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  • 301.
    Dahlin, Maria
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Nasal administration of compounds active in the central nervous system: Exploring the olfactory system2000Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The nasal administration of drugs offers advantages over administration by intravenous injection. Drugs can be rapidly absorbed through the nasal mucosa, resulting in a rapid onset of action, and also avoiding degradation in the gastrointestinal tract and first-pass metabolism in the liver. The olfactory receptor cells, which are in direct contact with both the environment and the central nervous system (CNS), are potential routes for drugs into the CNS. The olfactory pathway thus circumvents the blood brain barrier (BBB) which prevents many systemically administered drugs from entering the brain.

    The studies used compounds active in the CNS and the experiments were performed in rodents. The nasal bioavailability of (S)-UH-301, NXX-066 and [3H]-dopamine was investigated in a rat model; uptake into the cerebrospinal fluid (CSF) was compared after nasal and intravenous administration. The concentrations of S-UH-301 and NXX-066 in plasma and CSF were measured with high performance liquid chromatography. The possible transfer of dopamine and neurotensin along the olfactory pathway after nasal administration to mice was studied using brain tissue sampling and autoradiography. The radioactivity content in blood, CSF and dissected brain tissue samples after administration of [3H]-dopamine and [3H]-neurotensin was assessed using liquid scintillation, and thin layer chromatography (TLC) was used to investigate the metabolic fate of [3H]-dopamine.

    The results of this thesis suggest that nasal administration of CNS-active compounds with low oral bioavailability is an interesting and workable alternative to intravenous injection. The small lipophilic compounds (S)-UH-301 and NXX-066 were rapidly and completely absorbed after nasal administration, although hard evidence of direct transfer from the nose remains elusive. Radioactivity measurements in the olfactory bulb following nasal administration of

    [3H]-dopamine and [3H]-neurotensin indicate that transfer occurred. The TLC results showed the presence of unchanged dopamine in the olfactory bulb but it is less clear from initial results with neurotensin, which radioactive products of this molecule reached the olfactory bulb, and further studies are required.

  • 302.
    Dahlin, Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergman, Ulrika
    Jansson, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Björk, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Brittebo, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Transfer of dopamine in the olfactory pathway following nasal administration in mice2000Inngår i: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 17, nr 6, s. 737-742Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: The aim of the study was to investigate whether dopamine is transferred along the olfactory pathway to the brain following nasal administration to mice. METHODS: [3H]-Dopamine was administered nasally or intravenously to female mice. Brain tissue samples were excised and the radioactive content was measured. The precise localisation of dopamine radioactivity in the brain was studied using autoradiography. The presence of dopamine or its metabolites in the olfactory bulb and mucosa was ascertained using thin layer chromatography (TLC). RESULTS: After administration of [3H]-dopamine into the right nostril, the amount of dopamine in the right bulb increased with time until. after 4 h, it was 27 times higher than in the left bulb. Among the other brain tissue samples, significantly higher amount of radioactivity was detected in the lateral olfactory tract. Radioactivity in the right olfactory bulb was shown by autoradiography to be selectively located in the peripheral layers 1 to 4 h after administration. Selective uptake of radioactivity was not seen in other regions of the brain. TLC data indicated that approximately 75% and 10% of the radioactivity in the olfactory bulb and mucosa, respectively, coeluted with dopamine. CONCLUSIONS: The results indicate that unchanged dopamine is transferred into the olfactory bulb following nasal administration of [3H]-dopamine.

  • 303. Danelian, E
    et al.
    Karlen, A
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Karlsson, R
    Winiwarter, S
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Hansson, A
    Lofas, S
    Lennernas, H
    Institutionen för farmaci.
    Hamalainen, MD
    SPR biosensor studies of the direct interaction between 27 drugs and a liposome surface: Correlation with fraction absorbed in humans2000Inngår i: J MED CHEMI, Vol. 43, s. 2083-Artikkel i tidsskrift (Fagfellevurdert)
  • 304.
    Darj, Elisabeth
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Axelsson, Ove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Lennernas, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Nilsson, S
    Natural micronized progesterone orally administered in postmenopausal hormone replacement therapy1995Inngår i: European Menopause Journal, ISSN 1381-2858, Vol. 2, s. 16-Artikkel i tidsskrift (Fagfellevurdert)
  • 305.
    Darwich, A. S.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Neuhoff, S.
    Jamei, M.
    Rostami-Hodjegan, A.
    Interplay of Metabolism and Transport in Determining Oral Drug Absorption and Gut Wall Metabolism: A Simulation Assessment Using the "Advanced Dissolution, Absorption, Metabolism (ADAM)" Model2010Inngår i: Current drug metabolism, ISSN 1389-2002, E-ISSN 1875-5453, Vol. 11, nr 9, s. 716-729Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Bioavailability of orally administered drugs can be influenced by a number of factors including release from the formulation, dissolution, stability in the gastrointestinal (GI) environment, permeability through the gut wall and first-pass gut wall and hepatic metabolism. Although there are various enzymes in the gut wall which may contribute to gut first pass metabolism, Cytochrome P450 (CYP) 3A has been shown to play a major role. The efflux transporter P-glycoprotein (P-gp; MDR1/ABCB1) is the most extensively studied drug efflux transporter in the gut and might have a significant role in the regulation of GI absorption. Although not every CYP3A substrate will have a high extent of gut wall first-pass extraction, being a substrate for the enzyme increases the likelihood of a higher first-pass extraction. Similarly, being a P-gp substrate does not necessarily pose a problem with the gut wall absorption however it may reduce bioavailability in some cases (e. g. when drug has low passive permeability). An on-going debate has focused on the issue of the interplay between CYP3A and P-gp such that high affinity to P-gp increases the exposure of drug to CYP3A through repeated cycling via passive diffusion and active efflux, decreasing the fraction of drug that escapes first pass gut metabolism (F-G). The presence of P-gp in the gut wall and the high affinity of some CYP3A substrates to this transporter are postulated to reduce the potential for saturating the enzymes, thus increasing gut wall first-pass metabolism for compounds which otherwise would have saturated CYP3A. Such inferences are based on assumptions in the modelling of oral drug absorption. These models should be as mechanistic as possible and tractable using available in vitro and in vivo information. We review, through simulation, this subject and examine the interplay between gut wall metabolism and efflux transporters by studying the fraction of dose absorbed into enterocytes (F-a) and F-G via systematic variation of drug characteristics, in accordance with the Biopharmaceutics Classification System (BCS) within one of the most physiological models of oral drug absorption currently available, respectively ADAM. Variables studied included the intrinsic clearance (CLint) and the Michaelis-Menten Constant (K-m) for CYP3A4 and P-gp (CLint-CYP3A4 and Km-CYP3A4, CLint-P-gp and Km-P-gp). The impact of CYP3A4 and P-gp intracellular topography were not investigated since a well-stirred enterocyte is assumed within ADAM. An increased CLint-CYP3A4 resulted in a reduced F-G whereas an increase in CLint-P-gp resulted in a reduced F-a, but interestingly decreased F-G too. The reduction in F-G was limited to certain conditions and was modest. Non-linear relationships between various parameters determining the permeability (e. g. P-app, CLint-P-gp, and Km-P-gp) and gut wall metabolism (e. g. CLint-CYP3A4, Km-CYP3A4) resulted in disproportionate changes in F-G compared to the magnitude of singular effects. The results suggest that P-gp efflux decreases enterocytic drug concentration for drugs given at reasonably high dose which possess adequate passive apparent permeability (high P-app), by de-saturating CYP3A4 in the gut resulting in a lower F-G. However, these findings were observed only in a very limited area of the parameters space matching very few herapeutic drugs (a group with very high metabolism, high turn-over by efflux transporters and low F-a). The systematic approach in this study enabled us to recognise the combination of parameter values where the potential interplay between metabolising enzymes and efflux transporters is expected to be highest, using a realistic range of parameter values taken from an intensive literature search.

  • 306.
    Darwich, Adam S.
    et al.
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Margolskee, Alison
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Pepin, Xavier
    AstraZeneca, London, England;Sanofi, Paris, France.
    Aarons, Leon
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Galetin, Aleksandra
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Rostami-Hodjegan, Amin
    Univ Manchester, Manchester M13 9PL, Lancs, England;Simcyp Ltd, Sheffield, S Yorkshire, England.
    Carlert, Sara
    AstraZeneca, Gothenburg, Sweden.
    Hammarberg, Maria
    AstraZeneca, Gothenburg, Sweden.
    Hilgendorf, Constanze
    AstraZeneca, Gothenburg, Sweden.
    Johansson, Pernilla
    AstraZeneca, Gothenburg, Sweden.
    Karlsson, Eva
    AstraZeneca, Gothenburg, Sweden.
    Murphy, Donal
    AstraZeneca, London, England.
    Tannergren, Christer
    AstraZeneca, Gothenburg, Sweden.
    Thorn, Helena
    AstraZeneca, Gothenburg, Sweden.
    Yasin, Mohammed
    AstraZeneca, London, England.
    Mazuir, Florent
    Sanofi, Paris, France.
    Nicolas, Olivier
    Sanofi, Paris, France.
    Ramusovic, Sergej
    Sanofi, Frankfurt, Germany.
    Xu, Christine
    Sanofi, Bridgewater, NJ USA.
    Pathak, Shriram M.
    Simcyp Ltd, Sheffield, S Yorkshire, England.
    Korjamo, Timo
    Orion Pharma, Espoo, Finland.
    Laru, Johanna
    Orion Pharma, Espoo, Finland;AstraZeneca, London, England.
    Malkki, Jussi
    Orion Pharma, Espoo, Finland.
    Pappinen, Sari
    Orion Pharma, Espoo, Finland.
    Tuunainen, Johanna
    Orion Pharma, Espoo, Finland.
    Dressman, Jennifer
    Goethe Univ Frankfurt Am Main, Frankfurt, Germany.
    Hansmann, Simone
    Goethe Univ Frankfurt Am Main, Frankfurt, Germany.
    Kostewicz, Edmund
    Goethe Univ Frankfurt Am Main, Frankfurt, Germany.
    He, Handan
    Novartis, New York, NY USA.
    Heimbach, Tycho
    Novartis, New York, NY USA.
    Wu, Fan
    Novartis, New York, NY USA.
    Hoft, Carolin
    AbbVie, Wiesbaden, Germany.
    Pang, Yan
    AbbVie, Wiesbaden, Germany.
    Bolger, Michael B.
    Simulat Plus Inc, Lancaster, CA USA.
    Huehn, Eva
    Simulat Plus Inc, Lancaster, CA USA.
    Lukacova, Viera
    Simulat Plus Inc, Lancaster, CA USA.
    Mullin, James M.
    Simulat Plus Inc, Lancaster, CA USA.
    Szeto, Ke X.
    Simulat Plus Inc, Lancaster, CA USA.
    Costales, Chester
    Pfizer, New York, NY USA.
    Lin, Jian
    Pfizer, New York, NY USA.
    McAllister, Mark
    Pfizer, Tadworth, Middx, England.
    Modi, Sweta
    Pfizer, New York, NY USA.
    Rotter, Charles
    Pfizer, New York, NY USA.
    Varma, Manthena
    Pfizer, Tadworth, Middx, England.
    Wong, Mei
    Pfizer, Tadworth, Middx, England.
    Mitra, Amitava
    Merck Sharp & Dohme Ltd, Hoddesdon, Herts, England.
    Bevernage, Jan
    Janssen, Beerse, Belgium.
    Biewenga, Jeike
    Janssen, Beerse, Belgium.
    Van Peer, Achiel
    Janssen, Beerse, Belgium.
    Lloyd, Richard
    GlaxoSmithKline, Brentford, Middx, England.
    Shardlow, Carole
    GlaxoSmithKline, Brentford, Middx, England.
    Langguth, Peter
    Johannes Gutenberg Univ Mainz, Mainz, Germany.
    Mishenzon, Irina
    Johannes Gutenberg Univ Mainz, Mainz, Germany.
    Nguyen, Mai Anh
    Brown, Jonathan
    Bristol Myers Squibb, Uxbridge, Middx, England.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Abrahamsson, Bertil
    AstraZeneca, Gothenburg, Sweden.
    IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 3: Identifying gaps in system parameters by analysing In Silico performance across different compound classes2017Inngår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 96, s. 626-642Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp (R) Simulator, and GastroPlus (TM)) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded "bottom-up" anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics parameters, it was found that oral bioavailability (F-oral) was underpredicted for compounds with low permeability, suggesting improper estimates of intestinal surface area, colonic absorption and/or lack of intestinal transporter information. Foralwas also underpredicted for acidic compounds, suggesting overestimation of impact of ionisation on permeation, lack of information on intestinal transporters, or underestimation of solubilisation of weak acids due to less than optimal intestinal model pH settings or underestimation of bile micelle contribution. F-oral was overpredicted for weak bases, suggesting inadequate models for precipitation or lack of in vitro precipitation information to build informed models. Relative bioavailability was underpredicted for both high logP compounds as well as poorly water-soluble compounds, suggesting inadequate models for solubility/dissolution, underperforming bile enhancement models and/or lack of biorelevant solubility measurements. These results indicate areas for improvement in model software, modelling approaches, and generation of applicable input data. However, caution is required when interpreting the impact of drug-specific properties in this exercise, as the availability of input parameters was heterogeneous and highly variable, and the modellers generally used the data "as is" in this blinded bottom-up prediction approach.

  • 307.
    Datta, A.
    et al.
    Bose Inst, Dept Biophys, P-1-12 CIT Scheme 7 M, Kolkata 700054, India.
    Bhattacharyya, D.
    Bose Inst, Dept Biophys, P-1-12 CIT Scheme 7 M, Kolkata 700054, India.
    Singh, Shalini
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Ghosh, A.
    Bose Inst, Dept Biophys, P-1-12 CIT Scheme 7 M, Kolkata 700054, India.
    Schmidtchen, A.
    Lund Univ, Div Dermatol & Venereol, Dept Clin Sci, SE-22184 Lund, Sweden.; Nanyang Technol Univ, Lee Kong Chian Sch Med, 11 Mandalay Rd, Singapore 308232, Singapore .
    Malmsten, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bhunia, A.
    Bose Inst, Dept Biophys, P-1-12 CIT Scheme 7 M, Kolkata 700054, India.
    Role of Aromatic Amino Acids in Lipopolysaccharide and Membrane Interactions of Antimicrobial Peptides for use in Plant Disease Control2016Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, nr 25, s. 13301-13317Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    KYE28(KYEITTIHNLFRKLTHRLFRRNFGYTLR), the representative sequence  of helix D of heparin co-factor II, was demonstrated to be potent against agronomically important Gram-negative plant pathogens X. vesicatoria and X. oryzae,capable of inhibiting disease symptoms in detached tomato leaves. NMR studies in presence of lipopolysaccharide provided structural insights into the mechanisms underlying this, notably in relation to outer membrane permeabilisation. The three-dimensional solution structure of KYE28 in LPS is characterised by a N-ter helical segment, an intermediate loop and an extended C-ter. The two termini are in close proximity to each other via aromatic packing interactions, while the positively charged residues formed an exterior polar shell. To further demonstrate the importance of the aromatic residues for this, a mutant peptide KYE28A, with Ala substitutions at F11, F19, F23 and Y25 showed attenuated antimicrobial activity at high salt concentrations, as well as lower membrane disruption and LPS binding abilities compared to KYE28. In contrast to KYE28, KYE28A adopted an opened out helical structure in LPS with extended N- and C-ter and a small break in between the helical segments. Aromatic packing interactions were completely lost, although hydrophobic interaction between the side chains of hydrophobic residues were still partly retained, imparting an amphipathic character and explaining its residual antimicrobial activity and LPS binding as observed from ellipsometry and ITC. We thus present important structural aspects of KYE28, constituting an aromatic zipper, of potential importance, for the development of novel plant protection agents and therapeutic agents.

  • 308. des Rieux, Anne
    et al.
    Ragnarsson, Eva G E
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Gullberg, Elisabet
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Preat, Veronique
    Schneider, Yves-Jacques
    Artursson, Per
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Transport of nanoparticles across an in vitro model of the human intestinal follicle associated epithelium.2005Inngår i: Eur J Pharm Sci, ISSN 0928-0987, Vol. 25, nr 4-5, s. 455-65Artikkel i tidsskrift (Fagfellevurdert)
  • 309. des Rieux, Anne
    et al.
    Ragnarsson, Eva GE
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Gullberg, Elisabet
    Prerat, Veronique
    Schneider, Yves-Jacques
    Artursson, Per
    Influence of nanoparticle properties on their transport across an in vitro model of the human intestinal follicle associated epithelium2005Inngår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, Vol. 25, s. 455-465Artikkel i tidsskrift (Fagfellevurdert)
  • 310.
    Dew, Noel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Catanionic Aggregates in Gels: Prolonged Drug Release and Potential Implications for Topical Use2011Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Gels are popular dosage forms.  This topical dosage form may be advantageous compared to oral or parenteral dosage forms. Favorable rheological or bioadhesive properties of gels might provide extended contact times at the site of administration compared to aqueous solutions. However, due to the high water content of gels, these are usually quickly emptied of the drug substance. One way of prolonging the drug release from gels is to contain the drug substance in catanionic aggregates in the gel. These aggregates are formed in solutions of oppositely charged surfactants and a drug can be used instead of one of the surfactants.

     

    In this thesis catanionic aggregates composed of drug substances and oppositely charged surfactants were studied and the possibility to use these aggregates for the purpose of prolonged drug release was investigated. The formation of catanionic aggregates when using drugs was found to be a common occurrence in addition to which, the oppositely charged surfactant can be varied and surfactants of natural origin with a low toxicity were used. Most combinations tested rendered either vesicles or elongated micelles. When the catanionic aggregates were contained in gels the drug release was substantially prolonged. The apparent diffusion coefficients were lowered 10-100 times compared to the reference gels. When gels with catanionic vesicles with substantial prolonged drug release were applied to skin the penetration rate was lowered extensively. No morphological differences were observed between skin samples that had been exposed to formulations containing catanionic aggregates and skin samples exposed to saline solution, air or formulations containing only the drug. Both conventional, covalently linked pre-formed gels and physical gels, where the catanionic vesicles form the cross-links upon interaction with the polymer, can be used for these purposes. When the effect of drug release on aggregate structure was studied, it was shown that vesicles are present in both conventional and physical gels throughout the drug release process.

     

    This thesis shows that catanionic aggregates contained in gels can present an advantageous formulation strategy to prolong the drug release, thereby improving the efficiency of gel formulations.

    Delarbeid
    1. Catanionic mixtures involving a drug: A rather general concept that can be utilized for prolonged drug release from gels
    Åpne denne publikasjonen i ny fane eller vindu >>Catanionic mixtures involving a drug: A rather general concept that can be utilized for prolonged drug release from gels
    2006 Inngår i: Journal of Pharmaceutical Sciences, ISSN 00223549, Vol. 95, nr 4, s. 769-780Artikkel i tidsskrift (Fagfellevurdert) Published
    Identifikatorer
    urn:nbn:se:uu:diva-96413 (URN)
    Tilgjengelig fra: 2007-11-16 Laget: 2007-11-16 Sist oppdatert: 2011-05-04bibliografisk kontrollert
    2. Catanionic aggregates formed from drugs and lauric or capric acids enable prolonged release from gels
    Åpne denne publikasjonen i ny fane eller vindu >>Catanionic aggregates formed from drugs and lauric or capric acids enable prolonged release from gels
    2008 (engelsk)Inngår i: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 323, nr 2, s. 386-394Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The aim of this study was to add to the range of charged surfactants that can be used to form catanionic aggregates with oppositely charged surface active drug substances, and to apply these aggregates to prolong drug release from gels. The surfactants used in this study, lauric and capric acids are of natural origin-unlike traditionally used, synthetic, surfactants. The mixtures of drug substances and oppositely charged surfactants were studied visually and with cryogenic transmission electron microscopy. Drug release from gels was studied with a modified USP paddle method. This study shows that lauric and capric acids are as, or even more, active in forming catanionic aggregates than traditionally used surfactants such as sodium dodecyl sulfate. It is shown that the length of the hydrophobic part of the surfactant plays an important role in the formation of pharmaceutically interesting catanionic aggregates. As seen in previous studies, using catanionic vesicles prolongs the drug release from gels and decreases the apparent diffusion coefficient by a factor of 10-50, compared to a gel containing only drug substance.

    Emneord
    catanionic, vesicles, drug substances, surfactants, prolonged release, gels
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-16541 (URN)10.1016/j.jcis.2008.04.008 (DOI)000256743300027 ()18479696 (PubMedID)
    Tilgjengelig fra: 2008-05-28 Laget: 2008-05-28 Sist oppdatert: 2018-01-12bibliografisk kontrollert
    3. Gel formation in systems composed of drug containing catanionic vesicles and oppositely charged hydrophobically modified polymer.
    Åpne denne publikasjonen i ny fane eller vindu >>Gel formation in systems composed of drug containing catanionic vesicles and oppositely charged hydrophobically modified polymer.
    2009 (engelsk)Inngår i: Colloids and Surfaces B: Biointerfaces, ISSN 0927-7765, E-ISSN 1873-4367, Vol. 70, nr 2, s. 187-197Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The aim of this study was to explore if mixtures of drug containing catanionic vesicles and polymers give rise to gel formation, and if so, if drug release from these gels could be prolonged. Catanionic vesicles formed from the drug substances alprenolol or tetracaine, and the oppositely charged surfactant sodium dodecyl sulphate were mixed with polymers. Three polymers with different properties were employed: one bearing hydrophobic modifications, one positively charged and one positively charged polymer bearing hydrophobic modifications. The structure of the vesicles before and after addition of polymer was investigated by using cryo-TEM. Gel formation was confirmed by using rheological measurements. Drug release was studied using a modified USP paddle method. Gels were observed to form only in the case when catanionic vesicles, most likely with a net negative charge, were mixed with positively charged polymer bearing lipophilic modifications. The release of drug substance from these systems, where the vesicles are not trapped within the gel but constitute a founding part of it, could be significantly prolonged. The drug release rate was found to depend on vesicle concentration to a higher extent than on polymer concentration.

    Emneord
    Catanionic, vesicle, gel, polymer, prolonged drug release
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-100131 (URN)10.1016/j.colsurfb.2008.12.021 (DOI)000265317400005 ()19167869 (PubMedID)
    Tilgjengelig fra: 2009-03-25 Laget: 2009-03-25 Sist oppdatert: 2018-01-13bibliografisk kontrollert
    4. Novel Gel Formulations with Catanionic Aggregates Enable Prolonged Drug Release and Reduced Skin Permeation
    Åpne denne publikasjonen i ny fane eller vindu >>Novel Gel Formulations with Catanionic Aggregates Enable Prolonged Drug Release and Reduced Skin Permeation
    2011 (engelsk)Inngår i: Journal of Pharmacy and Pharmacology (JPP), ISSN 0022-3573, E-ISSN 2042-7158, Vol. 63, nr 10, s. 1265-1273Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Objectives: The aim of this study was to investigate skin permeation rates of a drug substance when applied in novel gel formulations with catanionic aggregates.

    Methods: Reference gel without catanionic aggregates was compared with formulations with catanionic aggregates composed of tetracaine and either sodium dodecyl sulphate (SDS) or capric acid. Carbomer and SoftCAT were used to compare the effect of different gel types to elucidate if physically cross-linked, 'self-destructing' systems had benefits compared with classical, covalently cross-linked, gels.

    Key findings: The rheological investigation showed that the interactions between the SoftCAT polymer and tetracaine/SDS aggregates were stronger than when the tetracaine/capric acid aggregates were used. The skin permeation was measured ex vivo in horizontal Ussing chambers and the permeation of tetracaine was significantly lower when formulations with tetracaine/SDS aggregates were applied (P < 0.001), but not statistically different from the reference when capric acid was used.

    Conclusions: No morphological differences could be distinguished between the skin samples exposed to the different formulations or the reference. Skin permeation was compared with silicone sheet permeation and the results indicated that silicone sheets could be used as a model of skin when using these formulations.

    Emneord
    catanionic, gel, pig ear skin, silicone membrane, vesicle
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-147595 (URN)10.1111/j.2042-7158.2011.01339.x (DOI)000295093500002 ()
    Tilgjengelig fra: 2011-02-26 Laget: 2011-02-26 Sist oppdatert: 2017-12-11bibliografisk kontrollert
    5. Gel formulations containing catanionic vesicles composed of alprenolol and SDS: effects of drug release and skin penetration on aggregate structure
    Åpne denne publikasjonen i ny fane eller vindu >>Gel formulations containing catanionic vesicles composed of alprenolol and SDS: effects of drug release and skin penetration on aggregate structure
    Vise andre…
    2012 (engelsk)Inngår i: Colloids and Surfaces B: Biointerfaces, ISSN 0927-7765, E-ISSN 1873-4367, Vol. 89, s. 53-60Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    To fully utilize the extended contact time of gel formulations a novel formulation with drug containing catanionic aggregates offering prolonged drug release and skin penetration were investigated. This study aimed to further explore the drug release process from catanionic vesicles in gels. Catanionic vesicles were formed from alprenolol and sodium dodecyl sulphate. Physical gels composed of catanionic vesicles and a SoftCAT polymer were used as well as covalent Carbopol gels. Drug release was measured in vitro using a modified USP paddle method and the skin penetration was studied using dermatomized pig ear skin mounted in horizontal Ussing chambers. The aggregate structure was visualized with cryo-TEM during the drug release and skin penetration process. The study results show that catanionic vesicles are present in the formulations throughout the drug release process and during the clinically relevant skin application time. Hence, the decreased skin penetration rate stems from the prolonged release of drug substance from the gels. The rheological investigation shows that the gel structure of the physically cross-linked gels is maintained even as the drug substance is released and the gel volume is decreased.These findings indicate that the applicability of formulations like these is a future possibility.

    Emneord
    Catanionic, Gel, Vesicle, Drug release, Skin, Surfactant, Cryo-TEM, Rheology
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-147593 (URN)10.1016/j.colsurfb.2011.08.022 (DOI)000297495000008 ()
    Tilgjengelig fra: 2011-02-26 Laget: 2011-02-26 Sist oppdatert: 2017-12-11bibliografisk kontrollert
  • 311.
    Dew, Noel
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bramer, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Edsman, Katarina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Catanionic aggregates formed from drugs and lauric or capric acids enable prolonged release from gels2008Inngår i: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 323, nr 2, s. 386-394Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this study was to add to the range of charged surfactants that can be used to form catanionic aggregates with oppositely charged surface active drug substances, and to apply these aggregates to prolong drug release from gels. The surfactants used in this study, lauric and capric acids are of natural origin-unlike traditionally used, synthetic, surfactants. The mixtures of drug substances and oppositely charged surfactants were studied visually and with cryogenic transmission electron microscopy. Drug release from gels was studied with a modified USP paddle method. This study shows that lauric and capric acids are as, or even more, active in forming catanionic aggregates than traditionally used surfactants such as sodium dodecyl sulfate. It is shown that the length of the hydrophobic part of the surfactant plays an important role in the formation of pharmaceutically interesting catanionic aggregates. As seen in previous studies, using catanionic vesicles prolongs the drug release from gels and decreases the apparent diffusion coefficient by a factor of 10-50, compared to a gel containing only drug substance.

  • 312. Dew, Noel
    et al.
    Bramer, Tobias
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Edsman, Katarina
    Catanionic mixtures formed from drugs and lauric or capric acid enable prolonged release from gelsArtikkel i tidsskrift (Fagfellevurdert)
  • 313.
    Dew, Noel
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Edsman, Katarina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Björk, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Novel Gel Formulations with Catanionic Aggregates Enable Prolonged Drug Release and Reduced Skin Permeation2011Inngår i: Journal of Pharmacy and Pharmacology (JPP), ISSN 0022-3573, E-ISSN 2042-7158, Vol. 63, nr 10, s. 1265-1273Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: The aim of this study was to investigate skin permeation rates of a drug substance when applied in novel gel formulations with catanionic aggregates.

    Methods: Reference gel without catanionic aggregates was compared with formulations with catanionic aggregates composed of tetracaine and either sodium dodecyl sulphate (SDS) or capric acid. Carbomer and SoftCAT were used to compare the effect of different gel types to elucidate if physically cross-linked, 'self-destructing' systems had benefits compared with classical, covalently cross-linked, gels.

    Key findings: The rheological investigation showed that the interactions between the SoftCAT polymer and tetracaine/SDS aggregates were stronger than when the tetracaine/capric acid aggregates were used. The skin permeation was measured ex vivo in horizontal Ussing chambers and the permeation of tetracaine was significantly lower when formulations with tetracaine/SDS aggregates were applied (P < 0.001), but not statistically different from the reference when capric acid was used.

    Conclusions: No morphological differences could be distinguished between the skin samples exposed to the different formulations or the reference. Skin permeation was compared with silicone sheet permeation and the results indicated that silicone sheets could be used as a model of skin when using these formulations.

  • 314.
    Dew, Noel
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Edwards, Katarina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi.
    Edsman, Katarina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Gel formation in systems composed of drug containing catanionic vesicles and oppositely charged hydrophobically modified polymer.2009Inngår i: Colloids and Surfaces B: Biointerfaces, ISSN 0927-7765, E-ISSN 1873-4367, Vol. 70, nr 2, s. 187-197Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this study was to explore if mixtures of drug containing catanionic vesicles and polymers give rise to gel formation, and if so, if drug release from these gels could be prolonged. Catanionic vesicles formed from the drug substances alprenolol or tetracaine, and the oppositely charged surfactant sodium dodecyl sulphate were mixed with polymers. Three polymers with different properties were employed: one bearing hydrophobic modifications, one positively charged and one positively charged polymer bearing hydrophobic modifications. The structure of the vesicles before and after addition of polymer was investigated by using cryo-TEM. Gel formation was confirmed by using rheological measurements. Drug release was studied using a modified USP paddle method. Gels were observed to form only in the case when catanionic vesicles, most likely with a net negative charge, were mixed with positively charged polymer bearing lipophilic modifications. The release of drug substance from these systems, where the vesicles are not trapped within the gel but constitute a founding part of it, could be significantly prolonged. The drug release rate was found to depend on vesicle concentration to a higher extent than on polymer concentration.

  • 315.
    Dew, Noel
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Edwards, Katarina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Fysikalisk kemi.
    Eriksson, Jonny
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Fysikalisk kemi.
    Edsman, Katarina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Björk, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Gel formulations containing catanionic vesicles composed of alprenolol and SDS: effects of drug release and skin penetration on aggregate structure2012Inngår i: Colloids and Surfaces B: Biointerfaces, ISSN 0927-7765, E-ISSN 1873-4367, Vol. 89, s. 53-60Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To fully utilize the extended contact time of gel formulations a novel formulation with drug containing catanionic aggregates offering prolonged drug release and skin penetration were investigated. This study aimed to further explore the drug release process from catanionic vesicles in gels. Catanionic vesicles were formed from alprenolol and sodium dodecyl sulphate. Physical gels composed of catanionic vesicles and a SoftCAT polymer were used as well as covalent Carbopol gels. Drug release was measured in vitro using a modified USP paddle method and the skin penetration was studied using dermatomized pig ear skin mounted in horizontal Ussing chambers. The aggregate structure was visualized with cryo-TEM during the drug release and skin penetration process. The study results show that catanionic vesicles are present in the formulations throughout the drug release process and during the clinically relevant skin application time. Hence, the decreased skin penetration rate stems from the prolonged release of drug substance from the gels. The rheological investigation shows that the gel structure of the physically cross-linked gels is maintained even as the drug substance is released and the gel volume is decreased.These findings indicate that the applicability of formulations like these is a future possibility.

  • 316. Di, Li
    et al.
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Avdeef, Alex
    Ecker, Gerhard F.
    Faller, Bernard
    Fischer, Holger
    Houston, J. Brian
    Kansy, Manfred
    Kerns, Edward H.
    Kraemer, Stefanie D.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sugano, Kiyohiko
    Evidence-based approach to assess passive diffusion and carrier-mediated drug transport2012Inngår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 17, nr 15-16, s. 905-912Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Evidence supporting the action of passive diffusion and carrier-mediated (CM) transport in drug bioavailability and disposition is discussed to refute the recently proposed theory that drug transport is CM-only and that new transporters will be discovered that possess transport characteristics ascribed to passive diffusion. Misconceptions and faulty speculations are addressed to provide reliable guidance on choosing appropriate tools for drug design and optimization.

  • 317. Diakidou, A
    et al.
    Vertzoni, M
    Abrahamsson, Bertil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Dressman, J
    Reppas, C
    Simulation of gastric lipolysis and prediction of felodipine release from a matrix tablet in the fed stomach2009Inngår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 37, nr 2, s. 133-140Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The importance of intragastric lipolysis to felodipine release from a hydrophilic, extended release tablet in the fed stomach was assessed in USP II apparatus with the tablet fixed on a steel wire above the paddle. The release medium, homogenized long-life milk, was gradually digested with shots of acidic solutions of pepsin over the course of the experiment in absence and in presence of biorelevant concentrations of a lipase that was similar to human gastric lipase. Percentage tablet erosion at specific times in the same media was measured in separate experiments. The data were compared to published data for intragastric release in fed healthy adults. In all cases, felodipine release occurred under sink conditions. Lipase facilitated felodipine release from the eroded polymer, bringing the release profile closer to the in vivo data. Likewise, the relationship between tablet erosion and amount of released felodipine reflected the in vivo data only when lipase was added to the medium. It was concluded that modelling intragastric lipolysis is necessary in order to simulate felodipine release from the extended release tablets in the fed stomach.

  • 318. Diakidou, Amalia
    et al.
    Vertzoni, Maria
    Goumas, Konstantinos
    Söderlind, Erik
    Abrahamsson, Bertil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Dressman, Jennifer
    Reppas, Christos
    Characterization of the contents of ascending colon to which drugs are exposed after oral administration to healthy adults2009Inngår i: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 26, nr 9, s. 2141-2151Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: To characterize the contents of the ascending colon in healthy adults under fasting and fed state conditions, with a view to designing in vitro studies to explain/predict dosage form performance in the lower gut. METHODS: Twelve healthy adults participated in a two-phase crossover study. In Phase A, subjects were fasted (water allowed) overnight plus 5 h in the morning prior to colonoscopy (fasted state). In Phase B, subjects were fasted overnight, consumed a standard breakfast (960 kcal) in the morning, and were offered a light lunch 4.5 h later. In this phase, colonoscopy was performed 1 h after lunch (fed state). Volume, pH, and buffer capacity of colonic contents were measured immediately upon collection. After ultracentrifugation, the supernatant was further characterized. RESULTS: Free water content, pH, surface tension, and isobutyrate levels were lower in fed than in fasted subjects. On the other hand, buffer capacity, osmolality, acetate, butyrate, cholate, and chenodeoxycholate levels were higher in fed subjects. Carbohydrate content; protein content; and levels of long chain fatty acids, phosphatidylcholine, and cholesterol were not affected significantly by prandial state. CONCLUSION: Composition of fluids in the ascending colon is affected by feeding. This may affect the performance of products designed to deliver drug to the colon.

  • 319. Dickinson, Paul A
    et al.
    Lee, Wang Wang
    Stott, Paul W
    Townsend, Andy I
    Smart, John P
    Ghahramani, Parviz
    Hammett, Tracey
    Billett, Linda
    Behn, Sheena
    Gibb, Ryan C
    Abrahamsson, Bertil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Clinical relevance of dissolution testing in quality by design2008Inngår i: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 10, nr 2, s. 380-390Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Quality by design (QbD) has recently been introduced in pharmaceutical product development in a regulatory context and the process of implementing such concepts in the drug approval process is presently on-going. This has the potential to allow for a more flexible regulatory approach based on understanding and optimisation of how design of a product and its manufacturing process may affect product quality. Thus, adding restrictions to manufacturing beyond what can be motivated by clinical quality brings no benefits but only additional costs. This leads to a challenge for biopharmaceutical scientists to link clinical product performance to critical manufacturing attributes. In vitro dissolution testing is clearly a key tool for this purpose and the present bioequivalence guidelines and biopharmaceutical classification system (BCS) provides a platform for regulatory applications of in vitro dissolution as a marker for consistency in clinical outcomes. However, the application of these concepts might need to be further developed in the context of QbD to take advantage of the higher level of understanding that is implied and displayed in regulatory documentation utilising QbD concepts. Aspects that should be considered include identification of rate limiting steps in the absorption process that can be linked to pharmacokinetic variables and used for prediction of bioavailability variables, in vivo relevance of in vitro dissolution test conditions and performance/interpretation of specific bioavailability studies on critical formulation/process variables. This article will give some examples and suggestions how clinical relevance of dissolution testing can be achieved in the context of QbD derived from a specific case study for a BCS II compound.

  • 320.
    Diwakarla, Shanti
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nylander, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Grönbladh, Alfhild
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Vanga, Sudarsana Reddy
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik.
    Khan, Yasmin Shamsudin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik.
    Gutierrez-de-Teran, Hugo
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik.
    Sävmarker, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Ng, Leelee
    Monash Univ, Dept Physiol, Biomed Discovery Inst, Clayton, Vic 3800, Australia..
    Pham, Vi
    Biomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
    Lundback, Thomas
    Karolinska Inst, Chem Biol Consortium Sweden, Sci Life Lab, Div Translat Med & Chem Biol,Dept Med Biochem & B, S-17177 Solna, Sweden..
    Jenmalm-Jensen, Annika
    Karolinska Inst, Chem Biol Consortium Sweden, Sci Life Lab, Div Translat Med & Chem Biol,Dept Med Biochem & B, S-17177 Solna, Sweden..
    Svensson, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Zelleroth, Sofia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Engen, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Rosenström, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Åqvist, Johan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik.
    Chai, Siew Yeen
    Biomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures2016Inngår i: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 7, nr 10, s. 1383-1392Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The zinc metallopeptidase insulin regulated aminopeptidase (IRAP), which is highly expressed in the hippocampus and other brain regions associated with cognitive function, has been identified as a high-affinity binding site of the hexapeptide angiotensin IV (Ang IV). This hexapeptide is thought to facilitate learning and memory by binding to the catalytic site of IRAP to inhibit its enzymatic activity. In support of this hypothesis, low molecular weight, nonpeptide specific inhibitors of TRAP have been shown to enhance memory in rodent models. Recently, it was demonstrated that linear and macrocyclic Ang IV-derived peptides can alter the shape and increase the number of dendritic spines in hippocampal cultures, properties associated with enhanced cognitive performance. After screening a library of 10 500 drug like substances for their ability to inhibit IRAP, we identified a series of low molecular weight aryl sulfonamides, which exhibit no structural similarity to Ang IV, as moderately potent IRAP inhibitors:A structural and biological characterization of three of these aryl sulfonamides was performed. Their binding modes to human IRAP were explored by docking calculations combined with molecular dynamics simulations and binding affinity estimations using the linear interaction energy method. Two alternative binding modes emerged from this analysis, both of which correctly rank the ligands according to their experimental binding affinities for this series of compounds. Finally, we show that two of these drug-like IRAP inhibitors can alter dendritic spine morphology and increase spine density in primary cultures of hippocampal neurons.

  • 321. Drinkwater, Jess
    et al.
    Tully, Mary Patricia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Dornan, Tim
    The effect of gender on medical students' aspirations: a qualitative study2008Inngår i: Medical Education, ISSN 0308-0110, E-ISSN 1365-2923, Vol. 42, nr 4, s. 420-426Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: This study aimed to explore the effect of gender on medical students' aspirations. METHODS: The study design included purposive sampling and interim data interpretation to guide recruitment of medical students with a wide spectrum of opinions. Data were collected through audio-recorded, semi-structured, in-depth exploratory interviews, which were transcribed verbatim. Qualitative analysis was carried out by a female medical student researcher. Her evolving interpretation was constantly compared against the original data by male (doctor) and female (pharmacist) staff researchers in a systematic search for internal corroboration or disconfirmation. Causal associations consistently present in the data are reported. RESULTS: Six male and six female medical students in Years 3 and 4 shared a wish to achieve a work-life balance that allowed them to devote time to bringing up children while contributing usefully to society as doctors. However, women were readier to compromise professional attainment within their personal work-life balances. Their readiness derived from gendered stereotypes of women's social and professional roles, a lack of female professional role models, womens' greater awareness of the tensions between career and family, various other informal social influences, and a lack of positive career advice to counterbalance these influences. CONCLUSIONS: Better career advice and more flexible work opportunities are needed if the two-thirds of medical students who are women are to contribute specialist as well as generalist expertise to the medical workforce.

  • 322.
    Dubbelboer, Ilse R
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Biopharmaceutical investigations of doxorubicin formulations used in liver cancer treatment: Studies in healthy pigs and liver cancer patients, combined with pharmacokinetic and biopharmaceutical modelling2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    There are currently two types of drug formulation in clinical use in the locoregional treatment of intermediate hepatocellular carcinoma (HCC). In the emulsion LIPDOX, the cytostatic agent doxorubicin (DOX) is dissolved in the aqueous phase, which is emulsified with the oily contrast agent Lipiodol® (LIP). In the microparticular system DEBDOX, DOX is loaded into the drug-eluting entity DC Bead™.

    The overall aim of the thesis was to improve pharmaceutical understanding of the LIPDOX and DEBDOX formulations, in order to facilitate the future development of novel drug delivery systems. In vivo release of DOX from the formulations and the disposition of DOX and its active metabolite doxorubicinol (DOXol) were assessed in an advanced multisampling-site acute healthy pig model and in patients with HCC. The release of DOX and disposition of DOX and DOXol where further analysed using physiologically based pharmacokinetic (PBPK) and biopharmaceutical (PBBP) modelling. The combination of in vivo investigations and in silico modelling could provide unique insight into the mechanisms behind drug release and disposition.

    The in vivo release of DOX from LIPDOX is not extended and controlled, as it is from DEBDOX. With both formulations, DOX is released as a burst during the early phase of administration. The in vivo release of DOX from LIPDOX was faster than from DEBDOX in both pigs and patients. The release from DEBDOX was slow and possibly incomplete. The in vivo release of DOX from LIPDOX and DEBDOX could be described by using the PBBP model in combination with in vitro release profiles.

    The disposition of DOX and DOXol was modelled using a semi-PBPK model containing intracellular binding sites. The contrast agent Lipiodol® did not affect the hepatobiliary disposition of DOX in the pig model. The control substance used in this study, cyclosporine A, inhibited the biliary excretion of DOX and DOXol but did not alter metabolism in healthy pigs. The disposition of DOX is similar in healthy pigs and humans, which was shown by the ease of translation of the semi-PBPK pig model to the human PBBP model.

    Delarbeid
    1. The Effects of Lipiodol and Cyclosporin A on the Hepatobiliary Disposition of Doxorubicin in Pigs
    Åpne denne publikasjonen i ny fane eller vindu >>The Effects of Lipiodol and Cyclosporin A on the Hepatobiliary Disposition of Doxorubicin in Pigs
    Vise andre…
    2014 (engelsk)Inngår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, nr 4, s. 1301-1313Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Doxorubicin (DOX) emulsified in Lipiodol (LIP) is used as local palliative treatment for unresectable intermediate stage hepatocellular carcinoma. The objective of this study was to examine the poorly understood effects of the main excipient in the drug delivery system, LIP, alone or together with cyclosporin A (CsA), on the in vivo liver disposition of DOX. The advanced, multi-sampling-site, acute pig model was used; samples were collected from three blood vessels (v. portae, v. hepatica and v. femoralis), bile and urine. The four treatment groups (TI-TIV) all received two intravenous 5 min infusions of DOX into an ear vein: at 0 and 200 min. Before the second dose, the pigs received a portal vein infusion of saline (TI), LIP (TII), CsA (TIII) or LIP and CsA (TIV). Concentrations of DOX and its active metabolite doxorubicinol (DOXol) were analyzed using UPLC-MS/MS. A multi-compartment model was developed to describe the distribution of DOX and DOXol in plasma, bile and urine. LIP did not affect the pharmacokinetics of DOX or DOXol. CsA (TIII and TIV) had no effect on the plasma pharmacokinetics of DOX, but a 2-fold increase in exposure to DOXol and a significant decrease in hepatobiliary clearance of DOX and DOXol was observed. Model simulations supported that CsA inhibits 99% of canalicular biliary secretion of both DOX and DOXol, but does not affect the metabolism of DOX to DOXol. In conclusion, LIP did not interact with transporters, enzymes and/or biological membranes important for the hepatobiliary disposition of DOX.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-222282 (URN)10.1021/mp4007612 (DOI)000334092700022 ()24558959 (PubMedID)
    Tilgjengelig fra: 2014-04-09 Laget: 2014-04-09 Sist oppdatert: 2018-01-11bibliografisk kontrollert
    2. In vivo Drug Delivery Performance of Lipiodol-based Emulsion or Drug-eluting Beads in Patients with Hepatocellular Carcinoma
    Åpne denne publikasjonen i ny fane eller vindu >>In vivo Drug Delivery Performance of Lipiodol-based Emulsion or Drug-eluting Beads in Patients with Hepatocellular Carcinoma
    Vise andre…
    2017 (engelsk)Inngår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, nr 2, s. 448-458Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Doxorubicin (DOX) delivered in a lipiodol-based emulsion (LIPDOX) or in drug-eluting beads (DEBDOX) is used as palliative treatment in patients with intermediate-stage hepatocellular carcinoma (HCC). The primary objective of this study was to evaluate the in vivo delivery performance of DOX from LIPDOX or DEBDOX in HCC patients using the local and systemic pharmacokinetics of DOX and its main metabolite doxorubicinol (DOXol). Urinary excretion of DOX and DOXol, and their short-term safety and anti-tumor effects were also evaluated. In this open, prospective, non-randomized multi-center study, LIPDOX (n=13) or DEBDOX (n=12) were injected into the feeding arteries of the tumor. Local (vena cava/hepatic vein orifice) and systemic (peripheral vein) plasma concentrations of DOX and DOXol were determined in samples obtained up to 6 h and 7 days after treatment. Tumor response was assessed using computed tomography or magnetic resonance imaging. The Cmax and AUC0-24 h for DOX were 5.6-fold and 2.4-fold higher in LIPDOX vs DEBDOX recipients, respectively (p <0.001). After 6 h, the respective mean proportions of the dose remaining in the liver or drug-delivery system (DDS) were 49% for LIPDOX and 88% for DEBDOX. LIPDOX releases DOX faster than DEBDOX in HCC patients and provides more extensive local and systemic exposure (AUC) to DOX and DOXol initially (0-7 days). DEBDOX formulation has a release and distribution of DOX that is more restricted and rate controlled than LIPDOX.

    Emneord
    doxorubicin, doxorubicinol, drug eluting beads, local delivery, local therapy, hepatocellular carcinoma, liver cancer, lipiodol, transarterial chemoembolization, transarterial infusion chemotherapy
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-311314 (URN)10.1021/acs.molpharmaceut.6b00886 (DOI)000393630100012 ()27997198 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council, S21-2011-373
    Tilgjengelig fra: 2016-12-22 Laget: 2016-12-22 Sist oppdatert: 2018-01-13bibliografisk kontrollert
    3. A Model -Based Approach To Assessing the Importance of Intracellular Binding Sites in Doxorubicin Disposition
    Åpne denne publikasjonen i ny fane eller vindu >>A Model -Based Approach To Assessing the Importance of Intracellular Binding Sites in Doxorubicin Disposition
    2017 (engelsk)Inngår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, nr 3, s. 686-698Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Doxorubicin is an anticancer agent, which binds reversibly to topoisomerase I and II, intercalates to DNA base pairs, and generates free radicals. Doxorubicin has a high tissue:plasma partition coefficient and high intracellular binding to the nucleus and other subcellular compartments. The metabolite doxorubicinol has an extensive tissue distribution. This porcine study investigated whether the traditional implementation of tissue binding, described by the tissue:plasma partition coefficient (K-p,K-t),could be used to appropriately analyze and/or simulate tissue doxorubicin and doxorubicinol concentrations in healthy pigs, when applying a physiologically based pharmacokinetic (PBPK) model approach, or whether intracellular binding is required in the semi-PBPK model. Two semi-PBPK models were developed and evaluated using doxorubicin and doxorubicinol concentrations in healthy pig blood, bile, and urine and kidney and liver tissues. In the generic semi-PBPK model, tissue binding was described using the conventional K-p,K-t approach. In the binding-specific semi-PBPK model, tissue binding was described using intracellular binding sites. The best semi-PBPK model was validated against a second data set of healthy pig blood and bile concentrations. Both models could be used for analysis and simulations of biliary and urinary excretion of doxorubicin and doxorubicinol and plasma doxorubicinol concentrations in pigs, but the binding-specific model was better at describing plasma doxorubicin concentrations. Porcine tissue concentrations were 400- to 1250-fold better captured by the binding-specific model. This model adequately predicted plasma doxorubicin concentration time and biliary doxorubicin excretion profiles against the validation data set. The semi-PBPK models applied were similarly effective for analysis of plasma concentrations and biliary and urinary excretion of doxorubicin and doxorubicinol in healthy pigs. Inclusion of intracellular binding in the doxorubicin semi-PBPK models was important to accurately describe tissue concentrations during in vivo conditions.

    sted, utgiver, år, opplag, sider
    AMER CHEMICAL SOC, 2017
    Emneord
    doxorubicin, physiologically based pharmacokinetic modeling, PBPK, pig
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-320394 (URN)10.1021/acs.molpharmaceut.6b00974 (DOI)000395847000012 ()28182434 (PubMedID)
    Tilgjengelig fra: 2017-04-20 Laget: 2017-04-20 Sist oppdatert: 2018-01-13bibliografisk kontrollert
    4. Porcine and human in vivo predictions for doxorubicin containing formulations used in locoregional HCC treatment
    Åpne denne publikasjonen i ny fane eller vindu >>Porcine and human in vivo predictions for doxorubicin containing formulations used in locoregional HCC treatment
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-331567 (URN)
    Tilgjengelig fra: 2017-10-15 Laget: 2017-10-15 Sist oppdatert: 2018-01-13
  • 323.
    Dubbelboer, Ilse R
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Dahlgren, David
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Rat intestinal drug permeability: A status report and summary of repeated determinations2019Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, s. 364-376Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Intestinal permeability is a key biopharmaceutical variable in pharmaceutical research and development, and regulatory assessment. In situ rat models are often used to predict the corresponding human intestinal permeability data. The rat single-pass intestinal perfusion (SPIP) and intestinal closed loop (ICL) models are commonly applied. The primary objective of this study was to collect, summarize, and evaluate all the available intestinal permeability data for drugs that have been obtained using these two in-situ rat models. The permeability data were also investigated for variability between the experimental designs. The literature survey found 635 permeability determinations for 90 drugs. The studies were performed on the jejunum (n = 284), whole small intestine (n = 111), colon (n = 108), ileum (n = 101), and duodenum (n = 30). All the SPIP (n = 484) and ICL (n = 147) permeability values were summarized in an easily accessible database. There was wide variability in the intestinal permeability to each drug between studies, which was unrelated to the permeability class of the drug. There was no relationship between rat intestinal permeability and luminal pH, luminal drug concentration, rat strain, experimental method, or intestinal region. There was, however, a correlation between permeability values determined in the same laboratory. This report showed that the SPIP and ICL methods are important in situ models for understanding and predicting intestinal drug absorption. However, conclusions based on permeability values sourced from different laboratories may not be reliable. Because each permeability study is unique and because between- and even within-laboratory variability can be substantial, data from individual studies should preferably be interpreted separately.

  • 324.
    Dubbelboer, Ilse R
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lilienberg, Elsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Ahnfelt, Emelie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Axén, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Treatment of intermediate stage hepatocellular carcinoma: a review of intrahepatic doxorubicin drug-delivery systems2014Inngår i: Therapeutic delivery, ISSN 2041-5990, E-ISSN 2041-6008, Vol. 5, nr 4, s. 447-466Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The biopharmaceutical properties of doxorubicin delivered via two drug-delivery systems (DDSs) for the palliative treatment of unresectable hepatocellular carcinoma were reviewed with relation to the associated liver and tumor (patho)physiology. These two DDSs, doxorubicin emulsified with Lipiodol(®) and doxorubicin loaded into DC Bead(®) are different regarding tumor delivery, release rate, local bioavailability, if and how they can be given repeatedly, biodegradability, length of embolization and safety profile. There have been few direct head-to-head comparisons of these DDSs, and in-depth investigations into their in vitro and in vivo performance is warranted.

  • 325.
    Dubbelboer, Ilse R
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lilienberg, Elsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Bondesson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Piquette-Miller, Micheline
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    The Effects of Lipiodol and Cyclosporin A on the Hepatobiliary Disposition of Doxorubicin in Pigs2014Inngår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, nr 4, s. 1301-1313Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Doxorubicin (DOX) emulsified in Lipiodol (LIP) is used as local palliative treatment for unresectable intermediate stage hepatocellular carcinoma. The objective of this study was to examine the poorly understood effects of the main excipient in the drug delivery system, LIP, alone or together with cyclosporin A (CsA), on the in vivo liver disposition of DOX. The advanced, multi-sampling-site, acute pig model was used; samples were collected from three blood vessels (v. portae, v. hepatica and v. femoralis), bile and urine. The four treatment groups (TI-TIV) all received two intravenous 5 min infusions of DOX into an ear vein: at 0 and 200 min. Before the second dose, the pigs received a portal vein infusion of saline (TI), LIP (TII), CsA (TIII) or LIP and CsA (TIV). Concentrations of DOX and its active metabolite doxorubicinol (DOXol) were analyzed using UPLC-MS/MS. A multi-compartment model was developed to describe the distribution of DOX and DOXol in plasma, bile and urine. LIP did not affect the pharmacokinetics of DOX or DOXol. CsA (TIII and TIV) had no effect on the plasma pharmacokinetics of DOX, but a 2-fold increase in exposure to DOXol and a significant decrease in hepatobiliary clearance of DOX and DOXol was observed. Model simulations supported that CsA inhibits 99% of canalicular biliary secretion of both DOX and DOXol, but does not affect the metabolism of DOX to DOXol. In conclusion, LIP did not interact with transporters, enzymes and/or biological membranes important for the hepatobiliary disposition of DOX.

  • 326.
    Dubbelboer, Ilse R
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lilienberg, Elsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Karalli, Amar
    Karolinska Univ Hosp Huddinge, Dept Radiol, Stockholm.; Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm.
    Axelsson, Rimma
    Karolinska Univ Hosp Huddinge, Dept Radiol, Stockholm.; Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm.
    Brismar, Torkel B
    Karolinska Univ Hosp Huddinge, Dept Radiol, Stockholm.; Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm.
    Ebeling Barbier, Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Norén, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Gastrointestinalkirurgi.
    Duraj, Frans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Gastrointestinalkirurgi.
    Mikael, Hedeland
    Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, Uppsala.
    Bondesson, Ulf
    Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, Uppsala.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Stål, Per
    Karolinska Inst, Dept Internal Med Huddinge, Unit Gastroenterol, Stockholm.; Karolinska Univ Hosp Huddinge, Dept Digest Dis, Stockholm.
    Nyman, Rickard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Reply to "Comment on 'In Vivo Drug Delivery Performance of Lipiodol-Based Emulsion or Drug-Eluting Beads in Patients with Hepatocellular Carcinoma'"2018Inngår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, nr 1, s. 336-340Artikkel i tidsskrift (Fagfellevurdert)
  • 327.
    Dubbelboer, Ilse R.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lilienberg, Elsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    A Model -Based Approach To Assessing the Importance of Intracellular Binding Sites in Doxorubicin Disposition2017Inngår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, nr 3, s. 686-698Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Doxorubicin is an anticancer agent, which binds reversibly to topoisomerase I and II, intercalates to DNA base pairs, and generates free radicals. Doxorubicin has a high tissue:plasma partition coefficient and high intracellular binding to the nucleus and other subcellular compartments. The metabolite doxorubicinol has an extensive tissue distribution. This porcine study investigated whether the traditional implementation of tissue binding, described by the tissue:plasma partition coefficient (K-p,K-t),could be used to appropriately analyze and/or simulate tissue doxorubicin and doxorubicinol concentrations in healthy pigs, when applying a physiologically based pharmacokinetic (PBPK) model approach, or whether intracellular binding is required in the semi-PBPK model. Two semi-PBPK models were developed and evaluated using doxorubicin and doxorubicinol concentrations in healthy pig blood, bile, and urine and kidney and liver tissues. In the generic semi-PBPK model, tissue binding was described using the conventional K-p,K-t approach. In the binding-specific semi-PBPK model, tissue binding was described using intracellular binding sites. The best semi-PBPK model was validated against a second data set of healthy pig blood and bile concentrations. Both models could be used for analysis and simulations of biliary and urinary excretion of doxorubicin and doxorubicinol and plasma doxorubicinol concentrations in pigs, but the binding-specific model was better at describing plasma doxorubicin concentrations. Porcine tissue concentrations were 400- to 1250-fold better captured by the binding-specific model. This model adequately predicted plasma doxorubicin concentration time and biliary doxorubicin excretion profiles against the validation data set. The semi-PBPK models applied were similarly effective for analysis of plasma concentrations and biliary and urinary excretion of doxorubicin and doxorubicinol in healthy pigs. Inclusion of intracellular binding in the doxorubicin semi-PBPK models was important to accurately describe tissue concentrations during in vivo conditions.

  • 328.
    Dubbelboer, Ilse R
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Pavlovic, Natasa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Heindryckx, Femke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Liver Cancer Cell Lines Treated with Doxorubicin under Normoxia and Hypoxia: Cell Viability and Oncologic Protein Profile2019Inngår i: Cancers, ISSN 2072-6694, Vol. 11, nr 7, artikkel-id 1024Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hepatocellular carcinoma is often treated with a combination of doxorubicin and embolization, exposing it to high concentrations and hypoxia. Separation of the possible synergistic effect of this combination in vivo is difficult. Here, treatment with doxorubicin, under hypoxia or normoxia in different liver cancer cell lines, was evaluated. Liver cancer cells HepG2, Huh7, and SNU449 were exposed to doxorubicin, hypoxia, or doxorubicin + hypoxia with different duration. Treatment response was evaluated with cell viability, apoptosis, oxidative stress, and summarized with IC50. The protein profile of a 92-biomarker panel was analyzed on cells treated with 0 or 0.1 mu M doxorubicin during 6 or 72 h, under normoxia or hypoxia. Hypoxia decreased viability of HepG2 and SNU499. HepG2 was least and SNU449 most tolerant to doxorubicin treatment. Cytotoxicity of doxorubicin increased over time in HepG2 and Huh7. The combination of doxorubicin + hypoxia affected the cells differently. Normalized protein expression was lower for HepG2 than Huh7 and SNU449. Hierarchical clustering separated HepG2 from Huh7 and SNU449. These three commonly used cell lines have critically different responses to chemotherapy and hypoxia, which was reflected in their different protein expression profile. These different responses suggest that tumors can respond differently to the combination of local chemotherapy and embolization.

  • 329.
    Dubbelboer, Ilse R.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Porcine and human in vivo predictions for doxorubicin containing formulations used in locoregional HCC treatmentManuskript (preprint) (Annet vitenskapelig)
  • 330.
    Dubbelboer, Ilse R
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Porcine and Human In Vivo Simulations for Doxorubicin-Containing Formulations Used in Locoregional Hepatocellular Carcinoma Treatment2018Inngår i: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 20, nr 6, artikkel-id 96Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It is important to be able to simulate and predict formulation effects on the pharmacokinetics of a drug in order to optimize effectivity in clinical practice and drug development. Two formulations containing doxorubicin are used in the treatment of hepatocellular carcinoma (HCC): a Lipiodol-based emulsion (LIPDOX) and a loadable microbead system (DEBDOX). Although equally effective, the formulations are vastly different, and little is known about the parameters affecting doxorubicin release in vivo. However, mathematical modeling can be used to predict doxorubicin release properties from these formulations and its in vivo pharmacokinetic (PK) profiles. A porcine semi-physiologically based pharmacokinetic (PBPK) model was scaled to a human physiologically based biopharmaceutical (PBBP) model that was altered to include HCC. DOX in vitro and in vivo release data from LIPDOX or DEBDOX were collected from the literature and combined with these in silico models. The simulated pharmacokinetic profiles were then compared with observed porcine and human HCC patient data. DOX pharmacokinetic profiles of LIPDOX-treated HCC patients were best predicted from release data sets acquired by in vitro methods that did not use a diffusion barrier. For the DEBDOX group, the best predictions were from the in vitro release method with a low ion concentration and a reduced loading dose. The in silico modeling combined with historical release data was effective in predicting in vivo plasma exposure. This can give useful insights into the release method properties necessary for correct in vivo predictions of pharmacokinetic profiles of HCC patients dosed with LIPDOX or DEBDOX.

  • 331.
    Duong, Dinh Thuy
    et al.
    Nanyang Technol Univ, Lee Kong Chian Sch Med, 11 Mandalay Rd, Singapore 308232, Singapore.
    Singh, Shalini
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bagheri, Mojtaba
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Univ Tehran, Inst Biochem & Biophys, Peptide Chem Lab, Tehran 1417614335, Iran..
    Verma, Navin Kumar
    Nanyang Technol Univ, Lee Kong Chian Sch Med, 11 Mandalay Rd, Singapore 308232, Singapore..
    Schmidtchen, Artur
    Nanyang Technol Univ, Lee Kong Chian Sch Med, 11 Mandalay Rd, Singapore 308232, Singapore.;Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, SE-22184 Lund, Sweden..
    Malmsten, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Pronounced peptide selectivity for melanoma through tryptophan end-tagging2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 24952Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Effects of oligotryptophan end-tagging on the uptake of arginine-rich peptides into melanoma cells was investigated under various conditions and compared to that into non-malignant keratinocytes, fibroblasts, and erythrocytes, also monitoring resulting cell toxicity. In parallel, biophysical studies on peptide binding to, and destabilization of, model lipid membranes provided mechanistic insight into the origin of the selectivity between melanoma and non-malignant cells. Collectively, the results demonstrate that W-tagging represents a powerful way to increase selective peptide internalization in melanoma cells, resulting in toxicity against these, but not against the non-malignant cells. These effects were shown to be due to increased peptide adsorption to the outer membrane in melanoma cells, caused by the presence of anionic lipids such as phosphatidylserine and ganglioside GM1, and to peptide effects on mitochondria membranes and resulting apoptosis. In addition, the possibility of using W-tagged peptides for targeted uptake of nanoparticles/drug carriers in melanoma was demonstrated, as was the possibility to open up the outer membrane of melanoma cells in order to facilitate uptake of low Mw anticancer drugs, here demonstrated for doxorubicin.

  • 332. Dérand, H
    et al.
    Malmsten, M
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Protein interfacial behaviour in microfabricated analysis systems and microarrays.2003Inngår i: Biopolymers at interfaces. 2nd Ed., Marcel Dekker, Inc. , 2003Kapittel i bok, del av antologi (Annet vitenskapelig)
  • 333. Edler, David
    et al.
    Stenstedt, Kristina
    Ohrling, Katarina
    Hallström, Marja
    Karlgren, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Ingelman-Sundberg, Magnus
    Ragnhammar, Peter
    The expression of the novel CYP2W1 enzyme is an independent prognostic factor in colorectal cancer: a pilot study.2009Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 45, nr 4, s. 705-712Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIM

    Cytochrome P450 (CYP) enzymes are important for drug metabolism. A novel cytochrome P450 enzyme, CYP2W1, has recently been identified. This enzyme is mainly found in foetal colon tissue and in tumour tissue. In this pilot study, we have investigated the expression of CYP2W1 in 162 tumours from patients with stages II and III colorectal cancer.

    METHODS

    The expression of CYP2W1 enzyme was immunohistochemically detected using a polyclonal antibody. Staining intensity was defined using a visual grading scale from 0 to 3. Grades 0-2 were classified as low, and grade 3 was classified as high expression of CYP2W1.

    RESULTS

    About 64% of the tumours expressed a low level of CYP2W1-expression, and 36% expressed a high level. CYP2W1-expression was an independent prognostic factor for overall survival (p=0.007), where a high expression was associated with a worse clinical outcome.

    CONCLUSIONS

    Immunohistochemically assessed expression of CYP2W1 is an independent prognostic factor in patients with stages II and III colorectal cancer.

  • 334.
    Edsman, K
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Carlfors, J
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Harju, K
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Rheological evaluation and ocular contact time of some carbomer gels for ophthalmic use1996Inngår i: INTERNATIONAL JOURNAL OF PHARMACEUTICS, Vol. 137, s. 233-Artikkel i tidsskrift (Fagfellevurdert)
  • 335.
    Edsman, K
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Carlfors, J
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Petersson, R
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Rheological evaluation of poloxamer as an in situ gel for ophthalmic use1998Inngår i: EUR J PHARMACEUTICAL SCI , Vol. 6, s. 105-Artikkel i tidsskrift (Fagfellevurdert)
  • 336.
    Edsman, Katarina
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Hägerström, Helene
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Pharmaceutical applications of mucoadhesion for the non-oral routes.2005Inngår i: J Pharm Pharmacol, ISSN 0022-3573, Vol. 57, nr 1, s. 3-22Artikkel i tidsskrift (Fagfellevurdert)
  • 337. Edström Hagerwall, Anneli M. L.
    et al.
    Rydengard, Victoria
    Fernlund, Per
    Morgelin, Matthias
    Baumgarten, Maria
    Cole, Alexander M.
    Malmsten, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Kragelund, Birthe B.
    Sorensen, Ole E.
    beta-Microseminoprotein Endows Post Coital Seminal Plasma with Potent Candidacidal Activity by a Calcium- and pH-Dependent Mechanism2012Inngår i: PLoS Pathogens, ISSN 1553-7366, Vol. 8, nr 4, s. e1002625-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The innate immune factors controlling Candida albicans are mostly unknown. Vulvovaginal candidiasis is common in women and affects approximately 70-75% of all women at least once. Despite the propensity of Candida to colonize the vagina, transmission of Candida albicans following sexual intercourse is very rare. This prompted us to investigate whether the post coital vaginal milieu contained factors active against C. albicans. By CFU assays, we found prominent candidacidal activity of post coital seminal plasma at both neutral and the acid vaginal pH. In contrast, normal seminal plasma did not display candidacidal activity prior to acidification. By antifungal gel overlay assay, one clearing zone corresponding to a protein band was found in both post coital and normal seminal plasma, which was subsequently identified as beta-microseminoprotein. At neutral pH, the fungicidal activity of beta-microseminoprotein and seminal plasma was inhibited by calcium. By NMR spectroscopy, amino acid residue E-71 was shown to be critical for the calcium coordination. The acidic vaginal milieu unleashed the fungicidal activity by decreasing the inhibitory effect of calcium. The candidacidal activity of beta-microseminoprotein was mapped to a fragment of the C-terminal domain with no structural similarity to other known proteins. A homologous fragment from porcine beta-microseminoprotein demonstrated calcium-dependent fungicidal activity in a CFU assay, suggesting this may be a common feature for members of the beta-microseminoprotein family. By electron microscopy, beta-microseminoprotein was found to cause lysis of Candida. Liposome experiments demonstrated that beta-microseminoprotein was active towards ergosterol-containing liposomes that mimic fungal membranes, offering an explanation for the selectivity against fungi. These data identify beta-microseminoprotein as an important innate immune factor active against C. albicans and may help explain the low sexual transmission rate of Candida.

  • 338.
    Edueng, Khadijah
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Molecular Mechanisms Influencing the Performance of Amorphous Formulations for Poorly Water-Soluble Drugs2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Crystallisation is a concern for amorphous formulation because it compromises the solubility-enhancing benefit gained from amorphisation. Traditionally, amorphous formulation had been designed primarily based on trial-and-error approach. The success rate for amorphous formulation is unimpressive, due to a poor understanding of the formulation itself, especially with regard to its crystallisation behaviour. Therefore, this thesis aimed to propose a strategic approach for rational design of amorphous formulations, as opposed to the trial-and-error approach. This can be achieved by understanding what drives the crystallisation of amorphous drug, and when and how the amorphous drug crystallises. The information can guide the selection of drugs, excipients and preparation method to achieve amorphous formulations with favourable features.

    In the first part of the thesis, a systematic protocol was proposed to identify mechanisms via which crystallisation takes place when amorphous drug is dissolved. The stabilisation strategy of supersaturation produced upon dissolution of amorphous drug was then recommended depending on the crystallisation mechanisms. A molecular dynamics (MD) simulations was used to understand drug-polymer interaction during supersaturation. It was revealed that hydrogen bond interaction is an important in stabilising supersaturation. The factors affecting glass-forming ability and long-term physical stability such as preparation method and humidity were then highlighted in the second study. A follow-up study was performed to elucidate the potential complications in using a standardised differential scanning calorimetry to classify promiscuous glass formers into any specific glass-forming ability/glass stability class. In the subsequent study, the effect of physical aging and/or crystallisation of amorphous drugs during storage on supersaturation potential was addressed. It was shown that, minor crystallisation of amorphous drug upon storage did not have a significant impact on the supersaturation potential during dissolution. Instead, the crystallisation pathway of the amorphous drug during dissolution plays a more important role in determining the supersaturation behaviour of some drugs. Finally, the impact of (i) drug loading on physical stability, supersaturation, drug/polymer miscibility, and (ii) the physical aging and/or crystallisation upon storage on supersaturation potential of spray-dried solid dispersions with HPMC-AS were discussed in the last study. It was observed that the effect of drug loading on physical stability and supersaturation, and the effect of physical aging and/or crystallisation during storage on supersaturation potential is highly drug-dependent. Similarly, the stabilisation effect of HPMC-AS varied across model drugs, drug loadings and crystallisation pathways (i.e. in solid or during dissolution). The Flory-Huggins interaction parameter calculated using MD simulations revealed good miscibility between the drugs and HPMC-AS at drug loadings investigated. In the presence of water molecules, various structural organizations of the drugs and HPMC-AS complexes were observed. Taken together, this thesis provides an improved understanding of crystallisation behaviour of amorphous formulations, which is useful to guide a rational design of amorphous formulations.

    Delarbeid
    1. Mechanism-based selection of stabilization strategy for amorphous formulations: Insights into crystallization pathways
    Åpne denne publikasjonen i ny fane eller vindu >>Mechanism-based selection of stabilization strategy for amorphous formulations: Insights into crystallization pathways
    2017 (engelsk)Inngår i: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 256, s. 193-202Artikkel i tidsskrift (Fagfellevurdert) 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.

    sted, utgiver, år, opplag, sider
    ELSEVIER SCIENCE BV, 2017
    Emneord
    Amorphous, Crystallization, Solid-state, Dissolution, Stabilization, Polymer, Supersaturation
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-329635 (URN)10.1016/j.jconrel.2017.04.015 (DOI)000403324800017 ()28412224 (PubMedID)
    Forskningsfinansiär
    EU, European Research Council, 638965Swedish Research Council, 2014-3309
    Tilgjengelig fra: 2017-09-25 Laget: 2017-09-25 Sist oppdatert: 2019-08-14bibliografisk kontrollert
    2. Long-term physical (in)stability of spray-dried amorphous drugs: relationship with glass-forming ability and physicochemical properties
    Åpne denne publikasjonen i ny fane eller vindu >>Long-term physical (in)stability of spray-dried amorphous drugs: relationship with glass-forming ability and physicochemical properties
    2019 (engelsk)Inngår i: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 11, nr 9, artikkel-id 425Artikkel i tidsskrift (Annet vitenskapelig) Published
    HSV kategori
    Forskningsprogram
    Farmaceutisk vetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-390255 (URN)10.3390/pharmaceutics11090425 (DOI)000489151700053 ()31438566 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council, 621-2011-2445Swedish Research Council, 621-2014-3309
    Tilgjengelig fra: 2019-08-07 Laget: 2019-08-07 Sist oppdatert: 2019-11-08bibliografisk kontrollert
    3. Classification of promiscuous glass-formers: Limitations of differential scanning calorimetry
    Åpne denne publikasjonen i ny fane eller vindu >>Classification of promiscuous glass-formers: Limitations of differential scanning calorimetry
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Forskningsprogram
    Farmaceutisk vetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-390254 (URN)
    Tilgjengelig fra: 2019-08-07 Laget: 2019-08-07 Sist oppdatert: 2019-08-14
    4. Supersaturation Potential of Amorphous Active Pharmaceutical Ingredients after Long-Term Storage
    Åpne denne publikasjonen i ny fane eller vindu >>Supersaturation Potential of Amorphous Active Pharmaceutical Ingredients after Long-Term Storage
    Vise andre…
    2019 (engelsk)Inngår i: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 24, nr 15, artikkel-id 2731Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    This study explores the effect of physical aging and/or crystallization on the supersaturation potential and crystallization kinetics of amorphous active pharmaceutical ingredients (APIs). Spray-dried, fully amorphous indapamide, metolazone, glibenclamide, hydrocortisone, hydrochlorothiazide, ketoconazole, and sulfathiazole were used as model APIs. The parameters used to assess the supersaturation potential and crystallization kinetics were the maximum supersaturation concentration (Cmax,app), the area under the curve (AUC), and the crystallization rate constant (k). These were compared for freshly spray-dried and aged/crystallized samples. Aged samples were stored at 75% relative humidity for 168 days (6 months) or until they were completely crystallized, whichever came first. The solid-state changes were monitored with differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. Supersaturation potential and crystallization kinetics were investigated using a tenfold supersaturation ratio compared to the thermodynamic solubility using the µDISS Profiler. The physically aged indapamide and metolazone and the minimally crystallized glibenclamide and hydrocortisone did not show significant differences in their Cmax,app and AUC when compared to the freshly spray-dried samples. Ketoconazole, with a crystalline content of 23%, reduced its Cmax,app and AUC by 50%, with Cmax,app being the same as the crystalline solubility. The AUC of aged metolazone, one of the two compounds that remained completely amorphous after storage, significantly improved as the crystallization kinetics significantly decreased. Glibenclamide improved the most in its supersaturation potential from amorphization. The study also revealed that, besides solid-state crystallization during storage, crystallization during dissolution and its corresponding pathway may significantly compromise the supersaturation potential of fully amorphous APIs.

    Emneord
    physical aging, crystallization, amorphous, supersaturation potential, crystallization kinetics, nucleation pathway, crystal growth, dissolution, solvent shift, spray-drying
    HSV kategori
    Forskningsprogram
    Farmaceutisk vetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-389887 (URN)10.3390/molecules24152731 (DOI)000482441100054 ()31357587 (PubMedID)
    Forskningsfinansiär
    EU, European Research Council, 63896Swedish Research Council, 621-2014-330Swedish Research Council, 621-2011-2445
    Tilgjengelig fra: 2019-07-30 Laget: 2019-07-30 Sist oppdatert: 2019-10-02bibliografisk kontrollert
    5. The influence of drug loading and drug-polymer interactions on physical stability and supersaturation of spray-dried solid dispersions
    Åpne denne publikasjonen i ny fane eller vindu >>The influence of drug loading and drug-polymer interactions on physical stability and supersaturation of spray-dried solid dispersions
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Forskningsprogram
    Farmaceutisk vetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-390257 (URN)
    Tilgjengelig fra: 2019-08-07 Laget: 2019-08-07 Sist oppdatert: 2019-08-14
  • 339.
    Edueng, Khadijah
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergström, Christel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Gråsjö, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Mahlin, Denny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Long-term physical (in)stability of spray-dried amorphous drugs: relationship with glass-forming ability and physicochemical properties2019Inngår i: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 11, nr 9, artikkel-id 425Artikkel i tidsskrift (Annet vitenskapelig)
  • 340.
    Edueng, Khadijah
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergström, Christel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Mahlin, Denny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Astra Zeneca.
    Classification of promiscuous glass-formers: Limitations of differential scanning calorimetryManuskript (preprint) (Annet vitenskapelig)
  • 341.
    Edueng, Khadijah
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Kabedev, Aleksei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Ekdahl, Alyssa
    Mahlin, Denny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Morgen, Michael
    Baumann, John
    Mudie, Deanna
    Bergström, Christel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    The influence of drug loading and drug-polymer interactions on physical stability and supersaturation of spray-dried solid dispersionsManuskript (preprint) (Annet vitenskapelig)
  • 342.
    Edueng, Khadijah
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Kulliyyah of Pharmacy, International Islamic University Malaysia, Bandar Indera Mahkota, Malaysia.
    Mahlin, Denny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergström, Christel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    The Need for Restructuring the Disordered Science of Amorphous Drug Formulations2017Inngår i: Pharmaceutical Research, ISSN 0724-8741, Vol. 34, nr 9, s. 1754-1772Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The alarming numbers of poorly soluble discovery compounds have centered the efforts towards finding strategies to improve the solubility. One of the attractive approaches to enhance solubility is via amorphization despite the stability issue associated with it. Although the number of amorphous-based research reports has increased tremendously after year 2000, little is known on the current research practice in designing amorphous formulation and how it has changed after the concept of solid dispersion was first introduced decades ago. In this review we try to answer the following questions: What model compounds and excipients have been used in amorphous-based research? How were these two components selected and prepared? What methods have been used to assess the performance of amorphous formulation? What methodology have evolved and/or been standardized since amorphous-based formulation was first introduced and to what extent have we embraced on new methods? Is the extent of research mirrored in the number of marketed amorphous drug products? We have summarized the history and evolution of amorphous formulation and discuss the current status of amorphous formulation-related research practice. We also explore the potential uses of old experimental methods and how they can be used in tandem with computational tools in designing amorphous formulation more efficiently than the traditional trial-and-error approach.

  • 343.
    Edueng, Khadijah
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. International Islamic University Malaysia.
    Mahlin, Denny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Astra Zeneca.
    Gråsjö, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Nylander, Olivia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Thakrani, Manish
    Department of Pharmacy, University College London, UK.
    Bergström, Christel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Supersaturation Potential of Amorphous Active Pharmaceutical Ingredients after Long-Term Storage2019Inngår i: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 24, nr 15, artikkel-id 2731Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This study explores the effect of physical aging and/or crystallization on the supersaturation potential and crystallization kinetics of amorphous active pharmaceutical ingredients (APIs). Spray-dried, fully amorphous indapamide, metolazone, glibenclamide, hydrocortisone, hydrochlorothiazide, ketoconazole, and sulfathiazole were used as model APIs. The parameters used to assess the supersaturation potential and crystallization kinetics were the maximum supersaturation concentration (Cmax,app), the area under the curve (AUC), and the crystallization rate constant (k). These were compared for freshly spray-dried and aged/crystallized samples. Aged samples were stored at 75% relative humidity for 168 days (6 months) or until they were completely crystallized, whichever came first. The solid-state changes were monitored with differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. Supersaturation potential and crystallization kinetics were investigated using a tenfold supersaturation ratio compared to the thermodynamic solubility using the µDISS Profiler. The physically aged indapamide and metolazone and the minimally crystallized glibenclamide and hydrocortisone did not show significant differences in their Cmax,app and AUC when compared to the freshly spray-dried samples. Ketoconazole, with a crystalline content of 23%, reduced its Cmax,app and AUC by 50%, with Cmax,app being the same as the crystalline solubility. The AUC of aged metolazone, one of the two compounds that remained completely amorphous after storage, significantly improved as the crystallization kinetics significantly decreased. Glibenclamide improved the most in its supersaturation potential from amorphization. The study also revealed that, besides solid-state crystallization during storage, crystallization during dissolution and its corresponding pathway may significantly compromise the supersaturation potential of fully amorphous APIs.

  • 344.
    Edueng, Khadijah
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Int Islamic Univ Malaysia, Kulliyyah Pharm, Jalan Istana, Kuantan 25200, Pahang, Malaysia..
    Mahlin, Denny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Larsson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergström, Christel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Mechanism-based selection of stabilization strategy for amorphous formulations: Insights into crystallization pathways2017Inngår i: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 256, s. 193-202Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 345.
    Edvinsson, Dan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Ulleråker, Akademiska sjukhuset.
    Bingefors, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lindström, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lewander, Tommy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Ulleråker, Akademiska sjukhuset.
    ADHD-related symptoms among adults in out-patient psychiatry and female prison inmates as compared with the general population2010Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 115, nr 1, s. 30-40Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective. To compare the prevalence of symptoms consistent with attention deficit hyperactivity disorder (ADHD) and related problems in adults in the general population, out-patient psychiatry (where females are in majority), and female convicts. Method. A questionnaire based on the DSM-IV criteria of ADHD, reported childhood symptoms, reading and spelling problems, difficulties and suffering, and general assessment of functioning (GAF) was distributed to samples of the general population, open care psychiatry, and female prison inmates. Completed questionnaires were received from 517/1000, 349/400, and 50/65 of the three samples, respectively. Results. Symptoms consistent with ADHD were more than three times higher in out-patient psychiatry than in the general population (6.6% versus 2.1%), with a male-to-female ratio of 1.6-1.7. The severity of symptoms and frequencies of associated disabilities were similar in men and women. ADHD symptoms and related problems occurred in 50% of the female prisoners, which is similar to male prisoners according to the literature. Conclusion. The high prevalence of symptoms and disabilities of ADHD in women should lead to awareness of the disorder in both sexes and be addressed in terms of diagnostic work-up, treatment, and rehabilitation.

  • 346.
    Edvinsson, Dan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Lindström, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Bingefors, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lewander, Tommy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Ekselius, Lisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Gender differences of axis I and II comorbidity in subjects diagnosed with attention-deficit hyperactivity disorder as adults2013Inngår i: Acta Neuropsychiatrica, ISSN 0924-2708, E-ISSN 1601-5215, Vol. 25, nr 3, s. 165-174Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: To investigate gender differences in psychiatric comorbidity patients diagnosed with attention-deficit hyperactivity disorder (ADHD) as adults. Methods: Interviews about current ADHD symptoms and psychiatric comorbidity on axis I and II (Structured Clinical Interview for DSM-IV axis I and axis II) were conducted in a clinical cohort of 168 patients (78 women, 90 men). Independent information on childhood and current symptoms was collected from parents, partners and patient files. Results: The lifetime prevalence of psychiatric comorbidity on axis I reached 92%, and current comorbidity, including autism spectrum disorders and Tourette's syndrome, was 47%. Women had a higher lifetime prevalence of mood and eating disorders compared with men, where substance-use disorders were more frequent. Ten per cent of patients fulfilled diagnostic criteria for a personality disorder. When excluding the general diagnostic criteria, 46% of the patients endorsed the specific criteria for at least one personality disorder. Gender differences were identified with predominance of histrionic personality traits in women and conduct disorder in men. Conclusion: Patients diagnosed with ADHD as adults display an extremely high lifetime axis I comorbidity with a gender-specific pattern similar to the general population. No gender differences were identified with regard to personality disorders; however, an increased prevalence of deviant personality traits was confirmed. This study stresses the importance of evaluating comorbidity among patients diagnosed with ADHD as adults to secure optimal treatment.

  • 347.
    Ek, R
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