RESUMO
In this research, 3D-printed antifungal buccal films (BFs) were manufactured as a potential alternative to commercially available antifungal oral gels addressing key considerations such as ease of manufacturing, convenience of administration, enhanced drug efficacy and suitability of paediatric patients. The fabrication process involved the use of a semi-solid extrusion method to create BFs from zein-Poly-Vinyl-Pyrrolidone (zein-PVP) polymer blend, which served as a carrier for drug (miconazole) and taste enhancers. After manufacturing, it was determined that the disintegration time for all films was less than 10 min. However, these films are designed to adhere to buccal tissue, ensuring sustained drug release. Approximately 80% of the miconazole was released gradually over 2 h from the zein/PVP matrix of the 3D printed films. Moreover, a detailed physicochemical characterization including spectroscopic and thermal methods was conducted to assess solid state and thermal stability of film constituents. Mucoadhesive properties and mechanical evaluation were also studied, while permeability studies revealed the extent to which film-loaded miconazole permeates through buccal tissue compared to commercially available oral gel formulation. Histological evaluation of the treated tissues was followed. Furthermore, in vitro antifungal activity was assessed for the developed films and the commercial oral gel. Finally, films underwent a two-month drug stability test to ascertain the suitability of the BFs for clinical application. The results demonstrate that 3D-printed films are a promising alternative for local administration of miconazole in the oral cavity.
Assuntos
Antifúngicos , Candidíase Bucal , Liberação Controlada de Fármacos , Miconazol , Impressão Tridimensional , Miconazol/administração & dosagem , Miconazol/química , Miconazol/farmacocinética , Antifúngicos/administração & dosagem , Antifúngicos/química , Antifúngicos/farmacocinética , Administração Bucal , Candidíase Bucal/tratamento farmacológico , Humanos , Zeína/química , Mucosa Bucal/metabolismo , Mucosa Bucal/microbiologia , Povidona/química , Permeabilidade , Sistemas de Liberação de Medicamentos/métodos , Animais , Química Farmacêutica/métodos , CriançaRESUMO
Since the local treatment of oral candidiasis usually requires long-term administration of the antifungal drug, an ideal dosage form should be able to maintain the drug release over an extended period, assuring an adequate concentration at the infection site. In this context, we have considered the possibility of a buccal delivery of miconazole nitrate (MN) by mucoadhesive polymeric matrices. The loading of the antifungal drug in a hydrophilic matrix was made possible by taking advantage of the amphiphilic nature of liposomes (LP). The MN-loaded LP were prepared by a thin film evaporation method followed by extrusion, while solid matrices were obtained by freeze-drying a suspension of the LP in a polymeric solution based on chitosan (CH), sodium hyaluronate (HYA), or hydroxypropyl methylcellulose (HPMC). MN-loaded LP measured 284.7 ± 20.1 nm with homogeneous size distribution, adequate drug encapsulation efficiency (86.0 ± 3.3 %) and positive zeta potential (+47.4 ± 3.3). CH and HYA-based formulations almost completely inhibited C. albicans growth after 24 h, even if the HYA-based one released a higher amount of the drug. The CH-based matrix also provided the best mucoadhesive capacity and therefore represents the most promising candidate for the local treatment of oral candidiasis.
Assuntos
Antifúngicos , Candida albicans , Candidíase Bucal , Quitosana , Liberação Controlada de Fármacos , Derivados da Hipromelose , Lipossomos , Miconazol , Antifúngicos/administração & dosagem , Antifúngicos/química , Antifúngicos/farmacocinética , Miconazol/administração & dosagem , Miconazol/química , Miconazol/farmacocinética , Candidíase Bucal/tratamento farmacológico , Candida albicans/efeitos dos fármacos , Derivados da Hipromelose/química , Administração Bucal , Quitosana/química , Quitosana/administração & dosagem , Adesividade , Ácido Hialurônico/química , Ácido Hialurônico/administração & dosagem , Polímeros/química , Sistemas de Liberação de Medicamentos , Mucosa Bucal/metabolismo , Mucosa Bucal/microbiologiaRESUMO
Hydrophilic drugs could be incorporated into the skin surface by manes of Lipogel. This study aimed to prepare miconazole lipogel with natural ingredients to enhance drug permeability using dimethyl Sulfoxide (DMSO). The miconazole lipogels, A1 (without DMSO) and A2 (with DMSO) were formulated and evaluated for organoleptic evaluation, pH, viscosity, stability studies, freeze-thawing, drug release profile and drug permeation enhancement. Results had stated that prepared lipogel's pH falls within the acceptable range required for topical delivery (4 to 6) while both formulations show good results in organoleptic evaluation. The A2 formulation containing DMSO shows better permeation of miconazole (84.76%) on the artificial skin membrane as compared to A1 lipogel formulation (50.64%). In in-vitro drug release studies, A2 for-mulation showed 87.48% drug release while A1 showed just 60.1% drug release from lipogel. Stability studies were performed on model formulations under environmental conditions and both showed good spreadibility, stable pH, free of grittiness and good consistency in formulation. The results concluded that A2 formulation containing DMSO shows better results as compared to DMSO-free drug lipogel.
Assuntos
Dimetil Sulfóxido , Liberação Controlada de Fármacos , Géis , Miconazol , Permeabilidade , Miconazol/administração & dosagem , Miconazol/química , Miconazol/farmacocinética , Dimetil Sulfóxido/química , Viscosidade , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Absorção Cutânea/efeitos dos fármacos , Química Farmacêutica , Composição de Medicamentos , Antifúngicos/administração & dosagem , Antifúngicos/química , Antifúngicos/farmacocinética , Administração CutâneaRESUMO
Melanoma, arguably the deadliest form of skin cancer, is responsible for the majority of skin-cancer-related fatalities. Innovative strategies concentrate on new therapies that avoid the undesirable effects of pharmacological or medical treatment. This article discusses the chemical structures of [(MTZ)2AgNO3], [(MTZ)2Ag]2SO4, [Ag(MCZ)2NO3], [Ag(MCZ)2BF4], [Ag(MCZ)2SbF6] and [Ag(MCZ)2ClO4] (MTZ-metronidazole; MCZ-miconazole) silver(I) compounds and the possible relationship between the molecules and their cytostatic activity against melanoma cells. Molecular Hirshfeld surface analysis and computational methods were used to examine the possible association between the structure and anticancer activity of the silver(I) complexes and compare the cytotoxicity of the silver(I) complexes of metronidazole and miconazole with that of silver(I) nitrate, cisplatin, metronidazole and miconazole complexes against A375 and BJ cells. Additionally, these preliminary biological studies found the greatest IC50 values against the A375 line were demonstrated by [Ag(MCZ)2NO3] and [(MTZ)2AgNO3]. The compound [(MTZ)2AgNO3] was three-fold more toxic to the A375 cells than the reference (cisplatin) and 15 times more cytotoxic against the A375 cells than the normal BJ cells. Complexes of metronidazole with Ag(I) are considered biocompatible at a concentration below 50 µmol/L.
Assuntos
Antineoplásicos , Complexos de Coordenação , Melanoma , Metronidazol , Miconazol , Prata , Humanos , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Melanoma/patologia , Miconazol/farmacologia , Miconazol/química , Prata/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Metronidazol/química , Metronidazol/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologiaRESUMO
The main objective of this study was to investigate the metabolism of miconazole, an azole antifungal drug. Miconazole was subjected to incubation with human liver microsomes (HLM) to mimic phase I metabolism reactions for the first time. Employing a combination of an HLM assay and UHPLC-HRMS analysis enabled the identification of seven metabolites of miconazole, undescribed so far. Throughout the incubation with HLM, miconazole underwent biotransformation reactions including hydroxylation of the benzene ring and oxidation of the imidazole moiety, along with its subsequent degradation. Additionally, based on the obtained results, screen-printed electrodes (SPEs) were optimized to simulate the same biotransformation reactions, by the use of a simple, fast, and cheap electrochemical method. The potential toxicity of the identified metabolites was assessed using various in silico models.
Assuntos
Espectrometria de Massas , Miconazol , Microssomos Hepáticos , Miconazol/química , Miconazol/metabolismo , Humanos , Cromatografia Líquida de Alta Pressão/métodos , Microssomos Hepáticos/metabolismo , Espectrometria de Massas/métodos , Técnicas Eletroquímicas/métodos , Antifúngicos/química , Antifúngicos/metabolismo , BiotransformaçãoRESUMO
People with immune deficiency are at risk of developing infections caused by several bacterial and fungal species. In this work, chitosan-coated miconazole was developed by a simple sol-gel method. Miconazole is considered an effective drug to treat vaginal infection-causing bacteria and fungi. The coating of chitosan with miconazole nitrate showed the highest drug loading efficiency (62.43%) and mean particle size (2 µm). FTIR spectroscopic analysis confirmed the entrapment of miconazole nitrate into chitosan polymer. The antifungal result demonstrated that MN@CS microgel possessed notable anti-Aspergillus fumigatus and Candida albicans activity in lower doses. Antibacterial activity results revealed excellent bacterial growth inhibition of MN@CS microgel towards human skin infectious pathogens Escherichia coli and Staphylococcus aureus. The biocompatibility studies of In vitro cell viability and Artemia salina lethality assay suggested that MN@CS microgel is more biosafe and suitable for human external applications. In the future, it will be an efficient anti-inflammatory agent for the treatment of vaginal infections.
Assuntos
Candidíase Vulvovaginal , Quitosana , Microgéis , Feminino , Humanos , Miconazol/farmacologia , Miconazol/química , Miconazol/uso terapêutico , Candidíase Vulvovaginal/tratamento farmacológico , Quitosana/química , Microgéis/uso terapêutico , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Antifúngicos/química , Candida albicans , Complicações Pós-OperatóriasRESUMO
Vaginal candidiasis is a common form of infection in women caused by Candida species. Due to several drawbacks of conventional treatments, the current research is attempted to formulate and optimize a miconazole nitrate-loaded in situ spray gel for vaginal candidiasis. The stimuli-responsive (pH and thermo-responsive) polymers selected for the in situ gel were chitosan and poloxamer 407, respectively, whereas hydroxypropyl methylcellulose (HPMC) was introduced in the formulation to further improve the mucoadhesive property. The dispersion of each polymer was carried out using the cold method, whereas the optimization of the formulation was achieved using Box-Behnken statistical design considering viscosity and gelation temperature as dependent variables. Present design achieved the optimized outcome with HPMC, poloxamer and chitosan at 0.52% (w/v), 18.68% (w/v) and 0.41% (w/v), respectively. Evaluation of drug-excipients compatibility was performed using differential scanning calorimetry, Fourier transform infrared spectroscopy, and thermogravimetric analysis where the results showed the absence of any chemical interaction between the polymers and drug component. The optimized formulation showed gelation temperature at 31°C allowing in situ phase transition in a vaginal environment; pH of 4.21 is suitable for use in the vaginal cavity, and appropriate viscosity (290 cP) at storage temperature (below 30°C) would allow spraying at ease, whereas strong mucoadhesive force (22.4±0.513 g) would prevent leaking of the formulation after application. The drug release profile showed sustained release up to 24 h with a cumulative drug release of 81.72%, which is significantly better than the marketed miconazole nitrate cream. In addition, an improved antifungal activity could be correlated to the sustained release of the drug from the formulation. Finally, the safety of the formulation was established while tested on HaCaT cell lines. Based on our findings, it could be concluded that the in situ hydrogel formulation using stimuli-responsive polymers could be a viable alternative to the conventional dosage form that can help to reduce the frequency of administration with ease of application to the site of infection, thus will provide better patient compliance.
Assuntos
Candidíase Vulvovaginal , Quitosana , Feminino , Humanos , Miconazol/química , Miconazol/uso terapêutico , Preparações de Ação Retardada/química , Quitosana/química , Candidíase Vulvovaginal/tratamento farmacológico , Antifúngicos/química , Poloxâmero/química , Géis/químicaRESUMO
We previously reported that conjugates of antimicrobial peptide fragment analogues and poly (lactic-co-glycolic) acid (PLGA) enhance antimicrobial activity and that the conjugated micelle structure is an effective tool for antimicrobial drug delivery. In recent years, the delivery of antimicrobial peptides to targets for antimicrobial activity has attracted attention. In this study, we targeted Candida albicans, a causative organism of catheter-related bloodstream infections, which is refractory to antimicrobial agents and is currently a problem in medical practice. We evaluated the antifungal activity of CKR12 (a mutant fragment of the human cathelicidin peptide, LL-37)-PLGA-miconazole (MCZ) micelles using nanotechnology with MCZ delivery. The prepared CKR12-PLGA-MCZ micelles were characterised by measuring dynamic light scattering, zeta potential, dilution stability, and drug release. CKR12-PLGA-MCZ micelles showed higher antifungal activity than CKR12-PLGA micelles and MCZ solution. Furthermore, scanning and transmission electron microscopy suggested that CKR12-PLGA-MCZ micelles disrupted both cell wall and cell membrane of C. albicans. Our results revealed a synergistic effect of antifungal activity using a combination of antimicrobial peptide fragment analogues and MCZ, and that MCZ is a promising tool for the delivery to target microorganisms.
Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Miconazol/farmacologia , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Antifúngicos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Candidíase/metabolismo , Candidíase/microbiologia , Micelas , Miconazol/química , CatelicidinasRESUMO
BACKGROUND: Metabolic abnormalities in patients with gastric adenocarcinoma lead to drug resistance and poor prognosis. Therefore, this study aimed to explore biomarkers that can predict the prognostic risk of gastric adenocarcinoma by analyzing drug metabolism-related genes. METHODS: The RNA-seq and clinical information on gastric adenocarcinoma were downloaded from the UCSC and gene expression omnibus databases. Univariate and least absolute shrinkage and selection operator regression analyses were used to identify the prognostic gene signature of gastric adenocarcinoma. The relationships between gastric adenocarcinoma prognostic risk and tumor microenvironment were assessed using CIBERSORT, EPIC, QUANTISEQ, MCPCounter, xCell, and TIMER algorithms. The potential drugs that could target the gene signatures were predicted in WebGestalt, and molecular docking analysis verified their binding stabilities. RESULTS: Combined with clinical information, an eight-gene signature, including GPX3, ABCA1, NNMT, NOS3, SLCO4A1, ADH4, DHRS7, and TAP1, was identified from the drug metabolism-related gene set. Based on their expressions, risk scores were calculated, and patients were divided into high- and low-risk groups, which had significant differences in survival status and immune infiltrations. Risk group was also identified as an independent prognostic factor of gastric adenocarcinoma, and the established prognostic and nomogram models exhibited excellent capacities for predicting prognosis. Finally, miconazole and niacin were predicted as potential therapeutic drugs for gastric adenocarcinoma that bond stably with NOS3 and NNMT through hydrogen interactions. CONCLUSIONS: This study proposed a drug metabolism-related eight-gene signature as a potential biomarker to predict the gastric adenocarcinoma prognosis risks.
Assuntos
Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Inativação Metabólica/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Adenocarcinoma/tratamento farmacológico , Adulto , Idoso , Biomarcadores Tumorais/genética , Glibureto/química , Glibureto/metabolismo , Glibureto/farmacocinética , Humanos , Miconazol/química , Miconazol/farmacocinética , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Nomogramas , Prognóstico , Mapas de Interação de Proteínas/genética , Proteínas/química , Proteínas/genética , Reprodutibilidade dos Testes , Fatores de Risco , Neoplasias Gástricas/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
Background: Alzheimer's disease is a multifactorial neurological disorder seen in elderly people. Loss of cholinergic transmission and unbalanced tryptophan metabolism kynurenine pathway have been demonstrated in neuropsychiatric diseases. Methods & results: Among the two series of synthesized compounds, compounds 5c and 5h were identified as effective dual BChE/IDO1 inhibitors, with well-balanced micromolar activity. Compounds 5c and 5h exhibited promising ability to ameliorate behavioral impairment by Morris water maze. The safety of miconazole analogs was also validated by PC12 and SH-SY5Y cell lines. Conclusion: These results highlight the ability of 5c and 5h to treat Alzheimer's disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Miconazol/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Electrophorus , Cavalos , Humanos , Masculino , Camundongos , Miconazol/síntese química , Miconazol/química , Modelos Moleculares , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , RatosRESUMO
A series of selenium-containing miconazole derivatives were identified as potent antifungal drugs in our previous study. Representative compound A03 (MIC = 0.01 µg/mL against C.alb. 5314) proved efficacious in inhibiting the growth of fungal pathogens. However, further study showed lead compound A03 exhibited potential hemolysis, significant cytotoxic effect and unfavorable metabolic stability and was therefore modified to overcome these drawbacks. In this article, the further optimization of selenium-containing miconazole derivatives resulted in the discovery of similarly potent compound B17 (MIC = 0.02 µg/mL against C.alb. 5314), exhibiting a superior pharmacological profile with decreased rate of metabolism, cytotoxic effect and hemolysis. Furthermore, compound B17 showed fungicidal activity against Candida albicans and significant effects on the treatment of resistant Candida albicans infections. Meanwhile, compound B17 not only could reduce the ergosterol biosynthesis pathway by inhibiting CYP51, but also inhibited biofilm formation. More importantly, compound B17 also shows promising in vivo efficacy after intraperitoneal injection and the PK study of compound B17 was evaluated. In addition, molecular docking studies provide a model for the interaction between the compound B17 and the CYP51 protein. Overall, we believe that these selenium-containing miconazole compounds can be further developed for the potential treatment of fungal infections.
Assuntos
Inibidores de 14-alfa Desmetilase/química , Antifúngicos/química , Miconazol/química , Selênio/química , Esterol 14-Desmetilase/química , Inibidores de 14-alfa Desmetilase/metabolismo , Inibidores de 14-alfa Desmetilase/farmacologia , Inibidores de 14-alfa Desmetilase/uso terapêutico , Animais , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Sítios de Ligação , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Candida/fisiologia , Candidíase/tratamento farmacológico , Candidíase/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Desenho de Fármacos , Meia-Vida , Humanos , Camundongos , Miconazol/metabolismo , Miconazol/farmacologia , Miconazol/uso terapêutico , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Esterol 14-Desmetilase/metabolismo , Relação Estrutura-AtividadeRESUMO
In a previous article, we reported on the higher toxicity of silver(I) complexes of miconazole [Ag(MCZ)2NO3 (1)] and [Ag(MCZ)2ClO4 (2)] in HepG2 tumor cells compared to the corresponding salts of silver, miconazole and cisplatin. Here, we present the synthesis of two silver(I) complexes of miconazole containing two new counter ions in the form of Ag(MCZ)2X (MCZ = 1-[2-(2,4-dichlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole]; X = BF4- (3), SbF6- (4)). The novel silver(I) complexes were characterized by elemental analysis, 1H NMR, 13C NMR and infrared (IR) spectroscopy, electrospray ionization (ESI)-MS spectrometry and X-ray-crystallography. In the present study, the antimicrobial activity of all obtained silver(I) complexes of miconazole against six strains of Gram-positive bacteria, five strains of Gram-negative bacteria and yeasts was evaluated. The results were compared with those of a silver sulfadiazine drug, the corresponding silver salts and the free ligand. Silver(I) complexes exhibited significant activity against Gram-positive bacteria, which was much better than that of silver sulfadiazine and silver salts. The highest antimicrobial activity was observed for the complex containing the nitrate counter ion. All Ag(I) complexes of miconazole resulted in much better inhibition of yeast growth than silver sulfadiazine, silver salts and miconazole. Moreover, the synthesized silver(I) complexes showed good or moderate activity against Gram-negative bacteria compared to the free ligand.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Complexos de Coordenação/síntese química , Miconazol/química , Prata/química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Leveduras/efeitos dos fármacosRESUMO
People with weakened immune systems are at risk of developing candidiasis which is a fungal infection caused by several species of Candida genus. In this work, polymeric nanoparticles containing miconazole nitrate and the anesthetic lidocaine clorhydrate were developed. Miconazole was chosen as a typical drug to treat buccopharyngeal candidiasis whereas lidocaine may be useful in the management of the pain burning, and pruritus caused by the infection. Nanoparticles were synthesized using chitosan and gelatin at different ratios ranging from 10:90 to 90:10. The nano-systems presented nanometric size (between 80 and 300 nm in water; with polydispersion index ranging from 0.120 to 0.596), and positive Z potential (between 20.11 and 37.12 mV). The determined encapsulation efficiency ranges from 65 to 99% or 34 to 91% for miconazole nitrate and lidocaine clorhydrate, respectively. X-ray diffraction and DSC analysis suggested that both drugs were in amorphous state in the nanoparticles. Finally, the systems fitted best the Korsmeyer-Peppas model showing that the release from the nanoparticles was through diffusion allowing a sustained release of both drugs and prolonged the activity of miconazole nitrate over time against Candida albicans for at least 24 h.
Assuntos
Candida albicans/isolamento & purificação , Candidíase/tratamento farmacológico , Lidocaína/administração & dosagem , Miconazol/administração & dosagem , Nanopartículas/química , Polímeros/química , Antifúngicos/administração & dosagem , Antifúngicos/química , Varredura Diferencial de Calorimetria , Quitosana , Humanos , Lidocaína/química , Miconazol/química , Nanopartículas/administração & dosagem , Difração de Raios XRESUMO
Aim: The identification of drugs for the coronavirus disease-19 pandemic remains urgent. In this manner, drug repurposing is a suitable strategy, saving resources and time normally spent during regular drug discovery frameworks. Essential for viral replication, the main protease has been explored as a promising target for the drug discovery process. Materials & methods: Our virtual screening pipeline relies on the known 3D properties of noncovalent ligands and features of crystalized complexes, applying consensus analyses in each step. Results: Two oral (bedaquiline and glibenclamide) and one buccal drug (miconazole) presented 3D similarity to known ligands, reasonable predicted binding modes and micromolar predicted binding affinity values. Conclusion: We identified three approved drugs as promising inhibitors of the main viral protease and suggested design insights for future studies for development of novel selective inhibitors.
Assuntos
Antivirais/farmacologia , Betacoronavirus/enzimologia , Infecções por Coronavirus/tratamento farmacológico , Descoberta de Drogas , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Betacoronavirus/efeitos dos fármacos , COVID-19 , Proteases 3C de Coronavírus , Infecções por Coronavirus/virologia , Cisteína Endopeptidases/metabolismo , Diarilquinolinas/química , Diarilquinolinas/farmacologia , Desenho de Fármacos , Glibureto/química , Glibureto/farmacologia , Humanos , Ligantes , Miconazol/química , Miconazol/farmacologia , Modelos Moleculares , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/virologia , Inibidores de Proteases/química , SARS-CoV-2 , Proteínas não Estruturais Virais/metabolismoRESUMO
Topical candidiasis is a known skin fungal infection which is usually treated by conventional dosage forms such as cream, gel, emulgel which are having numerous adverse effects on skin. To overcome such disadvantages, different novel drug delivery systems have been considered. Polymer based nano-particulate systems have shown good skin penetration after topical application. Therefore, in the present study the main focus was on the pathology, pathogenesis, and consequently topical treatment of candidiasis. Nanogel containing miconazole have been prepared from the natural polymers i.e. gelatin and chitosan. The nanogel of miconazole (100 mg) nitrate was formulated by modified emulsification-diffusion technique and characterized for different parameters. From all the seven nanogel formulations named as F1 to F7, F1 (Gelatin and Chitosan in the percentage of 82.85 and 17.15 respectively) have been selected as model formulations. The reason behind that was as per ICH stability guideline, the formulations F1 was found optimum and stable. Miconazole nanogel formulations F1 also showed the maximum release i.e. 78 % approximately. XRD showed the formulated nanogel was in crystalline shape. In summary, the miconazole nanogel drug delivery systems have two main advantages i.e. they are topical preparation as well as nano sized. It can be postulated that nanogel may be a best approach to treat the fungal skin diseases.
Assuntos
Antifúngicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Miconazol/administração & dosagem , Animais , Composição de Medicamentos , Estabilidade de Medicamentos , Feminino , Camundongos , Miconazol/química , Nanogéis , Polímeros/química , Espectroscopia de Infravermelho com Transformada de Fourier , ViscosidadeRESUMO
Nadifloxacin, mometasone furoate and miconazole nitrate are formulated together as a topical antifungal dosage form. In this work, a reversed-phase ultra-performance liquid chromatographic method coupled with a diode array detector (RP-UPLC-DAD) was developed and validated to determine nadifloxacin, mometasone furoate and miconazole nitrate simultaneously in their bulk powder, in pharmaceutical preparation and in spiked human plasma samples. Separation was achieved on an ACQUITY UPLC C18 column of 2.2 µm particle size (2.1 × 100 mm) via isocratic elution using a mobile phase consisting of methanol, acetonitrile and water with ratio (50:20:30; v/v/v) and 0.1 g ammonium acetate, then pH was adjusted to (7.00) using acetic acid, flow rate 0.6 mL/min, temperature 30°C and UV detection at 220 nm. The method is linear in a range from 5 to 400 µg/mL for both nadifloxacin and miconazole nitrate and from 20 to 500 µg/mL for mometasone furoate. The method was validated according to the ICH guidelines then applied successfully to determine the mentioned drugs in their pharmaceutical preparation and spiked human plasma samples. For plasma samples, the results showed that the method can determine nadifloxacin, mometasone furoate and miconazole nitrate in human plasma samples with high accuracy and precision.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Fluoroquinolonas/análise , Miconazol/análise , Furoato de Mometasona/análise , Quinolizinas/análise , Cromatografia de Fase Reversa , Fluoroquinolonas/sangue , Fluoroquinolonas/química , Humanos , Limite de Detecção , Modelos Lineares , Miconazol/sangue , Miconazol/química , Furoato de Mometasona/sangue , Furoato de Mometasona/química , Quinolizinas/sangue , Quinolizinas/química , Reprodutibilidade dos TestesRESUMO
The purpose of this study was to prepare poly(lactide-co-glycolide) (PLGA) microspheres (MS) loaded with itraconazole (ITCZ) or miconazole (MCZ) under different evaporation temperatures (25 or 40°C) using an oil-in-water emulsion solvent evaporation method in order to evaluate the initial burst release of drug. Loading efficiencies were comparatively good and the diameters of prepared drug-loaded PLGA MS were around 20 µm in all formulations. The release rates of ITCZ-PLGA MS prepared at 40°C showed a significantly restricted release profile compared with the corresponding ITCZ-PLGA MS prepared at 25°C. This difference in release rate of ITCZ was thought to be caused by the self-healing effect of PLGA, as the glass transition temperature of PLGA is around 40°C. With respect to the MCZ-PLGA MS, the initial burst release was similar in formulations prepared at both 25 and 40°C. Scanning electron microscope results suggested that the initial burst release was due to the localization of MCZ on the surface of MCZ-PLGA MS at higher concentrations. Differential scanning calorimetry measurements suggested complete amorphization of MCZ in MCZ-PLGA MS, whereas crystalline ITCZ was detected in the ITCZ-PLGA MS. This complete amorphization of MCZ is considered to be one of the reasons for the initial burst release.
Assuntos
Portadores de Fármacos/química , Itraconazol , Miconazol , Microesferas , Poliglactina 910 , Varredura Diferencial de Calorimetria , Composição de Medicamentos , Itraconazol/química , Miconazol/químicaRESUMO
Vulvovaginal candidiasis (VVC) is caused mainly by the opportunistic fungus Candida albicans, and its yeast to hyphae transition is considered a major virulence factor. Farnesol is a molecule that inhibits yeast to hyphae transition. The increased incidence of VVC has influenced a need for developing new therapeutic strategies. The objective was to develop a mucoadhesive nanostructured system composed of miconazole and farnesol co-encapsulated within chitosan nanoparticles. The miconazole presented a minimal inhibitory concentration (MIC) of 1 µg/ml against C. albicans. The farnesol was capable of inhibiting yeast to hyphae transition at levels greater or equal to 300 µM. The combination of miconazole and farnesol showed no change in miconazole MIC. Chitosan nanoparticles containing miconazole and farnesol were prepared by ionic gelation and showed favorable characteristics for use on mucous membranes. They showed size variation and polydispersion index (PDI) after 30 days, but the efficiency of drug encapsulation was maintained. Regarding toxicity in cultured fibroblasts (BALB/c 3T3) the nanoparticles were considered nontoxic. The nanoparticles showed antifungal activity against the C. albicans strain used with MICs of 2.5 µg/ml and 2 µg/ml for nanoparticles containing miconazole or miconazole/farnesol, respectively. Nanoparticles containing farnesol inhibited yeast to hyphae transition at concentrations greater than or equal to 240 µM. The in vivo antifungal activity was assessed in the murine model for VVC. The results suggested that chitosan nanoparticles containing miconazole and farnesol were effective at inhibiting fungal proliferation. Additionally, chitosan nanoparticles containing farnesol were capable of decreasing the pathogenicity of infection, demonstrated through the absence of inflammation.
Assuntos
Candida albicans/efeitos dos fármacos , Candidíase Vulvovaginal/tratamento farmacológico , Farneseno Álcool , Miconazol , Nanopartículas/química , Animais , Antifúngicos/síntese química , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Células 3T3 BALB , Candida albicans/crescimento & desenvolvimento , Candidíase Vulvovaginal/patologia , Cápsulas , Quitosana/química , Modelos Animais de Doenças , Farneseno Álcool/química , Farneseno Álcool/farmacologia , Farneseno Álcool/uso terapêutico , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Miconazol/química , Miconazol/farmacologia , Miconazol/uso terapêutico , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Nanopartículas/uso terapêuticoRESUMO
OBJECTIVES: In this study, polymeric nanoparticles based on chitosan incorporating the antifungal miconazole nitrate were fabricated and testedin vivo using murine vulvovaginal candidiasis. METHODS: Nanoparticles prepared by the ionotropic gelation method presented 200 to 300 nm diameter and polydispersity indexes ranging from 0.2 to 0.4. The nanoparticles were prepared to incorporate 63.9 mg/mL of miconazole nitrate to be testedin vivo. Murine vulvovaginal candidiasis was standardized using estradiol valerate before the animals were challenged by Candida albicans. RESULTS: The treatment using chitosan nanoparticles within miconazole nitrate presented the same therapeutic efficacy as miconazole nitrate in a commercial cream formulation, however using the antifungal content about seven-fold lower. This increase in the miconazole nitrate's therapeutic efficacy is may be due to the down-regulation of interleukin 10 (IL-10) expression. CONCLUSIONS: Our data represent a proof of concept that can be exploited to achieve an alternative and promising therapy for the treatment of vulvovaginal candidiasis.
Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candidíase Vulvovaginal/tratamento farmacológico , Quitosana/química , Miconazol/farmacologia , Nanopartículas/administração & dosagem , Administração Intravaginal , Animais , Antifúngicos/química , Candidíase Vulvovaginal/microbiologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Miconazol/química , Nanopartículas/químicaRESUMO
Oropharyngeal candidiasis is a recurrent oral infection caused by Candida species. Gel formulation containing miconazole nitrate is the most common approach for treating oral candidiasis. However, traditional oral topical antifungal therapies have many limitations, including short contact time with the oral mucosa and the necessity to administrate various doses per day. Thus, the aim of this work was to formulate composited microparticulated systems based on combinations of mucoadhesive cationic, anionic, and nonionic polymers that could protect and modify the drug release rate and therefore avoid a fast dilution of the drug by saliva. Microparticulated systems were prepared by the spray drying method employing chitosan, gelatin, and hydroxypropyl methylcellulose. The morphology of the systems was investigated by scanning electron microscopy; drug crystallinity was studied by X-ray, while interactions between polymers were analyzed by infrared spectroscopy. Drug release and halo zone test were employed to analyze the release and activity of the systems loaded with miconazole against Candida albicans cultures. The most appropriate microparticulated system was the one based on chitosan and gelatin which showed homogeneous morphology (mean size of 1.7 ± 0.5 µm), a protective effect of the drug, and better antifungal effect against Candida culture than miconazole nitrate and the other assayed systems. Taking into account these results, this approach should be seriously considered for further evaluation of its safety and in vivo efficacy to be considered as an alternative therapeutic system for the treatment of oral candidiasis.