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Bergström, ChristelORCID iD iconorcid.org/289172612
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Publications (10 of 63) Show all publications
Yang, J., Alvebratt, C., Lu, X., Bergström, C., Strömme, M. & Welch, K. (2018). Amorphous Magnesium Carbonate Nanoparticles with Strong Stabilizing Capability for Amorphous Ibuprofen. International Journal of Pharmaceutics, 548(1), 515-521
Open this publication in new window or tab >>Amorphous Magnesium Carbonate Nanoparticles with Strong Stabilizing Capability for Amorphous Ibuprofen
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2018 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 548, no 1, p. 515-521Article in journal (Refereed) Published
Abstract [en]

Formulating active pharmaceutical ingredients (APIs) in the amorphous state can increase their apparent aqueous solubility and dissolution rate and consequently improve their bioavailability. This study demonstrates, for the first time, the ability to stabilize an API in the amorphous state using a solid dispersion of magnesium carbonate nanoparticles within the API. Specifically, high proportions of ibuprofen were able to be stabilized in the amorphous state using as little as 17% wt/wt amorphous magnesium carbonate nanoparticles, and drug release rates 83 times faster than from the crystalline state were achieved. Biocompatibility of the nanoparticles was demonstrated in vitro using human dermal fibroblasts and stability of the nanocomposite formulation was verified with a storage time of six months. The success of this novel formulation provides a promising approach for achieving improved apparent solubility and enhanced bioavailability of drugs.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Magnesium carbonate, Nanoparticles, Nanocomposite, Amorphous, Ibuprofen, Solubility, Dissolution
National Category
Nano Technology Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-354506 (URN)10.1016/j.ijpharm.2018.07.021 (DOI)000440552100050 ()29981897 (PubMedID)
Funder
Swedish Research Council
Available from: 2018-06-20 Created: 2018-06-20 Last updated: 2018-11-12Bibliographically approved
Keemink, J. & Bergström, C. (2018). Caco-2 Cell Conditions Enabling Studies of Drug Absorptionfrom Digestible Lipid-Based Formulations. Pharmaceutical research, 35(4), Article ID 74.
Open this publication in new window or tab >>Caco-2 Cell Conditions Enabling Studies of Drug Absorptionfrom Digestible Lipid-Based Formulations
2018 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 35, no 4, article id 74Article in journal (Refereed) Published
Abstract [en]

Purpose To identify conditions allowing the use of cell-based models for studies of drug absorption during in vitro lipolysis of lipid-based formulations (LBFs). Methods Caco-2 was selected as the cell-based model system. Monolayer integrity was evaluated by measuring mannitol permeability after incubating Caco-2 cells in the presence of components available during lipolysis. Pure excipients and formulations representing the lipid formulation classification system (LFCS) were evaluated before and after digestion. Porcine mucin was evaluated for its capacity to protect the cell monolayer. Results Most undigested formulations were compatible with the cells (II-LC, IIIB-LC, and IV) although some needed mucin to protect against damaging effects (II-MC, IIIB-MC, LC, and IIIA-LC). The pancreatic extract commonly used in digestion studies was incompatible with the cells but the Caco-2 monolayers could withstand immobilized recombinant lipase. Upon digestion, long chain formulations caused more damage to Caco-2 cells than their undigested counterparts whereas medium chain formulations showed better tolerability after digestion. Conclusions Most LBFs and components thereof (undigested and digested) are compatible with Caco-2 cells. Pancreatic enzyme is not tolerated by the cells but immobilized lipase can be used in combination with the cell monolayer. Mucin is beneficial for critical formulations and digestion products.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Caco-2 cells, digestion, intestinal absorption, lipid-based formulation
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-342749 (URN)10.1007/s11095-017-2327-8 (DOI)000441807000003 ()29484506 (PubMedID)
Funder
EU, European Research Council, 638965Swedish Research Council, 2014-3309
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-11-05Bibliographically approved
Bergström, C. A. & Larsson, P. (2018). Computational prediction of drug solubility in water-based systems: qualitative and quantitative approaches used in the current drug discovery and development setting. International Journal of Pharmaceutics, 540(1-2), 185-193
Open this publication in new window or tab >>Computational prediction of drug solubility in water-based systems: qualitative and quantitative approaches used in the current drug discovery and development setting
2018 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 540, no 1-2, p. 185-193Article, review/survey (Refereed) Published
Abstract [en]

In this review we will discuss recent advances in computational prediction of solubility in water-based solvents. Our focus is set on recent advances in predictions of biorelevant solubility in media mimicking the human intestinal fluids and on new methods to predict the thermodynamic cycle rather than prediction of solubility in pure water through quantitative structure property relationships (QSPR). While the literature is rich in QSPR models for both solubility and melting point, a physicochemical property strongly linked to the solubility, recent advances in the modelling of these properties make use of theory and computational simulations to better predict these properties or processes involved therein (e.g. solid state crystal lattice packing, dissociation of molecules from the lattice and solvation). This review serves to provide an update on these new approaches and how they can be used to more accurately predict solubility, and also importantly, inform us on molecular interactions and processes occurring during drug dissolution and solubilisation.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-342632 (URN)10.1016/j.ijpharm.2018.01.044 (DOI)000427584900019 ()
Funder
EU, European Research Council, 638965
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-04-05Bibliographically approved
Alskär, L. C., Keemink, J., Johannesson, J., Porter, C. J. & Bergström, C. A. S. (2018). Impact of Drug Physicochemical Properties on Lipolysis-Triggered Drug Supersaturation and Precipitation from Lipid-Based Formulations. Molecular Pharmaceutics, 15(10), 4733-4744
Open this publication in new window or tab >>Impact of Drug Physicochemical Properties on Lipolysis-Triggered Drug Supersaturation and Precipitation from Lipid-Based Formulations
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2018 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 10, p. 4733-4744Article in journal (Refereed) Published
Abstract [en]

In this study we investigated lipolysis-triggered supersaturation and precipitation of a set of model compounds formulated in lipid-based formulations (LBFs). The purpose was to explore the relationship between precipitated solid form and inherent physicochemical properties of the drug. Eight drugs were studied after formulation in three LBFs, representing lipid-rich (extensively digestible) to surfactant-rich (less digestible) formulations. In vitro lipolysis of drug-loaded LBFs were conducted, and the amount of dissolved and precipitated drug was quantified. Solid form of the precipitated drug was characterized with polarized light microscopy (PLM) and Raman spectroscopy. A significant solubility increase for the weak bases in the presence of digestion products was observed, in contrast to the neutral and acidic compounds for which the solubility decreased. The fold-increase in solubility was linked to the degree of ionization of the weak bases and thus their attraction to free fatty acids. A high level of supersaturation was needed to cause precipitation. For the weak bases, the dose number indicated that precipitation would not occur during lipolysis; hence, these compounds were not included in further studies. The solid state analysis proved that danazol and griseofulvin precipitated in a crystalline form, while niclosamide precipitated as a hydrate. Felodipine and indomethacin crystals were visible in the PLM, whereas the Raman spectra showed presence of amorphous drug, indicating amorphous precipitation that quickly crystallized. The solid state analysis was combined with literature data to allow analysis of the relationship between solid form and the physicochemical properties of the drug. It was found that low molecular weight and high melting temperature increases the probability of crystalline precipitation, whereas precipitation in an amorphous form was favored by high molecular weight, low melting temperature, and positive charge.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
Keywords
Poorly water-soluble drugs, lipid digestion, physicochemical properties, precipitation, solid state, supersaturation
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-366563 (URN)10.1021/acs.molpharmaceut.8b00699 (DOI)000446413400041 ()30142268 (PubMedID)
Funder
EU, European Research Council, 638965Swedish Research Council, 621-2011-2445, 621-2014-3309
Available from: 2018-11-21 Created: 2018-11-21 Last updated: 2018-12-03Bibliographically approved
Tsume, Y., Patel, S., Fotaki, N., Bergström, C., Amidon, G. L., Brasseur, J. G., . . . Amidon, G. E. (2018). In Vivo Predictive Dissolution and Simulation Workshop Report: Facilitating the Development of Oral Drug Formulation and the Prediction of Oral Bioperformance. AAPS Journal, 20(6), Article ID UNSP 100.
Open this publication in new window or tab >>In Vivo Predictive Dissolution and Simulation Workshop Report: Facilitating the Development of Oral Drug Formulation and the Prediction of Oral Bioperformance
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2018 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 20, no 6, article id UNSP 100Article in journal (Refereed) Published
Keywords
dissolution, formulation prediction, in vivo prediction, simulation
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-364120 (URN)10.1208/s12248-018-0260-3 (DOI)000443962900001 ()30191341 (PubMedID)
Available from: 2018-10-29 Created: 2018-10-29 Last updated: 2018-10-29Bibliographically approved
Clulow, A. J., Parrow, A., Hawley, A., Khan, J., Pham, A. C., Larsson, P., . . . Boyd, B. J. (2017). Characterization of Solubilizing Nanoaggregates Present in Different Versions of Simulated Intestinal Fluid. Journal of Physical Chemistry B, 121(48), 10869-10881
Open this publication in new window or tab >>Characterization of Solubilizing Nanoaggregates Present in Different Versions of Simulated Intestinal Fluid
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2017 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 121, no 48, p. 10869-10881Article in journal (Refereed) Published
Abstract [en]

The absorption of hydrophobic drugs and nutrients from the intestine is principally determined by the amount that can be dissolved by the endogenous fluids present in the gut. Human intestinal fluids (HIFs) comprise a complex mixture of bile salts, phospholipids, steroids and glycerides that vary in composition in the fed and fasted state and between subjects. A number of simulated intestinal fluid (SIF) compositions have been developed to mimic fasted and fed state intestinal conditions and allow the in vitro determination of drug solubility as a proxy for the maximum dissolved concentration it is possible to reach. In particular these solvents are used during the development of lipophilic and poorly water-soluble drugs but questions remain around the differences that may arise from the source and methods of preparation of these fluids. In this work, a range of SIFs were studied using small angle X-ray scattering (SAXS), cryogenic -transmission electron microscopy (cryo-TEM) and molecular dynamics (MD) simulations in order to analyze their structures. In-house prepared SIFs based on sodium taurodeoxycholate (NaTDC) and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) formed oblate ellipsoidal micelles irrespective of lipid concentration and preparation conditions. In contrast, commercially available SIFs based on sodium taurocholate and lecithin formed prolate ellipsoidal micelles in the fed state and vesicles in the fasted state. These structural variations are the likely reason for the dramatic differences sometimes observed in the solubility enhancements for hydrophobic drugs, nutrients and digestion products when using different SIFs. However, the structural homogeneity of the NaTDC/DOPC micelles makes them ideal candidates for standardizing SIF formulations as the structures of the solubilizing nanoaggregates therein are not sensitive to the preparation method.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2017
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-340253 (URN)10.1021/acs.jpcb.7b08622 (DOI)000417672200014 ()29090933 (PubMedID)
Funder
Australian Research Council, DP160102906, FT120100697EU, European Research Council, 638965Swedish Research Council, 2014-3309EU, Horizon 2020, 654000
Available from: 2018-01-31 Created: 2018-01-31 Last updated: 2018-01-31Bibliographically approved
Andersson, S. B. E., Alvebratt, C. & Bergström, C. (2017). Controlled Suspensions Enable Rapid Determinations of Intrinsic Dissolution Rate and Apparent Solubility of Poorly Water-Soluble Compounds. Pharmaceutical research, 34(9), 1805-1816
Open this publication in new window or tab >>Controlled Suspensions Enable Rapid Determinations of Intrinsic Dissolution Rate and Apparent Solubility of Poorly Water-Soluble Compounds
2017 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 34, no 9, p. 1805-1816Article in journal (Refereed) Published
Abstract [en]

Purpose: To develop a small-scale set-up to rapidly and accurately determine the intrinsic dissolution rate (IDR) and apparent solubility of poorly water-soluble compounds.

Methods: The IDR and apparent solubility (S-app) were measured in fasted state simulated intestinal fluid (FaSSIF) for six model compounds using wet-milled controlled suspensions (1.0% (w/w) PVP and 0.2% (w/w) SDS) and the mu DISS Profiler. Particle size distribution was measured using a Zetasizer and the total surface area was calculated making use of the density of the compound. Powder and disc dissolution were performed and compared to the IDR of the controlled suspensions.

Results: The IDR values obtained from the controlled suspensions were in excellent agreement with IDR from disc measurements. The method used low amount of compound (mu g-scale) and the experiments were completed within a few minutes. The IDR values ranged from 0.2-70.6 mu g/min/cm(2) and the IDR/S-app ratio ranged from 0.015 to 0.23. This ratio was used to indicate particle size sensitivity on intestinal concentrations reached for poorly water-soluble compounds.

Conclusions: The established method is a new, desirable tool that provides the means for rapid and highly accurate measurements of the IDR and apparent solubility in biorelevant dissolution media. The IDR/S-app is proposed as a measure of particle size sensitivity when significant solubilization may occur.

Keywords
apparent solubility, controlled suspensions, dissolution-limited drug absorption, intrinsic dissolution rate, particle size reduction
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-333062 (URN)10.1007/s11095-017-2188-1 (DOI)000406495100006 ()28620887 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 115369
Available from: 2017-11-09 Created: 2017-11-09 Last updated: 2018-01-13Bibliographically approved
Yang, J., Alvebratt, C., Zhang, P., Zardán Gómez de la Torre, T., Strömme, M., Bergström, C. & Welch, K. (2017). Enhanced release of poorly water-soluble drugs from synergy between mesoporous magnesium carbonate and polymers. International Journal of Pharmaceutics, 525(1), 183-190
Open this publication in new window or tab >>Enhanced release of poorly water-soluble drugs from synergy between mesoporous magnesium carbonate and polymers
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2017 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 525, no 1, p. 183-190Article in journal (Refereed) Published
Abstract [en]

The need to combat poor water solubility has increased interest in supersaturating drug delivery systems. In this study, amorphous mesoporous magnesium carbonate (MMC) was used as a drug carrier to achieve supersaturation of tolfenamic acid and rimonabant, two drug compounds with low aqueous solubility. The potential synergy between MMC and hydroxypropyl methylcellulose (HPMC), a polymer commonly included as a precipitation inhibitor in drug delivery systems, was explored with the aim of extending the time that high supersaturation levels were maintained. Release was studied under physiological conditions using USP-2 dissolution baths. A new small-scale method was developed to enable measurement of the initial drug release occurring when the MMC is immersed in the water phase. It was shown that MMC and HPMC together resulted in significant supersaturation and that the polymer enabled both the achievement of a higher API concentration and extension of the supersaturation period. The new small-scale release method showed that the release was linearly increasing with the dose and that similar release rates were observed for the two model compounds. It was hence concluded that the MMC release was diffusion limited for the compounds explored.

Keywords
Magnesium carbonate, Mesoporous, Hydroxypropyl methylcellulose, Tolfenamic acid, Rimonabant, Supersaturation
National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-320987 (URN)10.1016/j.ijpharm.2017.04.018 (DOI)000401112300019 ()28396244 (PubMedID)
Funder
VINNOVASwedish Research Council
Available from: 2017-04-27 Created: 2017-04-27 Last updated: 2018-09-03Bibliographically approved
Plum, J., Madsen, C. M., Teleki, A., Bevernage, J., Mathews, C. d., Karlsson, E. M., . . . Mullertz, A. (2017). Investigation of the Intra- and Interlaboratory Reproducibility of a Small Scale Standardized Supersaturation and Precipitation Method. Molecular Pharmaceutics, 14(12), 4161-4169
Open this publication in new window or tab >>Investigation of the Intra- and Interlaboratory Reproducibility of a Small Scale Standardized Supersaturation and Precipitation Method
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2017 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 12, p. 4161-4169Article in journal (Refereed) Published
Abstract [en]

The high number of poorly water-soluble compounds in drug development has increased the need for enabling formulations to improve oral bioavailability. One frequently applied approach is to induce supersaturation at the absorptive site, e.g., the small intestine, increasing the amount of dissolved compound available for absorption. However, due to the stochastic nature of nucleation, supersaturating drug delivery systems may lead to inter- and intrapersonal variability. The ability to define a feasible range with respect to the supersaturation level is a crucial factor for a successful formulation. Therefore, an in vitro method is needed, from where the ability of a compound to supersaturate can be defined in a reproducible way. Hence, this study investigates the reproducibility of an in vitro small scale standardized supersaturation and precipitation method (SSPM). First an intralaboratory reproducibility study of felodipine was conducted, after which seven partners contributed with data for three model compounds; aprepitant, felodipine, and fenofibrate, to determine the interlaboratory reproducibility of the SSPM. The first part of the SSPM determines the apparent degrees of supersaturation (aDS) to investigate for each compound. Each partner independently determined the maximum possible aDS and induced 100, 87.5, 75, and 50% of their determined maximum possible aDS in the SSPM. The concentration time profile of the supersaturation and following precipitation was obtained in order to determine the induction time (t(ind)) for detectable precipitation. The data showed that the absolute values of t(ind) and aDS were not directly comparable between partners, however, upon linearization of the data a reproducible rank ordering of the three model compounds was obtained based on the beta-value, which was defined as the slope of the In(t(ind)) versus In(aDS)(-2) plot. Linear regression of this plot showed that aprepitant had the highest beta-value, 15.1, while felodipine and fenofibrate had comparable beta-values, 4.0 and 4.3, respectively. Of the five partners contributing with full data sets, 80% could obtain the same rank order for the three model compounds using the SSPM (aprepitant > felodipine approximate to fenofibrate). The alpha-value is dependent on the experimental setup and can be used as a parameter to evaluate the uniformity of the data set. This study indicated that the SSPM was able to obtain the same rank order of the beta-value between partners and, thus, that the SSPM may be used to classify compounds depending on their supersaturation propensity.

Keywords
supersaturation, precipitation, oral drug delivery, variability
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-339902 (URN)10.1021/acs.molpharmaceut.7b00419 (DOI)000417342400005 ()29043811 (PubMedID)
Available from: 2018-01-23 Created: 2018-01-23 Last updated: 2018-03-08Bibliographically approved
Edueng, K., Mahlin, D., Larsson, P. & Bergström, C. (2017). Mechanism-based selection of stabilization strategy for amorphous formulations: Insights into crystallization pathways. Journal of Controlled Release, 256, 193-202
Open this publication in new window or tab >>Mechanism-based selection of stabilization strategy for amorphous formulations: Insights into crystallization pathways
2017 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 256, p. 193-202Article in journal (Refereed) Published
Abstract [en]

We developed a step-by-step experimental protocol using differential scanning calorimetry (DSC), dynamic vapour sorption (DVS), polarized light microscopy (PLM) and a small-scale dissolution apparatus (mu DISS Profiler) to investigate the mechanism (solid-to-solid or solution-mediated) by which crystallization of amorphous drugs occurs upon dissolution. This protocol then guided how to stabilize the amorphous formulation. Indapamide, metolazone, glibenclamide and glipizide were selected as model drugs and HPMC (Pharmacoat 606) and PVP (K30) as stabilizing polymers. Spray-dried amorphous indapamide, metolazone and glibenclamide crystallized via solution-mediated nucleation while glipizide suffered from solid-to-solid crystallization. The addition of 0.001%-0.01% (w/v) HPMC into the dissolution medium successfully prevented the crystallization of supersaturated solutions of indapamide and metolazone whereas it only reduced the crystallization rate for glibenclamide. Amorphous solid dispersion (ASD) formulation of glipizide and PVP K30, at a ratio of 50:50% (w/w) reduced but did not completely eliminate the solid-to-solid crystallization of glipizide even though the overall dissolution rate was enhanced both in the absence and presence of HPMC. Raman spectroscopy indicated the formation of a glipizide polymorph in the dissolution medium with higher solubility than the stable polymorph. As a complementary technique, molecular dynamics (MD) simulations of indapamide and glibenclamide with HPMC was performed. It was revealed that hydrogen bonding patterns of the two drugs with HPMC differed significantly, suggesting that hydrogen bonding may play a role in the greater stabilizing effect on supersaturation of indapamide, compared to glibenclamide.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2017
Keywords
Amorphous, Crystallization, Solid-state, Dissolution, Stabilization, Polymer, Supersaturation
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-329635 (URN)10.1016/j.jconrel.2017.04.015 (DOI)000403324800017 ()28412224 (PubMedID)
Funder
EU, European Research Council, 638965Swedish Research Council, 2014-3309
Available from: 2017-09-25 Created: 2017-09-25 Last updated: 2018-01-13Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/289172612

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