Evaluation of drug permeation under fed state conditions using mucus-covered Caco-2 cell epithelium

Birch, Ditlev; Diedrichsen, Ragna Guldsmed; Christophersen, Philip C.; Mu, Huiling; Nielsen, Hanne Mørck

doi:10.1016/j.ejps.2018.02.032

Cited by 36 publications

(15 citation statements)

References 72 publications

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“…By necessity there are reductions in the concentrations of bile salts in the SIF used in vitro compared to intestinal aspirates (e.g., free fatty acids). Other investigators have opted to use full biorelevant media and overcome damage to Caco-2 monolayers using overlying biosimilar mucus [93,94]. It may be that studies with SIF should begin with more robust in situ models such as the rat single pass intestinal perfusion [83,95,96].…”

Section: Recent Highlightsmentioning

confidence: 99%

Application of Permeation Enhancers in Oral Delivery of Macromolecules: An Update

et al. 2019

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The application of permeation enhancers (PEs) to improve transport of poorly absorbed active pharmaceutical ingredients across the intestinal epithelium is a widely tested approach. Several hundred compounds have been shown to alter the epithelial barrier, and although the research emphasis has broadened to encompass a role for nanoparticle approaches, PEs represent a key constituent of conventional oral formulations that have progressed to clinical testing. In this review, we highlight promising PEs in early development, summarize the current state of the art, and highlight challenges to the translation of PE-based delivery systems into safe and effective oral dosage forms for patients.

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Section: Recent Highlightsmentioning

confidence: 99%

Application of Permeation Enhancers in Oral Delivery of Macromolecules: An Update

et al. 2019

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“…The alkaline phosphatase activity on the AP side of the cell monolayer was higher than that on the BL side, and its activity value was about 12 times that of the latter. It meant that the alkaline phosphatase distribution was extremely asymmetric ( Billat et al, 2017 ; Birch et al, 2018 ), indicating that the cells have been polarized.…”

Section: Resultsmentioning

confidence: 99%

Investigation of the Uptake and Transport of Aspirin Eugenol Ester in the Caco-2 Cell Model

et al. 2022

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Background: Aspirin eugenol ester (AEE) is a novel medicinal compound synthesized by esterification of aspirin with eugenol using the prodrug principle. AEE has the pharmacological activities of being anti-inflammatory, antipyretic, analgesic, anti-cardiovascular diseases, and anti-oxidative stress However, its oral bioavailability is poor, and its intestinal absorption and transport characteristics are still unknown.Objective: The purpose of this study was to investigate the uptake and transport mechanisms of AEE in Caco-2 cells.Methods: The effects of time, concentration, and temperature on the transport and uptake of AEE were studied.Results: The results showed that a higher concentration of salicylic acid (SA) was detected in the supernatant of cell lysates and cell culture medium, while AEE was not detected. Therefore, the content change of AEE was expressed as the content change of its metabolite SA. In the uptake experiment, when the factors of time, concentration, and temperature were examined, the uptake of SA reached the maximum level within 30 min, and there was concentration dependence. In addition, low temperature (4°C) could significantly reduce the uptake of SA in Caco-2 cells. In the transport experiment, under the consideration of time, concentration, and temperature, the transepithelial transport of SA from AP-BL and BL-AP sides was time-dependent. The amount of SA transported in Caco-2 cells increased with the increase of concentration, but the transmembrane transport rate had no correlation with the concentration. This phenomenon may be due to the saturation phenomenon of high concentration. The efflux ratio (ER) was less than 1, which indicated that their intestinal transport mechanism was passive transport. Moreover, the temperature had a significant effect on the transport of AEE.Conclusion: In summary, intestinal absorption of AEE through Caco-2 cell monolayers was related to passive transport. The uptake and transport of AEE were concentration-dependent, and temperature significantly affected their uptake and transport. The absorption and transport characteristics of AEE may contribute to the exploration of mechanisms of absorption and transport of chemosynthetic drugs in vitro.

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“…This over-prediction is in part because Caco-2 monolayers do not secrete mucus, such that Caco-2 is much more sensitive to membrane disruptors (i.e., surfactants) than in vivo . Mucus creates a steric and interactive barrier against intestinal permeation such that its presence (or absence) may impact drug permeation ( 65 ). Therefore, the in vivo implication of an enhancement in in vitro Caco-2 permeability by an excipient is not clear.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Excipient Risk in BCS Class I and III Biowaivers

Metry

Polli

2022

AAPS J

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The objective of this review article is to summarize literature data pertinent to potential excipient effects on intestinal drug permeability and transit. Despite the use of excipients in drug products for decades, considerable research efforts have been directed towards evaluating their potential effects on drug bioavailability. Potential excipient concerns stem from drug formulation changes (e.g., scale-up and post-approval changes, development of a new generic product). Regulatory agencies have established in vivo bioequivalence standards and, as a result, may waive the in vivo requirement, known as a biowaiver, for some oral products. Biowaiver acceptance criteria are based on the in vitro characterization of the drug substance and drug product using the Biopharmaceutics Classification System (BCS). Various regulatory guidance documents have been issued regarding BCS-based biowaivers, such that the current FDA guidance is more restrictive than prior guidance, specifically about excipient risk. In particular, sugar alcohols have been identified as potential absorption-modifying excipients. These biowaivers and excipient risks are discussed here.

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Evaluation of drug permeation under fed state conditions using mucus-covered Caco-2 cell epithelium

Cited by 36 publications

References 72 publications

Application of Permeation Enhancers in Oral Delivery of Macromolecules: An Update

Application of Permeation Enhancers in Oral Delivery of Macromolecules: An Update

Investigation of the Uptake and Transport of Aspirin Eugenol Ester in the Caco-2 Cell Model

Evaluation of Excipient Risk in BCS Class I and III Biowaivers

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