel gel than conventional gel. Our results show that moxifloxacin can be efficiently used topically in the management of burn wound infections along with other antibacterial agents. Since biofilm-mediated infections are on the rise especially in chronic bacterial disease, therefore, a preparation containing antibiofilm agent-like Boswellia as one of the excipients would be more meaningful.

Stimuli Responsive In Situ Gelling Systems Loaded with PLGA Nanoparticles of Moxifloxacin Hydrochloride for Effective Treatment of Periodontitis.

The objectives of the present research work were systematic development of novel in situ gel formulation containing nanoparticles for localised delivery of moxifloxacin against bacterial periodontitis. PLGA nanoparticles were prepared and optimised in a systematic manner. Factor screening was performed with the help of half-factorial design to identify the influential factors, while response surface optimisation of the nanoparticles was conducted using central composite design. The optimum nanoparticle formulation was chosen on the basis of lower particle size, higher drug entrapment and controlled drug release characteristics up to 1 week time period, while the optimum in situ gel was selected on the basis of faster gelling and higher viscosity and gel strength properties for improved retention in the periodontium. In vivo histopathological studies and in vivo gamma scintigraphy studies revealed the extended release, superior efficacy and enhanced retention of nanoparticle-loaded in situ gelling system. Results obtained from in vivo histopathological studies after 1 week treatment with in situ gel formulation containing nanoparticles of moxifloxacin were found to be better than with 3 weeks treatment of marketed gel formulation. Overall, the studies ratify successful development of an effective site-specific drug delivery system with enhanced biopharmaceutical attributes for the periodontitis treatment.