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Bergström, ChristelORCID iD iconorcid.org/289172612
Alternative names
Publications (10 of 81) Show all publications
Alvebratt, C., Denning, T., Prestidge, C., Bergström, C. & Strömme, M. (2019). Advanced methodologies to study in vitro digestion of a lipid-loaded mesoporous drug carrier. In: Preclinical Form and Formulation for Drug Discovery, Gordon Research Conference 2019: . Paper presented at Preclinical Form and Formulation for Drug Discovery, Gordon Research Conference. June 9-14 2019. Waterville Valley, USA..
Open this publication in new window or tab >>Advanced methodologies to study in vitro digestion of a lipid-loaded mesoporous drug carrier
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2019 (English)In: Preclinical Form and Formulation for Drug Discovery, Gordon Research Conference 2019, 2019Conference paper, Oral presentation with published abstract (Refereed)
National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-389520 (URN)
Conference
Preclinical Form and Formulation for Drug Discovery, Gordon Research Conference. June 9-14 2019. Waterville Valley, USA.
Available from: 2019-07-16 Created: 2019-07-16 Last updated: 2019-11-07Bibliographically approved
Hossain, M. S., Berg, S., Bergström, C. & Larsson, P. (2019). Aggregation Behavior of Medium Chain Fatty Acids Studied by Coarse-Grained Molecular Dynamics Simulation. AAPS PharmSciTech, 20, Article ID 61.
Open this publication in new window or tab >>Aggregation Behavior of Medium Chain Fatty Acids Studied by Coarse-Grained Molecular Dynamics Simulation
2019 (English)In: AAPS PharmSciTech, ISSN 1530-9932, E-ISSN 1530-9932, Vol. 20, article id 61Article in journal (Refereed) Published
Abstract [en]

Medium chain fatty acids (MCFA) are digestion products of lipid-rich food and lipid-based formulations, and they are used as transient permeability enhancers in formulation of poorly permeable compounds. These molecules may promote drug absorption by several different processes, including solubilization, increased membrane fluidity, and increased paracellular transport through opening of the tight junctions. Therefore, understanding the aggregation behavior of MCFAs is important. A number of studies have measured the critical micelle concentration (CMC) of MCFAs experimentally. However, CMC is highly dependent on system conditions like pH, temperature, and the ionic strength of the buffer used in different experimental techniques. In this study, we investigated the aggregation behavior of four different MCFAs using the coarse-grained molecular dynamics (CG-MD) simulations with the purpose to explore if CG-MD can be used to study MCFA interactions occurring in water. The ratio of deprotonated and non-charged MCFA molecules were manipulated to assess aggregation behavior under different pH conditions and within the box sizes of 22x22x44nm(3) and 44nm(3) for 1s. CMCs were calculated by performing CG-MD simulations with an increasing number of MCFAs. The resulting aggregate size distribution and number of free MCFA molecules were used to determine the CMC. The CMCs from simulations for C-8, C-10, and C-12 were 1.8-3.5-fold lower than the respective CMCs determined experimentally by the Wilhelmy method. However, the variation of MCFA aggregate sizes and morphologies at different pH conditions is consistent with previous experimental observation. Overall, this study suggests that CG-MD is suitable for studying colloidal systems including various MCFAs.

Place, publisher, year, edition, pages
SPRINGER, 2019
Keywords
medium chain fatty acid, aggregation, critical micelle concentration, coarse-grained molecular dynamics, fatty acid aggregation behavior, experiment simulation comparison
National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-375214 (URN)10.1208/s12249-018-1289-4 (DOI)000455320100007 ()30627943 (PubMedID)
Funder
VINNOVA, Dnr 2017-02690EU, European Research Council, 638965Swedish Research Council, 2014-3309
Available from: 2019-01-29 Created: 2019-01-29 Last updated: 2019-01-29Bibliographically approved
Bergström, C., Box, K., Holm, R., Matthews, W., McAllister, M., Mullertz, A., . . . Teleki, A. (2019). Biorelevant intrinsic dissolution profiling in early drug development: Fundamental, methodological, and industrial aspects. European journal of pharmaceutics and biopharmaceutics, 139, 101-114
Open this publication in new window or tab >>Biorelevant intrinsic dissolution profiling in early drug development: Fundamental, methodological, and industrial aspects
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2019 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 139, p. 101-114Article, review/survey (Refereed) Published
Abstract [en]

Intrinsic dissolution rate (IDR) is the surface specific dissolution rate of a drug. In early drug development, this property (among other parameters) is measured in order to compare different polymorphs and salt forms, guide formulation decisions, and to provide a quality marker of the active pharmaceutical ingredient (API) during production. In this review, an update on different methods and small-scale techniques that have recently evolved for determination of IDR is provided. The importance of biorelevant media and the hydrodynamic conditions of dissolution are also discussed. Different preparation techniques for samples are presented with a focus on disc, particle- and crystal-based methods. A number of small-scale techniques are then described in detail, and their applicability domains are identified. Finally, an updated industrial perspective is provided about IDR's place in the early drug development process.

Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-386370 (URN)10.1016/j.ejpb.2019.03.011 (DOI)000468711400011 ()30862481 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 115369
Available from: 2019-06-24 Created: 2019-06-24 Last updated: 2019-06-24Bibliographically approved
Keemink, J., Sjögren, E., Holm, R. & Bergström, C. A. S. (2019). Does the Intake of Ethanol Affect Oral Absorption of Poorly Soluble Drugs?. Journal of Pharmaceutical Sciences, 108(5), 1765-1771
Open this publication in new window or tab >>Does the Intake of Ethanol Affect Oral Absorption of Poorly Soluble Drugs?
2019 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 108, no 5, p. 1765-1771Article in journal (Refereed) Published
Abstract [en]

The presence of ethanol in gastrointestinal (GI) fluids may increase the solubility of poorly water-soluble drugs. This suggests that intake of ethanol with such compounds could result in increased drug absorption in the stomach and duodenum because of the greater concentration gradient present. To test this hypothesis, in vitro dissolution of 2 poorly soluble compounds (indomethacin and felodipine) was studied in simulated GI rat fluids in the presence or absence of ethanol. Results were used to predict plasma exposure of the compounds using the software PK-Sim. Finally, in vivo plasma exposure in rats was investigated after oral dosing followed by immediate administration of water or ethanol. Despite increased solubility in GI fluids in the presence of ethanol, simulations predicted a negligible effect on absorption. This was confirmed in the rat study where oral intake of indomethacin or felodipine with ethanol did not increase in vivo plasma exposure. A possible explanation for the lack of an effect may be that dilution, absorption, and transfer of ethanol upon arrival in the stomach resulted in intragastric and intraduodenal ethanol concentrations that did not reach the levels required to affect local solubility.

Keywords
ethanol, solubility, drug absorption, poorly water-soluble compounds
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-392063 (URN)10.1016/j.xphs.2018.12.006 (DOI)000477746900012 ()30562491 (PubMedID)
Funder
Swedish Research Council, 2014-3309
Available from: 2019-09-10 Created: 2019-09-10 Last updated: 2019-09-10Bibliographically approved
Alskär, L. C., Parrow, A., Keemink, J., Pernilla, J., Abrahamsson, B. & Bergström, C. A. S. (2019). Effect of lipids on absorption of carvedilol in dogs: Is coadministration of lipids as efficient as a lipid-based formulation?. Journal of Controlled Release, 304, 90-100
Open this publication in new window or tab >>Effect of lipids on absorption of carvedilol in dogs: Is coadministration of lipids as efficient as a lipid-based formulation?
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2019 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 304, p. 90-100Article in journal (Refereed) Published
Abstract [en]

Lipid-based formulations (LBFs) is a formulation strategy for enabling oral delivery of poorly water-soluble drugs. However, current use of this strategy is limited to a few percent of the marketed products. Reasons for that are linked to the complexity of LBFs, chemical instability of pre-dissolved drug and a limited understanding of the influence of LBF intestinal digestion on drug absorption. The aim of this study was to explore intestinal drug solubilization from a long-chain LBF, and evaluate whether coadministration of LBF is as efficient as a lipidbased drug formulation containing the pre-dissolved model drug carvedilol. Thus, solubility studies of this weak base were performed in simulated intestinal fluid (SIF) and aspirated dog intestinal fluid (DIF). DIF was collected from duodenal stomas after dosing of water and two levels (1 g and 2 g) of LBF. Similarly, the in vitro SIF solubility studies were conducted prior to, and after addition of, undigested or digested LBF. The DIF fluid was further characterized for lipid digestion products (free fatty acids) and bile salts. Subsequently, carvedilol was orally administered to dogs in a lipid-based drug formulation and coadministered with LBF, and drug plasma exposure was assessed. In addition to these studies, in vitro drug absorption from the different formulation approaches were evaluated in a lipolysis-permeation device, and the obtained data was used to evaluate the in vitro in vivo correlation. The results showed elevated concentrations of free fatty acids and bile salts in the DIF when 2 g of LBF was administered, compared to only water. As expected, the SIF and DIF solubility data revealed that carvedilol solubilization increased by the presence of lipids and lipid digestion products. Moreover, coadministration of LBF and drug demonstrated equal plasma exposure to the lipid-based drug formulation. Furthermore, evaluation of in vitro absorption resulted in the same rank order for the LBFs as in the in vivo dog study. In conclusion, this study demonstrated increased intestinal solubilization from a small amount of LBF, caused by lipid digestion products and bile secretion. The outcomes also support the use of coadministration of LBF as a potential dosing regimen in cases where it is beneficial to have the drug in the solid form, e.g. due to chemical instability in the lipid vehicle. LBFs.

Keywords
Intestinal digestion, in vivo dog study, lipid-based formulation, coadministration, absorption, in vitro in vivo correlation (IVIVC)
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-366566 (URN)10.1016/j.jconrel.2019.04.038 (DOI)000473719700009 ()31047962 (PubMedID)
Funder
Swedish Research Council, 621-2011-2445Swedish Research Council, 621-2014-3309EU, European Research Council, 638965
Available from: 2018-11-21 Created: 2018-11-21 Last updated: 2019-08-16Bibliographically approved
Amidon, G. E., Anderson, B. D., Balthasar, J. P., Bergström, C. A. .., Huang, S.-M., Kasting, G., . . . Yu, L. (2019). Fifty-Eight Years and Counting: High-Impact Publishing in Computational Pharmaceutical Sciences and Mechanism-Based Modeling. Journal of Pharmaceutical Sciences, 108(1), 2-7
Open this publication in new window or tab >>Fifty-Eight Years and Counting: High-Impact Publishing in Computational Pharmaceutical Sciences and Mechanism-Based Modeling
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2019 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 108, no 1, p. 2-7Article in journal (Refereed) Published
Abstract [en]

With this issue of the Journal of Pharmaceutical Sciences, we celebrate the nearly 6 decades of contributions to mechanistic-based modeling and computational pharmaceutical sciences. Along with its predecessor, The Journal of the American Pharmaceutical Association: Scientific Edition first published in 1911, JPharmSci has been a leader in the advancement of pharmaceutical sciences beginning with its inaugural edition in 1961. As one of the first scientific journals focusing on pharmaceutical sciences, JPharmSci has established a reputation for publishing high-quality research articles using computational methods and mechanism-based modeling. The journal’s publication record is remarkable. With over 15,000 articles, 3000 notes, and more than 650 reviews from industry, academia, and regulatory agencies around the world, JPharmSci has truly been the leader in advancing pharmaceutical sciences.

Keywords
absorption, distribution, metabolism, and excretion (ADME), biophysical model(s), in silico modeling, in vitro model(s), mathematical model(s), mechanistic modeling, molecular modeling, pharmacokinetic-pharmacodynamic (PKPD) modeling, physiologically based pharmacokinetic (PBPK) modeling
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-377372 (URN)10.1016/j.xphs.2018.11.002 (DOI)000456898100002 ()30423338 (PubMedID)
Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-02-25Bibliographically approved
Keemink, J., Martensson, E. & Bergström, C. (2019). Lipolysis-Permeation Setup for Simultaneous Study of Digestion and Absorption in Vitro. Molecular Pharmaceutics, 16(3), 921-930
Open this publication in new window or tab >>Lipolysis-Permeation Setup for Simultaneous Study of Digestion and Absorption in Vitro
2019 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 16, no 3, p. 921-930Article in journal (Refereed) Published
Abstract [en]

Lipid-based formulations (LBFs) are a delivery strategy to enhance intestinal absorption of poorly water-soluble drugs. LBF performance is typically evaluated by in vitro lipolysis studies, but these do not accurately predict the in vivo performance. One possible reason is the absence of an absorptive membrane driving sink conditions in the serosal compartment. To explore the impact of absorption under sink conditions on the performance evaluation, we developed a lipolysis-permeation setup that allows simultaneous investigation of intestinal digestion of an LBF and drug absorption. The setup consists of two chambers, an upper one for digestion (luminal), and a lower, receiving one (serosal), separated by a Caco-2 monolayer. Digestions were performed with immobilized lipase, instead of the pancreatic extract typically used during lipolysis, since the latter has proven incompatible with Caco-2 cells. Danazol-loaded LBFs were used to develop the setup, and fenofibrate-loaded LBFs were used to establish an in vitro in vivo correlation. As in regular lipolysis studies, our setup allows for the evaluation of (i) the extent of digestion and (ii) drug distribution in different phases present during lipolysis of drug-loaded LBFs (i.e., oil, aqueous, and solid phase). In addition, our setup can determine drug permeation across Caco-2 monolayers and hence, the absorptive flux of the compound. The presence of the absorptive monolayer and sink conditions tended to reduce aqueous drug concentrations and supersaturation in the digestion chamber. The drug transfer across the Caco-2 membrane accurately reflected in vivo drug exposure upon administration of three different LBFs loaded with fenofibrate, where the traditional lipolysis setup failed to predict in vivo performance. As the new setup reflects the dynamic processes occurring in the gastrointestinal tract, it is a valuable tool that can be used in the development of LBFs prior to in vivo studies.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2019
Keywords
intestinal digestion, absorption, lipid-based formulation, Caco-2, in vitro in vivo correlation
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-380490 (URN)10.1021/acs.molpharmaceut.8b00811 (DOI)000460600400001 ()30628771 (PubMedID)
Funder
EU, European Research Council, 638965Swedish Research Council, 2014-3309
Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-03-28Bibliographically approved
Edueng, K., Bergström, C., Gråsjö, J. & Mahlin, D. (2019). Long-term physical (in)stability of spray-dried amorphous drugs: relationship with glass-forming ability and physicochemical properties. Pharmaceutics, 11(9), Article ID 425.
Open this publication in new window or tab >>Long-term physical (in)stability of spray-dried amorphous drugs: relationship with glass-forming ability and physicochemical properties
2019 (English)In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 11, no 9, article id 425Article in journal (Other academic) Published
National Category
Social and Clinical Pharmacy
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-390255 (URN)10.3390/pharmaceutics11090425 (DOI)000489151700053 ()31438566 (PubMedID)
Funder
Swedish Research Council, 621-2011-2445Swedish Research Council, 621-2014-3309
Available from: 2019-08-07 Created: 2019-08-07 Last updated: 2019-11-08Bibliographically approved
Sou, T., Kukavica-Ibrulj, I., Soukarieh, F., Halliday, N., Levesque, R. C., Williams, P., . . . Bergström, C. A. S. (2019). Model-Based Drug Development in Pulmonary Delivery: Pharmacokinetic Analysis of Novel Drug Candidates for Treatment of Pseudomonas aeruginosa Lung Infection. Journal of Pharmaceutical Sciences, 108(1), 630-640
Open this publication in new window or tab >>Model-Based Drug Development in Pulmonary Delivery: Pharmacokinetic Analysis of Novel Drug Candidates for Treatment of Pseudomonas aeruginosa Lung Infection
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2019 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 108, no 1, p. 630-640Article in journal (Refereed) Published
Abstract [en]

Antibiotic resistance is a major public health threat worldwide. In particular, about 80% of cystic fibrosis patients have chronic Pseudomonas aeruginosa (PA) lung infection resistant to many current antibiotics. We are therefore developing a novel class of antivirulence agents, quorum sensing inhibitors (QSIs), which inhibit biofilm formation and sensitize PA to antibiotic treatments. For respiratory conditions, targeted delivery to the lung could achieve higher local concentrations with reduced risk of adverse systemic events. In this study, we report the pharmacokinetics of 3 prototype QSIs after pulmonary delivery, and the simultaneous analysis of the drug concentration-time profiles from bronchoalveolar lavage, lung homogenate and plasma samples, using a pharmacometric modeling approach. In addition to facilitating the direct comparison and selection of drug candidates, the developed model was used for dosing simulation studies to predict in vivo exposure following different dosing scenarios. The results show that systemic clearance has limited impact on local drug exposure in the lung after pulmonary delivery. Therefore, we suggest that novel QSIs designed for pulmonary delivery as targeted treatments for respiratory conditions should ideally have a long residence time in the lung for local efficacy with rapid clearance after systemic absorption for reduced risk of systemic adverse events.

Keywords
pulmonary drug delivery, pharmacometrics, PK/PD modeling, preclinical pharmacokinetics, absorption, solubility, metabolic clearance, distribution, disposition, simulations
National Category
Pharmacology and Toxicology Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-377374 (URN)10.1016/j.xphs.2018.09.017 (DOI)000456898100066 ()30257195 (PubMedID)
Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-02-25Bibliographically approved
Alhalaweh, A., Alzghoul, A. & Bergström, C. A. S. (2019). Molecular Drivers of Crystallization Kinetics for Drugs in Supersaturated Aqueous Solutions. Journal of Pharmaceutical Sciences, 108(1), 252-259
Open this publication in new window or tab >>Molecular Drivers of Crystallization Kinetics for Drugs in Supersaturated Aqueous Solutions
2019 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 108, no 1, p. 252-259Article in journal (Refereed) Published
Abstract [en]

In this study, we explore molecular properties of importance in solution-mediated crystallization occurring in supersaturated aqueous drug solutions. Furthermore, we contrast the identified molecular properties with those of importance for crystallization occurring in the solid state. A literature data set of 54 structurally diverse compounds, for which crystallization kinetics from supersaturated aqueous solutions and in melt-quenched solids were reported, was used to identify molecular drivers for crystallization kinetics observed in solution and contrast these to those observed for solids. The compounds were divided into fast, moderate, and slow crystallizers, and in silico classification was developed using a molecular K-nearest neighbor model. The topological equivalent of Grav3 (related to molecular size and shape) was identified as the most important molecular descriptor for solution crystallization kinetics; the larger this descriptor, the slower the crystallization. Two electrotopological descriptors (the atom-type E-state index for -Caa groups and the sum of absolute values of pi Fukui(+) indices on C) were found to separate the moderate and slow crystallizers in the solution. The larger these descriptors, the slower the crystallization. With these 3 descriptors, the computational model correctly sorted the crystallization tendencies from solutions with an overall classification accuracy of 77% (test set).

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2019
Keywords
crystallization, glass, in silico modeling, supersaturation, physicochemical properties, precipitation
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-377373 (URN)10.1016/j.xphs.2018.11.006 (DOI)000456898100043 ()30423342 (PubMedID)
Funder
Swedish Research Council, 621-2011-2445Swedish Research Council, 621-2014-3309
Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-02-25Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/289172612

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