Miconazole Research Articles

Comparative Evaluation of Effectiveness of Denture Adhesive after Incorporating Antifungal Agent – An In-vitro Study

Aims: The aim of current study is to evaluate adhesive force and qualitative mycological culture analysis of Denture adhesive (DA) after incorporating antifungal agent in various concentrations.
 Study Design: Experimental study.
 Place and Duration of Study: The current study was conducted at the Department of Prosthodontics, Mansarovar Dental College and Hospital, Bhopal (M. P.) from September 2017 to October 2018.
 Methodology: A total of 80 specimens were prepared with heat cured acrylic resin, out of which 40 were used for qualitative anti-microbiological test, and 40 were used for Adhesive force measurement test. Both test had four groups: Group A (Control group DA without MN); Group B (DA+MN 10%); Group C (DA+MN 20%); and Group D (DA+MN 30%).
 Results: The mean zone of inhibition was 8.85 ± 0.28 mm for 10% w/w Miconazole Nitrate (MN), 12.95±0.30 mm for 20% w/w MN, and 22.25 ± 0.38 mm for 30% w/w MN. There was a statistically highly significant (P< .001) difference between the groups, with an F value of 1077.8.
 Conclusion: Within the limitation of the study qualitative anti-microbial property for favorable laboratory performance can be achieved only after the addition of 20% w/w Miconazole Nitrate to denture adhesive paste.

Non-Pressurized Topical Spray Pharmaceutical-Methodology of Formulation Development and Quality Control Management

The medicine was given to the target site with a pressurized topical spray (aerosol pharmaceutical) and a non-pressurized topical spray solution by gently pressing the spray container against the skin and initiating the spray. Formulation components consists of product concentrate (one or more pharmaceutical drugs with relevant excipient) and packaging components (valves, pump, actuator, container). After formulation process development various quality control test like spray pattern, spray content uniformity and geometry, particulate matter, droplet size distribution, microbial limit, net content, pH, osmolarity, weight loss, leachability, viscosity, valves, actuators, diptubes, weight checking, leak test, valve discharge rate, dosage with valves, therapeutic activity, and toxicity studies to check the quality and efficacy. The benefit of Topical Spray Life Cycle Management (post-approval adjustments, 30-day supplements, annual report, Food and Drug Administration inspection and enforcement, cover letter, risk management standard and related information from the International Organization for Standardization) is that it covers the entire lifecycle of a topical spray, from conception through formulation design development to marketing. The product lifecycle management data offers regulatory bodies with a significant financial benefit. Topical non-pressurized sprays have been developed for a variety of applications due to their ease of use, environmental friendliness, low cost, and innovative technology. This review give details about meter dose topical spray of Estradiol, 1% tolnaftate, 2% Miconazole nitrate spray, 0.5% w/w Voriconazole spray, Clotrimazole transdermal apray, Lopinavir meter dose transdermal spray are studied by researcher. This review also enlisted patents and marketed formulation on topical spray from year 2007 to 2020.

Vaginal Tablets of Metronidazole (750 mg) plus Miconazole Nitrate (200 mg) versus Oral Metronidazole (2 g) for Bacterial Vaginosis: A Randomized Controlled Trial

Objective: To compare the cure rates, side effects, satisfaction, and recurrence rates of bacterial vaginosis (BV) in women having vaginal tablets of metronidazole (750 mg) plus miconazole (200 mg)—the “NPF group”—versus oral metronidazole (2 g)—the “MET group.”
 Materials and methods: This September 2019–March 2020 trial enrolled symptomatic women aged 18–45 years diagnosed with BV based on Amsel’s criteria. Excluded were women who were immunocompromised; allergic to metronidazole or miconazole; had BV episodes during the preceding 3 months; or had abnormal vaginal bleeding. After randomization with a ratio 1:1, another vaginal swab was done for Nugent scoring. Two weeks later, the evaluation using Amsel’s criteria and Nugent scores was repeated. Also, symptom resolution, side effects and satisfaction were evaluated. Symptomatic resolution referred to 75% improvement in discharge, irritation, itching, odor, and coital pain. At one and three months, subjective symptomatic recurrence was assessed by telephone.
 Results: Data on 70 participants were analyzed (NPF, N=34; MET, N=36). Their average age was 32.3±7.9 years (NPF, 34.1±8.1; MET, 30.6±7.3). Without statistical significance, NPF had higher symptom resolution (67.7% vs 58.3%; P=0.420), cure rate by Amsel criteria (82.4% vs 77.8%; P=0.632), and cure rate by Nugent scoring (35.3% vs 16.9%; P=0.075). Both groups reported high satisfaction (NPF, 8.5±1.4; MET, 7.9±2.0; P=0.125). Side effects were comparable, including appetite loss, metallic taste, nausea, and dizziness.
 Conclusion: For BV treatment, both vaginal ovules containing metronidazole (750 mg) plus miconazole nitrate (200 mg) and oral metronidazole (2 g) show comparable efficacy and side effects.

Formulation and Evaluation of Miconazole Nitrate Loaded Novel Nanoparticle Gel for Topical Delivery

The aim of the present research work is to design miconazole-loaded chitosan nanoparticles that could potentially assemble in wrinkle and hair follicles to provide prolong release to the skin tissue. The amount of drugs required for the preparation of nanoparticles was determined by studying the entrapment efficiency of preliminary batches. The emulsification/Solvent evaporation method was used for the preparation of nanoparticles. Different proportions of Miconazole Nitrate and Chitosan were dissolved in DCM. The size of the globules in the emulsion was reduced by a high energy shearing using a probe Sonicator at 50 % amplitude for 10 Minutes, followed by the addition of 10 ml 2% PVA. After overnight evaporation of DCM, for isolation of dried NPs, the NPs dispersion was centrifuged at 15,000 RCF for 30 minutes. The obtained particles were dispersed in de-ionized water and freeze-dried. 32 full factorial design was selected for optimization purposes. Prepared batches were evaluated for various parameters such as entrapment efficiency, production yield, particle size, zeta potential, and SEM. F5 batch was found to be optimized which was then used for the preparation of gel. Three levels of Carbopol934 and propylene glycol were used for the optimization of gel. The prepared gel was also evaluated for pH, drug content, viscosity, and spreadability. From the study, it was concluded that nanoparticle gel can be used for the treatment of various skin infections over the conventional gel.

Oral gel loaded by ethotransfersomes of antifungal drug for oral thrush: Preparation, characterization, and assessment of antifungal activity

Of all the clinical forms of candidiasis, the most common presentation is the acute pseudomembranous type, also known as oral thrush. It is characterized by scrapable superficial white plaques that resemble curdled milk. To come up with therapeutically efficacious drug-loaded formulations, the miconazole (MIC)-loaded ethotransfersome (ET) was investigated for its potential in alleviating oral thrush in the present research work. ETs are flexible liposome vesicles that combine the advantages of transfersomes and ethosomes. The MIC-loaded ET formulations were prepared and optimized using Design Expert software. To convert the optimized MIC loaded ET into a gel, the psyllium seed husk arabinoxylan hemicellulose (AXHc) was used because it has ulcer-healing properties. The cumulative amount permeated and the permeability coefficient for the optimized formula were markedly increased in contrast with other formulations. The antifungal activity was assessed by measuring the zone of inhibition against Candida albicans; it indicated the superior activity of the optimized MIC-ET-AXHc oral gel base formulation (27 mm), which was markedly greater than that of an MIC powder dispersed within the AXHc gel (15 mm), an MIC aqueous dispersion (12 mm), and a commercially available formulation (18 mm). The results of an in vivo pharmacodynamic study demonstrated that the optimized MIC-ET-AXHc oral gel base formulation has remarkably improved pharmacodynamic activity with a substantially reduced ulcer index score (0.5 ± 0.25) in contrast to other formulations and the marketed gel (2.0 ± 0.25). In the current research work, this combination of two potential carrier vesicles along with gelling agents with healing properties resulted in substantial increases in the membrane permeability across the buccal mucosa, antifungal activity, and healing of ulcers of the mouth.

Smart UV-spectrophotometric platforms for rapid green analysis of miconazole nitrate and nystatin in their combined suppositories and in vitro dissolution testing

Miconazole nitrate (MIC) and nystatin (NYS) combination has proven its effectiveness as a prodigious therapy to cure women's common infections; vaginal candidiasis and vaginal mycosis. Herein, six smart UV-spectrophotometric platforms depending on minimal mathematical manipulation steps were first introduced for the simultaneous green analysis of MIC and NYS in their pure forms and commercial vaginal suppositories without any preliminary separation steps. These platforms included dual-wavelength, ratio difference, mean centering of ratio spectra, first derivative ratio, ratio subtraction, and absorption correction methods. All of the aforementioned platforms could estimate MIC in a linear range of 90–900 µg/ml. While NYS was computed directly by zero-order spectrophotometry at its λ max (304 nm) in a linear range of 1–15 µg/ml without any interference by MIC even in low or high concentrations. Dual-wavelength and zero-order spectrophotometric platforms were successfully applied to study the dissolution profile of MIC and NYS in their combined formulation in compliance with FDA recommendations without excipients interference. According to ICH guidelines, all platforms were validated regarding the accuracy, precision, and selectivity producing satisfactory results within the accepted limits. Also, the suggested platforms’ results were statistically compared with each other and with those of the reported HPLC platform revealing no significant difference concerning accuracy and precision at p = .05. Accordingly, all proposed platforms are regarded as economic and eco-friendly alternatives to the expensive chromatographic platforms that utilize hazardous organic solvents during the analysis of cited drugs.

Formulation and Evaluation of Miconazole Nitrate Loaded Nanoparticles for Topical Delivery

The aim of the present work was to formulate and evaluate Miconazole nitrate (MN) polymeric nanoparticles (NPs) for systemic delivery of the active ingredient after topical administration. The Solvent evaporation approach was used to make nanoparticles for topical delivery of MN. Particle size, entrapment efficiency and SEM were all measured in MN-SLN. A consistent size distribution (PI 0.300) was used to generate aqueous NPs dispersions with a mean particle size less than 250 nm. After 3 months of storage, the produced semi-solid systems had a mean particle size of less than 250 nm and a PI of less than 0.500. The F5 formulation was been chosen as the model formulation from among the nine nanoparticle formulations developed (F1 to F9). The reason for this was that, according to the ICH stability guidelines, formulation F5 was judged to be optimal and stable. The F5 formulations of miconazole nanoparticles shows the highest entrapment efficiency (93.28%) and drug loading (86.64%). In conclusion, there are two major advantages of using miconazole nanoparticle drug delivery systems. i.e., they are topical preparations that assemble in the hair follicles and wrinkles to produce a systemic and local action. It is possible that nanoparticles will be the most effective treatment for fungal skin infections.

Solid and Semisolid Innovative Formulations Containing Miconazole-Loaded Solid Lipid Microparticles to Promote Drug Entrapment into the Buccal Mucosa.

The currently available antifungal therapy for oral candidiasis (OC) has various limitations restricting its clinical use, such as short retention time, suboptimal drug concentration and low patients compliance. These issues could be overcome using micro or nanotechnology. In particular, solid lipid microparticles (SLMs) resulted as a particularly promising penetration enhancer carrier for lipophilic drugs, such as the antifungal miconazole (MCZ). Based on these considerations, cetyl decanoate (here synthesized without the use of metal catalysis) was employed together with 1-hexadecanol to prepare MCZ-loaded SLMs. These resulted in a powder composed of 45–300 µm diameter solid spherical particles, able to load a high amount of MCZ in the amorphous form and characterized by a melting temperature range perfectly compatible with oromucosal administration (35–37 °C). Moreover, when compared to Daktarin® 2% oral gel in ex vivo experiments, SLMs were able to increase up to three-fold MCZ accumulation into the porcine buccal mucosa. The prepared SLMs were then loaded into a buccal gel or a microcomposite mucoadhesive buccal film and evaluated in terms of MCZ permeation and/or accumulation into porcine buccal mucosa by using lower doses than the conventional dosage form. The promising results obtained highlighted an enhancement in terms of MCZ accumulation even at low doses. Furthermore, the prepared buccal film was eligible as stable, reproducible and also highly mucoadhesive. Therefore, the formulated SLMs represent a penetration enhancer vehicle suitable to reduce the dose of lipophilic drugs to be administered to achieve the desired therapeutic effects, as well as being able to be effectively embedded into easily administrable solid or semisolid dosage forms.

Multifunctional Parachute-like Nanomotors for Enhanced Skin Penetration and Synergistic Antifungal Therapy.

Fungal infections in skin are extremely stubborn and seriously threaten human health. In the process of antifungal treatment, it is a huge challenge that the stratum corneum of the skin and fungal biofilms form the drug transport barrier. Herein, a near-infrared (NIR) laser-propelled parachute-like nanomotor loaded with miconazole nitrate (PNM-MN) is fabricated to enhance transdermal drug delivery for synergistic antifungal therapy. Due to asymmetrically spatial distribution, PNM can generate a thermal gradient under NIR laser irradiation, thereby forming effective self-thermophoretic propulsion. The self-propulsion and photothermal effect of PNM play a major role in promoting fungal uptake and biofilm adhesion. Moreover, under laser irradiation, PNM-MN can obliterate plankton Candida albicans and mature biofilms by combining pharmacological therapy and photothermal therapy. More importantly, the drug effectively penetrated the skin to reach the infected site using the nanomotor with NIR laser irradiation. Moreover, PNM-MN with a NIR laser can eradicate fungal infections caused by C. albicans and facilitate the abscess ablation, showing a therapeutic effect in vivo better than that of PNM with a NIR laser or free MN groups, with negligible histological toxicity. Taken together, NIR laser-propelled PNM-MN, as an antifungal nanoagent, provides a promising strategy for transdermal delivery and antifungal therapy.

The emerging threat of human‐use antifungals in sustainable and circular agriculture schemes

Societal Impact StatementRapidly growing global populations mandate greater crop productivity despite increasingly scarce natural resources, including freshwater. The adoption of sustainable agricultural practices seek to address such issues, but an unintended consequence is the exposure of agricultural soils and associated biota to emerging contaminants including azole pharmaceutical antifungals. We show that environmentally relevant exposure to three commonly prescribed azole antifungals can reduce mycorrhizal 33P transfer from the soil into the host plant. This suggests that exposure to azoles may have a significant impact on mycorrhizal‐mediated transfer of nutrients in soil‐plant systems. Understanding the unintended consequences of sustainable agricultural practices is needed to ensure the security and safety of future food production systems.Summary Sustainable farming practices are increasingly necessary to meet the demands of a growing population under constraints imposed by climate change. These practices, in particular the reuse of wastewater and amending soil with wastewater derived biosolids, provide a pathway for man‐made chemicals to enter the agricultural environment. Among the chemicals commonly detected in wastewater and biosolids are pharmaceutical azole antifungals. Fungi, in particular mycorrhiza‐forming fungal symbionts of plant roots, are key drivers of nutrient cycling in the soil–plant system. As such, greater understanding of the impacts of azole antifungal exposure in agricultural systems is urgently needed. We exposed wheat (Triticum aestivum L. cv. ‘Skyfall’) and arbuscular mycorrhizal fungi to environmentally relevant concentrations of three azole antifungals (clotrimazole, miconazole nitrate and fluconazole). We traced the mycorrhizal‐acquired 33P from the soil into the host plant in contaminated versus non‐contaminated soils and found 33P transfer from mycorrhizal fungi to host plants was reduced in soils containing antifungals. This represents a potentially major disruption to soil nutrient flows as a result of soil contamination. Our work raises the major issue of exposure of soil biota to pharmaceuticals such as azole antifungals, introduced via sustainable agricultural practices, as a potentially globally important disruptive influence on soil nutrient cycles. The impacts of these compounds on non‐target organisms, beneficial mycorrhizal fungi in particular, could have major implications on security and sustainability of future food systems.

Antifungal susceptibility of dermatophytes from racehorses in Japan.

Luliconazole (LCZ) is an imidazole antifungal medication that exhibits excellent activity against dermatophytes. As a topical cream and lotion (approved for human use), LCZ has demonstrated a broad spectrum of activity against human dermatophytoses. This is the first study to investigate the invitro susceptibility of clinical isolates from horse dermatophytoses to LCZ. No animals were used in this study. In the present study, the invitro susceptibilities of clinical isolates of dermatophytes to LCZ, clotrimazole (CTZ), miconazole (MCZ) and terbinafine (TRF) were investigated using the Clinical & Laboratory Standards Institute M38-A2 test. The minimum inhibitory concentrations (MICs) for all 16 clinical isolates of Trichophyton equinum, Microsporum equinum/canis and M.gypseum for LCZ were <0.03mg/L. The MICs of all isolates were <0.03-0.5mg/L for CTZ, 0.03-16mg/L for MCZ and <0.03-1mg/L for TRF. LCZ demonstrated a broad spectrum of activity against clinical isolates from horse dermatophytoses. We consider that LCZ will become the primary antifungal agent for treating horse dermatophytosis.

Nanocarriers of Miconazole or Fluconazole: Effects on Three-Species Candida Biofilms and Cytotoxic Effects In Vitro.

The contribution of different Candida species in oral fungal infections has stimulated the search for more effective therapies. This study assessed the antibiofilm effects of nanocarriers of miconazole (MCZ) or fluconazole (FLZ) on Candida biofilms, and their cytotoxic effects on murine fibroblasts. Three-species biofilms (Candida albicans/Candida glabrata/Candida tropicalis) were formed on 96-well plates, and they were treated with nanocarriers (iron oxide nanoparticles coated with chitosan—“IONPs-CS”) of MCZ or FLZ at 39/78/156 µg/mL; antifungals alone at 156 µg/mL and artificial saliva were tested as positive and negative controls, respectively. Biofilms were analyzed by colony forming units (CFU), biomass, metabolic activity, and structure/viability. The cytotoxicity (L929 cells) of all treatments was determined via 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) reduction assay. Data were submitted to one- or two-way ANOVA, followed by Tukey’s or Fisher LSD’s tests (p < 0.05). IONPs-CS-MCZ at 78 µg/mL promoted similar antibiofilm and cytotoxic effects compared with MCZ at 156 µg/mL. In turn, IONPs-CS-FLZ at 156 µg/mL was overall the most effective FLZ antibiofilm treatment, surpassing the effects of FLZ alone; this nanocarrier was also less cytotoxic compared with FLZ alone. It can be concluded that both nanocarriers are more effective alternatives to fight Candida biofilms compared with their respective positive controls in vitro, being a promising alternative for the treatment of oral fungal infections.

Sublimation thermodynamics of antifungal drugs: Tioconazole, miconazole and climbazole

The temperature dependence of the saturated vapour pressure of the antifungal drugs – tioconazole (TCZ), miconazole (MCZ) and climbazole (CLZ) – was determined by the inert gas carrier transfer method. The standard molar enthalpies of sublimation at T = 298.15 K calculated from these data were 117.2 ± 0.5 kJ·mol-1 for TCZ ± 0.9, 106.2 ± 1.0 kJ·mol-1 for MCZ and 113.3 kJ·mol-1for CLZ. The vaporization and sublimation enthalpies of the compounds were found by the Langmuir and Clausius-Clapeyron equations without determining the vapour pressures of the drugs. Sublimation enthalpies derived by both these methods were in good agreement. It was shown that it was possible to estimate the thermodynamic sublimation functions by applying the space clusterization approach to the studied and structurally related compounds. In addition, the temperature and enthalpy of fusion of the compounds were measured by differential scanning calorimetry.

Effects of Antifungal Carriers Based on Chitosan-Coated Iron Oxide Nanoparticles on Microcosm Biofilms.

Resistance of Candida species to conventional therapies has motivated the development of antifungal nanocarriers based on iron oxide nanoparticles (IONPs) coated with chitosan (CS). This study evaluates the effects of IONPs-CS as carriers of miconazole (MCZ) or fluconazole (FLZ) on microcosm biofilms. Pooled saliva from two healthy volunteers supplemented with C. albicans and C. glabrata was the inoculum for biofilm formation. Biofilms were formed for 96 h on coverslips using the Amsterdam Active Attachment model, followed by 24 h treatment with nanocarriers containing different concentrations of each antifungal (78 and 156 µg/mL). MCZ or FLZ (156 µg/mL), and untreated biofilms were considered as controls. Anti-biofilm effects were evaluated by enumeration of colony-forming units (CFUs), composition of the extracellular matrix, lactic acid production, and structure and live/dead biofilm cells (confocal laser scanning microscopy-CLSM). Data were analyzed by one-way ANOVA and Fisher LSD’s test (α = 0.05). IONPs-CS carrying MCZ or FLZ were the most effective treatments in reducing CFUs compared to either an antifungal agent alone for C. albicans and MCZ for C. glabrata. Significant reductions in mutans streptococci and Lactobacillus spp. were shown, though mainly for the MCZ nanocarrier. Antifungals and their nanocarriers also showed significantly higher proportions of dead cells compared to untreated biofilm by CLSM (p < 0.001), and promoted significant reductions in lactic acid, while simultaneously showing increases in some components of the extracellular matrix. These findings reinforce the use of nanocarriers as effective alternatives to fight oral fungal infections.

Treatment methods for vulvovaginal candidiasis in pregnancy

IntroductionVulvovaginal candidiasis (VVC) is one of the three most common vaginal infections of women. Our goal is to check which treatment method (vaginal or vaginal combined with oral) is more effective for each trimester to treat VVC. Materials and MethodA retrospective analysis was performed and vaginal culture results after treatment of 61 pregnant women who were treated with vaginal or vaginal plus oral antifungals, were collected. Women were grouped according to the method were treated and the trimester they were in. Patients who had used vaginal 750 mg metronidazole + 200 mg miconazole nitrate were determined as the vaginal treatment group. Patients who had used vaginal 750 mg metronidazole + 200 mg miconazole nitrate and oral 150 mg fluconazole were determined as the vaginal plus oral treatment group. ResultsWhen the patients were grouped according to treatment method, there were no significant differences in demographic characteristics except previous antibiotic use. Previous antibiotic use was significantly higher in the vaginal treatment group (p<0.05). There were no statistically significant differences between the recurrence of VVC in the vaginal and vaginal plus oral treatment group in the first, second, and third trimesters. DiscussionThe results of the study showed that the efficiency of the vaginal treatment was the same as the vaginal plus oral treatment in all three trimesters in the aspect of VVC recurrence. Local treatment of VVC has several advantageous features when compared with oral therapy including a low rate of adverse events, safe utilization during pregnancy, and breastfeeding.

Application of TLC-Spectrodensitometric and Chemometric Methods for Determination of Momenta® Cream: A Comparative Study Applied on Ternary Mixture

A comparative study for the validation and advancement of two analytical approaches applied for the simultaneous determination of Mometasone Furoate (MF), Miconazole Nitrate (MIC) and Gentamicin (GM) formulated in Momenta® cream. The first approach was TLC-spectrodensitometric method, which was advanced by separating the three components on TLC aluminum plates coated with silica gel 60 F254 using chloroform: methanol: formic acid (4:0.3:0.15, v/v/v) as a mobile phase, then scanned at 254nm using Camage TLC scanner 3 operated in reflectance-absorbance mode. The second approach was the chemometric method using two models: Partial Least Squares (PLS) and Principle Component Regression Model (PCR). The proposed approaches were validated according to ICH guidelines and were applied for the determination of the ternary mixtures in their analytical mixtures and pharmaceutical preparation.

Assessment of the mechanism of drug resistance in Trichophyton mentagrophytes in response to various substances

BackgroundTrichophyton mentagrophyte (TM), a zoonotic pathogen, has been endangering public health due to emerging drug resistance. Although increased attention is paid to this issue, there is very limited research available on drug resistance in TM. In this study, we studied the gene and proteomic changes, morphological changes, cellular fat localization, fat content changes, and biofilm of TM treated with different substances.ResultsThe TM growth curve showed a positive correlation with the concentration of Fenarimol (FE), genistein (GE), clotrimazole (KM), and Miconazole nitrate salt (MK). The morphology of TM cells changed in different degrees after treatment with different substances as observed by TEM and SEM. The results showed that under KM and berberine hydrochloride (BB) treatment, a total of 3305 differentially expressed genes were detected, with the highest number in the KM-treated group (578 up-regulated and 615 down-regulated). A total of 847 proteins and 1850 peptides were identified in TM proteomics. Nile red staining showed that the fat content of TM was significantly higher in the BB-, ethidium bromide- (EB), FE-, KM-, Adriamycin hydrochloride- (YA), and MK-treated group compared to the control group. Results of the biofilm thickness showed that it gradually increased under treatment with specific concentrations of KM or BB, which may be related to the up-regulation of ERG25 and CYP related gene proteins.ConclusionsIt is suggested that in order to effectively deal with dermatomycosis caused by TM, it is necessary to inhibit the expression of ERG25 and CYP related genes and fat metabolism, which can result in the inhibition of the production of biofilm by the fungus and solve the problem of fungal drug resistance in clinical settings.

Facile preparation of solid dispersions by dissolving drugs in N-vinyl-2-pyrrolidone and photopolymerization

Drug solid dispersions improve the dissolution of drugs in aqueous media for enhancement of oral bioavailability. The current preparation methods of drug solid dispersions mainly involve the evaporation of solvents or the melting of drugs and matrix. Here, we create a new and simple method for the preparation of drug solid dispersions by dissolving drugs in N-vinyl-2-pyrrolidone (NVP) and then NVP photopolymerization. A variety of drugs were explored to find whether they were suitable for this method and only some of them were soluble in NVP and formed transparent and hard solid dispersions, including fluconazole, ketoconazole, bifonazole, miconazole nitrate, sulfamethoxazole, aspirin, ibuprofen and artesunate. The formation of photocuring solid dispersions was highly related to the free radical scavenging function of drugs. Those drugs with strong free radical scavenging capability, including curcumin, resveratrol, quercetin, genistein, puerarin, nicergoline, olanzapine, indomethacin, did not form solid dispersions. They scavenged 2,2-diphenyl-1-picrylhydrazyl free radicals, which was demonstrated by ultraviolet spectrometry and electron spin resonance. The scavenging of free radicals stopped the chain polymerization of NVP. The Fourier transform infrared spectra, X-ray diffraction and differential scanning calorimetry of ibuprofen solid dispersions and artesunate solid dispersions showed the molecularly miscible state of the drugs and the hydrogen bonding between the drugs and polyvinyl pyrrolidone. The NVP-based solid dispersions of the two drugs had faster and more complete dissolution than their traditional solid dispersions. The NVP photopolymerization-based solid dispersion method provides a new choice for the production of solid dispersions in the research and industrial fields.

Combining Miconazole and Domiphen Bromide Results in Excess of Reactive Oxygen Species and Killing of Biofilm Cells.

Fungal biofilm-related infections are increasingly occurring. We previously identified a fungicidal antibiofilm combination, consisting of miconazole (MCZ) and the quaternary ammonium compound domiphen bromide (DB). DB eliminates tolerance rather than altering the susceptibility to MCZ of various Candida spp. Here we studied the mode of action of the MCZ-DB combination in more detail. We found that DB's action increases the permeability of the plasma membrane as well as that of the vacuolar membrane of Candida spp. Furthermore, the addition of DB affects the intracellular azole distribution. MCZ is a fungicidal azole that, apart from its well-known inhibition of ergosterol biosynthesis, also induces accumulation of reactive oxygen species (ROS). Interestingly, the MCZ-DB combination induced significantly more ROS in C. albicans biofilms as compared to single compound treatment. Co-administration of the antioxidant ascorbic acid resulted in abolishment of the ROS generated by MCZ-DB combination as well as its fungicidal action. In conclusion, increased intracellular MCZ availability due to DB's action results in excess of ROS and enhanced fungal cell killing.

A combined experimental and theoretical study of miconazole salts and cocrystals: crystal structures, DFT computations, formation thermodynamics and solubility improvement.

Experimental and theoretical screening of multi-component crystal forms of miconazole (MCL), an antifungal drug, with ten aliphatic dicarboxylic acids was performed. Seven multi-component molecular crystals were isolated and identified by different analytical techniques, including the powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TG), and solubility methods. The crystal structures of the MCL hemihydrate, two cocrystals with succinic ([MCL + SucAc] (2 : 1)) and fumaric acids ([MCL + FumAc] (2 : 1)) and one salt with maleic acid ([MCL + MleAc] (1 : 1)) were redetermined. The new cocrystal of MCL with adipic acid ([MCL + AdpAc] (2 : 1)) was investigated by single crystal X-ray diffractometry. It was found that the AdpAc molecule in the cocrystal has an unusual anticlinal conformation. The combination of periodic density functional theory (DFT) computations and quantum topology analysis confirmed the structure-directing role of the acid-imidazole heterosynthon for the considered crystals. The melting temperatures of all the studied multi-component crystals are between the values of the corresponding individual components except [MCL + MleAc] (1 : 1). A thermal analysis has shown that the thermodynamic and thermophysical characteristics of the considered two-component molecular crystals are strongly dependent both on specific interactions (presence of sites of donor-acceptor interactions and hydrogen bond formation) and on nonspecific interactions - molecule polarizability. Based on the sublimation thermodynamics database of molecular crystals, the standard sublimation thermodynamic functions of MCL were evaluated. The thermodynamic functions of multi-component crystal formation based on MCL were calculated and analyzed. Solubility experiments on the MCL multi-component crystals were carried out in isotonic aqueous buffer solutions at pH 1.2 and 6.8 and compared with the solubility of the MCL free base and its nitrate salt. It was found that the salt/cocrystal formation of MCL with dicarboxylic acids considerably increased the MCL solubility in pH 6.8 buffer. The biggest MCL solubility enhancement was observed in the [MCL + TartAc] (1 : 1) salt. The solubility value of MCL in the [MCL + TartAc] (1 : 1) salt is commensurate with the commercial MCL nitrate salt.