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1.
Chem Pharm Bull (Tokyo) ; 68(2): 155-160, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32009083

RESUMEN

Combination tablets containing multiple active pharmaceutical ingredients (APIs) are expected to improve patient convenience by decreasing the number of tablets to be taken; thus, numerous formulations containing multiple APIs have recently been developed. To allow for dose adjustments based on patient conditions, many tablets have a bisection line to allow equal division of tablets. However, there have been no investigations regarding content uniformity among divided combination tablets. Therefore, in this study, the content uniformity of combination tablets after division was investigated using near IR and low-frequency (LF) Raman spectroscopy imaging as well as the Japanese Pharmacopoeia (JP) content uniformity tests. As model drugs, five tablets of three combination drugs containing 3-(3,4-dihydroxyphenyl)-L-alanine (L-DOPA) and benserazide hydrochloride (BNS) as APIs for treating Parkinson's disease were bisected; the resultant 10 samples were subjected to the JP content uniformity tests. We found that acceptance values of L-DOPA and BNS were 11.0-21.9% and 13.3-17.5%, respectively, with some non-conformity to the maximum allowed acceptance value (15.0%) as per the current JP. Image analyses by near IR showed that L-DOPA, BNS, lactose, and corn starch were uniformly distributed in each tablet; moreover, LF Raman spectroscopy imaging also supported the result that L-DOPA, BNS, and lactose were evenly distributed. Therefore, drug content in the tablets was uniform; thus, careful manipulation was recommended in the tablet bisection. However, the results of bisection line specifications and hardness tests revealed that the ease of division differed depending on the tablets, which warrants attention.


Asunto(s)
Antiparkinsonianos/análisis , Benserazida/análisis , Levodopa/análisis , Espectroscopía Infrarroja Corta/métodos , Espectrometría Raman/métodos , Combinación de Medicamentos , Comprimidos
2.
Int J Pharm Compd ; 24(1): 77-82, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32023219

RESUMEN

This study reports on the stability of United States Pharmacopeia-grade metronidazole powder and commercially available metronidazole tablets in two dye-free oral suspending vehicles, namely Oral Mix and Oral Mix Sugar-Free. Metronidazole at 50 mg/mL was prepared individually in Oral Mix and Oral Mix Sugar-Free suspension vehicles and placed in 50-mL amber polyethyleneterephthalate bottles and 3-mL amber plastic syringes and stored at 4°C or 25°C/60% relative humidity for 90 days. The solutions were analyzed at the time of preparation and at 7 days, 14 days, 30 days, 45 days, 60 days, 75 days, and 90 days, with the concentration of metronidazole measured by high-performance liquid chromatography with photodiode array detection. The oral solutions were also monitored for pH, homogeneity, color, and odor. Except for the Oral Mix suspension of metronidazole prepared from the United States Pharmacopeia-grade powder and from the commercial tablet, when stored in pre-filled syringes, all the other preparations were stable at 4°C or 25°C/60% relative humidity for 90 days, with the metronidazole remaining within ± 10% of the initial concentration. The pH, color, odor, and resuspendability remained essentially unchanged. Metronidazole in Oral Mix and Oral Mix Sugar-Free oral suspensions, compounded from United States Pharmacopeia-grade powder or commercially available tablets, are a suitable alternative as an extemporaneously prepared medication.


Asunto(s)
Metronidazol , Administración Oral , Cromatografía Líquida de Alta Presión , Composición de Medicamentos/métodos , Estabilidad de Medicamentos , Suspensiones , Comprimidos/administración & dosificación , Estados Unidos
3.
Expert Opin Pharmacother ; 21(3): 261-273, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31914336

RESUMEN

Introduction: Hepatitis C virus (HCV) is estimated to infect approximately 70 million people worldwide. If left untreated, chronic infection can progress to cirrhosis, liver failure or hepatocellular carcinoma. The advent of new direct-acting antivirals (DAA) has revolutionized patients' chances of treatment and viral elimination. Currently, several DAA options are available on the market.Areas covered: This review focuses on the pharmacokinetics, efficacy, tolerability and safety profile of DCV-TRIO, a twice-daily fixed-dose combination of daclatasvir, asunaprevir and beclabuvir approved in Japan for the treatment of genotype 1 HCV infection.Expert opinion: The DCV-TRIO combination achieved good response rates in genotype 1 patients (SVR12 ≥ 95% in naïve subtype 1b), independently from IL28B genotype, cirrhotic status and prior interferon exposure. On the other hand, unsatisfying response rates were reported in DAA-experienced patients and the risk of RAS selection should not be underestimated. Moreover, DCV-TRIO lacks differentiation from its earlier-launched DAA rivals, presents an inconvenient twice-daily dosing schedule and is not recommended in patients with advanced liver and kidney disease. All these drawbacks considerably limit its effective commercial potential. However, it can be a therapeutic option against HCV in tailored approaches according to the needs of different markets across the world.Abbreviations AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ASV: asunaprevir; AUC: area under the curve; BCRP: Breast Cancer Resistance Protein; BCV: boceprevir; BID: bis in die; CI: confidence intervals; CLcr: creatinine clearance; DAA: direct acting antivirals; DCV: daclatasvir; EC50: Half maximal effective concentration; GT: genotype; HCV: Hepatitis C virus; IFN: Interferon; NHL: non-Hodgkin lymphoma; OATP: Organic anion transporting polypeptides; OR: odds ratio; P-gp: P-glycoprotein; PK: pharmacokinetics; QD: quo die; RAS: resistance-associated substitutions; SVR: sustained virological response; USD: Unites States dollar.


Asunto(s)
Benzazepinas/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Imidazoles/administración & dosificación , Indoles/administración & dosificación , Isoquinolinas/administración & dosificación , Sulfonamidas/administración & dosificación , Antivirales/uso terapéutico , Combinación de Medicamentos , Genotipo , Hepacivirus/efectos de los fármacos , Humanos , Cirrosis Hepática/prevención & control , Respuesta Virológica Sostenida , Comprimidos , Resultado del Tratamiento
4.
AAPS PharmSciTech ; 21(2): 39, 2020 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-31897724

RESUMEN

The development of orodispersible tablets (ODTs) for poorly soluble and poorly flowable drugs via direct compression is still a challenge. This work aimed to develop ODTs of poorly soluble drugs by combining cyclodextrins that form inclusion complexes to improve wetting and release properties, and directly compressible co-processed excipients able to promote rapid disintegration and solve the poor flowability typical of inclusion complexes. Carbamazepine (CBZ) and hydroxypropyl-ß-cyclodextrin (HPßCD) were used, respectively, as a model of a poorly soluble drug with poor flowability and as a solubilizing agent. Specifically, CBZ-an antiepileptic and anticonvulsant drug-may benefit from the studied formulation approach, since some patients have swallowing difficulties or fear of choking and are non-cooperative. Prosolv® ODT G2 and F-Melt® type C were the studied five-in-one co-processed excipients. The complex was prepared by kneading. Flow properties of all materials and main properties of the tablets were characterized. The obtained results showed that ODTs containing CBZ/HPßCD complex can be prepared by direct compression through the addition of co-processed excipients. The simultaneous use of co-processing and cyclodextrin technologies rendered ODTs with an in vitro disintegration time in accordance with the European Pharmacopoeia requirement and with a fast and complete drug dissolution. In conclusion, the combination of five-in-one co-processed excipients and hydrophilic cyclodextrins may help addressing the ODT formulation of poorly soluble drugs with poor flowability, by direct compression and with desired release properties.


Asunto(s)
2-Hidroxipropil-beta-Ciclodextrina/química , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/química , Carbamazepina/administración & dosificación , Carbamazepina/química , Rastreo Diferencial de Calorimetría , Composición de Medicamentos , Liberación de Fármacos , Excipientes , Comprimidos , Difracción de Rayos X
5.
AAPS PharmSciTech ; 21(2): 40, 2020 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-31897805

RESUMEN

There is a need to develop in vitro dissolution methods that discriminate for particle size of the manipulated abuse deterrent formulation (ADF) and that can be used for in vivo predictive models since dissolution methods developed for intact formulation might not be suitable for manipulated ones. A vertical diffusion cell (VDC) and United States Pharmacopeia (USP) Apparatus 1, 2, and 4 were evaluated for measuring the dissolution of intact and manipulated metoprolol succinate tablets with abuse deterrent-like properties. These tablets were physically manipulated to produce fine (106-500 µm) and coarse (500-1000 µm) powder samples. The VDC method was not able to discriminate the effect of particle size on drug release with varied stirring rate (200 to 800 rpm), molecular weight cut-off (MWCO, 3-5 kDa to 12-14 kDa) of the diffusion membrane, or composition and ionic strength (0.45% and 0.9%) of receiver medium. Standard and modified USP Apparatus 1 and 2 methods were assessed; however, large variations (RSD > 20%) were observed with USP Apparatus 1 for manipulated product dissolution and floating powder samples caused failure of auto-sampling when using standard USP Apparatus 2. For the USP Apparatus 4 dissolution method, packing configuration (1, 3, 8 layers and blend), ionic strength of dissolution medium (0.017, 0.077, and 0.154 M additional NaCl), and flow rate (4, 8, 16 mL/min) were studied to discriminate the effect of particle size on release. The USP Apparatus 4 dissolution method was optimized by using a packaging configuration of 8 layers with 8 mL/min flow rate which exhibited low variability and complete drug release and it could be used for in vivo predictive models. The dissolution method variables can be optimized for a specific product for desirable reproducibility and discriminatory power when using USP Apparatus 4.


Asunto(s)
Formulaciones Disuasorias del Abuso , Composición de Medicamentos/métodos , Liberación de Fármacos , Mal Uso de Medicamentos de Venta con Receta/prevención & control , Difusión , Metoprolol/administración & dosificación , Metoprolol/química , Modelos Teóricos , Peso Molecular , Tamaño de la Partícula , Polvos , Solubilidad , Comprimidos
6.
Drug Dev Ind Pharm ; 46(1): 146-158, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31894720

RESUMEN

The aim of this research was to assess the effect of polymer blend and effervescent components on the floating and swelling behaviors of swellable gastro-floating formulation as well as the drug release through a compartmental modeling analysis. Swellable gastro-floating formulation of freely water-soluble drug, metformin HCl as a drug model, was formulated and developed using D-optimal design. Polymer combination between interpolymer complex (IPC) (poly-vinyl acetate-copolymer methacrylate) and hydroxy propyl methyl cellulose (HPMC), and effervescent components were studied and optimized in this work. Several factors affecting the drug release behavior were determined e.g. swelling behavior, erosion behavior, and floating behavior were studied as well as the drug release through compartmental modeling analysis. The results revealed that the hydrophilic polymer was responsible for gas entrapment formed from effervescent reaction, meanwhile IPC contributed on maintaining the swollen matrix integrity through intermolecular polymer interaction. In addition, effervescent components played fundamental role in the formation of porous system as well as inducing burst release effect. Compartmental modeling provided different outlook about the drug release. Presence of IPC at a high proportion (10-15%) of the polymer blend modulated the changes of pattern of the drug release kinetics and mechanism. Finally, compartmental modeling-based approach was more adequate to describe the drug release kinetics and mechanism compared to the monophasic equation model correlating with process understanding of the drug release from swellable gastro-floating formulation.


Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Metacrilatos/química , Polímeros/química , Estómago/fisiología , Administración Oral , Liberación de Fármacos , Derivados de la Hipromelosa/química , Derivados de la Hipromelosa/farmacología , Cinética , Metacrilatos/farmacología , Comprimidos
7.
Int J Clin Pharmacol Ther ; 58(3): 177-182, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31933472

RESUMEN

OBJECTIVE: The objective of this study was to evaluate and compare the pharmacokinetics of domperidone tablets in Chinese healthy subjects both under fasting and fed conditions. MATERIALS AND METHODS: A total of 36 subjects were recruited to the monocentric pharmacokinetic study. All subjects were randomly divided into two groups. One group was given a single 10-mg oral dose of domperidone tablet after ~ 10 hours of fasting, and the other group was given the same oral dose of domperidone tablet 30 minutes after a high-fat meal. 18 blood samples were collected over 24 hours for every subject. Plasma concentrations of domperidone were analyzed by a rapid and sensitive UPLC-MS/MS assay, and the pharmacokinetic parameters were determined by the standard non-compartmental method. RESULTS: A significant difference was observed in the pharmacokinetics of domperidone between fasting and fed subjects. The AUC0-24h (area under curve of plasma concentration until the last concentration observed) was 75.71 h×µg/L in the fed subjects, which was much higher than AUC0-24h (56.76 h×µg/L) in the fasting subjects. For the fasting test, the T1/2 (elimination half-life) was 7.15 hours, Cmax (the maximum plasma concentration) was 16.97 µg/L, and tmax; was 0.79 hours. For the fed test, the T1/2 was 8.72 hours, Cmax was 15.11 µg/L, and tmax was 1.66 hours. T1/2 and tmax were both prolonged under fed condition when comparing fed condition to fasting condition. CONCLUSION: In this study, the absorption and elimination of domperidone was slowed down by a high-fat meal, with the mean tmax being 52% longer and T1/2 18% longer in fed subjects than in fasting subjects. In addition, a high-fat meal increased the exposure of domperidone, with the mean AUC being 25% more in fed subjects than in fasting subjects, which provided an important reference for the clinical application of domperidone in the Chinese population.


Asunto(s)
Cromatografía Líquida de Alta Presión , Domperidona/farmacocinética , Ayuno , Espectrometría de Masas en Tándem , Adolescente , Adulto , Área Bajo la Curva , Grasas de la Dieta/administración & dosificación , Femenino , Voluntarios Sanos , Humanos , Masculino , Comidas , Persona de Mediana Edad , Comprimidos , Equivalencia Terapéutica , Adulto Joven
8.
Anal Bioanal Chem ; 412(4): 1011-1024, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31897563

RESUMEN

Cabbage flower-like Ho3+/NiO nanostructure (CFL-Ho3+/NiO NSs) with significant electrocatalytic oxidation has been published for the first time. First, structure and morphology of CFL-Ho3+/NiO-NSs have been described by XRD, SEM, and EDX methods. Then, CFL-Ho3+/NiO-NSs have been applied as a modifier for simultaneous electrochemical detection of methotrexate (MTX) and carbamazepine (CBZ). Functions of the modified electrode have been dealt with through electrochemical impedance spectroscopy (EIS). It has been demonstrated that the electrode response has been linear from 0.001-310.0 µM with a limit of detection of 5.2 nM and 4.5 nM (3 s/m) through DPV for MTX and CBZ. Diffusion coefficient (D) and heterogeneous rate constant (kh) have been detected for MTX and CBZ oxidation at the surface of the modified electrode. Moreover, CFL-Ho3+/NiO-NS/GCE has been employed for determining MTX and CBZ in urine and drug specimens. Outputs showed the analyte acceptable recovery. Therefore, the electrode could be applied to analyze both analytes in drug prescription and clinical laboratories. Graphical abstract Electrochemical sensor based on bifunctional cabbage flower-like Ho3+/NiO nanostructures modified glassy carbon electrode for simultaneous detecting methotrexate and carbamazepine was fabricated.


Asunto(s)
Analgésicos no Narcóticos/farmacocinética , Carbamazepina/farmacocinética , Monitoreo de Drogas/métodos , Inmunosupresores/farmacocinética , Metotrexato/farmacocinética , Analgésicos no Narcóticos/análisis , Analgésicos no Narcóticos/sangre , Analgésicos no Narcóticos/orina , Carbamazepina/análisis , Carbamazepina/sangre , Carbamazepina/orina , Técnicas Electroquímicas/métodos , Holmio/química , Humanos , Inmunosupresores/análisis , Inmunosupresores/sangre , Inmunosupresores/orina , Límite de Detección , Metotrexato/análisis , Metotrexato/sangre , Metotrexato/orina , Nanoestructuras/química , Níquel/química , Oxidación-Reducción , Comprimidos
9.
Forensic Sci Int ; 307: 110143, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31931435

RESUMEN

The adverse health effects of falsified medicines for erectile dysfunction have been reported in Japan. We purchased tadalafil (Cialis) tablets online and assessed their authenticity and quality. Of the 45 samples we tested, nine were genuine, 23 were falsified, nine were unregistered/unlicensed samples, and the authenticity of four samples could not be ascertained. Observation of packaging and tablet size, weight, and color revealed differences between some genuine and falsified samples. All genuine samples contained the active pharmaceutical ingredient tadalafil at adequate quantities, while falsified samples contained sildenafil (Viagra). Some falsified samples contained insufficient quantities of tadalafil. All unregistered/unlicensed samples contained neither tadalafil nor sildenafil. Some falsified samples did not dissolve/disintegrate sufficiently. The status of most samples was detectable by Raman scattering and near-infrared spectroscopy. Restricting consumer access to falsified medicines can prevent undesirable health effects.


Asunto(s)
Comercio , Medicamentos Falsificados , Internet , Inhibidores de Fosfodiesterasa 5/química , Tadalafilo/química , Humanos , Japón , Espectroscopía Infrarroja Corta , Espectrometría Raman , Comprimidos
10.
Biomed Chromatogr ; 34(1): e4719, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31634417

RESUMEN

A quality by design (QbD) based high-resolution HPLC method is described for determination of impurities in apixaban (APX) in the tablet dosage form. Employing a simple and stability-indicating HPLC method, nine known impurities were quantified with good peak resolution. Mobile phase A (MP-A) was prepared with buffer and acetonitrile 90:10 v/v, while mobile phase B (MP-B) contained water and acetonitrile 10:90 v/v. The gradient program was 0 min, MP-A 75%, B 25%; 20 min, MP-A 65%, B 35%; 30 min, MP-A 40%, B 60%; 40min, MP-A 40%, B 60%; 42 min, MP-A 75%, B 25%; and 50 min, MP-A 75%, B 25%. The chromatographic separation was achieved using a Zorbax RX C18 250 × 4.6 mm column, 5 µm (1.0 ml min-1 , 280 nm, 50 µl) and a column temperature of 40°C. Several separation studies were carried out using design of experiments to optimize the method. Validation results confirm the applicability of the developed method for quality analysis and stability studies of the regular product on the manufacturing stream.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Cromatografía de Fase Inversa/métodos , Contaminación de Medicamentos , Pirazoles/análisis , Pirazoles/química , Piridonas/análisis , Piridonas/química , Estabilidad de Medicamentos , Límite de Detección , Modelos Lineales , Reproducibilidad de los Resultados , Comprimidos
11.
Int J Radiat Oncol Biol Phys ; 106(2): 320-328, 2020 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-31669562

RESUMEN

PURPOSE: Oral mucositis (OM) is a frequent and painful sequela of concomitant chemoradiation (CRT) used for the treatment of head and neck cancer (HNC) for which there is no effective intervention. This randomized, placebo-controlled study evaluated the efficacy of a novel, mucoadhesive topical tablet formulation of clonidine in mitigating CRT-induced OM in patients with HNC. METHODS AND MATERIALS: Patients with HNC undergoing adjuvant radiation therapy (60-66 Gy; 5 × 1.8-2.2 Gy/wk) with concomitant platinum-based chemotherapy received daily local clonidine at 50 µg (n = 56), 100 µg (n = 65), or placebo (n = 62) via a topical mucobuccal tablet starting 1 to 3 days before and continuing during treatment. The primary endpoint was the incidence of severe OM (severe OM [SOM], World Health Organization grade 3/4). RESULTS: SOM developed in 45% versus 60% (P = .06) of patients treated with clonidine compared with placebo and occurred for the first time at 60 Gy as opposed to 48 Gy (median; hazard ratio, 0.75 [95% confidence interval, 0.484-1.175], P = .21); median time to onset was 45 versus 36 days. Opioid analgesic use, mean patient-reported mouth and throat soreness, and CRT compliance were not significantly different between treatment arms. Adverse events were reported in 90.8% versus 98.4%, nausea in 49.6% versus 71.0%, dysphagia in 32.8% versus 48.4%, and reversible hypotension in 6.7% versus 1.6% of patients on clonidine versus placebo, respectively. CONCLUSIONS: Although the primary endpoint was not met, the positive trends of OM-associated outcomes suggest that the novel mucoadhesive tablet delivery of clonidine might favorably affect the course and severity of CRT-induced SOM and support further evaluation.


Asunto(s)
Quimioradioterapia/efectos adversos , Clonidina/administración & dosificación , Neoplasias de Cabeza y Cuello/radioterapia , Protectores contra Radiación/administración & dosificación , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Estomatitis/prevención & control , Administración Bucal , Adulto , Anciano , Analgésicos Opioides/administración & dosificación , Clonidina/efectos adversos , Intervalos de Confianza , Trastornos de Deglución/etiología , Método Doble Ciego , Esquema de Medicación , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Protectores contra Radiación/efectos adversos , Dosificación Radioterapéutica , Estomatitis/etiología , Comprimidos , Adulto Joven
12.
Cancer Sci ; 111(2): 536-547, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31778267

RESUMEN

Capmatinib is an oral, ATP-competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose-escalation results for capmatinib in advanced MET-positive solid tumor patients and dose expansion in advanced non-lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose-limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, Ctrough >EC90 (90% inhibition of c-MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose-expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near-complete immunohistochemically determined phospho-MET inhibition (H-score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high-level MET GCN (GCN ≥6) and MET-overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479).


Asunto(s)
Imidazoles/administración & dosificación , Neoplasias/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/metabolismo , Triazinas/administración & dosificación , Anciano , Cápsulas , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Imidazoles/efectos adversos , Imidazoles/farmacocinética , Masculino , Persona de Mediana Edad , Mutación , Neoplasias/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Comprimidos , Resultado del Tratamiento , Triazinas/efectos adversos , Triazinas/farmacocinética
13.
J Chromatogr Sci ; 57(10): 881-891, 2020 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-31609431

RESUMEN

In the present study, we developed a reliable and robust chromatographic method for the quantification of multivitamins in tablet samples by ultra-performance liquid chromatography (UPLC) with photodiode array detection. The vitamins nicotinamide, pyridoxine, riboflavin, and thiamin were analyzed and quantified in a total analysis time of 2.5 minutes, using hydrophilic interaction liquid chromatography stationary phase. Tocopherol acetate and cyanocobalamin were analyzed and quantified in a total analysis time of 2.5 minutes, using reversed-phase (RP)-UPLC. The analysis time reported here is lower than that of similar methods reported in the literature for single vitamin determination. The method linearity exhibits a good correlation coefficient (R2 = 0.998) with the relative residual standard deviation in the acceptable limit of 2.0%. The developed methods were validated, and the results demonstrated that the proposed analytical method showed to be selective, sensitive, accurate, and robust for the quantification of evaluated vitamins in multivitamin tablets. The work was fully developed in the quality control laboratory of a pharmaceutical industry in the Agroindustrial District of Anápolis (DAIA, Goiás, Brazil), where the product is manufactured.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Vitaminas/análisis , Interacciones Hidrofóbicas e Hidrofílicas , Límite de Detección , Modelos Lineales , Reproducibilidad de los Resultados , Comprimidos
14.
J Chromatogr Sci ; 57(10): 910-919, 2020 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-31644804

RESUMEN

A new ultra-high-performance liquid chromatography method for the simultaneous quantification of sofosbuvir, daclatasvir and ledipasvir was developed. Two combinations of these direct-acting antivirals are used in hepatitis C virus infection therapy and show high efficacy and safety. Fractional factorial design was used for screening the most influential factors on separation and time analysis. These significant factors were optimized using a central composite design. The optimum resolution was carried out by using a Waters XBridge C18 column (150 mm, 4.6 mm ID, 5 µm) at a temperature of 35°C ± 2°C and acetonitrile/sodium perchlorate buffer (10 mM, pH = 3.2) (40: 60 v/v) as mobile phase at a flow rate of 1.5 mL min-1. UV detection was set at λ = 210 nm. A short chromatographic separation time was achieved. The developed method was validated according to the accuracy profile approach and was found specific, precise, faithful and accurate. The detection limits were between 0.07 and 0.13 µg mL-1. Hence, this novel method can be employed for the routine quality control analysis and in dissolution profile studies of generics containing these products.


Asunto(s)
Bencimidazoles/análisis , Cromatografía Líquida de Alta Presión/métodos , Fluorenos/análisis , Imidazoles/análisis , Sofosbuvir/análisis , Bencimidazoles/química , Fluorenos/química , Imidazoles/química , Límite de Detección , Modelos Lineales , Reproducibilidad de los Resultados , Sofosbuvir/química , Comprimidos
15.
Int J Clin Pharmacol Ther ; 58(1): 57-65, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31347489

RESUMEN

OBJECTIVE: This study was conducted to evaluate the pharmacokinetic properties and bioequivalence of two oral formulations of canagliflozin: a newly developed generic formulation (test) and a branded formulation (reference). MATERIALS AND METHODS: A randomized, open-label, two-way crossover study was conducted in 55 healthy Chinese subjects. They were randomized to receive a single oral dose of 100 mg of test or reference canagliflozin tablets according to an open crossover design under fasting and fed states. Plasma canagliflozin concentrations were determined by liquid chromatography-tandem mass spectrometry, and the pharmacokinetic parameters maximum concentration (Cmax) and area under the concentration-time curve (AUC0-t and AUC0-∞) were used to evaluate bioequivalence. RESULTS: The geometric mean ratio 90% confidence intervals for fasting Cmax, AUC0-t, and AUC0-∞ were 85.14 - 114.40%, 102.14 - 106.51%, and 102.21 - 106.85%, respectively, and fed Cmax, AUC0-t, and AUC0-∞ were 90.15 - 107.17%, 97.38 - 102.19%, and 96.78 - 101.92%, respectively. The mean values of tmax were prolonged in the test compared with the reference formulations. In addition, the mean values of tmax and Cmax for both formulations were significantly different under fed compared with fasting conditions, while there was no significant difference in AUC0-t or AUC0-∞. CONCLUSION: The two types of canagliflozin tablets were bioequivalent under both fasting and fed states, and both were generally well tolerated.


Asunto(s)
Canagliflozina/administración & dosificación , Canagliflozina/farmacocinética , Administración Oral , Área Bajo la Curva , Cromatografía Liquida , Estudios Cruzados , Humanos , Comprimidos , Equivalencia Terapéutica
16.
Biomed Chromatogr ; 34(2): e4755, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31755118

RESUMEN

The main objective of this study was to establish an efficient extraction procedure for the estimation of telmisartan, amlodipine and chlorthalidone from their combination in sample matrix using an analytical quality by design approach. Initial screening studies were performed for optimization of a suitable diluent to extract active components from sample matrix. Further, the same study was extended for the identification of critical method attributes and the factors affecting the analytical target profile. This study also explains the rugged and robust quantitative determination of combinations drugs with a shorter run time. The design of experimental studies confirms that the current center point parameters are well suited to recoveries. The chromatographic separation was achieved with an X-Terra RP8, 150 × 4.6 mm, 3.5 µm column with an isocratic mobile phase (mixture of 20 mm aqueous ammonium acetate and acetonitrile). To demonstrate the stability-indicating nature of the optimized method, forced degradation studies were conducted and proved. The optimized method was validated according to International Conference on Harmonization guidelines.


Asunto(s)
Amlodipino/análisis , Clortalidona/análisis , Telmisartán/análisis , Amlodipino/química , Amlodipino/aislamiento & purificación , Clortalidona/química , Clortalidona/aislamiento & purificación , Cromatografía Líquida de Alta Presión/métodos , Combinación de Medicamentos , Límite de Detección , Modelos Lineales , Reproducibilidad de los Resultados , Proyectos de Investigación , Comprimidos , Telmisartán/química , Telmisartán/aislamiento & purificación
17.
Int J Clin Pharmacol Ther ; 58(2): 112-120, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31829925

RESUMEN

OBJECTIVE: The purpose of this study was to evaluate the bioequivalence of two formulations of atorvastatin using the reference-scaled average bioequivalence (RSABE) method and to study the pharmacokinetics of atorvastatin in healthy Chinese subjects under fed conditions. MATERIALS AND METHODS: A single-dose, randomized, open-label, four-way crossover study was conducted in healthy Chinese subjects after informed consent was obtained. Healthy subjects were randomly assigned to receive 20 mg of either the test or reference formulation, following a 7-day washout period. The formulations were considered bioequivalent if 90% confidence intervals (CIs) for the ln-transformed ratios and ratio of geometric means (GMR) of AUC and Cmax of atorvastatin were within the bioequivalence range (80 - 125%). Plasma atorvastatin, ortho-hydroxy atorvastatin and para-hydroxy atorvastatin concentrations were analyzed by liquid chromatography-tandem mass spectrometry. Tolerability was assessed during the entire study period. RESULTS: ANOVA indicated that the period, sequence, and formulation had no significant effect on the pharmacokinetic parameters (p < 0.05). The test formulation was bioequivalent to the marketed formulation as the 90% CIs for natural log-transformed ratios of atorvastatin of Cmax (88.45 - 103.57%), AUC0-t (98.08 - 104.89%) and AUC0-∞ (98.15 - 104.87%) were within equivalence limits (80 - 125%). No serious adverse events were found among the subjects. CONCLUSION: The RSABE approach was successful in evaluating the bioequivalence of these two formulations. This study confirmed that test and reference atorvastatin calcium tablets were bioequivalent under fed condition.


Asunto(s)
Atorvastatina/farmacocinética , Medicamentos Genéricos/farmacocinética , Administración Oral , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Humanos , Comprimidos , Equivalencia Terapéutica
18.
Int J Clin Pharmacol Ther ; 58(2): 121-127, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31699211

RESUMEN

BACKGROUND AND OBJECTIVE: Varenicline is an effective drug for smoking cessation. The aim of the present study was to compare the pharmacokinetics and safety profiles of two different varenicline formulations (varenicline tartrate (reference) and varenicline oxalate (test)), each containing 1 mg varenicline base in humans. MATERIALS AND METHODS: A randomized, open-label, two-sequence, two-period, single-dose crossover study with a 2-week washout period was conducted with 30 healthy male participants. Blood samples for the pharmacokinetic analysis of varenicline were collected up to 96 hours following the administration of each drug. Pharmacokinetic parameters were also calculated, including the peak plasma concentration (Cmax), area under the plasma concentration-time curve (AUC) from time zero to the time of the last measurable concentration (AUClast) as well as AUC from time zero to infinity (AUCinf). ANOVA for pharmacokinetic equivalence was assessed using log-transformed Cmax and AUC values, and the geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) were assessed as well. The safety profiles were also assessed. RESULTS: 27 participants completed the study. No significant differences were found for any pharmacokinetic parameters of varenicline between the two formulations. The observed average values of Cmax, AUClast, and AUCinf were 4.46 ng/mL, 97.68 ng×h/mL, and 101.60 ng×h/mL for reference and 4.54 ng/mL, 97.10 ng×h/mL, and 100.97 ng×h/mL for test, respectively. The GMRs and 90% CIs for Cmax, AUClast, and AUCinf were 1.0106 (0.9626 - 1.0610), 0.9904 (0.9540 - 1.0282), and 0.9885 (0.9517 - 1.0268), respectively. No clinically relevant changes were observed in the physical, biochemical, hematologic, electrocardiographic, or urinalysis findings during the study, and no serious adverse events were found. CONCLUSION: The results of the present study reveal that varenicline oxalate and varenicline tartrate have similar pharmacokinetic characteristics as varenicline, and that these two formulations exhibit pharmacokinetic equivalence to meet the regulatory criteria. Both varenicline formulations were generally well tolerated.


Asunto(s)
Oxalatos/farmacocinética , Vareniclina/farmacocinética , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Humanos , Masculino , Comprimidos , Equivalencia Terapéutica
19.
Spectrochim Acta A Mol Biomol Spectrosc ; 224: 117407, 2020 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-31404760

RESUMEN

As expired medical products can be repackaged and sold by unscrupulous counterfeiters, it is essential to find a rapid and convenient method for distinguishing expired and unexpired drugs. Standard detection methods such as high-performance liquid chromatography (HPLC) and thin-layer chromatography are complex, time-consuming, and require organic solvents (that are environmentally unfriendly). Additionally, the Pharmacopoeia publications do not include information about identifying expired drugs. In this study, we proposed a novel method for identifying expired medications based on Raman spectra and verified it using >20 types of expired (Old) and unexpired (New) drugs, each type from the same manufacturer. A portable Raman spectrometer was used to collect Raman spectra of all samples and the similarities between the Old and New drugs (SN-O) were evaluated. Drugs with SN-O values <0.9 were classified directly as expired drugs. For drugs with SN-O values >0.9, the content of active pharmaceutical ingredient (API) might be so low (below or around 10 wt%) that its Raman signal is largely obscured by that of the excipients. In such cases, changes in the API content are undetectable using the portable instrument. Therefore, we adopted Raman mapping technology and established a virtual imaging map to locate areas of high API content. The similarities between the Old or New spectrum and that of the API (SO-A and SN-A, respectively) were calculated after removing the signal from the excipients. Our novel methods provide a precise, rapid, convenient, and environmentally friendly way to identify expired drugs that is more effective than the standard HPLC assay.


Asunto(s)
Preparaciones Farmacéuticas/análisis , Espectrometría Raman/métodos , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/normas , Procesamiento de Señales Asistido por Computador , Comprimidos/análisis , Comprimidos/química , Comprimidos/normas
20.
Spectrochim Acta A Mol Biomol Spectrosc ; 224: 117388, 2020 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-31357052

RESUMEN

A new, selective and accurate spectrofluorimetric assay has been described for detection of Amisulpride and Memantine hydrochloride in pharmaceutical formulations and real plasma samples. The described assay depends on the reaction between the primary amino group of the selected drugs with acetyl acetone & formaldehyde in an acetate buffer of pH4.8. The derivatized product showed yellow fluorescence at λex=418nm and λem=484.5nm. The calibration graph was linear in the range of 0.05-0.5 and 0.2-1µgmL-1 for AMS and ME, orderly. The limits of detection were 0.0085 and 0.0153µgmL-1, and the limits of quantitation were 0.026 and 0.0464µgmL-1 for AMS and ME respectively. Validation of the described assay was in consonance with ICH guideline. Due to the sensitivity of the prescribed assay, it permits the determination of selected medications in biological sample quantitatively.


Asunto(s)
Amisulprida/sangre , Memantina/sangre , Espectrometría de Fluorescencia/métodos , Adulto , Femenino , Humanos , Concentración de Iones de Hidrógeno , Límite de Detección , Modelos Lineales , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Comprimidos
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