RESUMEN
Supramolecular structures based on cyclodextrins have been extensively used for drug delivery systems over decades. However, combining host and guest molecules in a pharmaceutical formulation is not a trivial process, being one of the majors concern the inclusion complex compatibility with other excipients presented in the final formulation. Herein, experimental and theoretical calculations were used to investigate the competition of sodium dodecyl sulfate (SDS) with atenolol (ATE) or losartan (LOS), antihypertensive drugs widely used in the treatment of hypertension. Our findings, using nuclear magnetic resonance and isothermal titrations calorimetry experiments and molecular dynamic simulations demonstrated that LOS remain included into CD cavity after excipient (SDS) addition, which was not verified for ATE ternary system, being the drug displaced by SDS molecule.
Asunto(s)
Antihipertensivos/química , Atenolol/química , Losartán/química , Dodecil Sulfato de Sodio/química , Tensoactivos/química , beta-Ciclodextrinas/química , Espectroscopía de Resonancia Magnética , Espectroscopía Infrarroja por Transformada de Fourier , TermodinámicaRESUMEN
The inhalatory route has emerged as an interesting non-invasive alternative for drug delivery. This allows both pulmonary (local) and systemic treatments (via alveolar absorption). Further advantages in terms of stability, dose and patient preference have often lead researchers to focus on dry powder inhaler delivery systems. Atenolol is an antihypertensive drug with low oral bioavailability and gastrointestinal side effects. Because atenolol possesses adequate permeation across human epithelial membranes, it has been proposed as a good candidate for inhalatory administration. In a previous work, atenolol was combined with alginic acid (AA) and microparticles were developed using spray-drying (SD) technology. Different AA/atenolol ratios, total feed solid content and operative variables were previously explored. In order to improve particle quality for inhalatory administration and the SD yield, in this work the AA acid groups not neutralized by atenolol were kept either free or neutralized to pHâ¼7 and two different SD cyclones were used. Particle morphology, flow properties, moisture uptake and in vitro aerosolization behavior at different pressure drops were studied. When the AA acid groups were neutralized, particle size decreased as a consequence of the lower feed viscosity. The SD yield and in vitro particle deposition significantly increased when a high performance cyclone was employed, and even when lactose carrier particles were not used. Although the in vitro particle deposition decreased when the storage relative humidity increased, the developed SD powders showed adequate characteristics to be administered by inhalatory route up to storage relative humidities of about 60%.
Asunto(s)
Administración por Inhalación , Alginatos/administración & dosificación , Atenolol/administración & dosificación , Sistemas de Liberación de Medicamentos , Pulmón/efectos de los fármacos , Aerosoles , Alginatos/química , Animales , Antihipertensivos/química , Atenolol/química , Desecación , Inhaladores de Polvo Seco , Liofilización , Ácido Glucurónico/administración & dosificación , Ácido Glucurónico/química , Ácidos Hexurónicos/administración & dosificación , Ácidos Hexurónicos/química , Humanos , Concentración de Iones de Hidrógeno , Lactosa/química , Microscopía Electrónica de Rastreo , Microesferas , Tamaño de la Partícula , Polvos , Presión , ViscosidadRESUMEN
The inhalatory route allows drug delivery for local or systemic treatments in a noninvasively way. The current tendency of inhalable systems is oriented to dry powder inhalers due to their advantages in terms of stability and efficiency. In this work, microparticles of atenolol (AT, basic antihypertensive drug) and alginic acid (AA, acid biocompatible polyelectrolyte) were obtained by spray drying. Several formulations, varying the relative composition AT/AA and the total solid content of the atomized dispersions, were tested. The powders were characterized by: Fourier Transform Infrared Spectroscopy, Differential Scanning Calorimetry and Powder X-ray Diffraction, while also the following properties were measured: drug load efficiency, flow properties, particles size and density, moisture content, hygroscopicity and morphology. The ionic interaction between AA and AT was demonstrated, then the new chemical entity could improve the drug targeting to the respiratory membrane and increase its time residence due to the mucoadhesive properties of the AA polymeric chains. Powders exhibited high load efficiencies, low moisture contents, adequate mean aerodynamic diameters and high cumulative fraction of respirable particles (lower than 10 µm).
Asunto(s)
Alginatos/química , Antihipertensivos/química , Atenolol/química , Microesferas , Rastreo Diferencial de Calorimetría , Química Farmacéutica , Ácido Glucurónico/química , Ácidos Hexurónicos/química , Concentración de Iones de Hidrógeno , Tamaño de la Partícula , Espectroscopía Infrarroja por Transformada de Fourier , Viscosidad , HumectabilidadRESUMEN
With the aim to provide more rational basis about the potentiality of hyaluronic acid (or hyaluronan) as drug carrier a set of ionic complexes of its acid form (HA) and its sodium salt (NaHA) with three model drugs (D) (atenolol, propranolol and lidocaine) were prepared. Besides NaHA subjected to hyalurodinase depolimerization (NaHA(d)) was also used. Transparent dispersions were obtained. They exhibited negative electrokinetic potential and a high degree of counterionic condensation with affinity constants (log Kcc) in the range of 5.8-6.1 for propranolol complexes (pK(a) 9.45) and 4.0-4.6 for lidocaine ones (pK(a) 7.92). Delivery rates of D from the complexes were measured in a Franz-type bicompartimental device. Loaded D were slowly released from the three types of complexes, even when a neutral salt was added to the dispersion placed in the donor compartment, revealing the high affinity between the protonated drugs and the ionisable groups of the polymer. Complex dispersions based on HA or on NaHA(d) exhibited lower viscosity than those of NaHA but their complexing ability remained unaltered. The results reported on equilibrium and release properties of Hyaluronan-model D complexes contribute to expand the use of HA and NaHA as drug carriers for different routes of administration.
Asunto(s)
Portadores de Fármacos/química , Ácido Hialurónico/química , Atenolol/química , Lidocaína/química , Propranolol/química , ViscosidadRESUMEN
This study investigated the degradation of atenolol, metoprolol and propranolol beta-blockers by ferrate (K2FeO4) in hospital wastewater and in aqueous solution. In the case of hospital wastewater, the effect of the independent variables pH and [Fe(VI)] was evaluated by means of response surface methodology. The results showed that Fe(VI) plays an important role in the oxidation-coagulation process, and the treatment of the hospital wastewater led to degradations above 90% for all the three ß-blockers, and to reductions of aromaticity that were close to 60%. In addition, only 17% of the organic load was removed. In aqueous solution, the degradation of the ß-blockers atenolol, metoprolol and propranolol was 71.7%, 24.7% and 96.5%, respectively, when a ratio of 1:10 [ß-blocker]:[Fe(VI)] was used. No mineralization was achieved, which suggests that there was a conversion of the ß-blockers to degradation products identified by liquid chromatography/mass spectrometry tandem. Degradation pathways were proposed, which took account of the role of Fe(VI). Furthermore, the ready biodegradability of the post-process samples was evaluated by using the closed bottle test, and showed an increase in biodegradability. The use of the ferrate advanced oxidation technology seems to be a useful means of ensuring the remediation of hospital and similar wastewater.
Asunto(s)
Antagonistas Adrenérgicos beta/química , Biodegradación Ambiental , Hierro/química , Contaminantes Químicos del Agua/química , Antagonistas Adrenérgicos beta/análisis , Atenolol/química , Cromatografía Liquida/métodos , Interpretación Estadística de Datos , Hospitales , Espectrometría de Masas/métodos , Residuos Sanitarios , Eliminación de Residuos Sanitarios/métodos , Metoprolol/análisis , Metoprolol/química , Modelos Teóricos , Oxidación-Reducción , Propranolol/análisis , Propranolol/química , Contaminantes Químicos del Agua/análisisRESUMEN
The study contributes with a first survey of pharmaceuticals in municipal wastewaters discharging into fresh and estuarine waters from areas with varying degrees of urbanization of Argentina. Analyses were done on the soluble fraction by HPLC-MS after SPE extraction. In all of the samples were detected caffeine and ibuprofen within the range of 0.9-44.2 and 0.4-13.0 µg/L, and lower levels of carbamazepine, atenolol and diclofenac between 0.2-2.3, 0.2-1.7 and <0.03-1.2 µg/L, respectively. Profiles of compounds were similar in all studied locations.
Asunto(s)
Aguas Residuales/química , Contaminantes Químicos del Agua/análisis , Argentina , Atenolol/análisis , Atenolol/química , Cafeína/análisis , Cafeína/química , Carbamazepina/análisis , Carbamazepina/química , Cromatografía Líquida de Alta Presión , Ciudades , Diclofenaco/análisis , Diclofenaco/química , Monitoreo del Ambiente , Humanos , Ibuprofeno/análisis , Ibuprofeno/química , Espectrometría de Masas , Preparaciones Farmacéuticas/análisis , Preparaciones Farmacéuticas/química , Contaminantes Químicos del Agua/químicaRESUMEN
A second-order multivariate calibration method based on a combination of unfolded partial least-squares (U-PLS) with residual bilinearization (RBL) has been applied to second-order data obtained from excitation-emission fluorescence matrices for determining atenolol in human urine, even in the presence of background interactions and fluorescence inner filter effects, which are both sample dependent. Atenolol is a cardioselective beta-blocker, which is considered a doping agent in shoot practice, so that its determination in urine can be required for monitoring the drug. Loss of trilinearity due to analyte-background interactions which may vary between samples, as well as inner filter effects, precludes the use of methods like parallel factor analysis (PARAFAC) that cannot handle trilinearity deviations, and justifies the employment of U-PLS. Successful analysis required to include the background in the calibration set. Unexpected components appear in new urine samples, different from those used in calibration set, requiring the second-order advantage which is obtained from a separate procedure known as residual bilinearization (RBL). Satisfactory results were obtained for artificially spiked urines, and also for real urine samples. They were statistically compared with those obtained applying a reference method based on high-performance liquid chromatography (HPLC).
Asunto(s)
Atenolol/orina , Cromatografía Líquida de Alta Presión/métodos , Análisis de los Mínimos Cuadrados , Espectrometría de Fluorescencia/métodos , Algoritmos , Atenolol/química , Calibración , Monitoreo de Drogas/métodos , Fluorescencia , Humanos , Reproducibilidad de los ResultadosRESUMEN
The independent determination of two beta-blocker agents, namely propranolol (PROP) and atenolol (ATN), in pharmaceutical formulations using square-wave voltammetry and a cathodically pretreated boron-doped diamond electrode is described. These electroanalytical determinations of propranolol or atenolol were carried out in 0.1molL(-1) H(2)SO(4) or 0.5molL(-1) NaNO(3) (pH 1.0, adjusted with concentrated HNO(3)), respectively. Excellent linear calibration curves, ranging from 0.20 to 9.0micromolL(-1) for PROP and from 2.0 to 41micromolL(-1) for ATN, with detection limits of 0.18 and 0.93micromolL(-1), respectively, were obtained. The obtained recoveries range from 93.9% to 105.0%, for PROP, and from 92.5% to 106.0%, for ATN. The proposed method was successfully applied in the determination of both beta-blockers in several pharmaceutical formulations (tablets), with results in close agreement at a 95% confidence level with those obtained using official spectrophotometric methods.
Asunto(s)
Atenolol/química , Boro/química , Técnicas de Química Analítica , Diamante/química , Preparaciones Farmacéuticas/análisis , Propranolol/química , Antagonistas Adrenérgicos beta/análisis , Química Farmacéutica/métodos , Electroquímica/métodos , Electrodos , Límite de Detección , Modelos Químicos , Potenciometría , ComprimidosRESUMEN
This article reports the development and delivery properties of swellable drug-polyelectrolyte matrices prepared with complexes of the acid form of carboxymethylcellulose (HCMC). Drug-polyelelectrolyte complexes (HCMC-D) were obtained by neutralization of HCMC with two model basic drugs (atenolol and metoclopramide). Characterization through FT-infrared spectroscopy, power X-ray diffraction, and DSC indicates the ionic nature of the interaction between the carboxylic groups of HCMC and the basic group of D. Matrices prepared by compacting (HCMC-D) alone or in a mixture with sodium carboxymethylcellulose were subjected to measurements of solvent up-take, dynamics of swelling, and release kinetics. Delivery rate of mixed matrices is a function of its composition and may be widely modulated. They exhibited anomalous delivery kinetics with Korsmeyer exponent n in the range 0.67-0.87. Experimental results indicate that the erosion of the hydrogel layer is the main delivery process.
Asunto(s)
Carboximetilcelulosa de Sodio/química , Sistemas de Liberación de Medicamentos/métodos , Preparaciones Farmacéuticas/química , Atenolol/administración & dosificación , Atenolol/química , Atenolol/farmacocinética , Disponibilidad Biológica , Tampones (Química) , Rastreo Diferencial de Calorimetría , Carboximetilcelulosa de Sodio/análogos & derivados , Metoclopramida/administración & dosificación , Metoclopramida/química , Metoclopramida/farmacocinética , Preparaciones Farmacéuticas/administración & dosificación , Reología , Espectroscopía Infrarroja por Transformada de Fourier , Agua/química , Difracción de Rayos XRESUMEN
We report microwave-assisted synthetic routes, the pharmacokinetic profile along with results from ulcerogenicity and mutagenicity studies of atenolol aspirinate, and an already described derivative, in which acetyl salicylic acid (aspirin) was connected to atenolol by an ester linkage. Atenolol aspirinate was stable towards aqueous hydrolysis but rapidly hydrolyzed in plasma (t(1/2) = 7.6 min). The results showed that the rapid and complete hydrolysis generates atenolol salicylate, which assumes a conformation stabilized by two intramolecular H-bonds, avoiding its further hydrolysis to salicylic acid and atenolol.
Asunto(s)
Antihipertensivos/farmacocinética , Aspirina/química , Atenolol/farmacocinética , Animales , Antihipertensivos/química , Antihipertensivos/metabolismo , Área Bajo la Curva , Atenolol/química , Atenolol/metabolismo , Mucosa Gástrica/efectos de los fármacos , Semivida , Humanos , Microondas , Modelos Moleculares , Pruebas de Mutagenicidad , Profármacos/química , Profármacos/metabolismo , Profármacos/farmacocinéticaRESUMEN
Atenolol [4-(2-hydroxy-isopropylaminopropoxy)-phenylacetamide], is a cardioselective beta1-adrenergic receptor blocking agent prescribed for treatment of hypertension, angina pectoris and cardiac arrhythmias. However, most of these medicines are not formulated for easy or accurate administration to children. Atenolol is unstable in solutions and therefore the development of a liquid dosage form is a significant challenge. Studies showed that the degradation rate of atenolol is dependent on the temperature, indicating higher stability at 4 degrees C. Atenolol syrup is stable for 9 days, with acceptable apearance. A second order model adequately described atenolol decomposition when stored as syrup. A stability-indicating method was developed and validated in order to evaluate these studies.
Asunto(s)
Antagonistas Adrenérgicos beta/administración & dosificación , Antagonistas Adrenérgicos beta/química , Atenolol/administración & dosificación , Atenolol/química , Química Farmacéutica , Niño , Cromatografía Líquida de Alta Presión , Estabilidad de Medicamentos , Humanos , Indicadores y Reactivos , Cinética , Estándares de Referencia , Reproducibilidad de los Resultados , Soluciones , Espectrofotometría UltravioletaRESUMEN
This study deals with the development and characterization of the delivery properties of swellable drug-polyelectrolyte matrices (SDPM) of alginic acid (AA). Complexes (AA-D)(x) in solid state were obtained by neutralization of AA with different molar proportions (x) of model basic drugs (D), in which D is atenolol, metoclopramide and propranolol. They were characterized by DSC, IR and X-ray diffraction. Matrices prepared by compaction of (AA-D)(x) alone or in a mixture with sodium alginate (NaAA) were subjected to measurements of solvent up-take, release kinetics and erosion in three media (water, buffer of pH 6.8 and 0.01 M HCl). In addition, the dynamics of swelling was also evaluated. All SDPM assayed exhibited a remarkable zero order of delivery in water and buffer of pH 6.8 and also in two-step delivery experiments: 2 h in acid medium followed by a second step at pH 6.8. Experimental results indicate that the erosion of the hydrogel layer is the main delivery process. Delivery rate, can be modulated either by varying the composition of (AA-D)(x) or by diluting it with NaAA.
Asunto(s)
Alginatos/química , Hidrogeles/química , Agua/química , Atenolol/química , Rastreo Diferencial de Calorimetría , Sistemas de Liberación de Medicamentos , Ácido Glucurónico/química , Dureza , Ácidos Hexurónicos/química , Metoclopramida/química , Propranolol/química , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos XRESUMEN
Different chemometric methods such as classical least squares (CLS), principal components regression (PCR) and partial least squares with one dependent variable (PLS-1) applied on UV spectral data (0 D) and on their first derivatives (1 D) were evaluated for the simultaneous quantification of samples containing mixtures of amiloride hydrochloride, atenolol, hydrochlorothiazide and timolol maleate. Their performances were compared by means of ANOVA tests, which evidenced that 0 D-PCR, 0D-PLS-1, 1D-PCR, 1D-PLS-1, were reproducible and gave statistically similar results, while 0 D-CLS and 1D-CLS displayed higher variances than the former and failed to comply with the Levene's variance homogeneity test at different stages of the method comparison and validation process. The four statistically equivalent procedures were successfully applied to the analysis of synthetic samples with two to four analytes and to commercial tablet preparations containing amiloride hydrochloride and hydrochlorothiazide alone or in association with atenolol or timolol maleate.
Asunto(s)
Amilorida/análisis , Atenolol/análisis , Hidroclorotiazida/análisis , Timolol/análisis , Amilorida/química , Atenolol/química , Química Farmacéutica , Hidroclorotiazida/química , Análisis de los Mínimos Cuadrados , Espectrofotometría Ultravioleta/métodos , Timolol/químicaRESUMEN
Resolution of binary mixtures of atenolol (ATE) and chlorthalidone (CTD) with minimum sample pre-treatment and without analyte separation has been successfully achieved, using a new and rapid method based on partial least squares (PLS1) analysis of UV spectral data. The simultaneous determination of both analytes was possible by PLS1 processing of sample absorbances between 255 and 300 nm for ATE and evaluation of absorbances in the 253-268 nm region for CTD. The mean recoveries for synthetic samples were 100.3 +/- 1.0% and 100.7 +/- 0.7% for ATE and CTD, respectively. Application of the proposed method to two commercial tablet preparations in the content uniformity test showed them to contain 103.5 +/- 0.8% and 104.9 +/- 1.8% ATE respectively, as well as 103.4 +/- 1.2% and 104.5 +/- 2.2% CTD. Use of this method also allowed the elaboration of dissolution profiles of the drugs in two commercial combined formulation products, through the simultaneous determination of both drugs during the dissolution test. At the dissolution time of 45 min specified by USP XXIV, both pharmaceutical formulations complied with the test.
Asunto(s)
Antihipertensivos/análisis , Atenolol/análisis , Clortalidona/análisis , Espectrofotometría Ultravioleta , Algoritmos , Antihipertensivos/administración & dosificación , Antihipertensivos/química , Atenolol/administración & dosificación , Atenolol/química , Calibración , Clortalidona/administración & dosificación , Clortalidona/química , Combinación de Medicamentos , Reproducibilidad de los Resultados , Espectrofotometría Ultravioleta/normas , ComprimidosRESUMEN
Atenolol (AT) and metoprolol (MT) are predominantly used in the treatment of angina pectoris, certain arrhythmias, systemic hypertension, and several other cardiovascular disorders. Both compounds are produced commercially in the racemic form, although the S-form is responsible for the desired biological effect. This paper describes a simple, rapid, precise, and accurate method for separating the enantiomers of AT and MT. AT isomers are separated by using a Chiralcel OD column (250 x 4.6 mm, 10 microm), hexane-ethanoldiethylamine-acetic acid (60 + 40 + 0.2 + 0.2, v/v/v/v) as the mobile phase, and a flow rate of 1.0 mL/min. MT isomers are separated by using a mobile phase with the same components in the following proportions (40 + 60 + 0.2 + 0.2, v/v/v/v) and a flow rate of 0.8 mL/min. Ultraviolet detection was at 276 nm for both analytes. The coefficients of variation (CVs) and average recoveries (ARs) for the R-enantiomers in samples A, B, C, D, and E were 1.15 and 101.06%, 0.74 and 99.25%, 1.05 and 102.57%, 0.84 and 101.57%, and 0.86 and 98.62%, respectively. The CVs and ARs for the S-enantiomers in samples A, B, C, D, and E were 1.33 and 98.87%, 0.99 and 100.76%, 1.17 and 101.69%, 1.26 and 100.39%, and 1.40 and 99.39%, respectively. The standard curves of R-AT, S-AT, R-MT, and S-MT showed good linearity over the concentration range studied with correlation coefficients of 0.9991, 0.998, 0.9988, and 0.999, respectively.
Asunto(s)
Antagonistas Adrenérgicos beta/análisis , Atenolol/análisis , Cromatografía Liquida/métodos , Metoprolol/análisis , Fenilcarbamatos , Antagonistas Adrenérgicos beta/administración & dosificación , Antagonistas Adrenérgicos beta/química , Antagonistas Adrenérgicos beta/normas , Atenolol/administración & dosificación , Atenolol/química , Atenolol/normas , Carbamatos , Celulosa/análogos & derivados , Humanos , Metoprolol/administración & dosificación , Metoprolol/química , Metoprolol/normas , Estándares de Referencia , Estereoisomerismo , ComprimidosRESUMEN
The separation and quantitative determination of atenolol isomers by chiral high-performance liquid chromatography (HPLC) are described. Atenolol isomers were separated using a Chiralcel OD column (250 x 4.6 mm, 10 microns); the mobile phase was hexane-ethanol-diethylamine (75:25:0.1 v/v/v); ultraviolet detection was at 276 nm; and flow rate was 0.7 ml/min. The coefficient of variation and average recovery of (R)-isomer were 0.60% and 100.37%, respectively, for sample A and 0.69% and 100.63%, respectively, for sample B. The coefficient of variation and average recovery of (S)-isomer were 0.59% and 100.33%, respectively, for sample A and 0.63% and 99.78%, respectively, for sample B.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacocinética , Atenolol/farmacocinética , Cromatografía Líquida de Alta Presión/métodos , Antagonistas Adrenérgicos beta/química , Atenolol/química , Isomerismo , ComprimidosRESUMEN
The production of polymeric complexes in many active drugs with reticulated povidone increased dissolved component percentage. In this work made use a coevaporation technique. Complex formation has been tested by X Ray Diffractometry and Differential Scanning Calorimetry. The percentage of dissolution was determined to the USP XXIII Edition methodology. As can be seen from the results, the Atenolol-reticulated Povidone complexes has greater solubility than the Atenolol mixed with Lactose as excipient.