RESUMEN
Sartans (angiotensin II receptor blockers, ARBs), drugs used in the treatment of hypertension, play a principal role in addressing the global health challenge of hypertension. In the past three years, their potential use has expanded to include the possibility of their application in the treatment of COVID-19 and neurodegenerative diseases (80 clinical studies worldwide). However, their therapeutic efficacy is limited by their poor solubility and bioavailability, prompting the need for innovative approaches to improve their pharmaceutical properties. This review discusses methods of co-crystallization and co-amorphization of sartans with nonpolymeric, low molecular, and stabilizing co-formers, as a promising strategy to synthesize new multipurpose drugs with enhanced pharmaceutical properties. The solid-state forms have demonstrated the potential to address the poor solubility limitations of conventional sartan formulations and offer new opportunities to develop dual-active drugs with broader therapeutic applications. The review includes an in-depth analysis of the co-crystal and co-amorphous forms of sartans, including their properties, possible applications, and the impact of synthetic methods on their pharmacokinetic properties. By shedding light on the solid forms of sartans, this article provides valuable insights into their potential as improved drug formulations. Moreover, this review may serve as a valuable resource for designing similar solid forms of sartans and other drugs, fostering further advances in pharmaceutical research and drug development.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II , Antihipertensivos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Antagonistas de Receptores de Angiotensina/química , Inhibidores de la Enzima Convertidora de Angiotensina/química , Antihipertensivos/química , SolubilidadRESUMEN
In this study, we synthesized a series of seven benzimidazole derivatives incorporating the structural acidic framework of angiotensin II (Ang II) type 1 receptor (AT1R) antagonists (ARA-II) employing a three-step reaction sequence. The chemical structures were confirmed by 1H NMR, 13C NMR and mass spectral data. Through biosimulation, compounds 1-7 were identified as computational safe hits, thus, best candidates underwent ex vivo testing against two distinct mechanisms implicated in hypertension: antagonism of the Ang II type 1 receptor and the blockade of calcium channel. Molecular docking studies helped to understand at the molecular level the dual vasorelaxant effects with the recognition sites of the AT1R and the L-type calcium channel. In an in vivo spontaneously hypertensive rat model (SHR), intraperitoneally administration of compound 1 at 20 mg/kg resulted in a 25 % reduction in systolic blood pressure, demonstrating both ex vivo vasorelaxant action and in vivo antihypertensive multitarget efficacy. ©2024 Elsevier.
Asunto(s)
Antihipertensivos , Bencimidazoles , Simulación del Acoplamiento Molecular , Ratas Endogámicas SHR , Bencimidazoles/química , Bencimidazoles/farmacología , Bencimidazoles/síntesis química , Animales , Antihipertensivos/farmacología , Antihipertensivos/síntesis química , Antihipertensivos/química , Ratas , Relación Estructura-Actividad , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Receptor de Angiotensina Tipo 1/metabolismo , Estructura Molecular , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/síntesis química , Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/química , Canales de Calcio Tipo L/metabolismoRESUMEN
More than 1 billion people worldwide suffer from hypertension; therefore, hypertension management has been categorized as a global health priority. Losartan potassium (LP) is an antihypertensive drug with a limited oral bioavailability of about 33% since it undergoes the initial metabolic cycle. Thus, nasal administration is a unique route to overcome first-pass metabolism. The investigation focused on the potential effects of LP-loaded spanlastic vesicles (SNVs) on LP pharmacodynamics and pharmacokinetic parameters, utilizing a thin-film hydration methodology established on a 3122 full factorial design. Entrapment efficiency (EE%) ranged from 39.8 ± 3.87.8 to 83.8 ± 2.92% for LP-SNVs. Vesicle size (VS) varied from 205.5 ± 6.5.10 to 445.1 ± 13.52 nm, and the percentage of LP released after 8 h (Q8h) ranged from 30.8 ± 3.10 to 68.8 ± 1.45%. LP permeated through the nasal mucosa during 24 h and flocculated from 194.1 ± 4.90 to 435.3 ± 13.53 µg/cm2. After twenty-four hours, the optimal LP-SNVs in-situ gel showed 2.35 times more permeation through the nasal mucosa than the LP solution. It also lowered systolic blood pressure, so it is thought to be better than the reference formulation in terms of pharmacodynamics. The pharmacokinetics studies demonstrated that the intranasal LP-SNVs gel boosted its bioavailability approximately 6.36 times compared to the oral LP solution. Our research showed that intranasal LP-SNVs could be a good nanoplatform because they are well-tolerated and have possible pharmacokinetics and pharmacodynamics.