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  • 1.
    Ahnfelt, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System2016In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 11, p. 3387-3398Article in journal (Refereed)
    Abstract [en]

    The release rate of doxorubicin (DOX) from the drug-delivery system (DDS), DC Bead, was studied by 2 miniaturized in vitro methods: free-flowing and sample reservoir. The dependencies of the release mechanisms on in vitro system conditions were investigated experimentally and by theoretical modeling. An inverse relationship was found between release rates and bead size, most likely due to the greater total surface area. The release rates correlated positively with temperature, release medium volume, and buffer strength, although the release medium volume had larger effect than the buffer strength. The sample reservoir method generated slower release rates, which described the in vivo release profile more accurately than the free-flowing method. There was no difference between a pH of 6.3 or 7.4 on the release rate, implying that the slightly acidic tumor microenvironment is less importance for drug release. A positive correlation between stirring rate and release rate for all DDS sizes was observed, which suggests film controlled release. Theoretical modeling highlighted the influence of local equilibrium of protonation, self-aggregation, and bead material interactions of DOX. The theoretical release model might describe the observed larger sensitivity of the release rate to the volume of the release medium compared to buffer strength. A combination of miniaturized in vitro methods and theoretical modeling are useful to identify the important parameters and processes for DOX release from a micro gel-based DDS.

  • 2.
    Alhalaweh, Amjad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Alzghoul, Ahmad
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computing Science.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Molecular Drivers of Crystallization Kinetics for Drugs in Supersaturated Aqueous Solutions2019In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 108, no 1, p. 252-259Article in journal (Refereed)
    Abstract [en]

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

  • 3.
    Amidon, Gregory E.
    et al.
    Univ Michigan, Ann Arbor, MI USA.
    Anderson, Bradley D.
    Univ Kentucky, Lexington, KY 40506 USA.
    Balthasar, Joseph P.
    SUNY Buffalo, Univ Buffalo, Buffalo, NY USA.
    Bergström, Christel A.S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Huang, Shiew-Mei
    US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA.
    Kasting, Gerald
    Univ Cincinnati, Cincinnati, OH USA.
    Kesisoglou, Filippos
    Merck & Co Inc, Kenilworth, NJ USA.
    Khinast, Johannes G.
    Graz Univ Technol, Inst Proc & Particle Engn, Graz, Austria.
    Mager, Donald E.
    SUNY Buffalo, Univ Buffalo, Buffalo, NY USA.
    Roberts, Christopher J.
    Univ Delaware, Newark, DE USA.
    Yu, Lian
    Univ Wisconsin, Madison, WI USA.
    Fifty-Eight Years and Counting: High-Impact Publishing in Computational Pharmaceutical Sciences and Mechanism-Based Modeling2019In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 108, no 1, p. 2-7Article in journal (Refereed)
    Abstract [en]

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

  • 4.
    Andersson, Sara B. E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Alvebratt, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bevernage, Jan
    Janssen Pharmaceut, Pharmaceut Sci, B-2340 Beerse, Belgium.
    Bonneau, Damien
    Sanofi Aventis Rech Dev, Chem & Pharmaceut Anal, F-34184 Montpellier, France.
    da Costa Mathews, Claudia
    Pfizer Ltd, Pharmaceut Sci, Drug Product Design, Sandwich CT13 9NJ, Kent, England.
    Dattani, Rikesh
    AstraZeneca, Prod Dev, Biopharmaceut, Macclesfield SK10 2NA, Cheshire, England.
    Edueng, Khadijah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    He, Yan
    Sanofi, Predev Sci, Waltham, MA 02451 USA.
    Holm, René
    Pharmaceut Sci & CMC Biol, DK-2500 Copenhagen, Denmark; Univ Copenhagen, Fac Hlth & Med Sci, Dept Pharm, DK-2100 Copenhagen, Denmark.
    Madsen, Cecilie
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Pharm, DK-2100 Copenhagen, Denmark.
    Müller, Thomas
    AbbVie Deutschland GmbH & Co KG, Drug Prod Dev, D-67061 Ludwigshafen, Germany.
    Muenster, Uwe
    Bayer Pharma AG, Res Ctr Aprath, Chem & Pharmaceut Dev, D-42096 Wuppertal, Germany.
    Müllertz, Anette
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Pharm, DK-2100 Copenhagen, Denmark.
    Ojala, Krista
    Orion Pharma, POB 65, Espoo 02101, Finland.
    Rades, Thomas
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Pharm, DK-2100 Copenhagen, Denmark.
    Sieger, Peter
    Boehringer Ingelheim GmbH & Co KG, Pharmaceut Dev, D-55218 Ingelheim, Germany.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Interlaboratory Validation of Small-Scale Solubility and Dissolution Measurements of Poorly Water-Soluble Drugs2016In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 9, p. 2864-2872Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to investigate the interlaboratory variability in determination of apparent solubility (Sapp) and intrinsic dissolution rate (IDR) using a miniaturized dissolution instrument. Three poorly water-soluble compounds were selected as reference compounds and measured at multiple laboratories using the same experimental protocol. Dissolution was studied in fasted-state simulated intestinal fluid and phosphate buffer (pH 6.5). An additional 6 compounds were used for the development of an IDR measurement guide, which was then validated with 5 compounds. The results clearly showed a need for a standardized protocol including both the experimental assay and the data analysis. Standardization at both these levels decreased the interlaboratory variability. The results also illustrated the difficulties in performing disc IDR on poorly water-soluble drugs because the concentrations reached are typically below the limit of detection. The following guidelines were established: for compounds with Sapp > 1 mg/mL, the disc method is recommended. For compounds with Sapp <100 μg/mL, IDR is recommended to be performed using powder dissolution. Compounds in the interval 100 μg/mL to 1 mg/mL can be analyzed with either of these methods.

  • 5.
    Bengtsson, Jörgen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Boström, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    The use of a deuterated calibrator for in vivo recovery estimations in microdialysis studies2008In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 97, no 8, p. 3433-3441Article in journal (Refereed)
    Abstract [en]

    One of the crucial issues in quantitative microdialysis is the reliability of recovery estimates to correctly estimate unbound drug tissue concentrations. If a deuterated calibrator is used for retrodialysis, the calibrator has the same properties as the study drug. However, recovery of the calibrator may be affected by the presence of the drug in the tissues. The aim of this study was to investigate the recovery of deuterated morphine with time in the absence and presence of morphine in rat tissues. Microdialysis probes were placed in the brain and blood of eight rats. Ringer's solution containing D3-morphine was perfused throughout the study and recovery was estimated. After a stabilization period of 3 h, an exponential infusion of morphine was administered over 4 h. The presence of morphine did not affect the recovery of D3-morphine from brain or blood. The average recovery values (SD) were 0.145 (0.039) and 0.131 (0.048) during the stabilization and infusion periods, respectively, for the brain probe and 0.792 (0.055) and 0.790 (0.084), respectively, for the blood probe. The recovery of deuterated morphine was stable over time in the brain and in blood, and was not affected by the presence of pharmacologically concentrations of morphine.

  • 6.
    Boström, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Oxycodone Pharmacokinetics and Pharmacodynamics in the Rat in the Presence of the P-Glycoprotein Inhibitor PSC8332005In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 94, no 5, p. 1060-1066Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to investigate the in vivo influence of the P-glycoprotein (P-gp) inhibitor PSC833 on the plasma pharmacokinetics, total brain concentrations and tail-flick latency of oxycodone in rats. Eight rats each received an infusion of PSC833 or vehicle without PSC833. One hour later, all animals received 0.3 mg/kg oxycodone as a 1-h infusion. Plasma samples were taken, and tail-flick latency was monitored during the infusion and for 2 h thereafter. The brains were collected at the end of the experiment. There were no differences between the two groups in area under the plasma oxycodone concentration-time curve from time zero to infinity, or oxycodone plasma clearance, volume of distribution at steady-state, or half-life. There were no differences in average total brain oxycodone concentrations at 180 min, nor were there any differences in average tail-flick latency for the PSC833 and control groups. In conclusion, coadministration of PSC833 did not alter the plasma pharmacokinetics, brain concentrations, or associated tail-flick latency of oxycodone, indicating that oxycodone is not a P-gp substrate in the rat. This has important clinical implications, as it indicates that oxycodone, unlike some other opioids, will not interact at the blood-brain barrier (BBB) with concomitantly administered P-gp substrates.

  • 7.
    Brohede, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences.
    Frenning, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Strömme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences.
    Characterization of the drug release process by investigation of its temperature dependence2004In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 93, no 7, p. 1796-1803Article in journal (Refereed)
    Abstract [en]

    Temperature-dependent drug release from disintegrating tablets made of NaCl-containing agglomerated micronized cellulose (AMC) granules has been studied to characterize the release process. Release measurements on tablets compacted at three different compaction pressures; 50, 100, and 200 MPa, were performed at seven different temperatures; 6, 23, 33, 43, 50, 55, and 63°C using the recently developed alternating ionic current method. Tablets compacted at different compaction pressures showed similar release rates. The release process was found to be diffusion-controlled, and the activation energy of the diffusion coefficient was comparable to that obtained for diffusion in pure water. The results show that the AMC granules in contact with water swell to a size and shape that is only slightly affected by their compaction history and the ion diffusion operates mainly within liquid-filled pores within the AMC granules. By using the temperature dependence of the release process, it was possible to reach this conclusion without any assumptions concerning the number and radii of the granules into which the tablets disintegrated. Further, the magnitude of the effective diffusion coefficient was found to be ∼7.5 · 10−10 cm2/s, which is ∼four orders of magnitude lower than for unhindered diffusion of Na+ and Cl in water but similar to the diffusion coefficient for protons and OH ions in microcrystalline cellulose.

  • 8.
    Brohede, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Valizadeh, Sima
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Frenning, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Percolative drug diffusion from cylindrical matrix systems with unsealed boundaries2007In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 96, no 11, p. 3087-3099Article in journal (Refereed)
    Abstract [en]

    Release of NaCl in both the axial and radial directions from cylindrical ethyl cellulose tablets were investigated by the alternating ionic current method. The pore structure of the investigated binary mixtures was examined by mercury porosimetry and scanning electron microscopy, and the nm range fractal surface dimension of tablet pore walls was extracted from krypton gas adsorption isotherms. The drug release was shown to consist of two overlapping processes of which the first was ascribed to dissolution of NaCl close to the tablet boundary followed by subsequent diffusion through a thin ethyl cellulose layer and a second from which a porosity percolation threshold of 0.22 could be extracted. As well, a cross-over to effective-medium behaviour at a porosity of 0.44 was observed. The presented findings showed that drug release from matrix tablets with unsealed tablet walls substantially differs from earlier investigated release processes for which the drug has only been allowed to escape through one of the flat tablet surfaces. Thus, the present study brings forward knowledge important for the tailoring of controlled drug delivery vehicles with optimum release patterns.

  • 9.
    Bylund, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bueters, Tjerk
    Presystemic metabolism of AZ'0908, a novel mPGES-1 inhibitor: An in vitro and in vivo cross-species comparison.2013In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 102, no 3, p. 1106-1115Article in journal (Refereed)
    Abstract [en]

    AZ'0908 is a novel microsomal prostaglandin E synthase-1 inhibitor intended for oral administration. Pharmacokinetic experiments in rats showed that bioavailability was much lower than anticipated and increased following pretreatment with the nonspecific cytochrome P450 (CYP) inhibitor 1-aminobenzotriazole, presumably by inhibition of intestinal metabolism. Stability experiments in rat liver and intestinal fractions revealed that the intrinsic clearance (Cl(int) ) was much higher in intestinal than in liver microsomes. Caco2 experiments showed that AZ'0908 was a substrate for breast cancer resistance protein. Permeability was generally high and the efflux component was saturable predicting good absorption. The Cl(int) values in human intestinal microsome and S9 fractions were low. A correlation occurred between in vitro intestinal metabolism and in vivo intestinal loss in rats and dogs. Enzyme identification experiments showed that human CYP2J2 was involved in the oxidation of AZ'0908. In rats, the major metabolic enzyme was not identified. However, rat CYP2J2 analogs were not investigated. Intestinal metabolism appeared to be a major occurrence, explaining intestinal loss of AZ'0908 in the rats. In view of good overall permeability, low in vitro intestinal turnover, and relative low intestinal abundance of CYP2J2, we predict that intestinal metabolism of AZ'0908 in human does not exert a major issue.

  • 10.
    Bäckström, Erica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. AstraZeneca R&D Gothenburg, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden..
    Boger, Elin
    AstraZeneca R&D Gothenburg, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden.;Univ Warwick, Sch Engn, Coventry CV4 7AL, W Midlands, England..
    Lundqvist, Anders
    AstraZeneca R&D Gothenburg, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden..
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fridén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. AstraZeneca R&D Gothenburg, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden..
    Lung Retention by Lysosomal Trapping of Inhaled Drugs Can Be Predicted In Vitro With Lung Slices2016In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 11, p. 3432-3439Article in journal (Refereed)
    Abstract [en]

    Modulating and optimizing the local pharmacokinetics of inhaled drugs by chemical design or formulation is challenged by the lack of predictive in vitro systems and in vivo techniques providing a detailed description of drug location in the lung. The present study investigated whether a new experimental setup of freshly prepared agarose-filled lung slices can be used to estimate lung retention in vitro, by comparing with in vivo lung retention after intratracheal instillation. Slices preloaded with inhaled beta-adrenergic compounds (salbutamol, formoterol, salmeterol, indacaterol or AZD3199) were incubated in a large volume of buffer (w/wo monensin to assess the role of lysosomal trapping), and the amount remaining in slices at different time points was determined with liquid chromatography-tandem mass spectrometry. The in vitro lung retention closely matched the in vivo lung retention (half-lives within 3-fold for 4/5 compounds), and monensin shortened the half-lives for all compounds. The results suggest that freshly prepared rat lungs slices can be used to predict lung retention and that slow kinetics of lysosomal trapping is a key mechanism by which retention in the lung and the effect duration of inhaled beta-adrenergic bronchodilators are prolonged.

  • 11.
    Bäckström, Erica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. AstraZeneca R&D, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden.
    Lundqvist, Anders
    AstraZeneca R&D, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden.
    Boger, Elin
    AstraZeneca R&D, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden.; Univ Warwick, Sch Engn, Coventry CV4 7AL, W Midlands, England.
    Svanberg, Petter
    AstraZeneca R&D, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden.
    Ewing, Pär
    AstraZeneca R&D, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fridén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. AstraZeneca R&D, Resp Inflammat & Autoimmun Innovat Med, S-43183 Molndal, Sweden.
    Development of a Novel Lung Slice Methodology for Profiling of Inhaled Compounds2016In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 2, p. 838-845Article in journal (Refereed)
    Abstract [en]

    The challenge of defining the concentration of unbound drug at the lung target site after inhalation limits the possibility to optimize target exposure by compound design. In this study, a novel rat lung slice methodology has been developed and applied to study drug uptake in lung tissue, and the mechanisms by which this occurs. Freshly prepared lung slices (500 μm) from drug-naive rats were incubated with drugs followed by determination of the unbound drug volume of distribution in lung (Vu,lung), as the total concentration of drug in slices divided by the buffer (unbound) concentration. Vu,lung determined for a set of inhaled drug compounds ranged from 2.21 mL/g for salbutamol to 2970 mL/g for dibasic compound A. Co-incubation with monensin, a modulator of lysosomal pH, resulted in inhibition of tissue uptake of basic propranolol to 13%, indicating extensive lysosomal trapping. Partitioning into cells was particularly high for the cation MPP+ and the dibasic compound A, likely because of the carrier-mediated transport and lysosomal trapping. The results show that different factors are important for tissue uptake and the presented method can be used for profiling of inhaled compounds, leading to a greater understanding of distribution and exposure of drug in the lung.

  • 12. Cristofoletti, Rodrigo
    et al.
    Nair, Anita
    Abrahamsson, Bertil
    AstraZeneca R&D, Mölndal, Sweden.
    Groot, D W
    Kopp, Sabine
    Langguth, Peter
    Polli, James E
    Shah, Vinod P
    Dressman, Jennifer B
    Biowaiver monographs for immediate release solid oral dosage forms: efavirenz2013In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 102, no 2, p. 318-329Article in journal (Refereed)
    Abstract [en]

    Literature data pertaining to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate-release (IR) solid oral dosage forms containing efavirenz as the only active pharmaceutical ingredient (API) are reviewed. Because of lack of conclusive data about efavirenz's permeability and its failure to comply with the "high solubility" criteria according to the Biopharmaceutics Classification System (BCS), the API can be classified as BCS Class II/IV. In line with the solubility characteristics, the innovator product does not meet the dissolution criteria for a "rapidly dissolving product." Furthermore, product variations containing commonly used excipients or in the manufacturing process have been reported to impact the rate and extent of efavirenz absorption. Despite its wide therapeutic index, subtherapeutic levels of efavirenz can lead to treatment failure and also facilitate the emergence of efavirenz-resistant mutants. For all these reasons, a biowaiver for IR solid oral dosage forms containing efavirenz as the sole API is not scientifically justified for reformulated or multisource drug products.

  • 13.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Direct In Vivo Human Intestinal Permeability (P-eff) Determined with Different Clinical Perfusion and Intubation Methods2015In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 104, no 9, p. 2702-2726Article, review/survey (Refereed)
    Abstract [en]

    Regional in vivo human intestinal effective permeability (P-eff) is calculated by measuring the disappearance rate of substances during intestinal perfusion. P-eff is the most relevant parameter in the prediction of rate and extent of drug absorption from all parts of the intestine. Today, human intestinal perfusions are not performed on a routine basis in drug development. Therefore, it would be beneficial to increase the accuracy of the in vitro and in silico tools used to evaluate the intestinal P-eff of novel drugs. This review compiles historical P-eff data from 273 individual measurements of 80 substances from 61 studies performed in all parts of the human intestinal tract. These substances include: drugs, monosaccharaides, amino acids, dipeptides, vitamins, steroids, bile acids, ions, fatty acids, and water. The review also discusses the determination and prediction of P-eff using in vitro and in silico methods such as quantitative structure-activity relationship, Caco-2, Ussing chamber, animal intestinal perfusion, and physiologically based pharmacokinetic (PBPK) modeling. Finally, we briefly outline how to acquire accurate human intestinal P-eff data by deconvolution of plasma concentration-time profiles following regional intestinal bolus dosing.

  • 14.
    Ehrhardt, Carsten
    et al.
    Trinity Coll Dublin, Trinity Biomed Sci Inst, Sch Pharm & Pharmaceut Sci, Dublin, Ireland..
    Backman, Per
    Mylan Global Resp Grp, Sandwich, Kent, England..
    Couet, William
    Univ Poitiers, CHU Poitiers, UFR Med Pharm, Inserm,U1070, Poitiers, France..
    Edwards, Chris
    GlaxoSmithKline Medicines Res Ctr, Refractory Resp Inflammat DPU, Stevenage, Herts, England..
    Forbes, Ben
    Kings Coll London, Inst Pharmaceut Sci, London, England..
    Fridén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. AstraZeneca R&D Gothenburg, Resp Inflammat & Autoimmun Innovat Med, Molndal, Sweden..
    Gumbleton, Mark
    Cardiff Univ, Sch Pharm & Pharmaceut Sci, Expt Therapeut, Cardiff, S Glam, Wales..
    Hosoya, Ken-Ichi
    Toyama Univ, Grad Sch Med & Pharmaceut Sci, Dept Pharmaceut, Toyama, Japan..
    Kato, Yukio
    Kanazawa Univ, Fac Pharmaceut Sci, Dept Mol Pharmacotherapeut, Kanazawa, Ishikawa, Japan..
    Nakanishi, Takeo
    Kanazawa Univ, Fac Pharmaceut Sci, Dept Membrane Transport & Biopharmaceut, Kanazawa, Ishikawa, Japan..
    Takano, Mikihisa
    Hiroshima Univ, Grad Sch Biomed & Hlth Sci, Hiroshima, Japan..
    Terasaki, Tetsuya
    Tohoku Univ, Grad Sch Pharmaceut Sci, Sendai, Miyagi, Japan..
    Yumoto, Ryoko
    Hiroshima Univ, Grad Sch Biomed & Hlth Sci, Hiroshima, Japan..
    Current Progress Toward a Better Understanding of Drug Disposition Within the Lungs: Summary Proceedings of the First Workshop on Drug Transporters in the Lungs2017In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 106, no 9, p. 2234-2244Article in journal (Refereed)
    Abstract [en]

    The School of Pharmacy and Pharmaceutical Sciences at Trinity College Dublin hosted the "1st Workshop on Drug Transporters in the Lungs" in September 2016 to discuss the impact of transporters on pulmonary drug disposition and their roles as drug targets in lung disease. The workshop brought together about 30 scientists from academia and pharmaceutical industry from Europe and Japan and addressed the primary questions: What do we know today, and what do we need to know tomorrow about transporters in the lung? The 3 themes of the workshop were: (1) techniques to study drug transporter expression and actions in the lungs; (2) drug transporter effects on pulmonary pharmacokinetics-case studies; and (3) transporters as drug targets in lung disease. Some of the conclusions of the workshop were: suitable experimental models that allow studies of transporter effects are available; data from these models convincingly show a contribution of both uptake and efflux transporters on pulmonary drug disposition; the effects of transporters on drug lung PK is now better conceptualized; some transporters are associated with lung diseases. However, more work is needed to establish which of the available models best translate to the clinical situation.

  • 15.
    Elversson, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Andersson, Karin M.
    Millqvist-Fureby, Anna
    An atomic force microscopy approach for assessment of particle density applied to single spray-dried carbohydrate particles2007In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 96, no 4, p. 905-912Article in journal (Refereed)
    Abstract [en]

    To evaluate an atomic force microscopy (AFM) approach for effective density analysis of single spray dried carbohydrate particles in order to investigate the internal structure of the particles. In addition, the AFM method was compared to an established technique, that is gas pycnometry. Resonant frequency AFM analysis was employed for determination of the mass of individual particles of spray-dried lactose, mannitol, and a mixture of sucrose/dextran (4:1). The effective particle density was calculated using the diameter of the spherical particles obtained from light microscopy. The apparent particle density was further analyzed with gas pycnometry. It was observed by microscopy that particles appeared either solid or hollow. A solid appearance applied to an effective particle density close to the true density of the material, whereas a density around 1 g/cm3 corresponded to a hollow appearance. However, carbohydrates, which crystallized during spray drying, for example, mannitol appeared solid but the average effective particle density was 0.95 g/cm3, indicating a continuous but porous structure. AFM measurements of effective particle density corroborate the suggestion of differences in particle structure caused by the varying propensity of carbohydrates to crystallize during spray drying, resulting in mainly either amorphous hollow or crystalline porous particles.

  • 16.
    Elversson, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Millqvist-Fureby, Anna
    Particle size and density in spray drying: effects of carbohydrate properties2005In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 94, no 9, p. 2049-2060Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to examine some fundamental aspects of the particle formation during spray drying, related to particle size and density. Particles were prepared in a laboratory spray dryer from carbohydrates with different solubility and crystallization propensity, such as lactose, mannitol, and sucrose/dextran 4:1. The feed concentrations ranged from 1% w/w to saturated and the size of droplets and particles were measured by laser diffraction. Particles were also characterized by various microscopy techniques (i.e., scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM), and light microscopy), differential scanning calorimetry (DSC), gas adsorption, and gas pycnometry. As demonstrated larger particles could be obtained by either increasing the droplet size during atomization; increasing the concentration of the feed solution; or decreasing the solubility of the solute. The apparent particle density, measured by gas pycnometry, was found negatively correlated to the feed concentration. Due to the nonlinear relationship between the feed concentration and the particle size, it was concluded that higher solids load would cause an increase in the effective particle density and that the reduction in the apparent particle density was a result of a gradually less permeable particle surface. Further, the crystallization propensity of the carbohydrate influenced the particle formation and resulted in either hollow or porous particles.

  • 17.
    Elversson, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Millqvist-Fureby, Anna
    Alderhorn, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Elofsson, Ulla
    Droplet and particle size relationship and shell thickness of inhalable lactose particles during spray drying2003In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 92, no 4, p. 900-910Article in journal (Refereed)
    Abstract [en]

    To find means of controlling the size and density of particles intended for inhalation the relationship between droplet and particle size during spray drying was investigated. Lactose solutions were atomized with a two-fluid nozzle and dried in a laboratory spray drier. The effects of nozzle orifice diameter, atomization airflow and feed concentration on droplet and particle size were examined. Mass median diameter of both droplets and particles were analyzed with laser diffraction. In addition, scanning electron microscopy and transmission electron microscopy were used for studies of particle shape and morphology. It was demonstrated that nozzle orifice diameter and airflow, but not feed concentration controlled the droplet size during atomization. Increasing droplet size increased particle size but the effect was also influenced by feed concentration. Particles from solutions of a low concentration (1% w/w) were smaller than those from higher concentrations (5-20% w/w). This may be partly explained by lower yields at higher feed concentrations, but may also be related to differences in drying rate. Spray-dried lactose solutions formed hollow particles, and it was suggested that the shell thickness of the particles increased with increasing feed concentration.

  • 18.
    Forsgren, Johan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Jämstorp, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Bredenberg, Susanne
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    A ceramic drug delivery vehicle for oral administration of highly potent opioids2010In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 99, no 1, p. 219-226Article in journal (Refereed)
    Abstract [en]

    Pellets composed of the ceramic material Halloysite and microcrystalline cellulose were synthesized with the aim of producing a drug delivery vehicle for sustained release of the opioid Fentanyl with low risk for dose dumping at oral intake of the highly potent drug. Drug release profiles of intact and crushed pellets, to simulate swallowing without or with chewing, in pH 6.8, pH 1, and in 48% ethanol were recorded in order to replicate the conditions in the small intestines, in the stomach, as well as cointake of the drug with alcohol. The drug release was analyzed by employing the Weibull equation, which showed that the release profiles were either governed by fickian diffusion (intact pellets in pH 6.8 and in ethanol) or by diffusion in a fractal or disordered pore network (intact pellets in pH 1 and crushed pellets in all solutions). A sustained release for approximately 3-4 h was obtained in all studied solutions from intact pellets, whereas crushed pellets released the drug content during approximately 2-3 h. The finding that a sustained release profile could be obtained both in alcohol and after crushing of the pellets, shows that the ceramic carrier under investigation, at least to some extent, hampers dose dumping, and may thus be a promising material in future developments of new opioid containing oral dosage forms.

  • 19.
    Fransén, Nelly
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Björk, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Edsman, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Changes in the mucoadhesion of powder formulations after drug application investigated with a simplified method2008In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 97, no 9, p. 3855-3864Article in journal (Refereed)
    Abstract [en]

    The residence time in the nasal cavity can be prolonged by dry particles that absorb water and subsequently increase the viscosity of the mucus layer. A novel nasal drug delivery system based on interactive mixtures has previously been developed, where fine particles of the active component are adhered to the surface of mucoadhesive carrier particles by dry mixing. The surface coverage may alter the original mucoadhesiveness of the carrier particles and to investigate this, a simplified tensile strength method was developed and evaluated. Reliable results were obtained with a plastic coated absorbent paper covered by a mucin solution as a substitution for porcine nasal mucosa and should also be applicable to other dry particle systems. The method showed that the swelling of sodium starch glycolate particles was slightly delayed, corresponding to the degree of hydrophobic surface coverage. Carrier particles of partly pregelatinized maize starch were not influenced by the addition of a hydrophobic substance, probably because of the rough particle shape that inhibited a complete surface coverage. It was concluded that the surface coverage of carrier particles in interactive mixtures only could cause a short delay in water absorption that should not affect their mucoadhesive characteristics in vivo.

  • 20.
    Frenning, Göran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science.
    Ek, Ragnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science.
    A new method for characterizing the release of drugs from tablets in low liquid surroundings2002In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 91, no 3, p. 776-784Article in journal (Refereed)
    Abstract [en]

    The purpose of this article is to introduce a method capable of determining early drug dissolution in small amounts of liquid. The method is based on the measurement of the alternating ionic current through a cell containing the dissolution medium and the substance to be dissolved. Both the initial and more prolonged absorption of liquid into tablets can also be determined by using the same technique. The method has been tested on two tablet formulations containing agglomerated micronized cellulose and NaCl as a model drug. Release of NaCl was delayed from both formulations; the extent of the delay was strongly formulation-dependent only when the surrounding liquid was in short supply. This finding shows that new drug dissolution phenomena may be encountered in small liquid volumes; these phenomena would not have been seen with the large volume methods normally used in in vitro dissolution tests. Hence, for formulations intended for sublingual, buccal, or rectal administration, i.e., in areas where liquid is scarce, in vitro dissolution tests should be performed in small volumes of dissolution medium.

  • 21.
    Hammarlund-Udenaes, Margareta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brouwer, Kim
    Nakashima, Emi
    Terasaki, Tetsuya
    Perspectives on a pharmacokinetics legend: C versus T (contributions over time)2013In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 102, no 9, p. 2889-2894Article in journal (Other academic)
  • 22.
    Hellrup, Joel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Alderborn, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Mahlin, Denny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Inhibition of Recrystallization of Amorphous Lactose in Nanocomposites Formed by Spray-Drying2015In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 104, no 11, p. 3760-3769Article in journal (Refereed)
    Abstract [en]

    This study aims at investigating the recrystallization of amorphous lactose in nanocomposites. In particular, the focus is on the influence of the nano- to micrometer length scale nanofiller arrangement on the amorphous to crystalline transition. Further, the relative significance of formulation composition and manufacturing process parameters for the properties of the nanocomposite was investigated. Nanocomposites of amorphous lactose and fumed silica were produced by co-spray-drying. Solid-state transformation of the lactose was studied at 43%, 84%, and 94% relative humidity using X-ray powder diffraction and microcalorimetry. Design of experiments was used to analyze spray-drying process parameters and nanocomposite composition as factors influencing the time to 50% recrystallization. The spray-drying process parameters showed no significant influence. However, the recrystallization of the lactose in the nanocomposites was affected by the composition (fraction silica). The recrystallization rate constant decreased as a function of silica content. The lowered recrystallization rate of the lactose in the nanocomposites could be explained by three mechanisms: (1) separation of the amorphous lactose into discrete compartments on a micrometer length scale (compartmentalization), (2) lowered molecular mobility caused by molecular interactions between the lactose molecules and the surface of the silica (rigidification), and/or (3) intraparticle confinement of the amorphous lactose.

  • 23.
    Hellrup, Joel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Mahlin, Denny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Confinement of Amorphous Lactose in Pores formed upon Co-Spray-Drying with Nanoparticles2017In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 106, no 1, p. 322-330Article in journal (Other academic)
    Abstract [en]

    This study aims at investigating factors influencing humidity induced recrystallization of amorphous lactose, produced by co-spray-drying with particles of cellulose nanocrystals (CNC) or sodium montmorillonite (Na-MMT). In particular, the focus is on how the nanoparticle shape and surface properties influence the nano- to micrometer length scale nanofiller arrangement in the nanocomposites and how the arrangements influence the mechanisms involved in the inhibition of the amorphous to crystalline transition. The nanocomposites were produced by co-spray-drying. Solid-state transformations were analyzed at 60-94% relative humidity using X-ray powder diffraction, microcalorimetry, and light microscopy. The recrystallization rate constant for the lactose/CNC and lactose/Na-MMT nanocomposites was lowered at nanofiller contents higher than 60% and were stable for months at 80% nanofiller. The most likely explanation to these results is spontaneous formations of mesoporous particle networks that the lactose is confined within upon co-spray-drying at high filler content. Compartmentalization and rigidification of the amorphous lactose proved to be less important mechanisms involved in the stabilization of lactose in the nanocomposites.

  • 24.
    Hu, Yang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fridén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Department of Drug Metabolism and Pharmacokinetics, Early Respiratory, Inflammation and Autoimmunity, R&D Biopharmaceuticals, AstraZeneca R&D, Gothenburg, Sweden.
    Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling.2019In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 108, no 10, p. 3425-3433Article in journal (Refereed)
    Abstract [en]

    This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation.

  • 25.
    Hu, Yang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rip, Jaap
    Eyesiu Medicine B.V..
    Gaillard, Pieter
    Eyesiu Medicines B.V./2-BBB Medicine B.V,.
    De lange, Elizabeth
    Leiden University.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The Impact of Liposomal Formulations on the Release and Brain Delivery of Methotrexate: : An In Vivo Microdialysis Study2017In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017Article in journal (Refereed)
    Abstract [en]

    The impact of liposomal formulations on the in vivo release and brain delivery of methotrexate (MTX) was quantitatively assessed in rats. Two PEGylated liposomal MTX formulations based on hydrogenated soy phosphatidylcholine (HSPC) or egg-yolk phosphatidylcholine (EYPC) were prepared. The drug release and uptake into the brain after intravenous administration of both formulations were compared with unformulated MTX by determining the released, unbound MTX in brain and plasma using microdialysis. Total MTX concentrations in plasma were determined using regular blood sampling. The administration of both high- and low-dose EYPC liposomes resulted in 10 times higher extent of MTX release in plasma compared to that obtained from HSPC liposomes (p < 0.05). MTX itself possessed limited brain uptake with steady-state unbound brain-to-plasma concentration ratio (Kp,uu) of 0.10 ± 0.06. Encapsulation in HSPC liposomes did not affect MTX brain uptake (Kp,uu 0.11 ± 0.05). In contrast, EYPC liposomes significantly improved MTX brain delivery with a 3-fold increase of Kp,uu (0.28 ± 0.14 and 0.32 ± 0.13 for high- and low-dose EYPC liposomal MTX, respectively, p < 0.05). These results provide unique quantitative evidence that liposomal formulations based on different phospholipids can result in very different brain delivery of MTX

  • 26.
    Hu, Yang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rip, Jaap
    Eyesiu Med BV, JH Oortweg 19, NL-2333 Leiden, Netherlands..
    Gaillard, Pieter J.
    Eyesiu Med BV, JH Oortweg 19, NL-2333 Leiden, Netherlands.;2 BBB Med BV, JH Oortweg 19, NL-2333 Leiden, Netherlands..
    de lange, Elizabeth C. M.
    Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Cluster Syst Pharmacol, Leiden, Netherlands..
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The Impact of Liposomal Formulations on the Release and Brain Delivery of Methotrexate: An In Vivo Microdialysis Study2017In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 106, no 9, p. 2606-2613Article in journal (Refereed)
    Abstract [en]

    The impact of liposomal formulations on the in vivo release and brain delivery of methotrexate (MTX) was quantitatively assessed in rats. Two PEGylated liposomal MTX formulations based on hydrogenated soy phosphatidylcholine (HSPC) or egg-yolk phosphatidylcholine (EYPC) were prepared. The drug release and uptake into the brain after intravenous administration of both formulations were compared with unformulated MTX by determining the released, unbound MTX in brain and plasma using microdialysis. Total MTX concentrations in plasma were determined using regular blood sampling. The administration of both high-and low-dose EYPC liposomes resulted in 10 times higher extent of MTX release in plasma compared to that obtained from HSPC liposomes (p < 0.05). MTX itself possessed limited brain uptake with steady-state unbound brain-to-plasma concentration ratio (K-p,K-uu) of 0.10 +/- 0.06. Encapsulation in HSPC liposomes did not affect MTX brain uptake (K-p,K-uu 0.11 +/- 0.05). In contrast, EYPC liposomes significantly improved MTX brain delivery with a 3-fold increase of Kp, uu (0.28 +/- 0.14 and 0.32 +/- 0.13 for high-and low-dose EYPC liposomal MTX, respectively, p < 0.05). These results provide unique quantitative evidence that liposomal formulations based on different phospholipids can result in very different brain delivery of MTX.

  • 27.
    Hägerström, Helene
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Edsman, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Strömme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Materials Science.
    Low-frequency dielectric spectroscopy as a tool for studying the compatibility between pharmaceutical gels and mucous tissue2003In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 92, no 9, p. 1869-1881Article in journal (Refereed)
    Abstract [en]

    This interdisciplinary work demonstrates how low-frequency dielectric spectroscopy, a technique that is frequently used within physics, can be used to assess the possibilities of intimate surface contact between a polymer gel and mucous tissue, which is generally considered to be the first step in the mucoadhesion process. The dielectric responses of five different gels, of freshly excised porcine nasal mucosa and of systems made by combining the two were measured. All spectra were modeled by a Randles electric circuit containing a diffusion element, a barrier resistance in parallel with a capacitance, and a high-frequency resistance. The results were used to create a measure of the compatibility between the gel and the mucus, which we have named the compatibility factor. Thus, the compatibility factor provides us with a measure of the ease with which a charged species passes the interface between a gel and the mucus layer. The compatibility factor is calculated from the high frequency (kHz region) response of the gel, of the mucosa, and of the combined system. The two highest compatibility factors in this study were obtained for gels based on crosslinked poly(acrylic acid) and chitosan, which was in agreement with the results from mucoadhesion measurements that were performed using a tensile strength method.

  • 28. Jacobson, Gunilla B.
    et al.
    Shinde, Rajesh
    McCullough, Rebecca L.
    Cheng, Nicholas J.
    Creasman, Adam
    Beyene, Amanuel
    Hickerson, Robyn P.
    Quan, Can
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Turner, Charlotta
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Kaspar, Roger L.
    Contag, Christopher H.
    Zare, Richard N.
    Nanoparticle Formation of Organic Compounds With Retained Biological Activity2010In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 99, no 6, p. 2750-2755Article in journal (Refereed)
    Abstract [en]

    Many pharmaceuticals are formulated as powders to aid drug delivery. A major problem is how to produce powders having high purity, controlled morphology, and retained bioactivity. We demonstrate the use of supercritical carbon dioxide as an antisolvent for meeting this need for two model drug systems, quercetin, a sparingly soluble antioxidant, and short interfering RNA (siRNA), which can silence genes. In both cases we achieve retention of bioactivity as well as a narrow particle size distribution in which the particles are free of impurities.

  • 29.
    Jämstorp, Erik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Bredenberg, Susanne
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Influence of drug distribution and solubility on release from geopolymer pellets: A finite element method study2012In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 101, no 5, p. 1803-1810Article in journal (Refereed)
    Abstract [en]

    This study investigates the influence of drug solubility and distribution on its release from inert geopolymer pellets of three different sizes (1.5 × 1.5, 3 × 6, and 6 × 6 mm), having the same geopolymer composition and containing highly potent opioid fentanyl, sumatriptan, theophylline, or saccharin. Scanning electron microscopy, nitrogen sorption, drug solubility, permeation, and release experiments were performed, and estimates of the drug diffusion coefficients and solubilities in the geopolymer matrix were derived with the aid of finite element method (FEM). FEM was further employed to investigate the effect of a nonuniform drug distribution on the drug release profile. When inspecting the release profiles for each drug, it was observed that their solubilities in the geopolymer matrix imposed a much greater influence on the drug release rate than their diffusion coefficients. Concentrating the initial drug load in FEM into nonuniformly distributed drug regions inside the matrix created drug release profiles that more closely resembled experimental data than an FEM-simulated uniform drug distribution did. The presented FEM simulations and visualization of drug release from geopolymers under varying initial and dynamic conditions should open up for more systematic studies of additional factors that influence the drug release profile from porous delivery vehicles.

  • 30.
    Jämstorp, Erik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Frenning, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Modeling structure-function relationships for diffusive drug transport in inert porous geopolymer matrices2011In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 100, no 10, p. 4338-4348Article in journal (Refereed)
    Abstract [en]

    A unique structure-function relationship investigation of mechanically strong geopolymer drug delivery vehicles for sustained release of potent substances is presented. The effect of in-synthesis water content on geopolymer pore structure and diffusive drug transport is investigated. Scanning electron microscopy, N(2) gas adsorption, mercury intrusion porosimetry, compression strength test, drug permeation, and release experiments are performed. Effective diffusion coefficients are measured and compared with corresponding theoretical values as derived from pore size distribution and connectivity via pore-network modeling. By solely varying the in-synthesis water content, mesoporous and mechanically strong geopolymers with porosities of 8%-45% are obtained. Effective diffusion coefficients of the model drugs Saccharin and Zolpidem are observed to span two orders of magnitude (∼1.6-120 × 10(-8) cm(2) /s), comparing very well to theoretical estimations. The ability to predict drug permeation and release from geopolymers, and materials alike, allows future formulations to be tailored on a structural and chemical level for specific applications such as controlled drug delivery of highly potent substances.

  • 31.
    Karlgren, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Science for Life Laboratory.
    Simoff, Ivailo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Backlund, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Science for Life Laboratory.
    Wegler, Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. AstraZeneca.
    Keiser, Markus
    Department of Clinical Pharmacology, Center of Drug Absorption and Transport, University Medicine of Greifswald, Greifswald, Germany..
    Handin, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Müller, Janett
    Department of Clinical Pharmacology, Center of Drug Absorption and Transport, University Medicine of Greifswald, Greifswald, Germany..
    Lundquist, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Jareborg, Anne-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Oswald, Stefan
    Department of Clinical Pharmacology, Center of Drug Absorption and Transport, University Medicine of Greifswald, Greifswald, Germany..
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Science for Life Laboratory.
    A CRISPR-Cas9 Generated MDCK Cell Line Expressing Human MDR1 Without Endogenous Canine MDR1 (cABCB1): An Improved Tool for Drug Efflux Studies.2017In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 106, no 9, p. 2909-2913Article in journal (Refereed)
    Abstract [en]

    Madin-Darby canine kidney (MDCK) II cells stably transfected with transport proteins are commonly used models for drug transport studies. However, endogenous expression of especially canine MDR1 (cMDR1) confounds the interpretation of such studies. Here we have established an MDCK cell line stably overexpressing the human MDR1 transporter (hMDR1; P-glycoprotein), and used CRISPR-Cas9 gene editing to knockout the endogenous cMDR1. Genomic screening revealed the generation of a clonal cell line homozygous for a 4-nucleotide deletion in the canine ABCB1 gene leading to a frameshift and a premature stop codon. Knockout of cMDR1 expression was verified by quantitative protein analysis and functional studies showing retained activity of the human MDR1 transporter. Application of this cell line allowed unbiased reclassification of drugs previously defined as both substrates and non-substrates in different studies using commonly used MDCK-MDR1 clones. Our new MDCK-hMDR1 cell line, together with a previously developed control cell line, both with identical deletions in the canine ABCB1 gene and lack of cMDR1 expression represent excellent in vitro tools for use in drug discovery.

  • 32.
    Keemink, Janneke
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Pharmeteus, Dag Hammarskjolds Vag 52B, S-75237 Uppsala, Sweden.
    Holm, Rene
    Johnson & Johnson, Janssen R&D, Drug Prod Dev, Turnhoutseweg 30, B-2340 Beerse, Belgium.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Does the Intake of Ethanol Affect Oral Absorption of Poorly Soluble Drugs?2019In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 108, no 5, p. 1765-1771Article in journal (Refereed)
    Abstract [en]

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

  • 33.
    Kusuhara, Hiroyuki
    et al.
    Univ Tokyo, Grad Sch Pharmaceut Sci, Lab Mol Pharmacokinet, Bunkyo Ku, Tokyo 1130033, Japan..
    Obach, R. Scott
    Pfizer Global Res & Dev, Dept Pharmacokinet Dynam & Metab, Groton, CT 06340 USA..
    Rostami-Hodjegan, Amin
    Univ Manchester, Ctr Appl Pharmacokinet Res, Manchester, Lancs, England.;Simcyp Ltd, Sheffield, S Yorkshire, England..
    Pang, K. Sandy
    Univ Toronto, Leslie Dan Fac Pharm, Toronto, ON, Canada..
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Derendorf, Hartmut
    Univ Florida, Dept Pharmaceut, Gainesville, FL 32608 USA..
    Artursson, Per
    Uppsala Univ, Dept Pharm, BMC, Box 580, S-75123 Uppsala, Sweden..
    Huang, Shiew-Mei
    US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA..
    Suzuki, Hiroshi
    Univ Tokyo, Univ Tokyo Hosp, Dept Pharm, Fac Med, Tokyo, Japan..
    Terasaki, Tetsuya
    Tohoku Univ, Grad Sch Pharmaceut Sci, Div Membrane Transport & Drug Targeting, Aoba Ku, 6-3 Aoba, Sendai, Miyagi 9808578, Japan..
    Professor Yuichi Sugiyama: A Brilliant, Creative, Amicable, Charming, and Humorous Pharmaceutical Scientist2017In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 106, no 9, p. 2188-2194Article in journal (Other academic)
  • 34.
    Lazorova, Lucia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hubatsch, Ina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ekegren, Jenny K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Gising, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Nakai, Daisuke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Zaki, Noha M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Norinder, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Structural Features Determining the Intestinal Epithelial Permeability and Efflux of Novel HIV-1 Protease Inhibitors2011In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 100, no 9, p. 3763-3772Article in journal (Refereed)
    Abstract [en]

    The primary aim of this study was to identify structural features that alter the intestinal epithelial permeability and efflux in a series of novel HIV-1 protease inhibitors (PIs). Eleven PIs were selected containing a tertiary alcohol in a transition-state mimicking scaffold, in which two substituents (R1 and R2) were varied systematically. Indinavir was selected as a reference compound. The apical-to-basolateral permeability was investigated in 2/4/A1 and Caco-2 monolayers. In addition, the basolateral-to-apical permeability was investigated in the Caco-2 monolayers and the efflux ratios were calculated. The absence of active drug transport processes in 2/4/A1 cells allowed identification and modeling of structural elements affecting the passive permeability. For instance, small aromatic R1 substituents and a small (bromo-) R2 substituent were associated with a high passive permeability. Efflux studies in Caco-2 cells indicated that amide-substituted neutral hydrophobic amino acids, such as valine and leucine, in the R1 position, reduced the apical-to-basolateral transport and enhanced the efflux. We conclude that our investigation revealed structural features that alter the intestinal epithelial permeability and efflux in the series of PIs and hope that these results can contribute to the synthesis of PIs with improved permeability and limited efflux properties.

  • 35. Linnankoski, Johanna
    et al.
    Mäkelä, Johanna
    Palmgren, Joni
    Mauriala, Timo
    Vedin, Charlotta
    Ungell, Anna-Lena
    Lazorova, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Urtti, Arto
    Yliperttula, Marjo
    Paracellular porosity and pore size of the human intestinal epithelium in tissue and cell culture models2010In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 99, no 4, p. 2166-2175Article in journal (Refereed)
    Abstract [en]

    The paracellular space defines the passive permeation of hydrophilic compounds in epithelia. The goal of this study was to characterise the paracellular permeation pathway in the human intestinal wall and differentiated epithelial cell models (MDCKII, Caco-2 and 2/4/A1). The permeabilities of hydrophilic polyethylene glycols (PEG) were investigated in diffusion chambers, and mass spectrometry was used to obtain accurate concentrations for each PEG molecule. The paracellular porosity and the size of the pores in the membranes were estimated from the PEG permeability data using an effusion-based approach. The porosities were found to be low (fraction 10−7–10−5 of the epithelial surface) in all investigated membranes. Two different pore sizes (radii 5–6 and >10 Å) were detected in the human intestinal epithelium and the Caco-2 and MDCKII cells, while only one (about 15 Å) in the 2/4/A1 monolayer. The paracellular porosities of the human small intestine and 2/4/A1 monolayers were larger (>10−7) than that of the MDCKII and Caco-2 cells (<10−7). We report for the first time the quantitative values describing both porosity and pore size of the paracellular space in the human intestine. The cell models deviate from the small intestine either with respect to porosity (Caco-2, MDCKII) or pore size distribution (2/4/A1).

  • 36.
    Miyake, Masateru
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Otsuka Pharmaceut Co Ltd, Formulat Res Inst, BA Project, 224-18 Ebino, Kawaguchi, Tokushima 7710182, Japan..
    Ragnarsson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nakai, Daisuke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    The Pro-inflammatory Cytokine Interleukin-6 Regulates Nanoparticle Transport Across Model Follicle-Associated Epithelium Cells2016In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 7, p. 2099-2104Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate whether the pro-inflammatory cytokines improved the function of the cell monolayer model of the human follicle-associated epithelium (FAE) of co-culture of Caco-2 cells on permeable filters with Raji B-cells underneath from the viewpoint of particle transport. Exposure to tumor necrosis factor-a resulted in an almost maintained epithelial integrity/paracellular permeability combined with an increased nanoparticle transport in a dose-dependent manner while the effects of interleukin (IL)-1 beta were limited. Exposure to IL-6 significantly enhanced the nanoparticle transport with the limited disruption of the cell monolayer integrity. The addition of IL-6 or tumor necrosis factor-a to Caco-2 monolayers without Raji B-cells did not enhance nanoparticle transport. In our IL-6 treated FAE model, the nanoparticle transport almost disappeared at 4 degrees C or after the addition of 5-(N-ethyl-N-isopropyl) amiloride, an inhibitor of macropinocytosis. Furthermore, IgA binding, presumably by a secretory IgA receptor, a marker of M-cells was observed on the apical side of our model FAE. These results indicate that the combined effect of IL-6 with unknown factors from Raji-B cells made the FAE model more functional with regard to nanoparticle transport. The IL-6 enhanced FAE model will be a useful platform for nanoparticle drug delivery research across the intestinal epithelium.

  • 37.
    Nordström, Josefina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Alderborn, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    The Granule Porosity Controls the Loss of Compactibility for Both Dry- and Wet-Processed Cellulose Granules but at Different Rate2015In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 104, no 6, p. 2029-2039Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the role of porosity on the compression behavior and tablet tensile strength for granules produced by a dry granulation procedure. Microcrystalline cellulose was used as a typical pharmaceutical excipient and a comparison was made with the effect of granule porosity on the compression behavior and tablet tensile strength of wet-processed granules of the same composition. Both the wet and dry granulation process caused a loss in compactibility of the material that was controlled by the granule porosity up to a critical point of porosity and friability. Above this threshold value of porosity, the granules nearly collapsed completely into primary particles during compression. In these cases, the micro-structure and tensile strength of the formed tablets resembled that of tablets formed from the original ungranulated powder.

  • 38.
    Nordström, Josefina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Klevan, Ingvild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Alderborn, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    A particle rearrangement index based on the Kawakita powder compression equation2009In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 98, no 3, p. 1053-1063Article in journal (Refereed)
    Abstract [en]

    In this article, the effect of original particle size on the Kawakita parameters, denoted a and b, has been studied using four model materials of different compression mechanics. It was found that fine powders, possibly showing significant particle rearrangement at low compression pressures, showed low values of parameter b(-1) and high values of parameter a. It is thus proposed that the product of these parameters is an indication of the overall contribution of particle rearrangement to the compression profile. Above a critical original particle size of a powder, particle rearrangement is negligible for the overall compression profile and below this critical particle size, particle rearrangement becomes significant. A critical particle size of about 40 microm was obtained. A classification of powders into groups dependent on the incidence of particle rearrangement is discussed and it is suggested that a rearrangement index and a classification system could be used as tools to enable rational interpretations of global compression parameters.

  • 39.
    Nordström, Josefina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Welch, Ken
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Frenning, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Alderborn, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    On the role of granule yield strength for the compactibility of granular solids2008In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 97, no 11, p. 4807-4814Article in journal (Refereed)
    Abstract [en]

    The objective of this article was to explore the relationship between mechanical properties of single granules and the evolution in tensile strength and tablet micro-structure. Granules of different expected deformation behavior were used as model materials. It is suggested that the role of plasticity in this context is twofold: firstly, to affect the rate of compactibility and thus the pressure range needed to reach the maximal attained tablet strength and, secondly, to affect the mode of deformation of the granules and thus the maximal attained tablet strength. A decrease in yield pressure of single granules increased the tablet tensile strength at a given compaction pressure. The yield pressure can be controlled by the granule composition and porosity.

  • 40.
    Paulsson, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Edsman, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Controlled drug release from gels using surfactant aggregates: I. Effect of lipophilic interactions for a series of uncharged substances2001In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 90, no 9, p. 1216-1225Article in journal (Refereed)
    Abstract [en]

    Gels are often used for the delivery of drugs because they have rheological properties that will give a long residence time. Most pharmaceutical gels consist of approximately 99% water and a polymer matrix that will not hinder the release of drugs with a small molecular weight. To fully take advantage of the residence time, it is necessary to have a sustained drug release. In this paper it is suggested that surfactant micelles can be used to control the release from gels. The in vitro release under physiological conditions of five parabens from four different poly(acrylic acid) gels (Carbopol 934, 940, 1342) and one gellan gum (Gelrite) gel was measured using a USP dissolution bath modified for gels, and the diffusion coefficients were calculated. The diffusion coefficient of uncharged parabens was generally lower in gels with lipophilic modifications, such as C1342, and the greatest effect was seen for butylparaben, with a diffusion that was 25% lower than that in C934 (lacking lipophilic modification). Addition of surfactant micelles to gels delayed the release of all the uncharged drugs in all types of gels studied. The slowest release was seen for butylparaben in a lipophilically modified gel with micelles present. The diffusion coefficient in such a system was almost 30 times smaller than that in C934 without micelles.

  • 41.
    Pazesh, Samaneh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Höckerfelt, Mina Heidarian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Berggren, Jonas
    Bramer, Tobias
    Alderborn, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Mechanism of Amorphisation of Micro-Particles of Griseofulvin During Powder Flow in a Mixer2013In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 102, no 11, p. 4036-4045Article in journal (Refereed)
    Abstract [en]

    The purpose of the research was to investigate the degree of solid-state amorphisation during powder flow and to propose a mechanism for this transformation. Micro-particles of griseofulvin (about 2m in diameter) were mixed in a shear mixer under different conditions to influence the inter-particulate collisions during flow, and the degree of amorphisation was determined by micro-calorimeter. The amorphisation of griseofulvin particles (GPs)during repeated compaction was also determined. The GPs generally became disordered during mixing in a range from about 6% to about 86%. The degree of amorphisation increased with increased mixing time and increased batch size of the mixer, whereas the addition of a lubricant to the blend reduced the degree of amorphisation. Repeated compaction using the press with ejection mode gave limited amorphisation, whereas repeated compaction without an ejection process gave minute amorphisation. It is concluded that during powder flow, the most important inter-particulate contact process that cause the transformation of a crystalline solid into an amorphous state is sliding. On the molecular scale, this amorphisation is proposed to be caused by vitrification, that is the melting of a solid because of the generation of heat during sliding followed by solidification into an amorphous phase.

  • 42.
    Persson, Anita M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Baumann, Kajsa
    Inst för kemi, Göteborgs universitet.
    Sundelöf, Lars-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindberg, Walter
    AstraZeneca, Mölndal.
    Sokolowski, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Design and Characterization of a New Miniaturized Rotating Disk Equipment for In Vitro Dissolution Rate Studies2008In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 97, no 8, p. 3344-3355Article in journal (Refereed)
    Abstract [en]

    A miniaturized apparatus for the determination of the apparent in vitro dissolution rate has been designed, constructed and characterized. The miniaturized apparatus was based on a low volume dissolution cell and a disk in a rotating magnetic bar. The disk tablet is pressed directly into the bar with a press designed and constructed for this purpose. It requires approximately 5 mg of substance. The disk was positioned eccentrically on the bar with an external flow of medium to increase the rate of solvent flow over the disk surface. Six different drug substances were used. The dissolution media were sodium phosphate buffer, pH 7.0, and ammonium acetate buffer, pH 6.8. All quantifications were made by integrating the dissolution cell with high-performance liquid chromatography (HPLC) using diode-array detection (DAD). The obtained results were compared with data from a conventional rotating disk equipment, where the disk was centrically mounted. The dissolution rates at 100 rpm seemed to be on an average of 2-3 times higher for the miniaturized apparatus (RSD 0.2-56%). The preliminary studies of this prototype indicate that the miniaturized rotating disk is a promising design for the qualitative estimation of dissolution rates of substances, for example during screening in early drug discovery.

  • 43.
    Persson, Ann-Sofie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ahmed, Hamzah
    Luleå Univ Technol, Dept Hlth Sci, Pharmaceut Res, SE97187 Luleå, Sweden.
    Velaga, Sitaram
    Luleå Univ Technol, Dept Hlth Sci, Pharmaceut Res, SE97187 Luleå, Sweden.
    Alderborn, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Powder Compression Properties of Paracetamol, Paracetamol Hydrochloride, and Paracetamol Cocrystals and Coformers2018In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 107, no 7, p. 1920-1927Article in journal (Refereed)
    Abstract [en]

    The objectivewas to study the relationship between crystal structure, particle deformation properties, and tablet-forming ability for the monoclinic formof paracetamol (PRA), 2 cocrystals and a salt crystal of PRA in addition to 2 coformers (oxalic acid and 4,4'-bipyridine). Thus, the structure-property-performance relationship was investigated. Analytical powder compression was used for determination of effective plasticity, as inferred from the Heckel yield pressure and the Frenning parameter, and the elastic deformation was determined from in-die tablet elastic recovery. The plasticity could not be linked to the crystal lattice structure as crystals containing zig-zag layers displayed similar plasticity as crystals containing slip planes. In addition, crystals containing slip planes displayed both high and low plasticity. The mechanical properties could not be linked to the tablet-forming ability as the tablet tensile strength, unexpectedly, displayed a tendency to reduce with increased plasticity. Furthermore, the elastic deformation could not explain the tablet-forming ability. It was concluded that no relationship between structure-property-performance for PRA and its cocrystals and salt could be established. Thus, it was indicated that to establish such a relationship, an improved knowledge of crystallographic structure and interparticle bonding during compaction is needed.

  • 44.
    Sadiq, Muhammad Waqas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Borgs, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Okura, Takashi
    Shimomura, Keita
    Kato, Sayaka
    Deguchi, Yoshiharu
    Jansson, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Björkman, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Terasaki, Tetsuya
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Diphenhydramine Active Uptake at the Blood-Brain Barrier and Its Interaction with Oxycodone in Vitro and in Vivo2011In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 100, no 9, p. 3912-3923Article in journal (Refereed)
    Abstract [en]

    Diphenhydramine (DPHM) and oxycodone are weak bases that are able to form cations. Both drugs show active uptake at the blood-brain barrier (BBB). There is thus a possibility for a pharmacokinetic interaction between them by competition for the same uptake transport system. The experiments of the present study were designed to study the transport of DPHM across the BBB and its interaction with oxycodone in vitro and in vivo. In vitro, the interaction between the drugs was studied using conditionally immortalized rat brain capillary endothelial cells (TR-BBB13 cells). The in vivo relevance of the in vitro findings was studied in rats using brain and blood microdialysis. DPHM was actively transported across the BBB in vitro (TR-BBB13 cells). Oxycodone competitively inhibited DPHM uptake with a K(i) value of 106 mu M. DPHM also competitively inhibited oxycodone uptake with a K(i) value of 34.7 mu M. In rats, DPHM showed fivefold higher unbound concentration in brain interstitial fluid (ISF) than in blood, confirming a net active uptake. There was no significant interaction between DPHM and oxycodone in vivo. This accords with the results of the in vitro experiments because the unbound plasma concentrations that could be attained in vivo, without causing adverse effects, were far below the Ki values.

  • 45.
    Sadiq, Muhammad Waqas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Boström, Emma
    Keizer, Ron
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Björkman, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Oxymorphone active uptake at the blood-brain barrier and population modeling of its pharmacokinetic-pharmacodynamic relationship2013In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 102, no 9, p. 3320-3331Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to characterize the blood–brain barrier (BBB) transport and pharmacokinetics–pharmacodynamics (PKPD) relationship of oxymorphone and to further elucidate its possible contribution to oxycodone analgesia. The BBB transport of oxymorphone was studied using microdialysis in male Sprague–Dawley rats. Samples from microdialysis blood and brain probes, brain tissue, and plasma were analyzed by liquid chromatography with tandem mass spectrometry. The effect was measured as tail-flick latency. The study consisted of a PKPD experiment with combined microdialysis and antinociceptive measurements (n = 8), and another antinociceptive effect experiment (n = 9) using a 10 times lower dose. The combined data were analyzed with an integrated PKPD model in nonlinear mixed effect modeling utilizing a specific method (M3) for handling missing PD observations. The concentration of unbound oxymorphone was higher in brain than in blood, with a ratio of 1.9 (RSE, 9.7%), indicating active uptake at the BBB. The integrated PKPD model described the oxymorphone BBB transport and PKPD relationship successfully, with an EC50 in the brain of 63 ng/mL, and the M3 method was able to address the issue of censored observations. Oxymorphone has active uptake transport at the BBB in rats, with moderate uptake clearance to the brain. Its contribution to analgesia after oxycodone administration is not significant.

  • 46.
    Schowen, Katharine Barbara
    et al.
    Univ Kansas, Dept Chem, Lawrence, KS 66045 USA..
    Schowen, Richard L.
    Univ Kansas, Dept Chem, Lawrence, KS 66045 USA.;Univ Kansas, Dept Mol Biosci, Lawrence, KS 66047 USA.;Univ Kansas, Dept Pharmaceut Chem, Lawrence, KS 66047 USA..
    Borchardt, Susan E.
    Borchardt, Paul M.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Audus, Kenneth L.
    Univ Kansas, Sch Pharm, Lawrence, KS 66047 USA..
    Augustijns, Patrick
    Katholieke Univ Leuven, Drug Delivery & Disposit, Dept Pharmaceut & Pharmacol Sci, B-3000 Leuven, Belgium..
    Nicolazzo, Joseph A.
    Monash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Parkville, Vic 3052, Australia..
    Raub, Thomas J.
    Eli Lilly & Co, Lilly Res Labs, Drug Disposit, Indianapolis, IN 46285 USA..
    Schoneich, Christian
    Univ Kansas, Dept Pharmaceut Chem, Lawrence, KS 66047 USA..
    Siahaan, Teruna J.
    Univ Kansas, Dept Pharmaceut Chem, Lawrence, KS 66047 USA..
    Takakura, Yoshi
    Kyoto Univ, Dept Biopharmaceut & Drug Metab, Grad Sch Pharmaceut Sci, Kyoto 6068501, Japan..
    Thakker, Dhiren R.
    Univ N Carolina, Div Pharmacotherapy & Expt Therapeut, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA..
    Wolfe, Michael S.
    Harvard Med Sch, Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, Boston, MA 02115 USA..
    A Tribute to Ronald T. Borchardt-Teacher, Mentor, Scientist, Colleague, Leader, Friend, and Family Man2016In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 2, p. 370-385Article in journal (Other academic)
  • 47. Selen, Arzu
    et al.
    Dickinson, Paul A.
    Mullertz, Anette
    Crison, John R.
    Mistry, Hitesh B.
    Cruanes, Maria T.
    Martinez, Marilyn N.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Wigal, Tim L.
    Swinney, David C.
    Polli, James E.
    Serajuddin, Abu T. M.
    Cook, Jack A.
    Dressman, Jennifer B.
    The Biopharmaceutics Risk Assessment Roadmap for Optimizing Clinical Drug Product Performance2014In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 103, no 11, p. 3377-3397Article in journal (Refereed)
    Abstract [en]

    The biopharmaceutics risk assessment roadmap (BioRAM) optimizes drug product development and performance by using therapy-driven target drug delivery profiles as a framework to achieve the desired therapeutic outcome. Hence, clinical relevance is directly built into early formulation development. Biopharmaceutics tools are used to identify and address potential challenges to optimize the drug product for patient benefit. For illustration, BioRAM is applied to four relatively common therapy-driven drug delivery scenarios: rapid therapeutic onset, multiphasic delivery, delayed therapeutic onset, and maintenance of target exposure. BioRAM considers the therapeutic target with the drug substance characteristics and enables collection of critical knowledge for development of a dosage form that can perform consistently for meeting the patient's needs. Accordingly, the key factors are identified and in vitro, in vivo, and in silico modeling and simulation techniques are used to elucidate the optimal drug delivery rate and pattern. BioRAM enables (1) feasibility assessment for the dosage form, (2) development and conduct of appropriate learning and confirming studies, (3) transparency in decision-making, (4) assurance of drug product quality during lifecycle management, and (5) development of robust linkages between the desired clinical outcome and the necessary product quality attributes for inclusion in the quality target product profile.

  • 48.
    Simoff, Ivailo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlgren, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Backlund, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala, Sweden.
    Lindström, Anne-Christine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gaugaz, Fabienne Z.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala, Sweden.
    Complete Knockout of Endogenous Mdr1 (Abcb1) in MDCK Cells by CRISPR-Cas92016In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 2, p. 1017-1021Article in journal (Refereed)
    Abstract [en]

    Madin-Darby canine kidney II cells transfected with one or several transport proteins are commonly used models to study drug transport. In these cells, however, endogenous transporters such as canine Mdr1/P-glycoprotein (Abcb1) complicate the interpretation of transport studies. The aim of this investigation was to establish a Madin-Darby canine kidney II cell line using CRISPR-Cas9 gene-editing technology to knock out endogenous canine Mdr1 (cMdr1) expression. CRISPR-Cas9-mediated Abcb1 homozygous disruption occurred at frequencies of around 20% and resulted in several genotypes. We selected 1 clonal cell line, cMdr1 KO Cl2, for further examination. Consistent with an on-target effect of CRISPR-Cas9 in specific regions of the endogenous canine Abcb1 gene, we obtained a cell clone with Abcb1 gene alterations and without any cMdr1 expression, as confirmed by genome sequencing and quantitative protein analysis. Functional studies of these cells, using digoxin and other prototypic MDR1 substrates, showed close to identical transport in the apical-to-basolateral and basolateral-to-apical directions, resulting in efflux ratios indistinguishable from unity.

  • 49.
    Sjögren, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Andersson, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sundgren-Andersson, Anna K.
    AstraZeneca R&D, Global Med Dev, SE-43183 Molndal, Sweden..
    Halldin, Magnus M.
    Karolinska Inst, AlzeCure Fdn, Sci Pk, SE-14157 Huddinge, Sweden..
    Stalberg, Olle
    Karlstad Univ, Dept Engn & Chem Sci, SE-65188 Karlstad, Sweden..
    Assessment of Free Drug Concentration in Cyclodextrin Formulations Is Essential to Determine Drug Potency in Functional In Vitro Assays2016In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 9, p. 2913-2920Article in journal (Refereed)
    Abstract [en]

    Cyclodextrins (CD) have the ability to form inclusion complexes with drugs and can be used as excipients to enhance solubility of poorly soluble drugs. To make accurate estimations of the potency of the drug, knowledge of the free drug concentration is important. The aim of this study was to evaluate the applicability of calculated free drug concentrations toward response measurements in a transient receptor potential vanilloid receptor-1 cell-based in vitro assay. This included accounting for potential competitive CD binding of 2 transient receptor potential vanilloid receptor-1 active entities: 1 antagonist, and 1 agonist (capsaicin). Solubility of the CD-drug complexes was measured, and the ligand to substrate affinity in CD formulations was determined according to the phase-solubility technique. The total concentration of antagonist, agonist, CD, and the binding constants between ligands and CD were used to calculate the free concentration of CD ligands. For capsaicin and 2 of the 3 investigated model drugs, the calculated free drug concentration was consistent with the experimental in vitro data while it was overestimated for one of the compounds. In conclusion, the suggested approach can be used to calculate free drug concentration and competitive binding in CD formulations for the application of cell-based drug functionality assays.

  • 50. Soares, Kelen C C
    et al.
    Rediguieri, Camila F
    Souza, Jacqueline
    Serra, Cristina Helena R
    Abrahamsson, Bertil
    Pharmaceutical Development, AstraZeneca R&D, Mölndal, Sweden.
    Groot, D W
    Kopp, Sabine
    Langguth, Peter
    Polli, James E
    Shah, Vinod P
    Dressman, Jennifer
    Biowaiver monographs for immediate-release solid oral dosage forms: Zidovudine (azidothymidine)2013In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 102, no 8, p. 2409-2423Article in journal (Refereed)
    Abstract [en]

    Literature data on the properties of zidovudine relevant to waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate-release (IR) solid oral dosage forms containing zidovudine alone or in combination with other active pharmaceutical ingredients (APIs) are reviewed. Solubility, dissolution, and permeability data for zidovudine, along with its dosing schedule, therapeutic index and pharmacokinetic properties, and reports related to BE/bioavailability were all taken into consideration. Data for solubility and permeability suggest that zidovudine belongs to Class I according to the Biopharmaceutics Classification System. Also, zidovudine is not a narrow therapeutic index drug. Although five out of 13 formulations tested in vivo (mostly of unreported composition) failed to show BE, it appears that in vitro studies performed according to biowaiver methods could predict in vivo behavior. Nevertheless, it is highly recommended that if a biowaiver is to be applied, excipient choices be limited to those found in IR drug products approved in International Conference on Harmonisation (ICH) or associated countries in the same dosage form (Table 2 of this monograph), in their usual amounts. These conclusions apply to products containing zidovudine as the only API and also to fixed combination products containing zidovudine with respect to the zidovudine component of the formulation.

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