Quality control and drug-drug interactions between commercially available Metoprolol and Glimepiride tablets

Abstract Quality is paramount and needs to be maintained throughout the shelf life of pharmaceuticals. The current study aimed to evaluate the quality, potency, and drug-drug interaction in an in vivo animal model by using two drugs, namely, metoprolol and glimepiride. Tablets were selected for their physical characteristics, such as shape, size, and color. Quality control tests, such as weight variation, hardness, friability, and disintegration tests, and invitro drug release studies were performed as per USP. Drug-drug interaction and in vivo studies were carried out according to the standard protocol of the animal ethics committee. Quality control tests of both the tablets were within the specified range. The cumulative release percentages of the drugs were 81.12% and 85.36% for Metoprolol Tartrate and Glimepiride, respectively, in a physiological buffer solution within 1 h. The combination of metoprolol and Glimepiride also significantly decreased the blood glucose level in diabetic animals. However, the blood glucose level increased in the group receiving metoprolol only, but the difference was not significant. The result suggested that the formulations are safe. However, the chronic use of this combination requires frequent monitoring of blood glucose level to improve its efficacy and for the patient's safety.

Highly Soluble Glimepiride and Irbesartan Co-amorphous Formulation with Potential Application in Combination Therapy.

One-third of the population of the USA suffers from metabolic syndrome (MetS). Treatment of patients with MetS regularly includes drugs prescribed simultaneously to treat diabetes and cardiovascular diseases. Therefore, the development of novel multidrug formulations is recommended. However, the main problem with these drugs is their low solubility. The use of binary co-amorphous systems emerges as a promising strategy to increase drug solubility. In the present study, irbesartan (IBS) and glimepiride (GMP), class II active pharmaceutical ingredients (API), widely used in the treatment of arterial hypertension and diabetes, were selected to develop a novel binary co-amorphous system with remarkable enhancement in the dissolution of both APIs. The phase diagram of IBS-GMP was constructed and co-amorphous systems were prepared by melt-quench, in a wide range of compositions. Dissolution profile (studied at pH 1.2 and 37°C for mole fractions 0.01, 0.1, and 0.5) demonstrated that the xGMP = 0.01 formulation presents the highest enhancement in its dissolution. GMP went from being practically insoluble to reach 3.9 ± 0.9 µg/mL, and IBS showed a 12-fold increment with respect to the dissolution of its crystalline form. Infrared studies showed that the increase in the dissolution profile is related to the intermolecular interactions (hydrogen bonds), which were dependent of composition. Results of structural and thermal characterization performed by XRD and DSC showed that samples have remained in amorphous state for more than 10 months of storage. This work contributes to the development of a highly soluble co-amorphous drugs with potential used in the treatment of MetS.

Pharmacokinetics and pharmacodynamics of glimepiride polymorphs.

Glimepiride (GLIM) is used as an oral antihyperglycemic agent for treatment of type 2 diabetes. The drug presents two polymorphic forms (GLIM form I and GLIM form II) described in the literature, and according to in vitro data, GLIM form II is about 3.5 times more soluble and releases 2 times the drug amount than GLIM form I in the physiological pH range. Considering the literature in vitro data and that the diabetes treatment demands glycemic control, avoiding abrupt fluctuations in the blood glucose levels, this work aimed to study the impact of GLIM polymorphism in the in vivo performance of GLIM solid oral dosages. For this, hard gelatin capsules with GLIM form I or II were prepared and orally administered in rats. After that, pharmacokinetic studies were performed by sampling animal blood at different times, and biochemical parameters (pharmacodynamic), such as glucose and insulin, were also evaluated. Our results showed that the in vitro data corroborate with our in vivo assays. GLIM form II provided higher plasma concentration of drug than form I (at baseline up to approximately 200 min after oral administration) and, consequently, increased insulin release and reduced levels of glucose, showing good correlation between pharmacokinetic and pharmacodynamics assays. Thus, this study demonstrated that GLIM polymorphs in oral dosages might alter the drug efficacy, which may expose the patients to risks, such as hypoglycemia.

Estudo comparativo da biodisponibilidade relativa de duas formulações de glimepirida em voluntários sadios de ambos os sexos após administração de uma dose única de um comprimido de 4 mg / Comparison study of two glimepiride formulations bioavailability in healthy volunteers of both sexes after a single dose administration

OBJETIVO: Comparar a biodisponibilidade de duas formulações de glimepirida em 26 voluntários sadios de ambos os sexos. MATERIAL E MÉTODOS: O estudo foi aberto, cruzado e randomizado com dois períodos e wash out de 14 dias. As amostras foram obtidas em um intervalo de 48 horas. As concentrações de glimepirida foram analisadas por HPLC MS/MS. Das curvas de concentração de glimepirida no plasma versus tempo, foram obtidos os seguintes parâmetros farmacocinéticos: ASC(0-t), ASC(0-∞), Cmax, Ke, Tmax e T1/2. RESULTADOS: A razão entre as média geométricas de Glimepirida/Amaryl® 4 mg foi de 102,35 por cento para ASC(0-t); 102,35 por cento para ASC(0-∞) e 99,31 por cento para Cmax. Os intervalos de confiança de 90 por cento (IC 90 por cento) foram de 92,62-109,55 por cento; 95,62-109,55 por cento e 88,60-111,32 por cento, respectivamente. CONCLUSÃO: Como o IC 90 por cento para Cmax, ASC(0-t) e ASC(0-∞) estava dentro do intervalo de 80-125 por cento, concluiu-se que ambas as formulações foram bioequivalentes de acordo com o grau e a extensão de sua absorção.

OBJECTIVE: To compare the bioavailability of two glimepiride 4-mg tablet formulation in 26 healthy volunteers of both sexes. MATERIAL AND METHODS: The study was conducted open with randomized two-period crossover design and a 14-day washout period. Samples were obtained over a 48-hour interval. Glimepiride concentrations were analyzed by LC-MS-MS. From the glimepiride plasma concentration versus time curves the following pharmacokinetic parameters were obtained: AUC(0-last), AUC(0-t), AUC(0-∞), Ke, T1/2, Cmax, and Tmax. RESULTS: Geometric mean of Glimepirida/Amaryl® 4 mg was 102.35 percent for AUC(0-t), 102.35 percent for AUC(0-∞) and 99.31 percent for Cmax. The 90 percent CI was 92.62-109.55 percent; 95.62-109.55 percent e 88.60-111.32 percent, respectively. CONCLUSION: Since the 90 percent CI for both Cmax, AUC(0-t), and AUC(0-∞) were within the interval of 80-125 percent, it was concluded that both formulations were bioequivalent, according to both the rate and extent of absorption.