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The drug delivery potential of liquid crystals (LCs) for ascorbyl palmitate (AP) was assessed, with the emphasis on the AP stability and release profile linked to microstructural rearrangement taking place along the dilution line being investigated by a set of complementary techniques. With high AP degradation observed after 56 days, two stabilization approaches, i.e., the addition of vitamin C or increasing AP concentration, were proposed. As a rule, LC samples with the lowest water content resulted in better AP stability (up to 52% of nondegraded AP in LC1 after 28 days) and faster API release (~18% in 8 h) as compared to the most diluted sample (29% of nondegraded AP in LC8 after 28 days, and up to 12% of AP released in 8 h). In addition, LCs exhibited a skin barrier-strengthening effect with up to 1.2-fold lower transepidermal water loss (TEWL) and 1.9-fold higher skin hydration observed in vitro on the porcine skin model. Although the latter cannot be linked to LCs' composition or specific microstructure, the obtained insight into LCs' microstructure contributed greatly to our understanding of AP positioning inside the system and its release profile, also influencing the overall LCs' performance after dermal application.
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Ácido Ascórbico , Cristales Líquidos , Fosfolípidos , Piel , Ácido Ascórbico/análogos & derivados , Ácido Ascórbico/química , Cristales Líquidos/química , Animales , Porcinos , Piel/metabolismo , Piel/efectos de los fármacos , Fosfolípidos/química , Liberación de Fármacos , Estabilidad de Medicamentos , Sistemas de Liberación de MedicamentosRESUMEN
Hydrophilic nanofibers offer promising potential for the delivery of drugs with diverse characteristics. Yet, the effects of different drugs incorporated into these nanofibers on their properties remain poorly understood. In this study, we systematically explored how model drugs, namely ibuprofen, carvedilol, paracetamol, and metformin (hydrochloride), affect hydrophilic nanofibers composed of polyethylene oxide and poloxamer 188 in a 1:1 weight ratio. Our findings reveal that the drug affects the conductivity and viscosity of the polymer solution for electrospinning, leading to distinct changes in the morphology of electrospun products. Specifically, drugs with low solubility in ethanol, the chosen solvent for polymer solution preparation, led to the formation of continuous nanofibers with uniform diameters. Additionally, the lower solubility of metformin in ethanol resulted in particle appearance on the nanofiber surface. Furthermore, the incorporation of more hydrophilic drugs increased the surface hydrophilicity of nanofiber mats. However, variations in the physicochemical properties of the drugs did not affect the drug loading and drug entrapment efficiency. Our research also shows that drug properties do not notably affect the immediate release of drugs from nanofibers, highlighting the dominant role of the hydrophilic polymers used. This study emphasizes the importance of considering specific drug properties, such as solubility, hydrophilicity, and compatibility with the solvent used for electrospinning, when designing hydrophilic nanofibers for drug delivery. Such considerations are crucial for optimizing the properties of the drug delivery system, which is essential for achieving therapeutic efficacy and safety.
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BACKGROUND: The antiepileptic drug lamotrigine (LTG) shows high pharmacokinetic variability due to genotype influence and concomitant use of glucuronidation inducers and inhibitors, both of which may be frequently taken by elderly patients. Our goal was to develop a reliable quantification method for lamotrigine and its main glucuronide metabolite lamotrigine-N2-glucuronide (LTG-N2-GLU) in dried blood spots (DBS) to enable routine therapeutic drug monitoring and to identify altered metabolic activity for early detection of drug interactions possibly leading to suboptimal drug response. RESULTS: The analytical method was validated in terms of selectivity, accuracy, precision, matrix effects, haematocrit, blood spot volume influence, and stability. It was applied to a clinical study, and the DBS results were compared to the concentrations determined in plasma samples. A good correlation was established for both analytes in DBS and plasma samples, taking into account the haematocrit and blood cell-to-plasma partition coefficients. It was demonstrated that the method is suitable for the determination of the metabolite-to-parent ratio to reveal the metabolic status of individual patients. CONCLUSIONS: The clinical validation performed confirmed that the DBS technique is a reliable alternative for plasma lamotrigine and its glucuronide determination.
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Administration of monoclonal antibodies (mAbs) is currently focused on subcutaneous injection associated with increased patient adherence and reduced treatment cost, leading to sustainable healthcare. The main bottleneck is low volume that can be injected, requiring highly concentrated mAb solutions. The latter results in increased solution viscosity with pronounced mAb aggregation propensity because of intensive protein-protein interactions. Small molecule excipients have been proposed to restrict the protein-protein interactions, contributing to reduced viscosity. The aim of the study was to discover novel compounds that reduce the viscosity of highly concentrated mAb solution. First, the chemical space of proline analogs was explored and 35 compounds were determined. Viscosity measurements revealed that 18 proline analogs reduced the mAb solution viscosity similar to or more than proline. The compounds forming both electrostatic and hydrophobic interactions with mAb reduced the viscosity of the formulation more efficiently without detrimentally effecting mAb physical stability. A correlation between the level of interaction and viscosity-reducing effect was confirmed with molecular dynamic simulations. Structure rigidity of the compounds and aromaticity contributed to their viscosity-reducing effect, dependent on molecule size. The study results highlight the novel proline analogs as an effective approach in viscosity reduction in development of biopharmaceuticals for subcutaneous administration.
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Anticuerpos Monoclonales , Prolina , Humanos , Anticuerpos Monoclonales/química , Viscosidad , Simulación de Dinámica Molecular , Excipientes/química , SolucionesRESUMEN
The chemical burden on the environment and human population is increasing. Consequently, regulatory risk assessment must keep pace to manage, reduce, and prevent adverse impacts on human and environmental health associated with hazardous chemicals. Surveillance of chemicals of known, emerging, or potential future concern, entering the environment-food-human continuum is needed to document the reality of risks posed by chemicals on ecosystem and human health from a one health perspective, feed into early warning systems and support public policies for exposure mitigation provisions and safe and sustainable by design strategies. The use of less-conventional sampling strategies and integration of full-scan, high-resolution mass spectrometry and effect-directed analysis in environmental and human monitoring programmes have the potential to enhance the screening and identification of a wider range of chemicals of known, emerging or potential future concern. Here, we outline the key needs and recommendations identified within the European Partnership for Assessment of Risks from Chemicals (PARC) project for leveraging these innovative methodologies to support the development of next-generation chemical risk assessment.
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Exposición a Riesgos Ambientales , Monitoreo del Ambiente , Humanos , Exposición a Riesgos Ambientales/análisis , Monitoreo del Ambiente/métodos , Monitoreo del Ambiente/normas , Contaminantes Ambientales/análisis , Sustancias Peligrosas/análisis , Espectrometría de Masas/métodos , Medición de Riesgo/métodosRESUMEN
Recently, the potentially highly carcinogenic N-nitrosamines (NAs) have become the focus of pharmaceutical regulatory authorities, the pharmaceutical industry and researchers because trace amounts have been detected in some drug products (DPs), resulting in drug supply shortages. In the absence of sufficient analytical methods for the determination of multiple regulated low-molecular-weight NAs in various DPs, a robust, selective, sensitive and accurate method based on sample preparation by solid phase extraction, followed by liquid chromatography high-resolution mass spectrometry for the simultaneous analysis of 13 regulated low-molecular-weight NAs was developed. The best results for the cleanup were obtained using Strata X-C SPE cartridge. The proposed method was successfully validated according to the USP general chapter ã1469ã, demonstrating its excellent linearity, accuracy and precision in wide analytical ranges, adjusted to NAs acceptable intake limits. The achieved limits of quantitation correspond to 30 % or less of the acceptable intake limits. The developed analytical method was applied to 16 commercially available DPs containing one to three active pharmaceutical ingredients with different physicochemical properties. Only N-Nitrosodimethylamine was detected in DPs containing ranitidine at levels exceeding the regulatory AI limits by 37.6 - 57.4-fold. In addition, the robustness of the method was confirmed on a considerable number of DPs containing different active ingredients, demonstrating the suitability of the analytical method for routine quality control of different DPs, thus mitigate the risk to human health.
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Técnicas de Química Analítica , Nitrosaminas , Preparaciones Farmacéuticas , Humanos , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida , Espectrometría de Masas , Nitrosaminas/análisis , Preparaciones Farmacéuticas/química , Extracción en Fase Sólida/métodos , Técnicas de Química Analítica/métodosRESUMEN
The objective of the present report was to develop and validate a simple, selective, and reproducible high-performance liquid chromatography method with UV detection suitable for routine therapeutic drug monitoring of the most commonly used antiepileptic drugs and some of their metabolites. Simple precipitation of plasma proteins with acetonitrile was used for sample preparation. 10,11-dihydrocarbamazepine was used as an internal standard. Chromatographic separation of the analytes was achieved by gradient elution on a Phenyl-Hexyl column at 40 °C, using methanol and potassium phosphate buffer (25 mM; pH 5.1) as a mobile phase. The method was validated according to the FDA guidelines for bioanalytical method validation. It showed to be selective, accurate, precise, and linear over the concentration ranges of 1-50 mg/L for phenobarbital, phenytoin, levetiracetam, rufinamide, zonisamide, and lacosamide; 0.5-50 mg/L for lamotrigine, primidone, carbamazepine and 10-monohydroxycarbazepine; 0.2-10 mg/L for carbamazepine metabolites: 10,11-trans-dihydroxy-10,11-dihydrocarbamazepine and carbamazepine-10,11-epoxide; 0.1-10 mg/L for oxcarbazepine; 2-100 mg/L for felbamate and 3-150 mg/L for ethosuximide. The suitability of the validated method for routine therapeutic drug monitoring was confirmed by quantification of the analytes in plasma samples from patients with epilepsy on combination antiepileptic therapy.
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Anticonvulsivantes , Monitoreo de Drogas , Humanos , Anticonvulsivantes/química , Cromatografía Líquida de Alta Presión/métodos , Monitoreo de Drogas/métodos , Carbamazepina/química , OxcarbazepinaRESUMEN
Estrogenic endocrine disruptors are one of the biggest ecotoxicological threats in water that pose a significant ecological burden and health-risk for humans due to their high biological activity and proven additive effects. Therefore, we have developed and validated the most comprehensive and ultra-sensitive analytical method published to date, for reliable quantification of 25 high-risk endocrine disruptors at their ecologically relevant concentrations: naturally excreted hormones (estradiol, estrone, estriol, testosterone, corticosterone, and progesterone), synthetic hormones used for contraception and menopausal symptoms (ethinylestradiol, drospirenone, chlormadinone acetate, norgestrel, gestodene, tibolone, norethindrone, dienogest, and cyproterone) and bisphenols (BPS, BPA, BPF, BPE, BPAF, BPB, BPC, and BPZ). It is based on a solid-phase extraction of water samples, followed by a robust dansyl chloride derivatization with detection by liquid chromatography-tandem mass spectrometry with a single sample preparation and two analytical methods using the same analytical column and mobile phases. The achieved limits of quantitation are in the sub-ng L-1 range, and detection limits as low as 0.02 ng L-1, meeting the newest proposal for environmental quality standards (EQS) by the EU water framework directive for estradiol and ethinylestradiol. The method was extensively validated and applied to seven representative Slovenian water samples, where we detected 21 out of 25 analytes; 13 were quantified in at least one sample. Estrone and progesterone were quantified in all samples, reaching levels up to 50 ng L-1; ethinylestradiol was higher than the current EQS (0.035 ng L-1) in three samples, and estradiol was above its EQS (0.4 ng L-1) in one sample, proving the method's applicability and the necessity for monitoring these pollutants.
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Disruptores Endocrinos , Estrona , Humanos , Cromatografía Liquida , Estrona/análisis , Disruptores Endocrinos/análisis , Espectrometría de Masas en Tándem/métodos , Progesterona , Estradiol/análisis , Etinilestradiol/análisis , Agua/químicaRESUMEN
Endocrine disrupting chemicals such as natural and synthetic steroid hormones and bisphenols are among the most important pollutants in the aquatic environment. We performed an environmental chemical analysis of five Slovenian water samples, two rivers, one groundwater, and the influent and effluent of wastewater treatment plants, with a highly sensitive analysis of twenty-five endocrine-disrupting compounds belonging to the groups of natural hormones, synthetic hormones, and bisphenols. Since these compounds are simultaneously present in the environment, it is important to study their individual effects as well as the effects of mixtures. We investigated in vitro the estrogenic potency of selected natural and synthetic steroid hormones and bisphenols detected in surface, ground and waste water in Slovenia using the OECD-validated transactivation assay on the cell line Hela9903. We predicted their mixture effects using the concentration addition model and compared them with experimentally determined values. Two mixing designs were used: a balanced design in which chemicals were combined in proportion to their individual EC50 values, and an unbalanced design with compounds in proportion to their measured concentrations in the environmental samples. The estrogenic effects of the experimental mixtures followed the concentration addition model. Real water samples exhibited weaker estrogenic effects, showing the great heterogeneity of the real water samples.
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Disruptores Endocrinos , Contaminantes Químicos del Agua , Aguas Residuales , Disruptores Endocrinos/toxicidad , Disruptores Endocrinos/análisis , Estrona/análisis , Estrógenos/análisis , Línea Celular , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/análisis , Monitoreo del AmbienteRESUMEN
N-nitrosamines are genotoxic compounds which can be found as impurities in drug substances and drug products used in the pharmaceutical industry. To date, several possible nitrosamine sources in drug products have been reported and this study aims to illuminate another one. A case of afatinib drug product was investigated, in which up to 50 ppb N-nitrosodimethylamine (NDMA) traces were detected. Afatinib was found to degrade to the secondary amine dimethylamine (DMA), forming NDMA with traces of nitrite in crospovidone. Two series of film-coated tablets were prepared with crospovidone from two different manufacturers, containing different levels of nitrites. Tablets were subjected to an accelerated stability study (40 °C/75% relative humidity) or stored at room temperature and levels of NDMA, DMA and nitrite in tablets were monitored. NDMA and nitrite were found on ppb levels, whereas DMA was detected on ppm levels. NDMA formation in the drug product was found to be time, temperature and nitrite dependent and it was emphasized that DMA and nitrite should be reduced. The accelerated stability study proved to be a useful tool for predicting nitrosamine formation in the drug product.
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Dimetilnitrosamina , Nitrosaminas , Humanos , Dimetilnitrosamina/metabolismo , Nitritos , Afatinib , Povidona , Concentración de Iones de HidrógenoRESUMEN
BACKGROUND: Individual B vitamins have many favorable effects on the skin and are common cosmetic ingredients. However, their formulation is demanding due to stability issues, which consequently affect the products' quality. AIMS: We aimed to determine the quality (labeling accuracy, content determination, and content-related quality control) and stability under long-term and accelerated storage conditions of a representative sample of commercial cosmetics containing the most common B vitamins - nicotinamide, dexpanthenol, pyridoxine, and cyanocobalamin. METHODS: Cyanocobalamin was determined by a previously published stability-indicating HPLC- diode array detector (DAD) method for the simultaneous determination of all hydrophilic vitamins. This method was additionally simplified and adjusted for the time-effective analysis of nicotinamide, dexpanthenol, and pyridoxine. Both methods were properly validated. RESULTS: All labeled B vitamins were present in the 36 tested products, mostly in contents, reported effective on the skin. Thus, a straightforward correlation between vitamin contents and product prices were not observed. The content-related quality control of eight products, which quantitively specify their content, revealed significantly lower nicotinamide contents (47% and 57%) in two products and appropriate or higher nicotinamide (102%-112%) and dexpanthenol (100%-104%) contents than declared in the remaining products. The 6-month long-term and accelerated stability studies demonstrated the products' physical stability, but also revealed dexpanthenol, pyridoxine, and cyanocobalamin degradation, while nicotinamide was mostly stable in the tested products. CONCLUSIONS: The obtained results provide an inside into the quality of commercial vitamin B cosmetics and highlight the importance of stability testing in the formulation of quality, efficient, and safe cosmetics.
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Complejo Vitamínico B , Humanos , Piridoxina/análisis , Vitamina A , Niacinamida/análisis , Vitamina K , Vitamina B 12RESUMEN
Nowadays, numerous skincare routines are used to rejuvenate aging skin. Retinoids are one of the most popular ingredients used in antiaging treatments. Among the representatives of retinoids, tretinoin is considered the most effective agent with proven antiaging effects on the skin and can be found in formulations approved as medicines for topical treatment of acne, facial wrinkles, and hyperpigmentation. Other retinoids present in topical medicines are used for various indications, but only tazarotene is also approved as adjunctive agent for treatment of facial fine wrinkling and pigmentation. The most commonly used retinoids such as retinol, retinaldehyde, and retinyl palmitate are contained in cosmeceuticals regulated as cosmetics. Since clinical efficacy studies are not required for marketing cosmetic formulations, there are concerns about the efficacy of these retinoids. From a formulation perspective, retinoids pose a challenge to researchers as a result of their proven instability, low penetration, and potential for skin irritation. Therefore, novel delivery systems based on nanotechnology are being developed to overcome the limitations of conventional formulations and improve user compliance. In this review, the clinical evidence for retinoids in conventional and nanoformulations for topical antiaging treatments was evaluated. In addition, an overview of the comparison clinical trials between tretinoin and other retinoids is presented. In general, there is a lack of evidence from properly designed clinical trials to support the claimed efficacy of the most commonly used retinoids as antiaging agents in cosmeceuticals. Of the other retinoids contained in medicines, tazarotene and adapalene have clinically evaluated antiaging effects compared to tretinoin and may be considered as potential alternatives for antiaging treatments. The promising potential of retinoid nanoformulations requires a more comprehensive evaluation with additional studies to support the preliminary findings.
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Cosmecéuticos , Fármacos Dermatológicos , Humanos , Retinoides/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Cosmecéuticos/uso terapéutico , Adapaleno , Tretinoina/uso terapéuticoRESUMEN
This study aimed to determine the in-use stability (t95%) of hydrocortisone sodium succinate (HSS) infusion solutions and provide evidence-based guidelines on their usability.HSS infusion solutions were prepared and stored as recommended by the manufacturer and under common conditions in our hospital. The effects of HSS concentration (1 and 4 mg/mL), solvent (isotonic saline and glucose), temperature (ambient and 30°C), and light on its stability were evaluated using a validated stability-indicating HPLC-UV method.HSS degradation followed first-order kinetics. No significant difference in its stability was observed between the two evaluated concentrations, solvents and light exposure (t95% between 25 and 30 h). Elevated temperature (30°C) affected HSS stability and significantly reduced the t95% (4.6-6.3 h).HSS infusion solutions are physically and chemically stable (Ë5% degradation) for at least 6 h if stored below 30°C. The in-use stability may be extended up to 24 h if stored below 24°C.
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Glucosa , Hidrocortisona , Cromatografía Líquida de Alta Presión/métodos , Estabilidad de Medicamentos , Sodio , Solventes , SuccinatosRESUMEN
The recent focus of pharmaceutical regulatory authorities has been oriented towards the mitigation of carcinogenic N-nitrosamines in drug products and different sources of N-nitrosamines have been revealed. Within this work, the elucidation of a further source of N-nitrosamines in drug products is reported. A case was investigated where traces of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) were detected in a finished dosage form, whereas they were not found in the bulk drug product. This led to an in-depth study of blister material as a potential source, wherein nitrocellulose primer in a lidding foil was identified as a risk factor. Nitrocellulose acts as a nitrosating agent for secondary amines, present in printing inks, forming N-nitrosamines in lidding foil. Their formation was confirmed by the addition of printing ink containing dimethylamine and diethylamine, or diethylamine alone, to lidding foil containing nitrocellulose primer. Their transfer to drug product during the blistering operation was demonstrated by solid-phase microextraction sampling of N-nitrosamine vapors on two commonly used types of pharmaceutical blistering machines, operating with plate sealing or roller sealing technology. Higher vapor amounts were detected on plate sealing equipment, where N-nitrosamine contamination was additionally confirmed in film-coated tablets and blister cavities of the finished dosage form.
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Vesícula , Nitrosaminas , Colodión , Dimetilnitrosamina , Humanos , Preparaciones FarmacéuticasRESUMEN
Cabotegravir is one of the newly approved human immunodeficiency virus (HIV) integrase enzyme inhibitors used for the prevention and treatment of HIV infection. It is the first approved long-acting injectable antiretroviral therapy for HIV and is also very effective in combination with rilpivirine, a non-nucleoside reverse transcriptase inhibitor. Therefore, future drug development involving cabotegravir can be expected. We developed an ultrahigh performance liquid chromatography (UHPLC) method compatible with mass spectrometry for the determination of eight cabotegravir impurities. The described method is able to differentiate cabotegravir and its related substances as well as its degradation products. Analytical quality by design principles were used for method development. The method is robust within the defined method operable design region: flow rate = 0.32-0.40 mL/min; column temperature = 30-40 °C; pH of mobile phase A = 3.25-3.75, and the final percent of acetonitrile in gradient = 50.0-60.0%. Inside the method operable design region, a working optimal point was selected: pump flow rate = 0.36 mL/min; column temperature = 35 °C; pH of mobile phase A = 3.5, and final percent of acetonitrile in gradient = 55%. Method validation was performed, and the following parameters were verified: accuracy, repeatability, linearity, response factors, detection limit, and quantification limit. All method validation results were within selected criteria. The presented method could be used for the development of new pharmaceutical products based on cabotegravir.
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In the present study, the oxidative degradation behavior of nifedipine (NIF) in amorphous solid dispersions (ASDs) prepared with poly(vinyl pyrrolidone) (PVP) with a short (K30) and a long (K90) chain length was investigated. The ASDs were prepared via dry ball-milling and analyzed using Fourier transform infrared (IR) spectroscopy, X-ray scattering, and differential scanning calorimetry. The ASDs were exposed to accelerated thermal-oxidative conditions using a pressurized oxygen headspace (120 °C for 1 day) and high temperatures at atmospheric pressure (60-120 °C for a period of 42 days). Additionally, solution-state oxidative degradation studies showed that pure NIF degrades to a greater extent than in the presence of PVP. Electronic structure calculations were performed to understand the impact of drug-polymer intermolecular interactions on the autoxidation of drugs. While no drug degradation was observed in freshly prepared ASD samples, alkyl free radicals were detected via electron paramagnetic resonance (EPR) spectroscopy. The free radicals were found to be consumed to a greater extent by PVP K30- than PVP K90-based ASDs upon exposure to high oxygen pressures. This was consistent with the greater solid-state oxidative degradation of NIF observed in ASDs with PVP K30 than with PVP K90. As no drug recrystallization occurred during this study period, the lower glass-transition temperature and presumed greater molecular mobility of PVP K30 and its ASD as compared to the PVP K90 system appear to contribute to the greater drug degradation in PVP-K30-based ASDs. The extent and the rate of oxidative degradation were higher in the case of PVP-K30-based ASD as compared to that in PVP-K90-based ASD, and the overall degradation increased with an increase in temperature. IR spectral analysis of drug-polymer interactions supports the electronic calculations of the oxidation process. We infer that, apart from the initial free radical content, the difference in the extent of drug-polymer intermolecular interactions in ASDs and amorphous stabilization during the forced oxidation experiments contribute to the observed differences in the autoxidative reactivity of the drug in ASDs with different PVP chain lengths. Overall, the chemical degradation of NIF in ASDs with two PVP chain lengths obtained from accelerated solid-state oxidation studies was in qualitative agreement with that obtained from long-term (3 years) storage under ambient conditions. The study highlights the ability of accelerated processes to determine the oxidative degradation behavior of polymeric ASDs and suggests that the polymer chain length could factor into chemical as well as physical stability considerations.
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Nifedipino , Povidona , Rastreo Diferencial de Calorimetría , Polímeros/química , Povidona/química , SolubilidadRESUMEN
The increasing use of substances with endocrine disruptive properties (EDs) not only impacts aquatic organisms but can also have a direct negative effect on human health. In this comprehensive worldwide review, we collected ecotoxicology and concentration data observed in surface water for 53 high-potency EDs and performed a risk assessment. The compounds were selected from the EU watchlist of priority substances, expanded with new compounds of emerging concern (total 41), where quantifiable data were available for the past three years (2018-2020). The risk quotients ranged from <0.01 for 22 substances to 1974 for tamoxifen. The frequency of samples in which the predicted no-effect concentrations were exceeded also varied, from 1.8% to 92.7%. By using the comprehensive multi-parameter risk assessment in our study, the most current to date, we determined that tamoxifen, imidacloprid, clothianidin, four bisphenols (BPA, BPF, BPS, and BPAF), PFOA, amoxicillin, and three steroid hormones (estriol, estrone, and cyproterone) pose significant risks in the environment. Comparing two structurally very similar bisphenols, BPA and BPB, suggested that the risk from BPB is currently underestimated by at least four orders of magnitude due to the lack of ecotoxicological data availability. The methodological limitations encountered suggest that a standardized methodology for data selection and assessment is necessary, highlighting the fact that some substances are currently under-represented in the field of ecotoxicological research. A new prioritization system is therefore presented, which provides a potential basis for new substances to be included in environmental monitoring lists.
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Disruptores Endocrinos , Organismos Acuáticos , Ecotoxicología , Disruptores Endocrinos/análisis , Disruptores Endocrinos/toxicidad , Monitoreo del Ambiente , Medición de RiesgoRESUMEN
Vitamin B12, also known as the anti-pernicious anemia factor, is an essential micronutrient totally dependent on dietary sources that is commonly integrated with food supplements. Four vitamin B12 forms-cyanocobalamin, hydroxocobalamin, 5'-deoxyadenosylcobalamin, and methylcobalamin-are currently used for supplementation and, here, we provide an overview of their biochemical role, bioavailability, and efficacy in different dosage forms. Since the effective quantity of vitamin B12 depends on the stability of the different forms, we further provide a review of their main reactivity and stability under exposure to various environmental factors (e.g., temperature, pH, light) and the presence of some typical interacting compounds (oxidants, reductants, and other water-soluble vitamins). Further, we explore how the manufacturing process and storage affect B12 stability in foods, food supplements, and medicines and provide a summary of the data published to date on the content-related quality of vitamin B12 products on the market. We also provide an overview of the approaches toward their stabilization, including minimization of the destabilizing factors, addition of proper stabilizers, or application of some (innovative) technological processes that could be implemented and contribute to the production of high-quality vitamin B12 products.
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Hidroxocobalamina , Vitamina B 12 , Vitamina B 12/química , Hidroxocobalamina/química , Suplementos Dietéticos , Vitaminas , DietaRESUMEN
We report here on improved uniformity of blends of micronised active pharmaceutical ingredients (APIs) using addition of spherical agglomerates of lactose and enhanced blend flow to improve tablet content uniformity with higher API loads. Micromeritic properties and intra-particle porosity (using nano-computed X-ray tomography) of recently introduced spherical agglomerates of lactose and two standard lactose grades for the direct compression processes were compared. Powder blends of the individual lactose types and different micronised API drug loads were prepared and subjected to specific conditions that can induce API segregation. Tablet content uniformity during direct compression was related to the lactose material attributes. The distinctive micromeritic properties of the lactose types showed that spherical agglomerates of lactose had high intra-particle porosity and increased specific surface area. The stability of binary blends after intense sieving was governed by the intra-particle porosity and surface roughness of the lactose particles, which determined the retention of the model substance. Greater intra-particle porosity, powder specific surface area, and particle size of the spherical agglomerates provided greater adhesion of micronised particles, compared to granulated and spray-dried lactose. Thus the spherical agglomerates provided enhanced final blend flow and uniformity of tablet content at higher drug loads.
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Portadores de Fármacos , Lactosa , Tamaño de la Partícula , Polvos , ComprimidosRESUMEN
OBJECTIVE: The purpose of this paper is to present the use of Design of Experiments and multivariate analysis for evaluation of a modified-release drug product stability to support post-approval lean stability approaches. The focus of the paper was to investigate potential root-causes for acceleration of dissolution upon stability. METHODS: For statistical evaluation of stability data, multiple linear regression statistics was used. The design space of the stability study was modeled using MODDE 12.1 software. For experimental set-up, parameters such as Temperature, Time, Packaging, Batch, and Active Pharmaceutical Ingredient supplier were selected. RESULTS: With multiple linear regression modeling of the all generated stability data until six months, we were able to identify or confirm the Stability-related quality attributes and Shelf life limiting attributes. From the multiple linear regression correlation coefficients, we have evaluated that decrease of an antioxidant upon stability could cause potential shift in dissolution. However, main factors for accelerated dissolution can be attributed to other material and process variables. In the last part of the study, we have shown the usefulness of these methodologies for supporting lean stability approaches. With enhanced drug product knowledge, we designed two reduced long-term stability studies and showed that with 'One-half' reduced design, we would still be able to confirm 24-month shelf life. CONCLUSIONS: Implementing Quality by design approaches on stability studies could reduce the need for excessive analytical testing, help to evaluate meaningfulness of the data and set a risk-based stability testing strategy.