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Over the past decade, topically applied drug products have experienced extraordinary price increases, due to the shortage of multisource generic drug products. This occurrence is mainly related to the underlying challenges evolved in topical bioequivalence documentation. Although there has been continuing regulatory efforts to present surrogate in vitro methods to clinical endpoint studies, there is still a continued need for cost- and time-efficient alternatives that account for product specificities. Hence, this work intended to expose bioequivalence assessment issues for complex topical formulations, and more specifically those related with product efficacy guidance. As a model drug and product, a bifonazole 10 mg/g cream formulation was selected and two different batches of the commercially available Reference Product (RP) were used: RP1 that displayed lower viscosity and RP4 which presented high, but not the highest, viscosity. In vitro human skin permeation testing (IVPT) was carried out and the results were evaluated by means of the traditional bioequivalence assessment approach proposed by the EMA, as well as by the Scaled Average Bioequivalence assessment approach proposed by the FDA. Based on previous experience, there was an expectation of a high level of variability in the results, thus alternative methods to evaluate local drug skin availability were developed. More specifically, an infected skin disease model, where ex vivo human skin was infected and ATP levels were used as a biological marker for monitoring antifungal activity after product application. The results showed that permeation equivalence could not be supported between the different RP batches. In contrast, this statistical difference between the formulation batches was not indicated in the disease model. Nevertheless, in pivotal IVPT studies, the lowest permeant formulation (RP4) evidenced a higher antifungal in vitro activity as reported by the lower levels of ATP. A critical appraisal of the results is likewise presented, focusing on an outlook of the real applicability of the regulatory guidances on this subject.
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Antifúngicos , Absorção Cutânea , Pele , Equivalência Terapêutica , Humanos , Antifúngicos/farmacocinética , Antifúngicos/administração & dosagem , Pele/metabolismo , Administração Cutânea , Viscosidade , Técnicas In Vitro , Creme para a Pele/farmacocinética , Creme para a Pele/administração & dosagemRESUMO
The COVID-19 pandemic exposes our vulnerability to viruses that acquire the ability to infect our cells. Classical disinfection methods are limited by toxicity. Existing medicines performed poorly against SARS-CoV-2 because of their specificity to targets in different organisms. We address the challenge of mitigating known and prospective viral infections with a new photosensitizer for antimicrobial photodynamic therapy (aPDT). Photodynamic inactivation is based on local oxidative stress, which is particularly damaging to enveloped viruses. We synthesized a cationic imidazolyl chlorin that reduced by > 99.999% of the percentage inhibition of amplification of SARS-CoV-2 collected from patients at 0.2 µM concentration and 4 J cm-2. Similar results were obtained in the prevention of infection of human ACE2-expressing HEK293T cells by a pseudotyped lentiviral vector exhibiting the S protein of SARS-CoV-2 at its surface. No toxicity to human epidermal keratinocytes (HaCaT) cells was found under similar conditions. aPDT with this chlorin offers fast and safe broad-spectrum photodisinfection and can be repeated with low risk of resistance.
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Anti-Infecciosos , Fotoquimioterapia , Humanos , Fármacos Fotossensibilizantes/química , Desinfecção , Pandemias , Células HEK293 , Estudos Prospectivos , Fotoquimioterapia/métodos , SARS-CoV-2 , Antivirais/farmacologiaRESUMO
Nitrosoalkenes react with 8-methyl-1,6-dihydropyrrolo[3,2-c]carbazole to give both 2- and 3-alkylated products via hetero-Diels-Alder reaction followed by the cycloadduct ring-opening. Quantum chemical calculations, at DFT level of theory, were carried out to investigate the regioselectivity of the cycloaddition of ethyl nitrosoacrylate with 1,6-dihydropyrrolo[3,2-c]carbazoles as well as with pyrrole and indole, allowing a more comprehensive analysis of the reactivity pattern of nitrosoalkenes with five-membered heterocycles. Furthermore, theoretical calculations confirmed that ethyl nitrosoacrylate reacts with these heterocycles via a LUMOheterodiene-HOMOdienophile controlled cycloaddition. The reactivity of one of the oxime-functionalized 1,6-dihydropyrrolo[3,2-c]carbazole was explored and a new hexahydropyrido[4',3':4,5]pyrrolo[3,2-c]carbazole system was obtained in high yield via a one-pot, two-step procedure.
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A new fluorinated manganese porphyrin, (Mn-TPP-p-CF3 ) is reported capable of providing, based on the Mn(III)/Mn(II) equilibrium, dual 1 H relaxivity and 19 Fâ NMR response to redox changes. The physical-chemical characterization of both redox states in DMSO-d6 /H2 O evidenced that the 1 H relaxometric and 19 Fâ NMR properties are appropriate for differential redox MRI detection. The Mn(III)-F distance (dMn-F =9.7-10â Å), as assessed by DFT calculations, is well tailored to allow for adequate paramagnetic effect of Mn(III) on 19 F T1 and T2 relaxation times. Mn-TPP-p-CF3 has a reversible Mn(II)/Mn(III) redox potential of 0.574â V vs. NHE in deoxygenated aqueous HEPES/ THF solution. The reduction of Mn(III)-TPP-p-CF3 in the presence of ascorbic acid is slowly, but fully reversed in the presence of air oxygen, as monitored by UV-Vis spectrometry and 19 Fâ NMR. The broad 1 H and 19 Fâ NMR signals of Mn(III)-TPP-p-CF3 disappear in the presence of 1â equivalent ascorbate replaced by a shifted and broadened 19 Fâ NMR signal from Mn(II)-TPP-p-CF3 . Phantom 19 F MR images in DMSO show a MRI signal intensity decrease upon reduction of Mn(III)-TPP-p-CF3 , retrieved upon complete reoxidation in air within ~24â h. 1 Hâ NMRD curves of the Mn(III)/(II)-TPP-p-CF3 chelates in mixed DMSO/water solvent have the typical shape of Mn(II)/Mn(III) porphyrins.
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In recent years, the regulatory mechanisms for topical generic product bioequivalence (BE) assessment have been subjected to noteworthy changes, with the FDA issuing product specific guidances, and the EMA adopting a more universal approach with the quality and equivalence of topical products draft guideline. The agencies advise on a modular strategy for BE documentation. Nevertheless, their scope, data analysis and criteria are rather distinct. This study aims to tackle bioequivalence assessment issues of complex topical formulations starting by statistical implications of the EMA/FDA approaches concerning the documentation of qualitative (Q1), quantitative (Q2), microstructure (Q3) and performance requirements (Q4). As a model drug product, a bifonazole 10 mg/g cream formulation was selected. For this specific formulation, the commercially available Reference Product (RP) was compared with two comparator products, also commercially available, referred to as comparator product A (CPA) and comparator product B (CPB). The former displays Q1 sameness and Q2 differences, whilst CPB is categorically considered as Q1/Q2 different. Furthermore, intending to establish a regulatory rationale for the submission of a generic product according to the updated regulatory requirements, the RP was likewise compared with a Test Product (TP). This formulation was designed to display equal Q1/Q2 profile to that of the RP. Validated rheology and in vitro release test (IVRT) methods were used to infer on Q3/Q4 characteristics. During rheology studies, statistically significant RP batch to batch differences were observed. Therefore, in an attempt to surpass this heterogeneity, the initial pool of RP batches was expanded to include RP product batches at different lifecycle stages. Despite this effort, it was not possible to classify the RP/TP, RP/CPA or RP/CPB as rheologically equivalent products. Nevertheless, product performance results, retrieved from IVRT, were able to sustain equivalence between the RP and the formulations exhibiting Q1 sameness (TP and CPA). It should however be mentioned, that for some RP batch combinations, the IVRT results failed to demonstrate equivalence according to the EMA requirements. Enlarging the RP batch pool was then a critical step in further understanding an optimum statistical approach for establishing equivalence in product performance. This study highlights the need to that a 'one-fits-all approach' may not be an optimum path way for establishing the regulatory strategy and requirements to support generic product bioequivalence.
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Antifúngicos , Medicamentos Genéricos , Equivalência Terapêutica , Medicamentos Genéricos/química , Técnicas In Vitro , ReologiaRESUMO
Details on the unexpected formation of two new (dimethylamino)methyl corrole isomers from the reaction of 5,10,15-tris(pentafluorophenyl)corrolatogallium(III) with sarcosine and paraformaldehyde are presented. Semi-empirical calculations on possible mechanism pathways seem to indicate that the new compounds are probably formed through a Mannich-type reaction. The extension of the protocol to the free-base 5,10,15-tris(pentafluorophenyl)corrole afforded an unexpected new seven-membered ring corrole derivative, confirming the peculiar behavior of corroles towards known reactions when compared to the well-behaved porphyrin counterparts.
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Porfirinas , Sarcosina , Porfirinas/química , IsomerismoRESUMO
BACKGROUND: Multiple sclerosis is an inflammatory and degenerative disease of the central nervous system (CNS) characterized by demyelination and concomitant axonal loss. The lack of a single specific test, and the similarity to other inflammatory diseases of the central nervous system, makes it difficult to have a clear diagnosis of multiple sclerosis. Therefore, laboratory tests that allows a clear and definite diagnosis, as well as to predict the different clinical courses of the disease are of utmost importance. Herein, we compared the cerebrospinal fluid (CSF) proteome of patients with multiple sclerosis (in the relapse-remitting phase of the disease) and other diseases of the CNS (inflammatory and non-inflammatory) aiming at identifying reliable biomarkers of multiple sclerosis. METHODS: CSF samples from the discovery group were resolved by 2D-gel electrophoresis followed by identification of the protein spots by mass spectrometry. The results were analyzed using univariate (Student's t test) and multivariate (Hierarchical Cluster Analysis, Principal Component Analysis, Linear Discriminant Analysis) statistical and numerical techniques, to identify a set of protein spots that were differentially expressed in CSF samples from patients with multiple sclerosis when compared with other two groups. Validation of the results was performed in samples from a different set of patients using quantitative (e.g., ELISA) and semi-quantitative (e.g., Western Blot) experimental approaches. RESULTS: Analysis of the 2D-gels showed 13 protein spots that were differentially expressed in the three groups of patients: Alpha-1-antichymotrypsin, Prostaglandin-H2-isomerase, Retinol binding protein 4, Transthyretin (TTR), Apolipoprotein E, Gelsolin, Angiotensinogen, Agrin, Serum albumin, Myosin-15, Apolipoprotein B-100 and EF-hand calcium-binding domain-containing protein. ELISA experiments allowed validating part of the results obtained in the proteomics analysis and showed that some of the alterations in the CSF proteome are also mirrored in serum samples from multiple sclerosis patients. CSF of multiple sclerosis patients was characterized by TTR oligomerization, thus highlighting the importance of analyzing posttranslational modifications of the proteome in the identification of novel biomarkers of the disease. CONCLUSIONS: The model built based on the results obtained upon analysis of the 2D-gels and in the validation phase attained an accuracy of about 80% in distinguishing multiple sclerosis patients and the other two groups.
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Esclerose Múltipla , Biomarcadores/líquido cefalorraquidiano , Eletroforese em Gel Bidimensional , Humanos , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico , Processamento de Proteína Pós-Traducional , Proteoma/análiseRESUMO
Fluorescence EEM spectra provide the "fingerprint" of water contamination and is a very efficient way to access the quality of water bodies. These multivariate datasets correspond to complex mixtures and are very rich in information. Graphical approaches have been used for decades to characterize and quantify different contamination sources. It is very important to resolve mixed signals in raw EEM spectra in terms of signal sources and respective composition profiles - signal sources allow the identification of contamination type, while concentration profiles quantify the respective contribution inside the mixtures. In order to be able to use robust modeling algorithms, the first task is to accurately estimate the number of contributions that are present. We demonstrate the ability of Singular value Decomposition (SVD) in accessing this information content in raw EEM datasets. To decompose raw EEM information, several algorithms are tested: PARAFAC, MCR-ALS and ICA. In this work we suggest a systematic unsupervised algorithm to process raw EEM spectra of water samples.
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Poluentes Químicos da Água , Água , Espectrometria de Fluorescência , Poluentes Químicos da Água/análiseRESUMO
The large-scale use of pesticides is one of the main causes of the dramatic degradation of our environment. Pesticides such as imidacloprid (IMID) have been linked to declines in bee health and toxicity to other beneficial insects. They pose a threat to human health due to their persistence in the environment and accumulation in the food chain. Therefore, it is essential to test possible environmentally-friendly solutions for their elimination. The present study evaluates the efficiency of microalgae Nannochloropsis sp. for the removal of IMID from synthetic wastewater. The influence of aeration, light, and the presence of UV radiation on the degradation of IMID were factors considered in the study. A rapid RP-HPLC method was developed and validated for the analysis and quantification of IMID in the context of bioremediation with microalgae. Nannochloropsis sp. removed 4.39 µg mL-1 from an initial content of 9.59 µg mL-1 (reaching approximately 50%) of IMID in the first 20 h. This study demonstrated that the removal of IMID by the marine microalgae Nannochloropsis sp. is both effective and light-dependent.
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Microalgas , Estramenópilas , Animais , Abelhas , Cromatografia Líquida de Alta Pressão , Neonicotinoides , Nitrocompostos , Águas Residuárias , ÁguaRESUMO
Pesticides are widely used in agriculture to increase and protect crop production. A substantial percentage of the active substances applied is retained in the soil or flows into water courses, constituting a very relevant environmental problem. There are several methods for the removal of pesticides from soils and water; however, their efficiency is still a challenge. An alternative to current methods relies on the use of effective adsorbents in removing pesticides which are, simultaneously, capable of releasing pesticides into the soil when needed. This reduces costs related to their application and waste treatments and, thus, overall environmental costs. In this paper, we describe the synthesis and preparation of activated carbon-containing poly(ß-cyclodextrin) composites. The composites were characterized by different techniques and their ability to absorb pesticides was assessed by using two active substances: cymoxanil and imidacloprid. Composites with 5 and 10 wt% of activated carbon showed very good stability, high removal efficiencies (>75%) and pesticide sorption capacity up to ca. 50 mg g-1. The effect of additives (NaCl and urea) was also evaluated. The composites were able to release around 30% of the initial sorbed amount of pesticide without losing the capacity to keep the maximum removal efficiency in sorption/desorption cycles.
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Carvão Vegetal/química , Géis/química , Praguicidas/análise , Praguicidas/isolamento & purificação , Propilenoglicóis/química , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/isolamento & purificação , beta-Ciclodextrinas/químicaRESUMO
In 2004, the Food and Drug Administration established the foundations for the application of process analytical technologies (PAT) in real-time control of the drug manufacturing process, where progress has been essentially directed to solid formulations. In order to enlarge the application of PAT principles to injectable drug products, the development of appropriate manufacturing process control tools is mandatory. Photoacoustics is a non-invasive technique with the potential for application in real-time control of the manufacturing process of injectable drug products. Herein, we applied a photoacoustic method for the determination of the concentration of salts (sodium chloride) in mono-salt formulations by measuring the changes induced in the speed of sound by density changes. This method was explored using two modes of generating the photoacoustic wave and two detectors with central frequencies of 10 MHz and 100 MHz. The results were analyzed using a 2k full-factorial design, considering the generation mode and detection as independent variables. The optimized method was subsequently validated according to the International Council for Harmonisation (ICH) standards. The method showed good linearity, precision, and accuracy, with a lower limit of quantification of 0.05% (w/v) of NaCl and a limit of detection of 0.02% (w/v) of NaCl. Due to its simplicity and high throughput, this method has potential applicability as PAT in the manufacturing of injectable drug products.
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A rapid reverse phase high-performance liquid chromatography (RP-HPLC) method was developed and validated for the simultaneous quantification of paracetamol, ibuprofen, olanzapine, simvastatin and simvastatin acid in the context of microalgae bioremediation. The method was validated according to the guidelines of the US Food and Drug Administration (FDA), the International Conference on Harmonization (ICH), and Eurachem with respect to system suitability, linearity, accuracy, precision, recovery, limits of detection and quantification, ruggedness, selectivity and specificity. The estimated limits of detection and quantification were, respectively, 0.03 and 0.10 µg mL-1 for paracetamol, 0.03 and 0.09 µg mL-1 for ibuprofen, 0.04 and 0.13 µg mL-1 for olanzapine, 0.27 and 0.83 µg mL-1 for simvastantin, and 0.05 and 0.14 µg mL-1 for simvastantin acid. The inter-day and intra-day precision results were within the acceptance limit of relative standard deviation (%RSD) of less than 2, and the percentage recovery was found to be within the required limits of 80-110%. The developed method is rapid, linear, precise, robust and accurate, and has been successfully applied to the determination of the above common pharmaceutical products during microalgae bioremediation.
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PURPOSE: Following the recent European Medicine Agency (EMA) draft guideline on quality and equivalence of topical products, a modular framework for bioequivalence assessment is proposed, wherein the qualitative, quantitative, microstructure and product performance sameness is demanded to support generic applications. Strict regulatory limits are now imposed, but, the suitability of these limits has been subject of intense debate. In this context, this paper aims to address these issues by characterizing a panel of 8 reference blockbuster semisolid topical products. METHODS: For each product, three batches were selected and, whenever possible, batches retrieved from different manufacturing sites were considered. Product microstructure was evaluated in terms of globule size, pH, rheological attributes and, if required, the thermal behaviour was also assessed. Performance was evaluated through in vitro release testing (IVRT). Finally, an integrated multivariate analysis was performed to highlight the features that most contribute for product variability. RESULTS: Marked differences were registered within reference products. Statistical analysis demonstrated that if EMA criteria are applied, none of the same product batches can be considered as equivalent. Rheological parameters as well as IVRT indicators account for the majority of batch-to-batch differences. CONCLUSIONS: Semisolid dosage forms exhibit intrinsic variability. This calls for the attention to the need of establishing reasonable equivalence criteria applied to generic drug products. Graphical abstract.
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Aprovação de Drogas , Medicamentos Genéricos/análise , Tecnologia Farmacêutica , Administração Tópica , Formas de Dosagem , Medicamentos Genéricos/administração & dosagem , Medicamentos Genéricos/normas , Controle de Qualidade , Equivalência TerapêuticaRESUMO
Pharmaceuticals and their metabolites are released into the environment by domestic, hospital, and pharmaceutical industry wastewaters. Conventional wastewater treatment technology does not guarantee effluents of high quality, and apparently clean water may be loaded with pollutants. In this study, we assess the performance and efficiency of free and immobilised cells of microalgae Nannochloropsis sp. in removing four pharmaceuticals, chosen for their occurrence or persistence in the environment. These are paracetamol, ibuprofen, olanzapine and simvastatin. The results showed that free microalgae cells remain alive for a longer time than the immobilised ones, suggesting the inhibition of cell proliferation by the polymeric matrix polyvinyl alcohol. Both cells, free and immobilised, respond differently to each pharmaceutical. The removal of paracetamol and ibuprofen by Nannochloropsis sp., after 24 h of culture, was significantly higher in immobilised cells. Free cells removed a significantly higher concentration of olanzapine than immobilised ones, suggesting a higher affinity to this molecule than to paracetamol and ibuprofen. The results demonstrate the effectiveness of Nannochloropsis sp. free cells for removing olanzapine and Nannochloropsis sp. immobilised cells for removing paracetamol and ibuprofen.
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Biodegradação Ambiental , Microalgas/metabolismo , Preparações Farmacêuticas/metabolismo , Poluentes Químicos da Água/metabolismo , Acetaminofen/metabolismo , Células Imobilizadas/química , Células Imobilizadas/metabolismo , Disruptores Endócrinos/metabolismo , Ibuprofeno/metabolismo , Microalgas/química , Microalgas/crescimento & desenvolvimento , Preparações Farmacêuticas/química , Álcool de Polivinil/química , Sinvastatina/metabolismo , Poluentes Químicos da Água/químicaRESUMO
The interaction between polyelectrolytes and metal ions is governed by different types of interactions, leading to the formation of different phases, from liquid state to weak gels, through an appropriate choice of metal ion/polyelectrolyte molar ratio. We have found that lanthanide ions, europium(III) and terbium(III), are able to form polymer composites with poly(sodium acrylate). That interaction enhances the luminescent properties of europium(III) and terbium(III), showing that Eu3+/poly(sodium acrylate) (PSA) and Tb3+/PSA composites have a highly intense red and green emission, respectively. The effect of cations with different valences on the luminescent properties of the polymer composites is analyzed. The presence of metal ions tends to quench the composite emission intensity and the quenching process depends on the cation, with copper(II) being by far the most efficient quencher. The interaction mechanism between lanthanoid ions and PSA is also discussed. The composites and their interactions with a wide range of cations and anions are fully characterized through stationary and non-stationary fluorescence, high resolution scanning electronic microscopy and X-ray diffraction.
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Gram-negative bacteria and bacteria in biofilms are very difficult to eradicate and are the most antibiotic-resistant bacteria. Therapeutic alternatives less susceptible to mechanisms of resistance are urgently needed to respond to an alarming increase of resistant nosocomial infections. Antibacterial photodynamic inactivation (PDI) generates oxidative stress that triggers multiple cell death mechanisms that are more difficult to counteract by bacteria. We explore PDI of multidrug-resistant bacterial strains collected from patients and show how positive charge distribution in the photosensitizer drug impacts the efficacy of inactivation. We demonstrate the relevance of size for drug diffusion in biofilms. The designed meso-imidazolyl porphyrins of small size with positive charges surrounding the macrocycle enabled the inactivation of bacteria in biofilms by 6.9 log units at 5 nM photosensitizer concentration and 5 J cm-2, which offers new opportunities to treat biofilm infections.
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Fotoquimioterapia , Fármacos Fotossensibilizantes , Antibacterianos/farmacologia , Bactérias , Biofilmes , Humanos , Fármacos Fotossensibilizantes/farmacologiaRESUMO
The EMA draft guideline on quality and equivalence of topical products and the FDA non-binding product specific guidances release has encouraged the establishment of a regulatory background for in vitro release testing (IVRT). Herein, a novel framework applicable to the development of a discriminatory IVRT method is described, according to analytical quality by design (aQbD) principles. A commercially available diclofenac emulgel formulation was used as model product. Through the definition of IVRT analytical target profile, a risk assessment analysis was carried out, in which the critical analytical attributes (in vitro release rate, cumulative amount released at an initial/final point and dose depletion) and critical method variables (medium, membrane and dosage regimen) were identified. Based on this information, a 3â¯×â¯2â¯×â¯3 full factorial design was performed. Statistical modeling and system desirability assessment enabled the selection of the most suitable IVRT parameters, which were fully validated according with new EMA requirements. These consisted of PBS:Ethanol (80:20, pHâ¯=â¯7.4), Tuffryn membranes and 300â¯mg of applied product. aQbD provided a comprehensive framework for developing a reliable and effective IVRT method. A thorough analysis of the new EMA draft guideline requirements revealed that some of the established criteria may be challenging to attain.
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Química Farmacêutica/métodos , Liberação Controlada de Fármacos , Administração Tópica , Diclofenaco/química , Emulsões , Géis , Legislação de MedicamentosRESUMO
Aerosol antibiotics are an interesting alternative to oral or intravenous therapy in Cystic Fibrosis lung infections. Levofloxacin (LVX) inhaled solution is already an effective option. In this study, the aim was the development of LVX-loaded PLGA microspheres (MS) for pulmonary administration as a dry powder. MS were prepared, for the first time, by a modified double emulsion solvent evaporation method with premix membrane homogenization. Aqueous phases were saturated with LVX and a fatty acid (lauric acid) was added to avoid the drug escaping from the organic phase. MS were characterized in terms of size, drug content, morphology and in vitro release properties. X-ray diffraction, Fourier-transform infrared spectroscopy, differential and gravimetric thermal analysis, and cytotoxicity analyses were performed. Results showed this new method increased the drug loading while maintaining an adequate (â¼5⯵m) particle size and controlled release. Compared to a solution for inhalation, these properties combined with the dry-powder nature of these MS will improve patient compliance. The incorporation of lauric acid was not advantageous because the particle size was higher and no improvements concerning the sustained release occurred. LVX was molecularly dispersed in the matrix, or it was in amorphous state, as confirmed by the physico-chemical analyses. Calu-3 cell viability assays demonstrated no cytotoxicity for these MS, making them a promising system for LVX pulmonary delivery.
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Antibacterianos/administração & dosagem , Levofloxacino/administração & dosagem , Microesferas , Antibacterianos/química , Antibacterianos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica/métodos , Preparações de Ação Retardada , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Inaladores de Pó Seco , Humanos , Ácidos Láuricos/química , Levofloxacino/química , Levofloxacino/toxicidade , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Solventes/químicaRESUMO
Cyclodextrins (Cds) are versatile carbohydrate hosts for developing multifunctional nanostructures of pharmaceutical interest. Factors affecting the thermodynamic signatures and stability of ß- and γ-Cd complexes are detailed at the atomic level. The MD/PMF-based method is combined with the description of the nature and strength of the inter-partner affinity. Naphthalene, adamantane and lycorine derivatives are used as models of drug-leading structures. Guest size affects Cd-guest contact and the inclusion degree, inducing Cd deformation, which opposes inclusion. Complexation depends on the available Cd cavity volume, as guest fitting variations and the enthalpy penalty from Cd deformation impact on the binding constants (promoting a reduction of up to 104). The often neglected Cd deformation plays, thus, an important role in the interaction behavior of larger cavity Cd-based systems, being crucial in carbohydrate-mediated recognition phenomena. It corresponds to an increase in energy of ca. 90â¯kJâ¯mol-1 in the simpler analyzed model system.
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Computational Chemistry is currently a synergistic assembly between ab initio calculations, simulation, machine learning (ML) and optimization strategies for describing, solving and predicting chemical data and related phenomena. These include accelerated literature searches, analysis and prediction of physical and quantum chemical properties, transition states, chemical structures, chemical reactions, and also new catalysts and drug candidates. The generalization of scalability to larger chemical problems, rather than specialization, is now the main principle for transforming chemical tasks in multiple fronts, for which systematic and cost-effective solutions have benefited from ML approaches, including those based on deep learning (e.g. quantum chemistry, molecular screening, synthetic route design, catalysis, drug discovery). The latter class of ML algorithms is capable of combining raw input into layers of intermediate features, enabling bench-to-bytes designs with the potential to transform several chemical domains. In this review, the most exciting developments concerning the use of ML in a range of different chemical scenarios are described. A range of different chemical problems and respective rationalization, that have hitherto been inaccessible due to the lack of suitable analysis tools, is thus detailed, evidencing the breadth of potential applications of these emerging multidimensional approaches. Focus is given to the models, algorithms and methods proposed to facilitate research on compound design and synthesis, materials design, prediction of binding, molecular activity, and soft matter behavior. The information produced by pairing Chemistry and ML, through data-driven analyses, neural network predictions and monitoring of chemical systems, allows (i) prompting the ability to understand the complexity of chemical data, (ii) streamlining and designing experiments, (ii) discovering new molecular targets and materials, and also (iv) planning or rethinking forthcoming chemical challenges. In fact, optimization engulfs all these tasks directly.