Enhanced dissolution/caco-2 permeability, pharmacokinetic and pharmacodynamic performance of re-dispersible eprosartan mesylate nanopowder

Shekhawat, Prachi B.; Bagul, Milind; Edwankar, Diptee; Pokharkar, Varsha

doi:10.1016/j.ejps.2019.02.021

Cited by 17 publications

(5 citation statements)

References 74 publications

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“…When Caco-2 cells grow on specific inserts and reach the complete confluence, they begin to differentiate, completing the process after 21 days [ 66 ]. This model is recognized as a valid GI barrier model, widely used in permeability assessment tests because it mimics intestinal physiology [ 67 , 68 ]. Thus, we used this model to investigate the effects on cell viability and barrier permeability for all SHDS-treated and untreated NBMs.…”

Section: Resultsmentioning

confidence: 99%

Changes of physico-chemical properties of nano-biomaterials by digestion fluids affect the physiological properties of epithelial intestinal cells and barrier models

et al. 2022

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Background The widespread use of nano-biomaterials (NBMs) has increased the chance of human exposure. Although ingestion is one of the major routes of exposure to NBMs, it is not thoroughly studied to date. NBMs are expected to be dramatically modified following the transit into the oral-gastric-intestinal (OGI) tract. How these transformations affect their interaction with intestinal cells is still poorly understood. NBMs of different chemical nature—lipid-surfactant nanoparticles (LSNPs), carbon nanoparticles (CNPs), surface modified Fe3O4 nanoparticles (FNPs) and hydroxyapatite nanoparticles (HNPs)—were treated in a simulated human digestive system (SHDS) and then characterised. The biological effects of SHDS-treated and untreated NBMs were evaluated on primary (HCoEpiC) and immortalised (Caco-2, HCT116) epithelial intestinal cells and on an intestinal barrier model. Results The application of the in vitro SDHS modified the biocompatibility of NBMs on gastrointestinal cells. The differences between SHDS-treated and untreated NBMs could be attributed to the irreversible modification of the NBMs in the SHDS. Aggregation was detected for all NBMs regardless of their chemical nature, while pH- or enzyme-mediated partial degradation was detected for hydroxyapatite or polymer-coated iron oxide nanoparticles and lipid nanoparticles, respectively. The formation of a bio-corona, which contains proteases, was also demonstrated on all the analysed NBMs. In viability assays, undifferentiated primary cells were more sensitive than immortalised cells to digested NBMs, but neither pristine nor treated NBMs affected the intestinal barrier viability and permeability. SHDS-treated NBMs up-regulated the tight junction genes (claudin 3 and 5, occludin, zonula occludens 1) in intestinal barrier, with different patterns between each NBM, and increase the expression of both pro- and anti-inflammatory cytokines (IL-1β, TNF-α, IL-22, IL-10). Notably, none of these NBMs showed any significant genotoxic effect. Conclusions Overall, the results add a piece of evidence on the importance of applying validated in vitro SHDS models for the assessment of NBM intestinal toxicity/biocompatibility. We propose the association of chemical and microscopic characterization, SHDS and in vitro tests on both immortalised and primary cells as a robust screening pipeline useful to monitor the changes in the physico-chemical properties of ingested NBMs and their effects on intestinal cells.

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Section: Resultsmentioning

confidence: 99%

Changes of physico-chemical properties of nano-biomaterials by digestion fluids affect the physiological properties of epithelial intestinal cells and barrier models

et al. 2022

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“…An eprosartan-mesylate nanopowder was developed and assessed at similar and reduced oral doses versus commercial eprosartan; that is, 62, 12.4, and 6.2 mg/kg versus 62 mg/kg, respectively. 29 Employing male Wistar rats with N(ω)-nitro-L-arginine methyl ester (a NOS [NO synthase] inhibitor)-induced hypertension, nanoformulation plasma concentrations at 62 and 12.4 mg/kg resulted in 5 and 1.5-fold increases in eprosartan. Also, oral nanopowder at 12.4 mg/kg yielded significant BP decline and maintenance similar to that seen with 62 mg/kg of eprosartan-alone, suggesting the nanoformulation was similarly effective at reduced dosage.…”

Section: Angiotensin II Receptor Blockersmentioning

confidence: 99%

Nanoparticle-Based Therapies in Hypertension

Story,

Aminoroaya,

Skelton

et al. 2023

Hypertension

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Nearly 1.4 billion people worldwide suffer from arterial hypertension, a significant risk factor for cardiovascular disease which is now the leading cause of death. Despite numerous drugs designed to treat hypertension, only ≈14% of hypertensive individuals have their blood pressure under control. A critical factor negatively impacting the efficacy of available treatments is their poor bioavailability. This leads to increased dosing requirements which can result in more side effects, resulting in patient noncompliance. A recent solution to improve dosing and bioavailability issues has been to incorporate drugs into nanoparticle carriers, with over 50 nanodrugs currently on the market across all diseases, and another 51 currently in clinical trials. Given their ability to improve solubility and bioavailability, nanoparticles may offer significant advantages in the formulation of antihypertensives to overcome pharmacokinetic shortcomings. To date, however, no antihypertensive nanoformulations have been clinically approved. This review assesses in vivo study data from preclinical antihypertensive nanoformulation development and testing. Combined, the results of these studies suggest nanoformulation of antihypertensive drugs may be a promising solution to overcome the poor efficacy of currently available antihypertensives, and with further advances has the potential to open paths for new substances that have heretofore been clinically unrealistic due to poor bioavailability.

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“…The dataset consisted of 1043 compounds with human f a , ,,,,,,,− 125 with rat f a , ,,,,,− and 484 compounds with Caco-2 P app ,,,,,,,,,,− ,,,− and human f a . When multiple permeability values were found for a single compound from more than one source, the geometric mean of the values was used as the point estimate.…”

Section: Experimental Sectionmentioning

confidence: 99%

Global Analysis of Models for Predicting Human Absorption: QSAR, In Vitro, and Preclinical Models

et al. 2021

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Models intended to predict intestinal absorption are an essential part of the drug development process. Although many models exist for capturing intestinal absorption, many questions still exist around the applicability of these models to drug types like "beyond rule of 5" (bRo5) and low absorption compounds. This presents a challenge as current models have not been rigorously tested to understand intestinal absorption. Here, we assembled a large, structurally diverse dataset of ∼1000 compounds with known in vitro, preclinical, and human permeability and/or absorption data. In silico (quantitative structure−activity relationship), in vitro (Caco-2), and in vivo (rat) models were statistically evaluated for predictive performance against this human intestinal absorption dataset. We expect this evaluation to serve as a resource for DMPK scientists and medicinal/computational chemists to increase their understanding of permeability and absorption model utility and applications for academia and industry.

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Enhanced dissolution/caco-2 permeability, pharmacokinetic and pharmacodynamic performance of re-dispersible eprosartan mesylate nanopowder

Cited by 17 publications

References 74 publications

Changes of physico-chemical properties of nano-biomaterials by digestion fluids affect the physiological properties of epithelial intestinal cells and barrier models

Changes of physico-chemical properties of nano-biomaterials by digestion fluids affect the physiological properties of epithelial intestinal cells and barrier models

Nanoparticle-Based Therapies in Hypertension

Global Analysis of Models for Predicting Human Absorption: QSAR, In Vitro, and Preclinical Models

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