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In the last few years, twin-screw wet granulation (TSWG) has become one of the key continuous pharmaceutical unit operations. Despite the many studies that have been performed, only little is known about the effect of the starting material properties on the stepwise granule formation along the length of the twin-screw granulator (TSG) barrel. Hence, this study obtained a detailed understanding of the effect of formulation properties (i.e., Active Pharmaceutical Ingredient (API) properties, formulation blend particle size distribution and formulation drug load) and process settings on granule formation in TSWG. An experimental set-up was used allowing the collection of granules at the different TSG compartments. Granules were characterized in terms of granule size, shape, binder liquid and API distributions. Liquid-to-solid (L/S) ratio was the only TSG process parameter impacting the granule size and shape evolution. Particle size and flow properties (e.g., flow rate index) had an important effect on the granule size and shape changes whereas water-related properties (e.g., water binding capacity and solubility) became influential at the last TSG compartments. The API solubility and L/S ratio were found to have a major impact on the distribution of binder liquid over the different granule size fractions. In the first TSG compartment (i.e., wetting compartment), the distribution of the API in the granules was influenced by its solubility in the granulation liquid.
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Tornillos Óseos , Agua , Solubilidad , Tamaño de la Partícula , Humectabilidad , Composición de Medicamentos , Tecnología FarmacéuticaRESUMEN
Twin-screw wet granulation (TSWG) stands out as a promising continuous alternative to conventional batch fluid bed- and high shear wet granulation techniques. Despite its potential, the impact of raw material properties on TSWG processability remains inadequately explored. Furthermore, the absence of supportive models for TSWG process development with new active pharmaceutical ingredients (APIs) adds to the challenge. This study tackles these gaps by introducing four partial least squares (PLS) models that approximate both the applicable liquid-to-solid (L/S) ratio range and resulting granule attributes (i.e., granule size and friability) based on initial material properties. The first two PLS models link the lowest and highest applicable L/S ratio for TSWG, respectively, with the formulation blend properties. The third and fourth PLS models predict the granule size and friability, respectively, from the starting API properties and applied L/S ratio for twin-screw wet granulation. By analysing the developed PLS models, water-related material properties (e.g., solubility, wettability, dissolution rate), as well as density and flow-related properties (e.g., flow function coefficient), were found to be impacting the TSWG processability. In addition, the applicability of the developed PLS models was evaluated by using them to propose suitable L/S ratio ranges (i.e., resulting in granules with the desired properties) for three new APIs and related formulations followed by an experimental validation thereof. Overall, this study helped to better understand the effect of raw material properties upon TSWG processability. Moreover, the developed PLS models can be used to propose suitable TSWG process settings for new APIs and hence reduce the experimental effort during process development.
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Tornillos Óseos , Tecnología Farmacéutica , Tamaño de la Partícula , Solubilidad , Humectabilidad , Composición de Medicamentos/métodos , Tecnología Farmacéutica/métodos , ComprimidosRESUMEN
The aim of this study was to develop antisense oligonucleotide tablet formulations using high-speed electrospinning. Hydroxypropyl-beta-cyclodextrin (HPßCD) was used as a stabilizer and as an electrospinning matrix. In order to optimize the morphology of the fibers, electrospinning of various formulations was carried out using water, methanol/water (1:1), and methanol as solvents. The results showed that using methanol could be advantageous due to the lower viscosity threshold for fiber formation enabling higher potential drug loadings by using less excipient. To increase the productivity of electrospinning, high-speed electrospinning technology was utilized and HPßCD fibers containing 9.1% antisense oligonucleotide were prepared at a rate of ~330 g/h. Furthermore, to increase the drug content of the fibers, a formulation with a 50% drug loading was developed. The fibers had excellent grindability but poor flowability. The ground fibrous powder was mixed with excipients to improve its flowability, which enabled the automatic tableting of the mixture by direct compression. The fibrous HPßCD-antisense oligonucleotide formulations showed no sign of physical or chemical degradation over the 1-year stability study, which also shows the suitability of the HPßCD matrix for the formulation of biopharmaceuticals. The obtained results demonstrate possible solutions for the challenges of electrospinning such as scale-up and downstream processing of the fibers.
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The present paper reports the powder filling of milled electrospun materials in vials, which contained voriconazole and sulfobutylether-ß-cyclodextrin. High-speed electrospinning was used for the production of the fibrous sample, which was divided into 6 parts. Each portion was milled using different milling methods and sizes of sieves to investigate whether the milling influences the powder and filling properties. Bulk and tapped density tests, laser diffraction and angle of repose measurements were applied to characterize the milled powders, while a vibratory feeder was used for the feeding experiments. The correlation between the material property descriptors and the feeding responses was investigated by multivariate data analysis. Based on the results, three samples were chosen for the vial filling, which was accomplished with 3400 mg electrospun material containing 200 mg voriconazole, representative of the commercial product. The feed rate was set to fit the 240 g/h production rate of the electrospinning and the relative standard deviation of three repeated vial filling was determined to see the accuracy of the process. This research shows that by applying a suitable milling method it is possible to process electrospun fibers to a powder, which can be filled into vials and used as reconstitution dosage forms.
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Emolientes , Tecnología Farmacéutica , Polvos , Prueba de Estudio Conceptual , VoriconazolRESUMEN
Electrospinning is a technology for manufacture of nano- and micro-sized fibers, which can enhance the dissolution properties of poorly water-soluble drugs. Tableting of electrospun fibers have been demonstrated in several studies, however, continuous manufacturing of tablets have not been realized yet. This research presents the first integrated continuous processing of milled drug-loaded electrospun materials to tablet form supplemented by process analytical tools for monitoring the active pharmaceutical ingredient (API) content. Electrospun fibers of an amorphous solid dispersion (ASD) of itraconazole and poly(vinylpyrrolidone-co-vinyl acetate) were produced using high speed electrospinning and afterwards milled. The milled fibers with an average fiber diameter of 1.6 ± 0.9 µm were continuously fed with a vibratory feeder into a twin-screw blender, which was integrated with a tableting machine to prepare tablets with ~ 10 kN compression force. The blend of fibers and excipients leaving the continuous blender was characterized with a bulk density of 0.43 g/cm3 and proved to be suitable for direct tablet compression. The ASD content, and thus the API content was determined in-line before tableting and at-line after tableting using near-infrared and Raman spectroscopy. The prepared tablets fulfilled the USP <905> content uniformity requirement based on the API content of ten randomly selected tablets. This work highlights that combining the advantages of electrospinning (e.g. less solvent, fast and gentle drying, low energy consumption, and amorphous products with high specific surface area) and the continuous technologies opens a new and effective way in the field of manufacturing of the poorly water-soluble APIs.
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Excipientes , Espectrometría Raman , Desecación , Composición de Medicamentos , Itraconazol , Comprimidos , Tecnología FarmacéuticaRESUMEN
Despite significant advances in the research domain of continuous twin screw granulation, limited information is currently available on the impact of raw material properties, especially considering batch-to-batch variability. The importance of raw material variability and subsequent mitigation of the impact of this variability on the manufacturing process and drug product was recently stressed in the Draft Guidance for Industry on Quality Considerations for Continuous Manufacturing by the U.S. Food and Drug Administration (FDA). Therefore, this study assessed the impact of microcrystalline cellulose (MCC) batch-to-batch variability and process settings in a continuous twin screw wet granulation and semi-continuous drying line. Based on extensive raw material characterization and subsequent principal component analysis, raw material variability was quantitatively introduced in the design of experiments approach by means of t1 and t2 scores. L/S ratio had a larger effect on critical granule attributes and processability than screw speed and drying time. A large impact of the t1 and t2 scores was found, indicating the importance of raw material attributes. For the studied formulation, it was concluded that MCC batches with a low water binding capacity, low moisture content and high bulk density generated granules with the most desirable quality attributes. Additionally, an innovative and quantitative approach towards mitigating batch-to-batch variability of raw materials was proposed, which is also applicable for additional excipients and APIs.
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Solid formulations of monoclonal antibodies present several advantages, such as improved stability and increased shelf-life as well as simpler storage and transportation. In this study, we present a gentle drying technology for monoclonal antibodies, applying the water soluble 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) as matrix, to prepare a solid reconstitution dosage form. High-speed electrospinning of an aqueous infliximab-containing HP-ß-CD solution was carried out at 25 °C resulting in fibers with an average diameter of 2.5 µm. The mAb-loaded electrospun fibers were successful to preserve the stability of infliximab in solid form. The results of size exclusion chromatography and gel electrophoresis indicated no significant increase in aggregate formation during the electrospinning process compared to the initial matrix solution. The binding activity of infliximab was preserved during electrospinning compared to the reference liquid formulation. Due to the enhanced surface area, excellent reconstitution capability, i.e. clear solution within 2 min without any vigorous mixing, could be achieved in a small-scale reconstitution test. The results of this work demonstrate that high-speed electrospinning is a very promising technique to manufacture the solid formulation of monoclonal antibodies for applications such as fast reconstitutable powders.
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Anticuerpos Monoclonales , Desecación , 2-Hidroxipropil-beta-Ciclodextrina , Polvos , Solubilidad , AguaRESUMEN
A model anaerobic bacterium strain from the gut microbiome (Clostridium butyricum) producing anti-inflammatory molecules was incorporated into polymer-free fibers of a water-soluble cyclodextrin matrix (HP-ß-CD) using a promising scaled-up nanotechnology, high-speed electrospinning. A long-term stability study was also carried out on the bacteria in the fibers. Effect of storage conditions (temperature, presence of oxygen) and growth conditions on the bacterial viability in the fibers was investigated. The viability of the sporulated anaerobic bacteria in the fibers was maintained during 12 months of room temperature storage in the presence of oxygen. Direct compression was used to prepare tablets from the produced bacteria-containing fibers after milling (using an oscillating mill) and mixing with tableting excipients, making easy oral administration of the bacteria possible. No significant decrease was observed in bacterial viability following the processing of the fibers (milling and tableting).
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Bacterias Anaerobias/aislamiento & purificación , Clostridium butyricum/aislamiento & purificación , Composición de Medicamentos , Microbioma Gastrointestinal , Anaerobiosis , Bacterias Anaerobias/genética , Clostridium butyricum/genética , Excipientes , Humanos , Filogenia , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN , Comprimidos , TemperaturaRESUMEN
In recent years, significant progress has been made in the field of continuous twin screw granulation. However, only limited knowledge is currently available on the impact of active pharmaceutical ingredient (API) properties on granule quality and processability. In this study, the response behavior of four formulations containing APIs (5-10% drug load) with diverse characteristics was compared to the behavior of the corresponding placebo formulation consisting of lactose, microcrystalline cellulose (MCC) and hydroxypropylmethylcellulose (HPMC). API selection was based on extensive material characterization, combining conventional testing with in silico descriptors. For each formulation, a design of experiments was set up, evaluating the impact of liquid to solid (L/S) ratio and screw speed. Response ranges, response behavior and processability of each of the four formulations proved very similar to the placebo formulation when an appropriate center point L/S ratio was chosen. Hence, this robust placebo formulation could prove useful by decreasing drug product development time and consequently providing patients with a faster access to innovative medicine. Additionally, APIs with similar properties exhibited highly comparable response behavior at similar L/S ratios, indicating the potential use of surrogate APIs in novel drug product development.
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Celulosa , Lactosa , Composición de Medicamentos , Humanos , Derivados de la Hipromelosa , Tamaño de la Partícula , Tecnología FarmacéuticaRESUMEN
In recent years, continuous manufacturing techniques, such as twin screw wet granulation, have gained significant momentum. Due to the large diversity of the (model) formulations and equipment, it is often difficult to generalize conclusions about the importance of process settings. As only limited knowledge is available on the importance of formulation variables, this study focused on the systematic quantification of both process as formulation effects on critical quality attributes of granules from several model formulations. Apart from conventional process and formulation variables, also non-conventional process factors such as nozzle diameter, nozzle orientation and inclusion of a new type of size control elements were evaluated using a Plackett-Burman screening design. Although effects were often formulation-dependent, liquid-to-solid ratio proved the most influential variable for all formulations. Furthermore, binder concentration had a clear effect on granule characteristics, whereas barrel fill level and barrel temperature were less influential. The novel type of size control elements improved granule size distribution and density. The impact of nozzle diameter and wet binder addition proved negligible towards granule properties. Overall it was apparent that lactose/MCC-based formulations correlated better than lactose-based formulations, indicating the possible process robustness of the first filler combination to accommodate API and excipient variability and to handle APIs with different characteristics.
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Química Farmacéutica/métodos , Composición de Medicamentos/métodos , Tornillos Óseos , Excipientes/química , Lactosa/química , Tamaño de la Partícula , Solubilidad , Comprimidos/química , Temperatura , Resistencia a la TracciónRESUMEN
Due to the numerous advantages over batch manufacturing, continuous manufacturing techniques such as twin screw wet granulation are rapidly gaining importance in pharmaceutical production. Since a large knowledge gap on the importance of formulation variables exists, this study systematically assessed the impact of different screw configurations and process settings on eight model formulations, varying in filler type, active pharmaceutical ingredient (API) characteristics and drug load. Although liquid to solid (L/S) ratio was the most influential variable for all formulations, also a large effect of the kneading element thickness was observed. Narrow kneading elements with a length to diameter ratio (L/D) of 1/6 had a significant detrimental effect on granule size, flow and strength compared to 1/4 L/D elements. The effects of kneading element distribution and barrel fill level were less pronounced. At low drug load, both filler types could be used to obtain granules with acceptable critical quality attributes (CQAs) for both APIs. Granulation at high drug load of the poorly soluble, poorly wettable API mebendazole proved challenging as it could not be processed using lactose as filler, in contrast to lactose/MCC. As formulations containing lactose/MCC as filler were less influenced by different screw configurations, process settings and API characteristics than formulations without MCC, lactose/MCC/HPMC was considered a promising platform formulation.
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Mebendazol/química , Metformina/química , Tecnología Farmacéutica/métodos , Celulosa/química , Composición de Medicamentos , Excipientes/química , Lactosa/química , Tamaño de la Partícula , Solubilidad , HumectabilidadRESUMEN
Despite the recent commercialization of several drug products manufactured through continuous manufacturing techniques, knowledge on the formulation aspect of these techniques, such as twin screw wet granulation, is still rather limited. Previous research identified lactose/MCC/HPMC as a robust platform formulation for several model formulations, although granulation of the high-dosed, poorly soluble API mebendazole proved challenging. Therefore, current research evaluated the binder addition method (wet or dry) as well as surfactant (SLS) addition when using PVP, instead of HPMC. Compared to the previous formulation, using HPMC as binder, all four formulations with PVP yielded significantly stronger granules at similar to significantly lower liquid to solid (L/S) ratios. Through the combination of four replicate center composite circumscribed designs, each evaluating the impact of screw speed and L/S ratio on granule quality attributes, the effect of the formulation variables was assessed. Overall, L/S ratio had the most significant impact on granule characteristics whereas the effect of screw speed was negligible. Similar granule quality attributes were obtained for each formulation, although the addition of SLS and wet binder addition significantly reduced the required L/S ratio to achieve the desired characteristics. This significant reduction could prove useful for processing other formulations requiring high amounts of moisture, which could otherwise not be dried at a high throughput due to the limited drying capacity of the dryer unit of the Consigma system.
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Excipientes/química , Mebendazol/administración & dosificación , Tensoactivos/química , Tecnología Farmacéutica , Derivados de la Hipromelosa/química , Mebendazol/química , Povidona/química , SolubilidadRESUMEN
Recently, electrospinning (ES) of fibers has been shown to be an attractive strategy for drug delivery. One of the main features of ES is that a wide variety of drugs can be loaded into the fibers to improve their bioavailability, to enhance dissolution, or to achieve controlled release. Besides, ES is a continuous technology with low energy consumption, which can make it a very economic production alternative to the widely used freeze drying and spray drying. However, the low production rate of laboratory-scaled ES has limited the industrial application of the technology so far. This article covers the various ES technologies developed for scaled-up fiber production with an emphasis on pharmaceutically relevant examples. The methods used for increasing the productivity are complied, which is followed by a review of specific examples from literature where these technologies are utilized to produce oral drug delivery systems. The different technologies are compared in terms of their basic principles, advantages, and limitations. Finally, the different downstream processing options to prepare tablets or capsules containing the electrospun drug are covered as well. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies.
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Industria Farmacéutica , Nanotecnología , Sistemas de Liberación de Medicamentos , Humanos , Nanofibras/químicaRESUMEN
The goals of this work were to evaluate if high-speed electrospinning can be used as a gentle and continuous drying technology to produce protein-containing cyclodextrin-based fibers from an aqueous solution and to convert the produced protein-cyclodextrin fibers into a directly compressible powder. A 400â¯mL/h feeding rate was used during the electrospinning experiments, corresponding to a ~270â¯g/h production rate of the dried material. The produced fibers were collected in a cyclone. The fibers were found grindable without secondary drying, and the ground powder was mixed with tableting excipients and was successfully tableted by direct compression. The model protein-type drug (ß-galactosidase) remained stable during each of the processing steps (electrospinning, grinding, tableting) and after 6 months of storage at room temperature in the tablets. The obtained results demonstrate that high speed electrospinning can be a gentle alternative to traditional drying methods used for protein-type drugs, and that tablet formulation is achievable from the electrospun material prepared this way.
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2-Hidroxipropil-beta-Ciclodextrina/química , Tecnología Farmacéutica/métodos , beta-Galactosidasa/química , Desecación , Estabilidad de Enzimas , Polvos , ComprimidosRESUMEN
The aims of this work were to develop a processable, electrospun formulation of a model biopharmaceutical drug, ß-galactosidase, and to demonstrate that higher production rates of biopharmaceutical-containing fibers can be achieved by using high-speed electrospinning compared to traditional electrospinning techniques. An aqueous solution of 7.6 w/w% polyvinyl alcohol, 0.6 w/w% polyethylene oxide, 9.9 w/w% mannitol, and 5.4 w/w% ß-galactosidase was successfully electrospun with a 30 mL/h feeding rate, which is about 30 times higher than the feeding rate usually attained with single-needle electrospinning. According to X-ray diffraction measurements, polyvinyl alcohol, polyethylene oxide, and ß-galactosidase were in an amorphous state in the fibers, whereas mannitol was crystalline (δ-polymorph). The presence of crystalline mannitol and the low water content enabled appropriate grinding of the fibrous sample without secondary drying. The ground powder was mixed with excipients commonly used during the preparation of pharmaceutical tablets and was successfully compressed into tablets. ß-galactosidase remained stable during each of the processing steps (electrospinning, grinding, and tableting) and after one year of storage at room temperature in the tablets. The obtained results demonstrate that high-speed electrospinning is a viable alternative to traditional biopharmaceutical drying methods, especially for heat sensitive molecules, and tablet formulation is achievable from the electrospun material prepared this way.
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The aims of this study were to evaluate electrospinning as a continuous alternative to freeze drying in the production of a reconstitution injection dosage form, and to prove that aqueous electrospinning can be realized with a high production rate at room temperature. High-speed electrospinning with a novel continuous cyclone collection was used to manufacture a formulation of the poorly water-soluble antifungal voriconazole (VOR) with sulfobutylether-ß-cyclodextrin (SBE-ß-CD). The freeze-dried, marketed product of this drug substance, Vfend® also contains SBE-ß-CD as excipient. SBE-ß-CD acted as a 'quasi-polymer', and it could be electrospun despite its low molecular mass (2163â¯Da). According to X-ray diffraction and differential scanning calorimetry, no traces of crystalline VOR were detectable in the fibers. Furthermore, Raman mapping and energy dispersive spectroscopy measurements showed a uniform distribution of amorphous VOR in the fibers. Reconstitution tests carried out with ground fibrous powder showed complete dissolution resulting in a clear solution after 30â¯s (similarly to Vfend®). The high productivity rate (~240â¯g/h) achieved using high-speed electrospinning makes this scaled-up, continuous and flexible manufacturing process capable of fulfilling the technological and capacity requirements of the pharmaceutical industry. This work shows that aqueous high-speed electrospinning, being a continuous and high-throughput process, is an economically viable production alternative to freeze drying.
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Antifúngicos/administración & dosificación , Tecnología Farmacéutica/métodos , Voriconazol/administración & dosificación , beta-Ciclodextrinas/química , Antifúngicos/química , Química Farmacéutica/métodos , Cristalización , Excipientes/química , Liofilización , Polvos , Solubilidad , Temperatura , Voriconazol/químicaRESUMEN
In chronic intestinal diseases like inflammatory bowel disease, parenteral administration of biopharmaceuticals is associated with numerous disadvantages including immune reactions, infections, low patient compliance, and toxicity caused by high systemic bioavailability. One alternative that can potentially overcome these limitations is oral administration of biopharmaceuticals, where the local delivery will reduce the systemic exposure and furthermore the manufacturing costs will be lower. However, the development of oral dosage forms that deliver the biologically active form to the intestines is one of the greatest challenges for pharmaceutical technologists due to the sensitive nature of biopharmaceuticals. The present article discusses the various drug delivery technologies used to produce orally administered solid dosage forms of biopharmaceuticals with an emphasis on colon-targeted delivery. Solid oral dosage compositions containing different types of colon-targeting biopharmaceuticals are compiled followed by a review of currently applied and emerging drying technologies for biopharmaceuticals. The different drying technologies are compared in terms of their advantages, limitations, costs and their effect on product stability.
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Productos Biológicos/química , Desecación , Sistemas de Liberación de Medicamentos , Tecnología Farmacéutica/métodos , Administración Oral , Animales , Productos Biológicos/administración & dosificación , Colon , HumanosRESUMEN
In the new European Basic Safety Standard (EU-BSS), a new reference level for indoor radon concentration in workplaces has recommended that the annual average activity concentration of indoor radon shall not be higher than 300Bqm-3. This paper describes the radon concentration level in an underground workplace (manganese ore mine) over long time intervals (4 years). Several common radon monitors devices - including NRPB and Raduet (as a passive method based on CR-39), AlphaGUARD PQ 2000Pro, SARAD EQF3220, TESLA and Pylon WLX (as active methods) - were used for continuous radon measurements. The output results were used, first, to comprised the result of each device, based on conditions present in underground mines; Second, to have comprehensive measurements about all factors that cause workers exposure to radiation (each monitoring device specified for a unique measurement). The results indicate that the mine's staff had successful efforts to reach the strict requirement of the new EU-BSS, and the average annual radon activity concentrations during the working hours were below 300Bqm-3 in the investigated period. The paper presents the effective dose calculations; applying different equilibrium factors suggested by the literature and calculated basing on our measurements at the site, concluding that the differences could be about threefold.
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Contaminantes Radiactivos del Aire/análisis , Manganeso , Minería , Radón/análisis , Contaminación del Aire Interior/análisis , Humanos , Hungría , Concentración Máxima Admisible , Exposición Profesional/análisis , Dosis de Radiación , Exposición a la Radiación/análisis , Monitoreo de Radiación/métodosRESUMEN
The bioavailability of the anthelminthic flubendazole was remarkably enhanced in comparison with the pure crystalline drug by developing completely amorphous electrospun nanofibres with a matrix consisting of hydroxypropyl-ß-cyclodextrin and polyvinylpyrrolidone. The thus produced formulations can potentially be active against macrofilariae parasites causing tropical diseases, for example, river blindness and elephantiasis, which affect altogether more than a hundred million people worldwide. The bioavailability enhancement was based on the considerably improved dissolution. The release of a dose of 40 mg could be achieved within 15 min. Accordingly, administration of the nanofibrous system ensured an increased plasma concentration profile in rats in contrast to the practically non-absorbable crystalline flubendazole. Furthermore, easy-to-grind fibers could be developed, which enabled compression of easily administrable immediate release tablets.
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Mebendazol/análogos & derivados , Nanofibras/química , Povidona/química , Comprimidos/química , beta-Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina , Administración Oral , Animales , Disponibilidad Biológica , Química Farmacéutica , Cristalización , Mebendazol/administración & dosificación , Mebendazol/química , RatasRESUMEN
The reuse of by-products and residue streams is an important topic due to environmental and financial aspects. Manganese clay is a residue of manganese ore processing and is generated in huge amounts. This residue may contain some radionuclides with elevated concentrations. In this study, the radon emanation features and the massic exhalation rate of the heat-treated manganese clay were determined with regard to brick production. From the manganese mud depository, 20 samples were collected and after homogenization radon exhalation characteristics were determined as a function of firing temperatures from 100 to 750 °C. The major naturally occurring radionuclides 40K, 226Ra and 232Th concentrations were 607 ± 34, 52 ± 6 and 40 ± 5 Bq kg-1, respectively, comparable with normal clay samples. Similar to our previous studies a strong correlation was found between the internal structure and the radon emanation. The radon emanation coefficient decreased by â¼96% from 0.23 at 100 °C to 0.01 at 750 °C. The massic radon exhalation rate of samples fired at 750 °C reduced by 3% compared to samples fired at 100 °C. In light of the results, reusing of manganese clay as a brick additive is possible without any constraints.