Mimicking regional and fasted/fed state conditions in the intestine with the mucus-PVPA in vitro model: The impact of pH and simulated intestinal fluids on drug permeability

Falavigna, Margherita; Klitgaard, Mette; Steene, Erik; Flaten, Gøril Eide

doi:10.1016/j.ejps.2019.02.035

Cited by 24 publications

(30 citation statements)

References 50 publications

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“…The change was however found to be to a different extent according to the specific drug, and a trend can be seen showing that permeation of the more hydrophilic drugs ATN and CAF (Table 1) was slowed down in the presence of mucin to a lower extent compared to the more lipophilic ones NPR and HYD ( Figure 5). This is in agreement with previous findings where the mucus-PVPA barriers were employed [20,21]. The impact of the mucin layer on the permeation of drugs with different physicochemical characteristics can be traced back to either the interaction or size filtering events described in Section 3.2.…”

Section: Permeability Of Drugs In the Presence And Absence Of Mucinsupporting

confidence: 90%

“…ATN, CAF, HYD, and NPR were quantified at 273, 272, 247, and 270 nm, respectively. Moreover, the electrical resistance across the PVPA barriers was measured to confirm their integrity and proper functionality, as previously described [20][21][22][23]. The P app (apparent permeability, cm/sec) of the investigated drugs was calculated by Equation (2).…”

Section: In Vitro Permeability Studymentioning

confidence: 99%

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Impact of Mucin on Drug Diffusion: Development of a Straightforward In Vitro Method for the Determination of Drug Diffusivity in the Presence of Mucin

et al. 2020

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Mucosal drug delivery accounts for various administration routes (i.e., oral, vaginal, ocular, pulmonary, etc.) and offers a vast surface for the permeation of drugs. However, the mucus layer which shields and lubricates all mucosal tissues can compromise drugs from reaching the epithelial site, thus affecting their absorption and therapeutic effect. Therefore, the effect of the mucus layer on drug absorption has to be evaluated early in the drug-development phase, prior to in vivo studies. For this reason, we developed a simple, cost-effective and reproducible method employing UV-visible localized spectroscopy for the assessment of the interaction between mucin and drugs with different physicochemical characteristics. The mucin–drug interaction was investigated by measuring the drug relative diffusivity (Drel) in the presence of mucin, and the method was validated by fitting experimental and mathematical data. In vitro permeability studies were also performed using the mucus-covered artificial permeation barrier (mucus–PVPA, Phospholipid Vesicle-based Permeation Assay) for comparison. The obtained results showed that the diffusion of drugs was hampered by the presence of mucin, especially at higher concentrations. This novel method proved to be suitable for the investigation on the extent of mucin–drug interaction and can be successfully used to assess the impact that the mucus layer has on drug absorption.

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Section: Permeability Of Drugs In the Presence And Absence Of Mucinsupporting

confidence: 90%

Section: In Vitro Permeability Studymentioning

confidence: 99%

Impact of Mucin on Drug Diffusion: Development of a Straightforward In Vitro Method for the Determination of Drug Diffusivity in the Presence of Mucin

et al. 2020

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“…This assessment was carried out by measuring the P app of the highly hydrophilic marker calcein and the electrical resistance across the PVPA barriers at the end of the permeability experiment. Calcein permeability values below 0.06 10 −6 cm/s and electrical resistance above 290 Ohm cm 2 indicate barrier integrity, as previously demonstrated [11,12]. As observed in Figure 1, the PVPA barriers maintained their integrity in all proposed setups, which indicated that the presence of mucus and mucus + SVF did not impair the functionality of the permeation barriers at the tested pH conditions.…”

Section: Validation Of the Vaginal-pvpa Model In Terms Of Barrier Intsupporting

confidence: 77%

“…The mucus layer was obtained as previously described [12] by hydrating mucin from porcine stomach type III with phosphate buffer saline (PBS) pH 4.6 or 7.0 in order to obtain a final concentration of 10 mg/mL.…”

Section: Preparation Of Mucus and Simulated Vaginal Fluidmentioning

confidence: 99%

“…Even though the above-mentioned in vitro models and simulated fluid serve as great tools in developing formulations for vaginal administration, the lack of a reproducible, artificial, simple, and high throughput in vitro permeation model closely mimicking the vaginal mucosa and its environment was the reason for modifying the already established mucus-PVPA (Phospholipid Vesicle-based Permeation Assay) in vitro permeability model [11] to closely mimic these conditions. We have shown earlier that the mucus-PVPA model is a reliable and predictive artificial permeation tool able to mimic intestinal mucosal barriers and aid in assessing mucosal drug permeability [11,12]. Moreover, the original PVPA barriers were previously used to study in vitro drug permeation from mucoadhesive formulations destined to the vaginal site [13].…”

Section: Introductionmentioning

confidence: 99%

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The Vaginal-PVPA: A Vaginal Mucosa-Mimicking In Vitro Permeation Tool for Evaluation of Mucoadhesive Formulations

et al. 2020

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Drug administration to the vaginal site has gained increasing attention in past decades, highlighting the need for reliable in vitro methods to assess the performance of novel formulations. To optimize formulations destined for the vaginal site, it is important to evaluate the drug retention within the vagina as well as its permeation across the mucosa, particularly in the presence of vaginal fluids. Herewith, the vaginal-PVPA (Phospholipid Vesicle-based Permeation Assay) in vitro permeability model was validated as a tool to evaluate the permeation of the anti-inflammatory drug ibuprofen from liposomal formulations (i.e., plain and chitosan-coated liposomes). Drug permeation was assessed in the presence and absence of mucus and simulated vaginal fluid (SVF) at pH conditions mimicking both the healthy vaginal premenopausal conditions and vaginal infection/pre-puberty/post-menopause state. The permeation of ibuprofen proved to depend on the type of formulation (i.e., chitosan-coated liposomes exhibited lower drug permeation), the mucoadhesive formulation properties and pH condition. This study highlights both the importance of mucus and SVF in the vaginal model to better understand and predict the in vivo performance of formulations destined for vaginal administration, and the suitability of the vaginal-PVPA model for such investigations.

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Exploring Mechanisms of Lipid Nanoparticle‐Mucus Interactions in Healthy and Cystic Fibrosis Conditions

Tafech,

Rokhforouz,

Leung

et al. 2024

Adv Healthcare Materials

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Mucus forms the first defense line of human lungs, and as such hampers the efficient delivery of therapeutics to the underlying epithelium. This holds particularly true for genetic cargo such as CRISPR‐based gene editing tools which cannot readily surmount the mucosal barrier. While lipid nanoparticles (LNPs) emerged as versatile non‐viral gene delivery systems that could help overcome the delivery challenge, many knowledge gaps remain, especially for diseased states such as cystic fibrosis (CF). This study provides fundamental insights into Cas9 mRNA or ribonucleoprotein‐loaded LNP‐mucus interactions in healthy and diseased states by assessing the impact of the genetic cargo, mucin sialylation, mucin concentration, ionic strength, pH, and polyethylene glycol (PEG) concentration and nature on LNP diffusivity leveraging experimental approaches and Brownian dynamics simulations. Taken together, this study identifies key mucus and LNP characteristics that are critical to enabling a rational LNP design for transmucosal delivery.This article is protected by copyright. All rights reserved

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Mimicking regional and fasted/fed state conditions in the intestine with the mucus-PVPA in vitro model: The impact of pH and simulated intestinal fluids on drug permeability

Cited by 24 publications

References 50 publications

Impact of Mucin on Drug Diffusion: Development of a Straightforward In Vitro Method for the Determination of Drug Diffusivity in the Presence of Mucin

Impact of Mucin on Drug Diffusion: Development of a Straightforward In Vitro Method for the Determination of Drug Diffusivity in the Presence of Mucin

The Vaginal-PVPA: A Vaginal Mucosa-Mimicking In Vitro Permeation Tool for Evaluation of Mucoadhesive Formulations

Exploring Mechanisms of Lipid Nanoparticle‐Mucus Interactions in Healthy and Cystic Fibrosis Conditions

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