The Experts below are selected from a list of 282 Experts worldwide ranked by ideXlab platform
Hans Lennernas - One of the best experts on this subject based on the ideXlab platform.
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Correlation of Intestinal Drug Permeability in Humans (In Vivo) with Experimentally and Theoretically Derived Parameters
Molecular Modeling and Prediction of Bioactivity, 2020Co-Authors: Anders Karlén, Hans Lennernas, Susanne Winiwarter, Nicholas M. Bonham, Anders HallbergAbstract:The extent of Intestinal Drug Absorption, often described by the fraction of Drug absorbed (Fa), is governed by several different processes: (a) dose/dissolution ratio, (b) chemical degradation and/or metabolism in the lumen, (c) complex binding in the lumen, Intestinal transit, and (d) effective permeability (Peff) across the Intestinal mucosa. In many cases Peff is considered to be the rate-limiting step in the overall Absorption process and is therefore an interesting parameter in bioavailability studies.
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Intestinal Drug Absorption and bioavailability: beyond involvement of single transport function.
Journal of Pharmacy and Pharmacology, 2020Co-Authors: Hans LennernasAbstract:Intestinal Drug Absorption and bioavailability: Beyond involvement of single transport function.
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Intestinal Absorption-modifying excipients: A current update on preclinical in vivo evaluations
European Journal of Pharmaceutics and Biopharmaceutics, 2019Co-Authors: David Dahlgren, Markus Sjöblom, Hans LennernasAbstract:Abstract Pharmaceutical excipients in Drug products are defined as pharmacologically inactive and are integral constituents of all types of oral dosage forms. However, some excipients may increase Drug Absorption by interacting with the mucosal membrane. If the strategy is to use an excipient with a potential to affect the processes determining the rate and/or extent of the Intestinal Drug Absorption, it is defined as an Absorption-modifying excipients (AME). These pharmaceutical excipients may act as AMEs, depending on the amounts applied, and accordingly influence bioequivalence assessment of innovative and generic Drug products, as well as enable oral delivery of peptides and oligonucleotides. This review discusses the mechanisms by which AMEs increase Drug Absorption, and especially permeation step. The focus is on the most recent data regarding how AMEs can be evaluated in preclinical models, with an emphasis on in situ and in vivo Intestinal Absorption models. The in vivo predictive value of these models is reviewed for five factors of clinical relevance for the Intestinal Absorption performance: (a) effect and response rate of AMEs, (b) mucosal exposure time and Intestinal transit of AMEs, (c) intraluminal AME dilution and prandial state, (d) mucosal recovery and safety, and (e) variability in the effects of the AMEs. We argue that any preclinical investigations of AMEs that fail to consider these processes will ultimately be of limited clinical value and add little to our understanding of how excipients affect Intestinal Drug Absorption.
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mechanistic modelling of Intestinal Drug Absorption the in vivo effects of nanoparticles hydrodynamics and colloidal structures
European Journal of Pharmaceutics and Biopharmaceutics, 2018Co-Authors: Carl Roos, J. Westergren, Hans Lennernas, David Dahlgren, Eric SjogrenAbstract:Particle size reduction is a traditional approach to increase the Intestinal Absorption of active pharmaceutical ingredients with poor Intestinal solubility, by increasing the particle dissolution ...
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Mechanistic modelling of Intestinal Drug Absorption – The in vivo effects of nanoparticles, hydrodynamics, and colloidal structures
European Journal of Pharmaceutics and Biopharmaceutics, 2018Co-Authors: C De Roos, J. Westergren, Hans Lennernas, David Dahlgren, Eric SjogrenAbstract:Particle size reduction is a traditional approach to increase the Intestinal Absorption of active pharmaceutical ingredients with poor Intestinal solubility, by increasing the particle dissolution rate. However, an increase in the dissolution rate cannot always fully explain the effects of nanoformulations, and a method of assessing the potential benefits of a nanoformulation in vivo would hence be of great value in Drug development. A novel mathematical model of a nanoformulation, including interlinked descriptions of the hydrodynamics, particle dissolution and diffusion of particles and colloidal structures (CS), was developed to predict the combined in vivo effects of these mechanisms on Drug Absorption. The model successfully described previously reported in vivo observations of nanoformulated aprepitant in rats, at various Drug concentrations and in the presence or absence of CS. The increase in Absorption rate was explained as a direct consequence of the increased Drug concentration at the membrane, caused by the contributing effects of the diffusion of both nanoparticles and CS into which the Drug had partitioned. Further simulations supported the conclusion that the model can be applied during Drug development to provide a priori assessments of the potential benefits of nanoformulations.
Eric Sjogren - One of the best experts on this subject based on the ideXlab platform.
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mechanistic modelling of Intestinal Drug Absorption the in vivo effects of nanoparticles hydrodynamics and colloidal structures
European Journal of Pharmaceutics and Biopharmaceutics, 2018Co-Authors: Carl Roos, J. Westergren, Hans Lennernas, David Dahlgren, Eric SjogrenAbstract:Particle size reduction is a traditional approach to increase the Intestinal Absorption of active pharmaceutical ingredients with poor Intestinal solubility, by increasing the particle dissolution ...
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Mechanistic modelling of Intestinal Drug Absorption – The in vivo effects of nanoparticles, hydrodynamics, and colloidal structures
European Journal of Pharmaceutics and Biopharmaceutics, 2018Co-Authors: C De Roos, J. Westergren, Hans Lennernas, David Dahlgren, Eric SjogrenAbstract:Particle size reduction is a traditional approach to increase the Intestinal Absorption of active pharmaceutical ingredients with poor Intestinal solubility, by increasing the particle dissolution rate. However, an increase in the dissolution rate cannot always fully explain the effects of nanoformulations, and a method of assessing the potential benefits of a nanoformulation in vivo would hence be of great value in Drug development. A novel mathematical model of a nanoformulation, including interlinked descriptions of the hydrodynamics, particle dissolution and diffusion of particles and colloidal structures (CS), was developed to predict the combined in vivo effects of these mechanisms on Drug Absorption. The model successfully described previously reported in vivo observations of nanoformulated aprepitant in rats, at various Drug concentrations and in the presence or absence of CS. The increase in Absorption rate was explained as a direct consequence of the increased Drug concentration at the membrane, caused by the contributing effects of the diffusion of both nanoparticles and CS into which the Drug had partitioned. Further simulations supported the conclusion that the model can be applied during Drug development to provide a priori assessments of the potential benefits of nanoformulations.
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in vivo mechanisms of Intestinal Drug Absorption from aprepitant nanoformulations
Molecular Pharmaceutics, 2017Co-Authors: Carl Roos, J. Westergren, Eric Sjogren, David Dahlgren, Staffan Berg, Bertil Abrahamsson, Christer Tannergren, Hans LennernasAbstract:Over recent decades there has been an increase in the proportion of BCS class II and IV Drug candidates in industrial Drug development. To overcome the biopharmaceutical challenges associated with the less favorable properties of solubility and/or Intestinal permeation of these substances, the development of formulations containing nanosuspensions of the Drugs has been suggested. The Intestinal Absorption of aprepitant from two nanosuspensions (20 μM and 200 μM total concentrations) in phosphate buffer, one nanosuspension (200 μM) in fasted-state simulated Intestinal fluid (FaSSIF), and one solution (20 μM) in FaSSIF was investigated in the rat single-pass Intestinal perfusion model. The disappearance flux from the lumen (Jdisapp) was faster for formulations containing a total concentration of aprepitant of 200 μM than for those containing 20 μM, but was unaffected by the presence of vesicles. The flux into the systemic circulation (Japp) and, subsequently, the effective diffusion constant (Deff) were cal...
Patrick Augustijns - One of the best experts on this subject based on the ideXlab platform.
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biopredictive in vitro testing methods to assess Intestinal Drug Absorption from supersaturating dosage forms
Journal of Drug Delivery Science and Technology, 2020Co-Authors: Bart Hens, Patrick Augustijns, Makoto Kataoka, Keisuke Ueda, Yasuhiro Tsume, Kohsaku Kawakami, Shinji YamashitaAbstract:Abstract The discovery pipelines in pharmaceutical companies are highly populated with poorly soluble compounds, demanding for an appropriate solution to overcome this problem. Generating supersaturated concentrations for these Drugs in the gastroIntestinal (GI) tract has been put forward as a promising strategy to assure sufficient systemic exposure after oral intake of the Drug. Numerous publications have shown to which extent supersaturating dosage forms can create supersaturated concentrations by testing these formulations in in vitro dissolution models. The obtained dissolution profiles can serve as a valuable input for computational software programs to simulate the systemic outcome of the Drug. To improve our fundamental knowledge and understanding of the impact of supersaturation/precipitation on oral Absorption, attempts have been made to develop biopredictive in vitro dissolution systems such as the GastroIntestinal Simulator (GIS), the dissolution/permeation system, and the biphasic test system. Moreover, aspiration studies in humans have been performed throughout the years to measure simultaneously GI and systemic concentrations of the Drug in order to directly envisage the impact of supersaturation on systemic exposure. This manuscript aims to provide a comprehensive review with respect to the predictive power of in vitro tools towards the in vivo performance of supersaturating dosage forms. Different case studies will be thoroughly presented where a plethora of supersaturating formulations was tested applying a biopredictive setting. Recent investigations on liquid-liquid phase separation of supersaturated solutions, which makes comprehension of the dissolution process of supersaturating dosage forms extremely challenging, are also discussed.
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in situ perfusion in rodents to explore Intestinal Drug Absorption challenges and opportunities
International Journal of Pharmaceutics, 2015Co-Authors: Jef Stappaerts, Joachim Brouwers, Pieter Annaert, Patrick AugustijnsAbstract:Abstract The in situ Intestinal perfusion technique in rodents is a very important Absorption model, not only because of its predictive value, but it is also very suitable to unravel the mechanisms underlying Intestinal Drug Absorption. This literature overview covers a number of specific applications for which the in situ Intestinal perfusion set-up can be applied in favor of established in vitro Absorption tools, such as the Caco-2 cell model. Qualities including the expression of Drug transporters and metabolizing enzymes relevant for human Intestinal Absorption and compatibility with complex solvent systems render the in situ technique the most designated Absorption model to perform transporter-metabolism studies or to evaluate the Intestinal Absorption from biorelevant media. Over the years, the in situ Intestinal perfusion model has exhibited an exceptional ability to adapt to the latest challenges in Drug Absorption profiling. For instance, the introduction of the mesenteric vein cannulation allows determining the appearance of compounds in the blood and is of great use, especially when evaluating the Absorption of compounds undergoing Intestinal metabolism. Moreover, the use of the closed loop Intestinal perfusion set-up is interesting when compounds or perfusion media are scarce. Compatibility with emerging trends in pharmaceutical profiling, such as the use of knockout or transgenic animals, generates unparalleled possibilities to gain mechanistic insight into specific Absorption processes. Notwithstanding the fact that the in situ experiments are technically challenging and relatively time-consuming, the model offers great opportunities to gain insight into the processes determining Intestinal Drug Absorption.
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ex vivo permeability experiments in excised rat Intestinal tissue and in vitro solubility measurements in aspirated human Intestinal fluids support age dependent oral Drug Absorption
European Journal of Pharmaceutical Sciences, 2010Co-Authors: Pieter Annaert, Joachim Brouwers, Ann Bijnens, Frank Lammert, Jan Tack, Patrick AugustijnsAbstract:Abstract The possible influence of advanced age on Intestinal Drug Absorption was investigated by determining the effects of aging on (i) solubility of model Drugs in human Intestinal fluids (HIF) obtained from two age groups (18–25 years; 62–72 years); and (ii) transepithelial permeation of model Drugs across Intestinal tissue excised from young, adult and old rats. Average equilibrium solubility values for 10 poorly soluble compounds in HIF aspirated from both age groups showed high interindividual variability, but did not reveal significant differences. Characterization of the HIF from both age groups demonstrated comparable pH profiles, while concentrations of individual bile salts showed pronounced variability between individuals, however without statistical differences between age groups. Transepithelial permeation of the transcellular probe metoprolol was significantly increased in old rats (38 weeks) compared to the younger age groups, while the modulatory role of P-glycoprotein in transepithelial talinolol transport was observed in adult and old rats but not in young rats. In conclusion, age-dependent permeability of Intestinal tissue (rather than age-dependent luminal Drug solubility) may contribute to altered Intestinal Drug Absorption in older patients compared to young adults.
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in vitro screening models to assess Intestinal Drug Absorption and metabolism
2008Co-Authors: S Deferme, Pieter Annaert, Patrick AugustijnsAbstract:Compounds intended for oral administration must have adequate biopharmaceutical properties in order to achieve therapeutic concentrations at the targeted site of action. Different models have been established for the parallel screening of these biopharmaceutical properties, including membrane-based models (PAMPA), cell culture-based models (such as Caco-2 and MDCK cell lines), and the Ussing chambers technique. In this chapter, the strengths and the drawbacks of these models are discussed, while examples of applications for these different models and suggestions to improve the models are provided. Finally, different in vitro methods for studying the Intestinal metabolism are also described. As the Intestinal Absorption process depends on a multitude of parameters, a single universal model accounting for all these parameters does not exist. Therefore, combination of different in vitro models should be considered in order to obtain better insights in Intestinal Drug Absorption in the different phases of Drug discovery and development.
David Dahlgren - One of the best experts on this subject based on the ideXlab platform.
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Biopharmaceutical aspects of Intestinal Drug Absorption : Regional permeability and Absorption-modifying excipients
2020Co-Authors: David DahlgrenAbstract:Before an orally administered Drug reaches the systemic circulation, it has to dissolve in the Intestinal fluids, permeate across the Intestinal epithelial cell barrier, and pass through the liver. ...
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Intestinal Absorption-modifying excipients: A current update on preclinical in vivo evaluations
European Journal of Pharmaceutics and Biopharmaceutics, 2019Co-Authors: David Dahlgren, Markus Sjöblom, Hans LennernasAbstract:Abstract Pharmaceutical excipients in Drug products are defined as pharmacologically inactive and are integral constituents of all types of oral dosage forms. However, some excipients may increase Drug Absorption by interacting with the mucosal membrane. If the strategy is to use an excipient with a potential to affect the processes determining the rate and/or extent of the Intestinal Drug Absorption, it is defined as an Absorption-modifying excipients (AME). These pharmaceutical excipients may act as AMEs, depending on the amounts applied, and accordingly influence bioequivalence assessment of innovative and generic Drug products, as well as enable oral delivery of peptides and oligonucleotides. This review discusses the mechanisms by which AMEs increase Drug Absorption, and especially permeation step. The focus is on the most recent data regarding how AMEs can be evaluated in preclinical models, with an emphasis on in situ and in vivo Intestinal Absorption models. The in vivo predictive value of these models is reviewed for five factors of clinical relevance for the Intestinal Absorption performance: (a) effect and response rate of AMEs, (b) mucosal exposure time and Intestinal transit of AMEs, (c) intraluminal AME dilution and prandial state, (d) mucosal recovery and safety, and (e) variability in the effects of the AMEs. We argue that any preclinical investigations of AMEs that fail to consider these processes will ultimately be of limited clinical value and add little to our understanding of how excipients affect Intestinal Drug Absorption.
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mechanistic modelling of Intestinal Drug Absorption the in vivo effects of nanoparticles hydrodynamics and colloidal structures
European Journal of Pharmaceutics and Biopharmaceutics, 2018Co-Authors: Carl Roos, J. Westergren, Hans Lennernas, David Dahlgren, Eric SjogrenAbstract:Particle size reduction is a traditional approach to increase the Intestinal Absorption of active pharmaceutical ingredients with poor Intestinal solubility, by increasing the particle dissolution ...
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Mechanistic modelling of Intestinal Drug Absorption – The in vivo effects of nanoparticles, hydrodynamics, and colloidal structures
European Journal of Pharmaceutics and Biopharmaceutics, 2018Co-Authors: C De Roos, J. Westergren, Hans Lennernas, David Dahlgren, Eric SjogrenAbstract:Particle size reduction is a traditional approach to increase the Intestinal Absorption of active pharmaceutical ingredients with poor Intestinal solubility, by increasing the particle dissolution rate. However, an increase in the dissolution rate cannot always fully explain the effects of nanoformulations, and a method of assessing the potential benefits of a nanoformulation in vivo would hence be of great value in Drug development. A novel mathematical model of a nanoformulation, including interlinked descriptions of the hydrodynamics, particle dissolution and diffusion of particles and colloidal structures (CS), was developed to predict the combined in vivo effects of these mechanisms on Drug Absorption. The model successfully described previously reported in vivo observations of nanoformulated aprepitant in rats, at various Drug concentrations and in the presence or absence of CS. The increase in Absorption rate was explained as a direct consequence of the increased Drug concentration at the membrane, caused by the contributing effects of the diffusion of both nanoparticles and CS into which the Drug had partitioned. Further simulations supported the conclusion that the model can be applied during Drug development to provide a priori assessments of the potential benefits of nanoformulations.
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in vivo mechanisms of Intestinal Drug Absorption from aprepitant nanoformulations
Molecular Pharmaceutics, 2017Co-Authors: Carl Roos, J. Westergren, Eric Sjogren, David Dahlgren, Staffan Berg, Bertil Abrahamsson, Christer Tannergren, Hans LennernasAbstract:Over recent decades there has been an increase in the proportion of BCS class II and IV Drug candidates in industrial Drug development. To overcome the biopharmaceutical challenges associated with the less favorable properties of solubility and/or Intestinal permeation of these substances, the development of formulations containing nanosuspensions of the Drugs has been suggested. The Intestinal Absorption of aprepitant from two nanosuspensions (20 μM and 200 μM total concentrations) in phosphate buffer, one nanosuspension (200 μM) in fasted-state simulated Intestinal fluid (FaSSIF), and one solution (20 μM) in FaSSIF was investigated in the rat single-pass Intestinal perfusion model. The disappearance flux from the lumen (Jdisapp) was faster for formulations containing a total concentration of aprepitant of 200 μM than for those containing 20 μM, but was unaffected by the presence of vesicles. The flux into the systemic circulation (Japp) and, subsequently, the effective diffusion constant (Deff) were cal...
Pieter Annaert - One of the best experts on this subject based on the ideXlab platform.
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in situ perfusion in rodents to explore Intestinal Drug Absorption challenges and opportunities
International Journal of Pharmaceutics, 2015Co-Authors: Jef Stappaerts, Joachim Brouwers, Pieter Annaert, Patrick AugustijnsAbstract:Abstract The in situ Intestinal perfusion technique in rodents is a very important Absorption model, not only because of its predictive value, but it is also very suitable to unravel the mechanisms underlying Intestinal Drug Absorption. This literature overview covers a number of specific applications for which the in situ Intestinal perfusion set-up can be applied in favor of established in vitro Absorption tools, such as the Caco-2 cell model. Qualities including the expression of Drug transporters and metabolizing enzymes relevant for human Intestinal Absorption and compatibility with complex solvent systems render the in situ technique the most designated Absorption model to perform transporter-metabolism studies or to evaluate the Intestinal Absorption from biorelevant media. Over the years, the in situ Intestinal perfusion model has exhibited an exceptional ability to adapt to the latest challenges in Drug Absorption profiling. For instance, the introduction of the mesenteric vein cannulation allows determining the appearance of compounds in the blood and is of great use, especially when evaluating the Absorption of compounds undergoing Intestinal metabolism. Moreover, the use of the closed loop Intestinal perfusion set-up is interesting when compounds or perfusion media are scarce. Compatibility with emerging trends in pharmaceutical profiling, such as the use of knockout or transgenic animals, generates unparalleled possibilities to gain mechanistic insight into specific Absorption processes. Notwithstanding the fact that the in situ experiments are technically challenging and relatively time-consuming, the model offers great opportunities to gain insight into the processes determining Intestinal Drug Absorption.
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ex vivo permeability experiments in excised rat Intestinal tissue and in vitro solubility measurements in aspirated human Intestinal fluids support age dependent oral Drug Absorption
European Journal of Pharmaceutical Sciences, 2010Co-Authors: Pieter Annaert, Joachim Brouwers, Ann Bijnens, Frank Lammert, Jan Tack, Patrick AugustijnsAbstract:Abstract The possible influence of advanced age on Intestinal Drug Absorption was investigated by determining the effects of aging on (i) solubility of model Drugs in human Intestinal fluids (HIF) obtained from two age groups (18–25 years; 62–72 years); and (ii) transepithelial permeation of model Drugs across Intestinal tissue excised from young, adult and old rats. Average equilibrium solubility values for 10 poorly soluble compounds in HIF aspirated from both age groups showed high interindividual variability, but did not reveal significant differences. Characterization of the HIF from both age groups demonstrated comparable pH profiles, while concentrations of individual bile salts showed pronounced variability between individuals, however without statistical differences between age groups. Transepithelial permeation of the transcellular probe metoprolol was significantly increased in old rats (38 weeks) compared to the younger age groups, while the modulatory role of P-glycoprotein in transepithelial talinolol transport was observed in adult and old rats but not in young rats. In conclusion, age-dependent permeability of Intestinal tissue (rather than age-dependent luminal Drug solubility) may contribute to altered Intestinal Drug Absorption in older patients compared to young adults.
-
in vitro screening models to assess Intestinal Drug Absorption and metabolism
2008Co-Authors: S Deferme, Pieter Annaert, Patrick AugustijnsAbstract:Compounds intended for oral administration must have adequate biopharmaceutical properties in order to achieve therapeutic concentrations at the targeted site of action. Different models have been established for the parallel screening of these biopharmaceutical properties, including membrane-based models (PAMPA), cell culture-based models (such as Caco-2 and MDCK cell lines), and the Ussing chambers technique. In this chapter, the strengths and the drawbacks of these models are discussed, while examples of applications for these different models and suggestions to improve the models are provided. Finally, different in vitro methods for studying the Intestinal metabolism are also described. As the Intestinal Absorption process depends on a multitude of parameters, a single universal model accounting for all these parameters does not exist. Therefore, combination of different in vitro models should be considered in order to obtain better insights in Intestinal Drug Absorption in the different phases of Drug discovery and development.
