In vivo methods for drug absorption – Comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for formulation/API/excipient characterization including food effects

Sjögren, Erik; Abrahamsson, Bertil; Augustijns, Patrick; Becker, D. E.; Bolger, Michael B.; Brewster, Marcus E.; Brouwers, Joachim; Flanagan, Talia; Harwood, Matthew D; Heinen, Christian; Holm, René; Juretschke, Hans-Paul; Kubbinga, Marlies; Lindahl, Anders; Lukáčová, Viera; Münster, Uwe; Neuhoff, Sibylle; Nguyễn, Mai Ánh; Peer, Achiel Van; Reppas, Christos; Rostami‐Hodjegan, Amin; Tannergren, Christer; Weitschies, Werner; Wilson, Clive G.; Zane, Patricia; Lennernäs, Hans; Langguth, Peter

doi:10.1016/j.ejps.2014.02.010

Cited by 232 publications

(181 citation statements)

References 605 publications

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“…This correlates well with the observation that the microcontainers interact with and adhere to the intestinal wall, thereby increasing the absorption rate of ASSF. When dosing the solution of furosemide, the furosemide is likely to be quickly flushed further down in the intestine (where absorption is not occurring) due to the continuing flow of fluid through the small intestine (Sjögren et al, 2014). It has earlier been reported that, unlike microparticles that experience a high intestinal and peristaltic shear, planar microdevices experience a low shear stress and remain in the upper intestine for a longer time (Hariharasudhan D. .…”

Section: In Situ Closed-loop Rat Intestinal Perfusionmentioning

confidence: 99%

Polymeric microcontainers improve oral bioavailability of furosemide

Nielsen

Melero

Keller

et al. 2016

International Journal of Pharmaceutics

117

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Microcontainers with an inner diameter of 223 µm are fabricated using the polymer SU-8, and evaluated in vitro, in situ and in vivo for their application as an advanced oral drug delivery system for the poorly water soluble drug furosemide. An amorphous sodium salt of furosemide (ASSF) is filled into the microcontainers followed by applying a lid using Eudragit L100. It is possible to control the drug release in vitro, and in vitro absorption studies show that the microcontainers are not a hindrance for absorption of ASSF. In situ perfusion studies in rats are performed with ASSF-filled microcontainers coated with Eudragit and compared to a furosemide solution. The absorption rate constant of ASSF confined in microcontainers is found to be significantly different from the solution, and by light microscopy, it is observed that the microcontainers are engulfed by the intestinal mucus. An oral bioavailability study in rats is performed with ASSF confined in microcontainers coated with Eudragit and a control group with ASSF in Eudragit-coated capsules. A relative bioavailability of 220% for the ASSF in microcontainers compared to ASSF in capsules is found. These studies indicate that the microcontainers could serve as a promising oral drug delivery system.

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Section: In Situ Closed-loop Rat Intestinal Perfusionmentioning

confidence: 99%

Polymeric microcontainers improve oral bioavailability of furosemide

Nielsen

Melero

Keller

et al. 2016

International Journal of Pharmaceutics

117

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“…The transit times in the stomach, small intestine, and large intestine of rats have been reported to be 15-30 min, 3-4 h, and 10-11 h, respectively (29). In comparison, the transit times in fasted humans have been reported to be 10-15 min (for liquids), 3-4 h, and 8-18 h, respectively (36).…”

Section: In Vitro-in Vivo Correlationmentioning

confidence: 99%

Influence of Copolymer Composition on In Vitro and In Vivo Performance of Celecoxib-PVP/VA Amorphous Solid Dispersions

Knopp

Nguyen

et al. 2016

AAPS J

Self Cite

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Abstract. Previous studies suggested that an amorphous solid dispersion with a copolymer consisting of both hydrophobic and hydrophilic monomers could improve the dissolution profile of a poorly watersoluble drug compared to the crystalline form. Therefore, this study investigated the influence of the copolymer composition of polyvinylpyrrolidone/vinyl acetate (PVP/VA) on the non-sink in vitro dissolution behavior and in vivo performance of celecoxib (CCX) amorphous solid dispersions. The study showed that the hydrophilic monomer vinylpyrrolidone (VP) was responsible for the generation of CCX supersaturation whereas the hydrophobic monomer vinyl acetate (VA) was responsible for the stabilization of the supersaturated solution. For CCX, there was an optimal copolymer composition around 50-60% VP content where further replacement of VP monomers with VA monomers did not have any biopharmaceutical advantages. A linear relationship was found between the in vitro AUC 0-4h and in vivo AUC 0-24h for the CCX:PVP/VA systems, indicating that the non-sink in vitro dissolution method applied in this study was useful in predicting the in vivo performance. These results indicated that when formulating a poorly water-soluble drug as an amorphous solid dispersion using a copolymer, the copolymer composition has a significant influence on the dissolution profile and in vivo performance. Thus, the dissolution profile of a drug can theoretically be tailored by changing the monomer ratio of a copolymer with respect to the required in vivo plasma-concentration profile. As this ratio is likely to be drug dependent, determining the optimal ratio between the hydrophilic (dissolution enhancing) and hydrophobic (crystallization inhibiting) monomers for a given drug is imperative.

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“…This combined approach appears to be promising for common chemicals, such as pharmaceuticals, since pre-systemic metabolism is known to potentially alter the molecular structure, thereby reducing the bioavailability of the parent compound. However, the potential impact of food matrices on the release, absorption and metabolism of these chemicals is often neglected [51,52].…”

Section: Westerhout Et Almentioning

confidence: 99%

Prediction of Oral Absorption of Nanoparticles from Biorelevant Matrices Using a Combination of Physiologically Relevant In Vitro and Ex Vivo Models

Westerhout¹,

Bellmann²,

Ee³

et al. 2017

J Food Chem Nanotechol

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The application of nanoparticles (NPs) in food products is ever increasing. For consumer safety it is essential to know the human oral bioavailability of these NPs. In the present study, a combination of physiologically relevant in vitro and ex vivo models are presented, which combined are considered to predict human intestinal digestion and absorption of NPs more accurately than commonly applied animal or cellular studies.First, a computer controlled dynamic in vitro gastrointestinal model (tiny-TIM) is used for simulation of the digestive processes upon gastro-intestinal passage of non-biodegradable aminated, carboxylated, or unmodified fluorescent polystyrene NPs (PS-NPs). Then, the pretreated (digested) PS-NPs were consequently evaluated for absorption using ex vivo porcine intestinal tissue.In this study, we found that the digestion of non-biodegradable aminated, carboxylated, or unmodified fluorescent polystyrene NPs (PS-NPs) leads to different bioaccessible concentrations, with unmodified PS-NP concentrations being 3.5-and 4.5-fold lower than the aminated and carboxylated PS-NPs, respectively. In addition, we observed a reduced absorption of PS-NPs by ex vivo porcine intestinal tissue from the digestive matrix when compared to the absorption of their undigested counterparts in Krebs-Ringer Bicarbonate (KRB) buffer. The current results prove that oral absorption of PS-NPs in humans is to be expected in vivo. In the risk assessment of potential oral exposure to NPs in food products it is therefore key that the exposure and hazard assessment are performed with the NPs in physiologically relevant conditions, since this may influence the absorption and hazard properties of the NPs.

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In vivo methods for drug absorption – Comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for formulation/API/excipient characterization including food effects

Cited by 232 publications

References 605 publications

Polymeric microcontainers improve oral bioavailability of furosemide

Polymeric microcontainers improve oral bioavailability of furosemide

Influence of Copolymer Composition on In Vitro and In Vivo Performance of Celecoxib-PVP/VA Amorphous Solid Dispersions

Prediction of Oral Absorption of Nanoparticles from Biorelevant Matrices Using a Combination of Physiologically Relevant In Vitro and Ex Vivo Models

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