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  • 1. Adler, Camille
    et al.
    Teleki, Alexandra
    Kuentz, Martin
    Multifractal Characterization of Pharmaceutical Hot-Melt Extrudates.2017In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 34, no 2, p. 321-332Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Multifractal geometry has become a powerful tool to describe complex structures in many fields. Our first aim was to combine imaging and multifractal analysis to better understand the microstructure of pharmaceutical extrudates. A second objective was to study erosion/dispersion behavior of the formulations because it would condition release of any drug.

    METHODS: Different formulations containing a lipid, a polymer and different silica based inorganic carriers were produced by hot-melt extrusion at various screw speeds. Multifractal analysis was based on scanning electron microscopy/energy dispersive X-Ray spectroscopy images. This microstructural analysis was complemented with dynamic optical imaging of formulation erosion/dispersion behavior.

    RESULTS: Multifractal analysis indicated that inorganic carrier type and concentration as well as the screw speed affected the microstructure of the extrudates. The aqueous erosion/dispersion study showed that only the type and concentration of inorganic carrier were important.

    CONCLUSIONS: The use of microstructural and dispersion analysis appeared to be complementary to better characterize and understand complex formulations obtained by hot-melt extrusion.

  • 2.
    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.
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Controlled Suspensions Enable Rapid Determinations of Intrinsic Dissolution Rate and Apparent Solubility of Poorly Water-Soluble Compounds2017In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 34, no 9, p. 1805-1816Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 3. Benet, Leslie Z.
    et al.
    Amidon, Gordon L.
    Barends, Dirk M.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Polli, James E.
    Shah, Vinod P.
    Stavchansky, Salomon A.
    Yu, Lawrence X.
    The use of BDDCS in classifying the permeability of marketed drugs2008In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 25, no 3, p. 483-488Article in journal (Refereed)
    Abstract [en]

    We recommend that regulatory agencies add the extent of drug metabolism (i.e., >or=90% metabolized) as an alternate method in defining Class 1 marketed drugs suitable for a waiver of in vivo studies of bioequivalence. That is, >or=90% metabolized is an additional methodology that may be substituted for >or=90% absorbed. We propose that the following criteria be used to define>or=90% metabolized for marketed drugs: Following a single oral dose to humans, administered at the highest dose strength, mass balance of the Phase 1 oxidative and Phase 2 conjugative drug metabolites in the urine and feces, measured either as unlabeled, radioactive labeled or nonradioactive labeled substances, account for >or=90% of the drug dosed. This is the strictest definition for a waiver based on metabolism. For an orally administered drug to be >or=90% metabolized by Phase 1 oxidative and Phase 2 conjugative processes, it is obvious that the drug must be absorbed. This proposal, which strictly conforms to the present>or=90% criteria, is a suggested modification to facilitate a number of marketed drugs being appropriately assigned to Class 1.

  • 4.
    Bergstrand, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Söderlind, Erik
    AstraZeneca R&D, Mölndal, Sweden.
    Eriksson, Ulf G
    AstraZeneca R&D, Mölndal, Sweden.
    Weitschies, Werner
    Institute of Pharmacy, University of Greifswald, Greifswald, Germany.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A semi-mechanistic modeling strategy for characterization of regional absorption properties and prospective prediction of plasma concentrations following administration of new modified release formulations2012In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 29, no 2, p. 574-584Article in journal (Refereed)
    Abstract [en]

    PURPOSE

    To outline and test a new modeling approach for prospective predictions of absorption from newly developed modified release formulations based on in vivo studies of gastro intestinal (GI) transit, drug release and regional absorption for the investigational drug AZD0837.

    METHODS

    This work was a natural extension to the companion article "A semi-mechanistic model to link in vitro and in vivo drug release for modified release formulations". The drug release model governed the amount of substance released in distinct GI regions over time. GI distribution of released drug substance, region specific rate and extent of absorption and the influence of food intake were estimated. The model was informed by magnetic marker monitoring data and data from an intubation study with local administration in colon.

    RESULTS

    Distinctly different absorption properties were characterized for different GI regions. Bioavailability over the gut-wall was estimated to be high in duodenum (70%) compared to the small intestine (25%). Colon was primarily characterized by a very slow rate of absorption.

    CONCLUSIONS

    The established model was largely successful in predicting plasma concentration following administration of three newly developed formulations for which no clinical data had been applied during model building.

  • 5.
    Bergstrand, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Söderlind, Erik
    AstraZeneca R&D, Mölndal, Sweden.
    Eriksson, Ulf G
    AstraZeneca R&D, Mölndal, Sweden.
    Weitschies, Werner
    University of Greifswald, Greifswald, Germany.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A Semi-mechanistic Modeling Strategy to Link In Vitro and In Vivo Drug Release for Modified Release Formulations2012In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 29, no 3, p. 695-706Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    To develop a semi-mechanistic model linking in vitro to in vivo drug release.

    METHODS:

    A nonlinear mixed-effects model describing the in vitro drug release for 6 hydrophilic matrix based modified release formulations across different experimental conditions (pH, rotation speed and ionic strength) was developed. It was applied to in vivo observations of drug release and tablet gastro intestinal (GI) position assessed with magnetic marker monitoring (MMM). By combining the MMM observations with literature information on pH and ionic strength along the GI tract, the mechanical stress in different parts of the GI tract could be estimated in units equivalent to rotation speed in the in vitro USP 2 apparatus.

    RESULTS:

    The mechanical stress in the upper and lower stomach was estimated to 94 and 134 rpm, respectively. For the small intestine and colon the estimates of mechanical stress was 93 and 38 rpm. Predictions of in vivo drug release including between subject/tablet variability was made for other newly developed formulations based on the drug release model and a model describing tablet GI transit.

    CONCLUSION:

    The paper outlines a modeling approach for predicting in vivo behavior from standard in vitro experiments and support formulation development and quality control.

  • 6.
    Bergstrom, Christel A. S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Charman, Susan A.
    Nicolazzo, Joseph A.
    Computational Prediction of CNS Drug Exposure Based on a Novel In Vivo Dataset2012In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 29, no 11, p. 3131-3142Article in journal (Refereed)
    Abstract [en]

    To develop a computational model for predicting CNS drug exposure using a novel in vivo dataset. The brain-to-plasma (B:P) ratio of 43 diverse compounds was assessed following intravenous administration to Swiss Outbred mice. B:P ratios were subjected to PLS modeling using calculated molecular descriptors. The obtained results were transferred to a qualitative setting in which compounds predicted to have a B:P ratio > 0.3 were sorted as high CNS exposure compounds and those below this value were sorted as low CNS exposure compounds. The model was challenged with an external test set consisting of 251 compounds for which semi-quantitative values of CNS exposure were available in the literature. The dataset ranged more than 1700-fold in B:P ratio, with 16 and 27 compounds being sorted as low and high CNS exposure drugs, respectively. The model was a one principal component model based on five descriptors reflecting molecular shape, electronegativity, polarisability and charge transfer, and allowed 74% of the compounds in the training set and 76% of the test set to be predicted correctly. A qualitative computational model has been developed which accurately classifies compounds as being high or low CNS exposure drugs based on rapidly calculated molecular descriptors.

  • 7.
    Bramer, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Paulsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Edwards, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Physical Chemistry.
    Edsman, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Catanionic drug-surfactant mixtures: Phase behavior and sustained release from gels2003In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 20, no 10, p. 1661-1667Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To study mixtures of SDS and the drugs diphenhydramine, tetracaine, and amitriptyline to compile phase diagrams and to investigate the use of interesting phases for sustained release from gels. METHODS: Phase diagrams were composed by studying large numbers of different compositions of negatively charged SDS and positively charged drug compounds visually, rheologically, and by cryotransmission electron microscopy. Drug release from Carbopol 940 and agar gels containing interesting phases, e.g., vesicle and branched micelle phases, was measured in vitro by the USP paddle method. RESULTS: Vesicles and elongated and branched micelles were formed on the SDS-rich side in all three systems examined. The tetracaine system differed from the other two in that it showed a vesicle area in the drug-rich side. Release of diphenhydramine from Carbopol 940 gels was slowed by at least a factor of 10 when in the form of vesicles or branched micelles. The same delay was found for both drug-rich and SDS-rich tetracaine vesicles. CONCLUSIONS: Mixtures of SDS and positively charged drugs form the same interesting phases as traditional catanionic mixtures. This may prove useful in obtaining functional controlled-release systems when using gels as drug carriers.

  • 8.
    Brussee, Janneke M.
    et al.
    Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands.
    Yu, Huixin
    Novartis, Basel, Switzerland;Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands.
    Krekels, Elke H. J.
    Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands.
    Palic, Semra
    Netherlands Canc Inst NKI, Amsterdam, Netherlands;Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands.
    Brill, Margreke J.E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Barrett, Jeffrey S.
    Sanofi, Translat Informat, Bridgewater, NJ USA;Childrens Hosp Philadelphia, Dept Pediat, Div Clin Pharmacol & Therapeut, Philadelphia, PA 19104 USA.
    Rostami-Hodjegan, Amin
    Univ Manchester, Ctr Appl Pharmacokinet Res, Manchester, Lancs, England;Simcyp Ltd, Sheffield, S Yorkshire, England.
    de Wildt, Saskia N.
    Erasmus MC Sophia Childrens Hosp, Dept Pediat Surg, Rotterdam, Netherlands;Radboud Univ Nijmegen, Dept Pharmacol & Toxicol, Med Ctr, Nijmegen, Netherlands;Erasmus MC Sophia Childrens Hosp, Intens Care, Rotterdam, Netherlands.
    Knibbe, Catherijne A. J.
    St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands;Leiden Univ, LACDR, Div Syst Biomed & Pharmacol, Leiden, Netherlands.
    Characterization of Intestinal and Hepatic CYP3A-Mediated Metabolism of Midazolam in Children Using a Physiological Population Pharmacokinetic Modelling Approach2018In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 35, no 9, article id 182Article in journal (Refereed)
    Abstract [en]

    Purpose Changes in drug absorption and first-pass metabolism have been reported throughout the pediatric age range. Our aim is to characterize both intestinal and hepatic CYP3A-mediated metabolism of midazolam in children in order to predict first-pass and systemic metabolism of CYP3A substrates. Methods Pharmacokinetic (PK) data of midazolam and 1-OH-midazolam from 264 post-operative children 1-18 years of age after oral administration were analyzed using a physiological population PK. modelling approach. In the model, consisting of physiological compartments representing the gastro-intestinal tract and liver,intrinsic intestinal and hepatic clearances were estimated to derive values for bioavailability and plasma clearance. Results The whole-organ intrinsic clearance in the gut wall and liver were found to increase with body weight, with a 105 (95% confidence interval (CI): 5-405) times lower intrinsic gut wall clearance than the intrinsic hepatic dearance (i.e. 5.08 L/h (relative standard error (RSE) 10%) versus 527 L/h (RSE 7%) for a 16 kg individual, respectively). When expressed per gram of organ, intrinsic clearance increases with increasing body weight in the gut wall, but decreases in the liver, indicating that CYP3A-mediated intrinsic clearance and local bioavailability in the gut wall and liver do not change with age in parallel. The resulting total bioavailability was found to be age-independent with a median of 20.8% in children (95%CI: 3.8-50.0%). Conclusion In conclusion, the intrinsic CYP3A-mediated gut wall clearance is substantially lower than the intrinsic hepatic CYP3A-mediated clearance in children from 1 to 18 years of age, and contributes less to the overall first-pass metabolism compared to adults.

  • 9.
    Buatois, Simon
    et al.
    F Hoffmann La Roche Ltd, Roche Pharma Res & Early Dev, Clin Pharmacol Roche Innovat Ctr Basel, Grenzacherstr 124, CH-4070 Basel, Switzerland.;Univ Paris Diderot, IAME, UMR 1137, INSERM,Sorbonne Paris Cite, Paris, France.;Roche SAS, Inst Roche, 30,Cours Ile Seguin, F-92650 Boulogne, France..
    Retout, Sylvie
    F Hoffmann La Roche Ltd, Roche Pharma Res & Early Dev, Clin Pharmacol Roche Innovat Ctr Basel, Grenzacherstr 124, CH-4070 Basel, Switzerland.;Roche SAS, Inst Roche, 30,Cours Ile Seguin, F-92650 Boulogne, France..
    Frey, Nicolas
    F Hoffmann La Roche Ltd, Roche Pharma Res & Early Dev, Clin Pharmacol Roche Innovat Ctr Basel, Grenzacherstr 124, CH-4070 Basel, Switzerland..
    Ueckert, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Item Response Theory as an Efficient Tool to Describe a Heterogeneous Clinical Rating Scale in De Novo Idiopathic Parkinson's Disease Patients2017In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 34, no 10, p. 2109-2118Article in journal (Refereed)
    Abstract [en]

    This manuscript aims to precisely describe the natural disease progression of Parkinson's disease (PD) patients and evaluate approaches to increase the drug effect detection power. An item response theory (IRT) longitudinal model was built to describe the natural disease progression of 423 de novo PD patients followed during 48 months while taking into account the heterogeneous nature of the MDS-UPDRS. Clinical trial simulations were then used to compare drug effect detection power from IRT and sum of item scores based analysis under different analysis endpoints and drug effects. The IRT longitudinal model accurately describes the evolution of patients with and without PD medications while estimating different progression rates for the subscales. When comparing analysis methods, the IRT-based one consistently provided the highest power. IRT is a powerful tool which enables to capture the heterogeneous nature of the MDS-UPDRS.

  • 10. Cao, Xianhua
    et al.
    Gibbs, Seth T.
    Fang, Lanyan
    Miller, Heather A.
    Landowski, Christopher P.
    Shin, Ho-Chul
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Zhong, Yanqiang
    Amidon, Gordon L.
    Yu, Lawrence X.
    Sun, Duxin
    Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model2006In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 23, no 8, p. 1675-1686Article in journal (Refereed)
    Abstract [en]

    Purpose. To study the correlation of intestinal absorption for drugs with various absorption routes between human and rat, and to explore the underlying molecular mechanisms for the similarity in drug intestinal absorption and the differences in oral bioavailability between human and rat.

    Materials and Methods. The intestinal permeabilities of 14 drugs and three drug-like compounds with different absorption mechanisms in rat and human jejunum were determined by in situ intestinal perfusion. A total of 48 drugs were selected for oral bioavailability comparison. Expression profiles of transporters and metabolizing enzymes in both rat and human intestines (duodenum and colon) were measured using GeneChip analysis.

    Results. No correlation (r(2) = 0.29) was found in oral drug bioavailability between rat and human, while a correlation (r(2) = 0.8) was observed for drug intestinal permeability with both carrier-mediated absorption and passive diffusion mechanisms between human and rat small intestine. Moderate correlation (with r(2) > 0.56) was also found for the expression levels of transporters in the duodenum of human and rat, which provides the molecular mechanisms for the similarity and correlation of drug absorption between two species. In contrast, no correlation was found for the expressions of metabolizing enzymes between rat and human intestine, which indicates the difference in drug metabolism and oral bioavailability in two species. Detailed analysis indicates that many transporters (such as PepT1, SGLT-1, GLUT5, MRP2, NT2, and high affinity glutamate transporter) share similar expression levels in both human and rat with regional dependent expression patterns, which have high expression in the small intestine and low expression in the colon. However, discrepancy was also observed for several other transporters (such as MDR1, MRP3, GLUT1, and GLUT3) in both the duodenum and colon of human and rat. In addition, the expressions of metabolizing enzymes (CYP3A4/CYP3A9 and UDPG) showed 12 to 193-fold difference between human and rat intestine with distinct regional dependent expression patterns.

    Conclusions. The data indicate that rat and human show similar drug intestinal absorption profiles and similar transporter expression patterns in the small intestine, while the two species exhibit distinct expression levels and patterns for metabolizing enzymes in the intestine. Therefore, a rat model can be used to predict oral drug absorption in the small intestine of human, but not to predict drug metabolism or oral bioavailability in human.

  • 11.
    Carlert, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Pålsson, Anna
    Hanisch, Gunilla
    von Corswant, Christian
    Nilsson, Catarina
    Lindfors, Lennart
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Predicting intestinal precipitation: a case example for a basic BCS class II drug2010In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 27, no 10, p. 2119-2130Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To investigate the prediction accuracy of in vitro and in vitro/in silico methods for in vivo intestinal precipitation of basic BCS class II drugs in humans. METHODS: Precipitation rate of a model drug substance, AZD0865 (pKa = 6.1; log K(D) = 4.2), was investigated in vitro using simulated intestinal media, and calculations of the crystallization rates were made with a theoretical model. Human intestinal precipitation was estimated by analysis of pharmacokinetic data from clinical studies at different doses. RESULTS: All in vitro models predicted rapid drug precipitation, where the intestinal concentration of dissolved AZD0865 at the highest dose tested was expected to decrease to half after less than 20 min. However, there was no indication of precipitation in vivo in humans as there was a dose proportional increase in drug plasma exposure. The theoretical model predicted no significant precipitation within the range of expected in vivo intestinal concentrations. CONCLUSIONS: This study indicated that simple in vitro methods of in vivo precipitation of orally administered bases overpredict the intestinal crystalline precipitation in vivo in humans. Hydrodynamic conditions were identified as one important factor that needs to be better addressed in future in vivo predictive methods.

  • 12.
    Chapman, Colin D
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Frey, William H
    Craft, Suzanne
    Danielyan, Lusine
    Hallschmid, Manfred
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Intranasal Treatment of Central Nervous System Dysfunction in Humans2013In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 30, no 10, p. 2475-2484Article, review/survey (Refereed)
    Abstract [en]

    One of the most challenging problems facing modern medicine is how to deliver a given drug to a specific target at the exclusion of other regions. For example, a variety of compounds have beneficial effects within the central nervous system (CNS), but unwanted side effects in the periphery. For such compounds, traditional oral or intravenous drug delivery fails to provide benefit without cost. However, intranasal delivery is emerging as a noninvasive option for delivering drugs to the CNS with minimal peripheral exposure. Additionally, this method facilitates the delivery of large and/or charged therapeutics, which fail to effectively cross the blood-brain barrier (BBB). Thus, for a variety of growth factors, hormones, neuropeptides and therapeutics including insulin, oxytocin, orexin, and even stem cells, intranasal delivery is emerging as an efficient method of administration, and represents a promising therapeutic strategy for the treatment of diseases with CNS involvement, such as obesity, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, autism spectrum disorders, seizures, drug addiction, eating disorders, and stroke.

  • 13. Chaurasia, Chandra S.
    et al.
    Müller, Markus
    Bashaw, Edward D.
    Benfeldt, Eva
    Bolinder, Jan
    Bullock, Ross
    Bungay, Peter M.
    DeLange, Elizabeth C. M.
    Derendorf, Hartmut
    Elmquist, William F.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Joukhadar, Christian
    Kellogg, Dean L.
    Lunte, Craig E.
    Nordström, Carl Henrik
    Rollema, Hans
    Sawchuk, Ronald J.
    Cheung, Belinda W. Y.
    Shah, Vinod P.
    Stahle, Lars
    Ungerstedt, Urban
    Welty, Devin F.
    Yeo, Helen
    AAPS-FDA workshop white paper: microdialysis principles, application and regulatory perspectives2007In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 24, no 5, p. 1014-1025Article in journal (Refereed)
    Abstract [en]

    Many decisions in drug development and medical practice are based on measuring blood concentrations of endogenous and exogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Also, most drugs with few notable exceptions exert their effects not within the bloodstream, but in defined target tissues into which drugs have to distribute from the central compartment. Assessing tissue drug chemistry has, thus, for long been viewed as a more rational way to provide clinically meaningful data rather than gaining information from blood samples. More specifically, it is often the extracellular (interstitial) tissue space that is most closely related to the site of action (biophase) of the drug. Currently microdialysis (microD) is the only tool available that explicitly provides data on the extracellular space. Although microD as a preclinical and clinical tool has been available for two decades, there is still uncertainty about the use of microD in drug research and development, both from a methodological and a regulatory point of view. In an attempt to reduce this uncertainty and to provide an overview of the principles and applications of microD in preclinical and clinical settings, an AAPS-FDA workshop took place in November 2005 in Nashville, TN, USA. Stakeholders from academia, industry and regulatory agencies presented their views on microD as a tool in drug research and development.

  • 14. Chen, Mei-Ling
    et al.
    Amidon, Gordon L
    Benet, Leslie Z
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Yu, Lawrence X
    The BCS, BDDCS, and regulatory guidances2011In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 28, no 7, p. 1774-1778Article in journal (Refereed)
  • 15.
    Dahlin, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergman, Ulrika
    Jansson, Björn
    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.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Transfer of dopamine in the olfactory pathway following nasal administration in mice2000In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 17, no 6, p. 737-742Article in journal (Refereed)
    Abstract [en]

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

  • 16. De Cock, Roosmarijn F W
    et al.
    Allegaert, Karel
    Sherwin, Catherine M T
    Nielsen, Elisabet I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    de Hoog, Matthijs
    van den Anker, Johannes N
    Danhof, Meindert
    Knibbe, Catherijne A J
    A Neonatal Amikacin Covariate Model Can Be Used to Predict Ontogeny of Other Drugs Eliminated Through Glomerular Filtration in Neonates2014In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 31, no 3, p. 754-767Article in journal (Refereed)
    Abstract [en]

    PURPOSE

    Recently, a covariate model characterizing developmental changes in clearance of amikacin in neonates has been developed using birth bodyweight and postnatal age. The aim of this study was to evaluate whether this covariate model can be used to predict maturation in clearance of other renally excreted drugs.

    METHODS

    Five different neonatal datasets were available on netilmicin, vancomycin, tobramycin and gentamicin. The extensively validated covariate model for amikacin clearance was used to predict clearance of these drugs. In addition, independent reference models were developed based on a systematic covariate analysis.

    RESULTS

    The descriptive and predictive properties of the models developed using the amikacin covariate model were good, and fairly similar to the independent reference models (goodness-of-fit plots, NPDE). Moreover, similar clearance values were obtained for both approaches. Finally, the same covariates as in the covariate model of amikacin, i.e. birth bodyweight and postnatal age, were identified on clearance in the independent reference models.

    CONCLUSIONS

    This study shows that pediatric covariate models may contain physiological information since information derived from one drug can be used to describe other drugs. This semi-physiological approach may be used to optimize sparse data analysis and to derive individualized dosing algorithms for drugs in children.

  • 17. Diakidou, Amalia
    et al.
    Vertzoni, Maria
    Goumas, Konstantinos
    Söderlind, Erik
    Abrahamsson, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Dressman, Jennifer
    Reppas, Christos
    Characterization of the contents of ascending colon to which drugs are exposed after oral administration to healthy adults2009In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 26, no 9, p. 2141-2151Article in journal (Refereed)
    Abstract [en]

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

  • 18.
    Ericsson, Therese
    et al.
    AstraZeneca R&D, Dept Drug Metab & Pharmacokinet DMPK Resp Inflamm, Gothenburg, Sweden..
    Fridén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. AstraZeneca R&D, Dept Drug Metab & Pharmacokinet DMPK Resp Inflamm, Gothenburg, Sweden.;AstraZeneca AB, Pepparedsleden 1, S-43150 Molndal, Sweden..
    Kärrman-Mårdh, Carina
    RIA IMED AstraZeneca R&D, Dept Translat Biol, Gothenburg, Sweden..
    Dainty, Ian
    RIA IMED AstraZeneca R&D, Biotech Unit, Gothenburg, Sweden..
    Grime, Ken
    AstraZeneca R&D, Dept Drug Metab & Pharmacokinet DMPK Resp Inflamm, Gothenburg, Sweden..
    Benchmarking of Human Dose Prediction for Inhaled Medicines from Preclinical In Vivo Data2017In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 34, no 12, p. 2557-2567Article in journal (Refereed)
    Abstract [en]

    A scientifically robust prediction of human dose is important in determining whether to progress a candidate drug into clinical development. A particular challenge for inhaled medicines is that unbound drug concentrations at the pharmacological target site cannot be easily measured or predicted. In the absence of such data, alternative empirical methods can be useful. This work is a post hoc analysis based on preclinical in vivo pharmacokinetic/pharmacodynamic (PK/PD) data with the aim to evaluate such approaches and provide guidance on clinically effective dose prediction for inhaled medicines. Five empirically based methodologies were applied on a diverse set of marketed inhaled therapeutics (inhaled corticosteroids and bronchodilators). The approaches include scaling of dose based on body weight or body surface area and variants of PK/PD approaches aiming to predict the therapeutic dose based on having efficacious concentrations of drug in the lung over the dosing interval. The most robust predictions of dose were made by body weight adjustment (90% within 3-fold) and by a specific PK/PD approach aiming for an average predicted 75% effect level during the dosing interval (80% within 3-fold). Scaling of dose based on body surface area consistently under predicted the therapeutic dose. Preclinical in vivo data and empirical scaling to man can be used as a baseline method for clinical dose predictions of inhaled medicines. The development of more sophisticated translational models utilizing free drug concentration and target engagement data is a desirable build.

  • 19.
    Ernest, C. Steven, II
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hooker, Andrew C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Methodological Comparison of In Vitro Binding Parameter Estimation: Sequential vs. Simultaneous Non-linear Regression2010In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 27, no 5, p. 866-877Article in journal (Refereed)
    Abstract [en]

    Analysis of simulated data was compared using sequential (NLR) and simultaneous non-linear regression (SNLR) to evaluate precision and accuracy of ligand binding parameter estimation. Commonly encountered experimental error, specifically residual error of binding measurements (RE), experiment-to-experiment variability (BEV) and non-specific binding (B-NS), were examined for impact of parameter estimation using both methods. Data from equilibrium, dissociation, association and non-specific binding experiments were fit simultaneously (SNLR) using NONMEM VI compared to the common practice of analyzing data from each experiment separately and assigning these as exact values (NLR) for estimation of the subsequent parameters. The greatest contributing factor to bias and variability in parameter estimation was RE of the measured concentrations of ligand bound; however, SNLR provided more accurate and less bias estimates. Subtraction of B-NS from total ligand binding data provided poor estimation of specific ligand binding parameters using both NLR and SNLR. Additional methods examined demonstrated that the use of SNLR provided better estimation of specific binding parameters, whereas there was considerable bias using NLR. NLR cannot account for BEV, whereas SNLR can provide approximate estimates of BEV. SNLR provided superior resolution of parameter estimation in both precision and accuracy compared to NLR.

  • 20.
    Espefält Westin, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Boström, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gråsjö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Björk, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Direct nose-to-brain transfer of morphine after nasal administration to rats2006In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 23, no 3, p. 565-572Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The aim of this study was to quantify the olfactory transfer of morphine to the brain hemispheres by comparing brain tissue and plasma morphine levels after nasal administration with those after intravenous administration. METHODS: Morphine (1.0 mg/kg body weight) was administered via the right nostril or intravenously as a 15-min constant-rate infusion to male rats. The content of morphine and its metabolite morphine-3-glucuronide in samples of the olfactory bulbs, brain hemispheres, and plasma was assessed using high-performance liquid chromatography, and the areas under the concentration-time curves (AUC) were calculated. RESULTS: At both 5 and 15 min after administration, brain hemisphere morphine concentrations after nasal administration were similar to those after i.v. administration of the same dose, despite lower plasma concentrations after nasal administration. The brain hemispheres/plasma morphine AUC ratios for the 0-5 min period were thus approximately 3 and 0.1 after nasal and i.v. administration, respectively, demonstrating a statistically significant early distribution advantage of morphine to the brain hemispheres via the nasal route. CONCLUSION: Morphine is transferred via olfactory pathways to the brain hemispheres, and drug transfer via this route significantly contributes to the early high brain concentrations after nasal administration to rats.

  • 21.
    Fagerberg, Jonas H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Karlsson, Eva
    Ulander, Johan
    Hanisch, Gunilla
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Computational Prediction of Drug Solubility in Fasted Simulated and Aspirated Human Intestinal Fluid2015In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 32, no 2, p. 578-589Article in journal (Refereed)
    Abstract [en]

    Purpose

    To develop predictive models of apparent solubility (Sapp) of lipophilic drugs in fasted state simulated intestinal fluid (FaSSIF) and aspirated human intestinal fluid (HIF).

    Methods

    Measured Sapp values in FaSSIF, HIF and phosphate buffer pH 6.5 (PhBpH6.5) for 86 lipophilic drugs were compiled and divided into training (Tr) and test (Te) sets. Projection to latent structure (PLS) models were developed through variable selection of calculated molecular descriptors. Experimentally determined properties were included to investigate their contribution to the predictions.

    Results

    Modest relationships between Sapp in PhBpH6.5 and FaSSIF (R2 = 0.61) or HIF (R2 = 0.62) were found. As expected, there was a stronger correlation obtained between FaSSIF and HIF (R2 = 0.78). Computational models were developed using calculated descriptors alone (FaSSIF, R2 = 0.69 and RMSEte of 0.77; HIF, R2 = 0.84 and RMSEte of 0.81). Accuracy improved when solubility in PhBpH6.5 was added as a descriptor (FaSSIF, R2 = 0.76 and RMSETe of 0.65; HIF, R2 = 0.86 and RMSETe of 0.69), whereas no improvement was seen when melting point (Tm) or logDpH 6.5 were included in the models.

    Conclusion

    Computational models were developed, that reliably predicted Sapp of lipophilic compounds in intestinal fluid, from molecular structures alone. If experimentally determined pH-dependent solubility values were available, this further improved the accuracy of the predictions.

  • 22.
    Fichtner, Frauke
    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.
    Welch, Ken
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Gaisford, Simon
    Alderborn, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Effect of surface energy on powder compactibility2008In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 25, no 12, p. 2750-9Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The influence of surface energy on the compactibility of lactose particles has been investigated. MATERIALS AND METHODS: Three powders were prepared by spray drying lactose solutions without or with low proportions of the surfactant polysorbate 80. Various powder and tablet characterisation procedures were applied. The surface energy of the powders was characterized by Inverse Gas Chromatography and the compressibility of the powders was described by the relationship between tablet porosity and compression pressure. The compactibility of the powders was analyzed by studying the evolution of tablet tensile strength with increasing compaction pressure and porosity. RESULTS: All powders were amorphous and similar in particle size, shape, and surface area. The compressibility of the powders and the microstructure of the formed tablets were equal. However, the compactibility and dispersive surface energy was dependent of the composition of the powders. CONCLUSION: The decrease in tablet strength correlated to the decrease in powder surface energy at constant tablet porosities. This supports the idea that tablet strength is controlled by formation of intermolecular forces over the areas of contact between the particles and that the strength of these bonding forces is controlled by surface energy which, in turn, can be altered by the presence of surfactants.

  • 23.
    Fransén, Nelly
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bredenberg, Susanne
    Björk, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Clinical study shows improved absorption of desmopressin with novel formulation2009In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 26, no 7, p. 1618-1625Article in journal (Refereed)
    Abstract [en]

    To create improved pharmaceutical formulations for nasal and sublingual   administration of desmopressin and investigate their pharmacokinetic   profiles in comparison with a commercial nasal liquid spray and finally  to evaluate the volunteers' opinions on the different dosage forms. Both formulations were based on the characteristics of interactive   mixtures. The nasal powder spray was produced by a rotary evaporator   technique with sodium starch glycolate as carrier material and the  sublingual tablet by direct compression after dry mixing with mannitol   as carrier. The clinical study was an open-label, randomised cross-over   pharmacokinetic study in healthy volunteers.   The nasal powder formulation gave a threefold increase in the   absorption, unaltered time to maximum plasma concentration and a   tendency to lower variability in the amount absorbed compared with the   liquid spray. The powder was reported to be more irritating than the   liquid but was still well accepted by the volunteers. The tablet did   not improve the uptake of desmopressin, likely because of a poor disintegration sublingually.   The nasal powder formulation is a promising new dosage form for the delivery of desmopressin and other compounds. The sublingual tablet has a beneficial means of production and may be further developed by decreasing its disintegration time.

  • 24.
    Gottipati, Gopichand
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berges, Alienor C.
    GlaxoSmithKline, London, England;AstraZeneca, IMED Biotech Unit, Early Clin Dev, Quantitat Clin Pharmacol, Cambridge, England.
    Yang, Shuying
    GlaxoSmithKline, London, England.
    Chen, Chao
    GlaxoSmithKline, London, England.
    Karlsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Plan, Elodie L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Item Response Model Adaptation for Analyzing Data from Different Versions of Parkinson's Disease Rating Scales2019In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 36, no 9, article id 135Article in journal (Refereed)
    Abstract [en]

    Purpose: The aim of this work was to allow combination of information from recent and historical trials in Parkinson's Disease (PD) by developing bridging methodology between two versions of the clinical endpoint.

    Methods: A previously developed Item Response Model (IRM), that described longitudinal changes in Movement Disorder Society (MDS) sponsored revision of Unified Parkinson's Disease Rating Scale (UPDRS) [MDS-UPDRS] data from the De Novo PD cohort in Parkinson's Progression Markers Initiative, was first adapted to describe baseline UPDRS data from two clinical trials, one in subjects with early PD and another in subjects with advanced PD. Assuming similar IRM structure, items of the UPDRS version were mapped to those in the MDS-UPDRS version. Subsequently, the longitudinal changes in the placebo arm of the advanced PD study were characterized.

    Results: The parameters reflecting differences in the shared items between endpoints were successfully estimated, and the model diagnostics indicated that mapping was better for early PD subjects (closer to De Novo cohort) than for advanced PD subjects. Disease progression for placebo in advanced PD patients was relatively shallow.

    Conclusion: An IRM able to handle two variants of clinical PD endpoints was developed; it can improve the utilization of data from diverse sources and diverse disease populations.

  • 25.
    Guiastrennec, Benjamin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Soderlind, Erik
    AstraZeneca, Pharmaceut Technol & Dev, Gothenburg, Sweden.;Janssen Pharmaceut NV, Turnhoutseweg 30, B-2340 Beerse, Belgium..
    Richardson, Sara
    AstraZeneca, Adv Drug Delivery Pharmaceut Sci Innovat Med & Ea, Gothenburg, Sweden..
    Peric, Alexandra
    AstraZeneca, Drug Metab & Pharmacokinet, Cardiovasc & Metab Dis, Innovat Med & Early Dev, Gothenburg, Sweden..
    Bergstrand, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    In Vitro and In Vivo Modeling of Hydroxypropyl Methylcellulose (HPMC) Matrix Tablet Erosion Under Fasting and Postprandial Status2017In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 34, no 4, p. 847-859Article in journal (Refereed)
    Abstract [en]

    To develop a model linking in vitro and in vivo erosion of extended release tablets under fasting and postprandial status. A nonlinear mixed-effects model was developed from the in vitro erosion profiles of four hydroxypropyl methylcellulose (HPMC) matrix tablets studied under a range of experimental conditions. The model was used to predict in vivo erosion of the HPMC matrix tablets in different locations of the gastrointestinal tract, determined by magnetic marker monitoring. In each gastrointestinal segment the pH was set to physiological values and mechanical stress was estimated in USP2 apparatus rotation speed equivalent. Erosion was best described by a Michaelis-Menten type model. The maximal HPMC release rate (V-MAX) was affected by pH, mechanical stress, HPMC and calcium hydrogen phosphate content. The amount of HPMC left at which the release rate is half of V-MAX depended on pH and calcium hydrogen phosphate. Mechanical stress was estimated for stomach (39.5 rpm), proximal (93.3 rpm) and distal (31.1 rpm) small intestine and colon (9.99 rpm). The in silico model accurately predicted the erosion profiles of HPMC matrix tablets under fasting and postprandial status and can be used to facilitate future development of extended release tablets.

  • 26.
    Hammarlund-Udenaes, Margareta
    et al.
    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.
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gupta, Anubha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    On the rate and extent of drug delivery to the brain2008In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 25, no 8, p. 1737-1750Article, review/survey (Refereed)
    Abstract [en]

    To define and differentiate relevant aspects of blood-brain barrier transport and distribution in order to aid research methodology in brain drug delivery. Pharmacokinetic parameters relative to the rate and extent of brain drug delivery are described and illustrated with relevant data, with special emphasis on the unbound, pharmacologically active drug molecule. Drug delivery to the brain can be comprehensively described using three parameters: Kp,uu (concentration ratio of unbound drug in brain to blood), CLin (permeability clearance into the brain), and Vu,brain (intra-brain distribution). The permeability of the blood-brain barrier is less relevant to drug action within the CNS than the extent of drug delivery, as most drugs are administered on a continuous (repeated) basis. Kp,uu can differ between CNS-active drugs by a factor of up to 150-fold. This range is much smaller than that for log BB ratios (Kp), which can differ by up to at least 2,000-fold, or for BBB permeabilities, which span an even larger range (up to at least 20,000-fold difference). Methods that measure the three parameters Kp,uu, CLin, and Vu,brain can give clinically valuable estimates of brain drug delivery in early drug discovery programmes.

  • 27.
    Hammarlund-Udenaes, Margareta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Paalzow, Lennart K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    de Lange, Elisabeth C M
    Drug equilibration across the blood-brain barrier: pharmacokinetic considerations based on the microdialysis method1997In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 14, no 2, p. 128-134Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The purpose of the study was to investigate the influence of different rates of transport into and out of the brain, including passive and active transport, on unbound brain concentrations and profile in relation to the blood concentration profile. Special emphasis is put on hydrophilic drugs. METHODS: Simulations were performed with a model including one body compartment and one brain compartment, with linear or saturable transport into and out of the brain. Comparisons were made with experimental results from microdialysis (MD) studies. RESULTS: Three features were evident when combining the MD results: 1) equilibration across the blood-brain barrier (BBB) is rapid, 2) half-life is similar in brain and blood for most drugs, and 3) unbound brain concentrations seldom reach the level of unbound blood concentrations. A low concentration ratio brain:blood is not mainly caused by a low influx, but rather by different influx and efflux clearances. Active transport out of the brain can explain the results, but also active transport into the brain under certain conditions. A small volume of distribution in brain vs. that in the rest of the body contributes to a rapid equilibration and similar half-lives. CONCLUSIONS: Assumptions of slow equilibration of hydrophilic drugs and similar unbound concentrations across the BBB at steady state are contradicted. The results are more in line with recent findings on the presence of P-glycoprotein and other transport mechanisms at the BBB. Non-passive transport across the BBB seems to be the case for almost all drugs studies with MD so far.

  • 28.
    Henin, Emilie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergstrand, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Weitschies, Werner
    Ernst Moritz Arndt Univ Greifswald, Dept Biopharmaceut & Pharmaceut Technol, D-17487 Greifswald, Germany. Univ Lyon 1, EMR Ciblage Therapeut Oncol 3738, Fac Med Lyon Sud, F-69921 Oullins, France..
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Meta-analysis of Magnetic Marker Monitoring Data to Characterize the Movement of Single Unit Dosage Forms Though the Gastrointestinal Tract Under Fed and Fasting Conditions2016In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 33, no 3, p. 751-762Article in journal (Refereed)
    Abstract [en]

    To develop a model predicting movement of non-disintegrating single unit dosage forms (or "tablet") through the gastrointestinal tract and characterizing the effect of food intake, based on Magnetic Marker Monitoring data, allowing real-time location of a magnetically labeled formulation. Five studies including 30 individuals in 94 occasions under 3 food status were considered. The mean residence time (MRT) of the tablet and the effect of food intake in proximal (PS) and distal stomach (DS), small intestine (SI), ascending (AC), transverse (TC) and descending colon (DC) were estimated using a Markov model for probabilities of movement. Under fasting conditions, tablet MRTs were 9.4 min in PS, 10.4 in DS, 246 in SI, 545 in AC, 135 in TC, and 286 in DC. A meal taken simultaneous to tablet intake prolonged tablet MRT to 99 min in PS and to 232 in DS; probability of gastric emptying increased of 89% each hour from 2.25 h after meal. The effect of a gastroileac reflex, caused by a secondary meal, accelerated the transit from terminal SI to AC. This model-based knowledge can be used as a part of mechanism-based models for drug absorption, applied for bottom-up predictions and/or top-down estimation.

  • 29.
    Hooker, Andrew C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Staatz, Christine E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Conditional weighted residuals (CWRES): a model diagnostic for the FOCE method2007In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 24, no 12, p. 2187-2197Article in journal (Refereed)
    Abstract [en]

    Purpose  Population model analyses have shifted from using the first order (FO) to the first-order with conditional estimation (FOCE) approximation to the true model. However, the weighted residuals (WRES), a common diagnostic tool used to test for model misspecification, are calculated using the FO approximation. Utilizing WRES with the FOCE method may lead to misguided model development/evaluation. We present a new diagnostic tool, the conditional weighted residuals (CWRES), which are calculated based on the FOCE approximation. Materials and Methods  CWRES are calculated as the FOCE approximated difference between an individual’s data and the model prediction of that data divided by the root of the covariance of the data given the model. Results  Using real and simulated data the CWRES distributions behave as theoretically expected under the correct model. In contrast, in certain circumstances, the WRES have distributions that greatly deviate from the expected, falsely indicating model misspecification. CWRES/WRES comparisons can also indicate if the FOCE estimation method will improve the results of an FO model fit to data. Conclusions  Utilization of CWRES could improve model development and evaluation and give a more accurate picture of if and when a model is misspecified when using the FO or FOCE methods.

  • 30.
    Ibrahim, Moustafa M. A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Helwan Univ, Dept Pharm Practice, Cairo, Egypt.
    Largajolli, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kjellsson, Maria C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Translation between two models; Application with integrated glucose homeostasis models2019In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 36, article id 86Article in journal (Refereed)
    Abstract [en]

    PurposeFor some biological systems, there exist several models with somewhat different features and perspectives. We propose an evaluation method for NLME models by analyzing real and simulated data from the model of main interest using a structurally different, but similar, NLME model. We showcase this method using the Integrated Glucose Insulin (IGI) model and the Integrated Minimal Model (IMM). Additionally, we try to map parameters carrying similar information between the two models.MethodsA bootstrap of real data and simulated datasets from both the IMM and IGI models were analyzed with the two models. Important parameters of the IMM were mapped to IGI parameters using a large IMM simulated dataset analyzed under the IGI model.ResultsComparison of the parameters estimated from real data and data simulated with the IMM and analyzed with the IGI model demonstrated differences between real and IMM-simulated data. Comparison of the parameters estimated from real data and data simulated with the IGI model and analyzed with the IMM also demonstrated differences but to a lower extent. The strongest parameter correlations were found for: insulin-dependent glucose clearance (IGI) similar to insulin sensitivity (IMM); insulin-independent glucose clearance (IGI) similar to glucose effectiveness (IMM); and insulin effect parameter (IGI) similar to insulin action (IMM).ConclusionsWe demonstrated a new approach to investigate models' ability to simulate real-life-like data, and the information captured in each model in comparison to real data, and the IMM clinically used parameters were successfully mapped to their corresponding IGI parameters.

  • 31. Jesson, Gerald
    et al.
    Brisander, Magnus
    Andersson, Per
    Demirbuker, Mustafa
    Derand, Helene
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Carbon Dioxide-Mediated Generation of Hybrid Nanoparticles for Improved Bioavailability of Protein Kinase Inhibitors2014In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 31, no 3, p. 694-705Article in journal (Refereed)
    Abstract [en]

    A versatile methodology is demonstrated for improving dissolution kinetics, gastrointestinal (GI) absorption, and bioavailability of protein kinase inhibitors (PKIs). The approach is based on nanoparticle precipitation by sub- or supercritical CO2 together with a matrix-forming polymer, incorporating surfactants either during or after nanoparticle formation. Notably, striking synergistic effects between hybrid PKI/polymer nanoparticles and surfactant added after particle formation is investigated. The hybrid nanoparticles, consisting of amorphous PKI embedded in a polymer matrix (also after 12 months), display dramatically increased release rate of nilotinib in both simulated gastric fluid and simulated intestinal fluid, particularly when surfactants are present on the hybrid nanoparticle surface. Similar results indicated flexibility of the approach regarding polymer identity, drug load, and choice of surfactant. The translation of the increased dissolution rate found in vitro into improved GI absorption and bioavalilability in vivo was demonstrated for male beagle dogs, where a 730% increase in the AUC(0-24h) was observed compared to the benchmark formulation. Finally, the generality of the formulation approach taken was demonstrated for a range of PKIs. Hybrid nanoparticles combined with surfactant represent a promising approach for improving PKI dissolution rate, providing increased GI absorption and bioavailability following oral administration.

  • 32.
    Juul, Rasmus Vestergaard
    et al.
    Univ Copenhagen, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark..
    Nyberg, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lund, Trine Meldgaard
    Univ Copenhagen, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark..
    Rasmussen, Sten
    Aalborg Univ Hosp, Orthopaed Surg Res Unit, Aalborg, Denmark.;Aalborg Univ Hosp, Dept Clin Med, Aalborg, Denmark..
    Kreilgaard, Mads
    Univ Copenhagen, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark..
    Christrup, Lona Louring
    Univ Copenhagen, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark..
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A Pharmacokinetic-Pharmacodynamic Model of Morphine Exposure and Subsequent Morphine Consumption in Postoperative Pain2016In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 33, no 5, p. 1093-1103Article in journal (Refereed)
    Abstract [en]

    To characterize the pharmacokinetic-pharmacodynamic (PK-PD) relationship between exposure of morphine and subsequent morphine consumption and to develop simulation tools for model validation. Dose, formulation and time of morphine administration was available from a published study in 63 patients receiving intravenous, oral immediate release or oral controlled release morphine on request after hip surgery. The PK-PD relationship between predicted exposure of morphine and morphine consumption was modeled using repeated time to event (RTTE) modeling in NONMEM. To validate the RTTE model, a visual predictive check method was developed with simulated morphine consumption given the exposure of preceding morphine administration. The probability of requesting morphine was found to be significantly related to the exposure of morphine as well as night/day. Oral controlled release morphine was more effective than intravenous and oral immediate release formulations at equivalent average concentrations. Maximum effect was obtained for 8 h by oral controlled release doses a parts per thousand yenaEuro parts per thousand 15 mg, where probability of requesting a new dose was reduced to 20% for a typical patient. This study demonstrates the first quantitative link between exposure of morphine and subsequent morphine consumption and introduces an efficient visual predictive check approach with simulation of adaptive dosing.

  • 33.
    Karlgren, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ahlin, Gustav
    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.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Palm, Johan
    AstraZeneca R&D, Mölndal, Sweden.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    In Vitro and In Silico Strategies to Identify OATP1B1 Inhibitors and Predict Clinical Drug-Drug Interactions2012In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 29, no 2, p. 411-426Article in journal (Other academic)
    Abstract [en]

    To establish in vitro and in silico models that predict clinical drug-drug interactions (DDIs) with the OATP1B1 (SLCO1B1) transporter. The inhibitory effect of 146 drugs and drug-like compounds on OATP1B1-mediated transport was studied in HEK293 cells. A computational model was developed to predict OATP1B1 inhibition. Concentration-dependent effects were investigated for six compounds; clinical DDIs were predicted by calculating change in exposure (i.e. R-values) in eight different ways. Sixty-five compounds were identified as OATP1B1 inhibitors at 20 mu M. The computational model predicted the test set with 80% accuracy for inhibitors and 91% for non-inhibitors. In vitro-in vivo comparisons underscored the importance of using drugs with known clinical effects as references. Thus, reference drugs, cyclosporin A, gemfibrozil, and fenofibrate, provided an inhibition interval to which three antiviral drugs, atazanavir, lopinavir, and amprenavir, could be compared and their clinical DDIs with OATP1B1 classified. Twenty-two new OATP1B1 inhibitors were identified, a predictive OATP1B1 inhibition in silico model was developed, and successful predictions of clinical DDIs were obtained with OATP1B1.

  • 34.
    Karlsson-Parra, Alex
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Immunicum AB, Gothenburg, Sweden.
    Kovacka, Juliana
    Immunicum AB, Gothenburg, Sweden.
    Heimann, Emilia
    Immunicum AB, Gothenburg, Sweden.
    Jorvid, Margareth
    Immunicum AB, Gothenburg, Sweden.
    Zeilemaker, Sijme
    Immunicum AB, Gothenburg, Sweden.
    Longhurst, Sharon
    Immunicum AB, Gothenburg, Sweden.
    Suenaert, Peter
    Immunicum AB, Gothenburg, Sweden.
    Ilixadencel - an Allogeneic Cell-Based Anticancer Immune Primer for Intratumoral Administration2018In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 35, no 8, article id UNSP 156Article, review/survey (Refereed)
    Abstract [en]

    Intratumoral administration of an immune primer is a therapeutic vaccine strategy aimed to trigger dendritic cell (DC)-mediated cross-presentation of cell-associated tumor antigens to cytotoxic CD8(+) T cells without the need for tumor antigen characterization. The prevailing view is that these cross-presenting DCs have to be directly activated by pathogen-associated molecular patterns (PAMPS), including Toll-like receptor ligands or live microbial agents like oncolytic viruses. Emerging data are however challenging this view, indicating that the cross-presenting machinery in DCs is suboptimally activated by direct PAMP recognition, and that endogenous inflammatory factors are the main drivers of DC-mediated cross-presentation within the tumor. Here we present preclinical mode of action data, CMC and regulatory data, as well as initial clinical data on ilixadencel. This cell-based drug product is an off-the-shelf immune primer, consisting of pro-inflammatory allogeneic DCs secreting high amounts of pro-inflammatory chemokines and cytokines at the time of intratumoral administration. The mechanism of action of ilixadencel is to induce recruitment and activation of endogenous immune cells, including NK cells that subsequently promotes cross-presentation of cell-associated tumor antigens by co-recruited DCs.

  • 35.
    Keemink, Janneke
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Caco-2 Cell Conditions Enabling Studies of Drug Absorptionfrom Digestible Lipid-Based Formulations2018In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 35, no 4, article id 74Article in journal (Refereed)
    Abstract [en]

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

  • 36.
    Kjellsson, Maria C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Ouellet, Daniele
    Corrigan, Brian
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Modeling sleep data for a new drug in development using Markov mixed-effects models2011In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 28, no 10, p. 2610-2627Article in journal (Refereed)
    Abstract [en]

    To characterize the time-course of sleep in insomnia patients as well as placebo and concentration-effect relationships of two hypnotic compounds, PD 0200390 and zolpidem, using an accelerated model-building strategy based on mixed-effects Markov models. Data were obtained in a phase II study with the drugs. Sleep stages were recorded during eight hours of sleep for two nights per treatment for the five treatments. First-order Markov models were developed for one transition at a time in a sequential manner; first a baseline model, followed by placebo and lastly the drug models. To accelerate the process, predefined models were selected based on a priori knowledge of sleep, including inter-subject and inter-occasion variability. Baseline sleep was described using piece-wise linear models, depending on time of night and duration of sleep stage. Placebo affected light sleep stages; drugs also affected slow-wave sleep. Administering PD 0200390 30 min earlier than standard dosing was shown through simulations to reduce latency to persistent sleep by 40%. The proposed accelerated model-building strategy resulted in a model well describing sleep patterns of insomnia patients with and without treatments.

  • 37.
    Kristoffersson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    David-Pierson, Pascale
    Parrott, Neil J
    Kuhlmann, Olaf
    Lave, Thierry
    Friberg, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nielsen, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simulation-Based Evaluation of PK/PD Indices for Meropenem Across Patient Groups and Experimental Designs2016In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 33, no 5, p. 1115-1125Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Antibiotic dose predictions based on PK/PD indices rely on that the index type and magnitude is insensitive to the pharmacokinetics (PK), the dosing regimen, and bacterial susceptibility. In this work we perform simulations to challenge these assumptions for meropenem and Pseudomonas aeruginosa.

    METHODS: A published murine dose fractionation study was replicated in silico. The sensitivity of the PK/PD index towards experimental design, drug susceptibility, uncertainty in MIC and different PK profiles was evaluated.

    RESULTS: The previous murine study data were well replicated with fT > MIC selected as the best predictor. However, for increased dosing frequencies fAUC/MIC was found to be more predictive and the magnitude of the index was sensitive to drug susceptibility. With human PK fT > MIC and fAUC/MIC had similar predictive capacities with preference for fT > MIC when short t1/2 and fAUC/MIC when long t1/2.

    CONCLUSIONS: A longitudinal PKPD model based on in vitro data successfully predicted a previous in vivo study of meropenem. The type and magnitude of the PK/PD index were sensitive to the experimental design, the MIC and the PK. Therefore, it may be preferable to perform simulations for dose selection based on an integrated PK-PKPD model rather than using a fixed PK/PD index target.

  • 38.
    Kullberg, Erika Bohl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Gedda, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Tumor-cell targeted EGF liposomes loaded with boronated acridine: Uptake and processing2003In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 20, no 2, p. 229-236Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    The aim of this work was to investigate the cellular binding and processing of polyethylene glycol-stabilized epidermal growth factor (EGF) liposomes. The liposomes were actively loaded with water-soluble boronated acridine (WSA), primarily developed for boron neutron capture therapy.

    METHODS:

    The uptake, internalization, and retention of EGF-liposome conjugates were studied in two cultured monolayer cell-lines, A-431 and U-343, with regard to the nuclide-label on the targeting agent, the carrier, and the load. The subcellular localization of WSA was studied using confocal microscopy.

    RESULTS:

    We found that the liposome complex was internalized after specific binding to the EGF receptor. After internalization in the tumor cells, WSA was distributed mainly in the cytoplasm and was shown to have long cellular retention, with 80% of the boron remaining after 48 h.

    CONCLUSIONS:

    The long retention of the compound and the cellular boron concentration reached makes these targeted liposomes interesting for further development toward boron neutron capture therapy.

  • 39. Kumar, Abhinav
    et al.
    Terakosolphan, Wachirun
    Hassoun, Mireille
    Vandera, Kalliopi-Kelli
    Novicky, Astrid
    Harvey, Richard
    Royall, Paul G
    Bicer, Elif Melis
    Eriksson, Jonny
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Edwards, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Valkenborg, Dirk
    Nelissen, Inge
    Hassall, Dave
    Mudway, Ian S
    Forbes, Ben
    A Biocompatible Synthetic Lung Fluid Based on Human Respiratory Tract Lining Fluid Composition.2017In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 34, no 12, p. 2454-2465Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To characterise a biorelevant simulated lung fluid (SLF) based on the composition of human respiratory tract lining fluid. SLF was compared to other media which have been utilized as lung fluid simulants in terms of fluid structure, biocompatibility and performance in inhalation biopharmaceutical assays.

    METHODS: The structure of SLF was investigated using cryo-transmission electron microscopy, photon correlation spectroscopy and Langmuir isotherms. Biocompatibility with A549 alveolar epithelial cells was determined by MTT assay, morphometric observations and transcriptomic analysis. Biopharmaceutical applicability was evaluated by measuring the solubility and dissolution of beclomethasone dipropionate (BDP) and fluticasone propionate (FP), in SLF.

    RESULTS: SLF exhibited a colloidal structure, possessing vesicles similar in nature to those found in lung fluid extracts. No adverse effect on A549 cells was apparent after exposure to the SLF for 24 h, although some metabolic changes were identified consistent with the change of culture medium to a more lung-like composition. The solubility and dissolution of BDP and FP in SLF were enhanced compared to Gamble's solution.

    CONCLUSION: The SLF reported herein constitutes a biorelevant synthetic simulant which is suitable to study biopharmaceutical properties of inhalation medicines such as those being proposed for an inhaled biopharmaceutics classification system.

  • 40. Larsen, Anne T
    et al.
    Åkesson, Pernilla
    Juréus, Anna
    Saaby, Lasse
    Abu-Rmaileh, Ragheb
    Abrahamsson, Bertil
    AstraZeneca, Pharmaceutical Development, Mölndal, Sweden .
    Østergaard, Jesper
    Müllertz, Anette
    Bioavailability of cinnarizine in dogs: effect of SNEDDS loading level and correlation with cinnarizine solubilization during in vitro lipolysis2013In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 30, no 12, p. 3101-3113Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To investigate the effect of increasing the loading level of the poorly soluble drug cinnarizine in a self-nanoemulsifying drug delivery system (SNEDDS) both in vitro and in vivo.

    METHODS: A fixed dose of cinnarizine was administered orally to dogs in solution in different amounts of SNEDDS vehicle. Furthermore, the SNEDDSs were characterised using the dynamic in vitro lipolysis model.

    RESULTS: Statistical differences in bioavailability were not obtained between the different amounts of SNEDDS vehicle, in spite of differences in the tendency of cinnarizine to precipitate during in vitro lipolysis of the treatments. Use of the SNEDDS concept decreased the variation in cinnarizine exposure observed between dogs as compared to administering cinnarizine in an aqueous suspension.

    CONCLUSIONS: Optimization of SNEDDSs towards keeping the drug compound in solution upon in vitro lipolysis of the SNEDDSs may not be as important as previously suggested.

  • 41.
    Lazorova, Lucia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gråsjö, Johan
    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.
    Bergström, Mats
    Wu, Feng
    Petterman-Bergström, Elisabeth
    Ögren, Mattias
    Långström, Bengt
    Quantification and imaging of mannitol transport through Caco-2 cell monolayers using a positron-emitting tracer1998In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 15, no 7, p. 1141-1144Article in journal (Refereed)
  • 42.
    Lindqvist, Annika
    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
    van Kregten, Joan
    Gaillard, Pieter J
    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.
    In vivo Functional Evaluation of Increased Brain Delivery of the Opioid Peptide DAMGO by Glutathione-PEGylated Liposomes2016In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 33, no 1, p. 177-185Article in journal (Refereed)
    Abstract [en]

    Purpose:

    The purpose of this study was to evaluate formulation factors causing improvement in brain delivery of a small peptide after encapsulation into a targeted nanocarrier in vivo.

    Methods:

    The evaluation was performed in rats using microdialysis, which enabled continuous sampling of the released drug in both the brain (striatum) and blood. Uptake in brain could thereby be studied in terms of therapeutically active, released drug.

    Results:

    We found that encapsulation of the peptide DAMGO in fast-releasing polyethylene glycol (PEG)ylated liposomes, either with or without the specific brain targeting ligand glutathione (GSH), doubled the uptake of DAMGO into the rat brain. The increased brain delivery was observed only when the drug was encapsulated into the liposomes, thus excluding any effects of the liposomes themselves on the blood-brain barrier integrity as a possible mechanism. The addition of a GSH coating on the liposomes did not result in an additional increase in DAMGO concentrations in the brain, in contrast to earlier studies on GSH coating. This may be caused by differences in the characteristics of the encapsulated compounds and the composition of the liposome formulations. 

    Conclusions:

    We were able to show that encapsulation into PEGylated liposomes of a peptide with limited brain delivery could double the drug uptake into the brain without using a specific brain targeting ligand.  

  • 43.
    Loryan, Irena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vikash, Sinha
    Claire, Mackie
    Van Peer, Achiel
    Drinkenburg, Wilhelmus
    Vermeulen, An
    Morrison, Denise
    Monshouwer, Mario
    Heald, Donald
    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.
    Mechanistic Understanding of Brain Drug Disposition to Optimize the Selection of Potential Neurotherapeutics in Drug Discovery2014In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 31, no 8, p. 2203-2219Article in journal (Refereed)
    Abstract [en]

    Purpose

    The current project was undertaken with the aim to propose and test an in-depth integrative analysis of neuropharmacokinetic (neuroPK) properties of new chemical entities (NCEs), thereby optimizing the routine of evaluation and selection of novel neurotherapeutics.

    Methods

    Forty compounds covering a wide range of physicochemical properties and various CNS targets were investigated. The combinatory mapping approach was used for the assessment of the extent of blood-brain and cellular barriers transport via estimation of unbound-compound brain (Kp,uu,brain) and cell (Kp,uu,cell) partitioning coefficients. Intra-brain distribution was evaluated using the brain slice method. Intra- and sub-cellular distribution was estimated via calculation of unbound-drug cytosolic and lysosomal partitioning coefficients.

    Results

    Assessment of Kp,uu,brain revealed extensive variability in the brain penetration properties across compounds, with a prevalence of compounds actively effluxed at the blood-brain barrier. Kp,uu,cell was valuable for identification of compounds with a tendency to accumulate intracellularly. Prediction of cytosolic and lysosomal partitioning provided insight into the subcellular accumulation. Integration of the neuroPK parameters with pharmacodynamic readouts demonstrated the value of the proposed approach in the evaluation of target engagement and NCE selection.

    Conclusions

    With the rather easily-performed combinatory mapping approach, it was possible to provide quantitative information supporting the decision making in the drug discovery setting.

  • 44.
    Marchand, Sandrine
    et al.
    INSERM U1070, Pole Biol Sante, F-86073 Poitiers 9, France.;Univ Poitiers, Fac Med & Pharm, F-86073 Poitiers 9, France.;CHU Poitiers, Lab Toxicol & Pharmacocinet, F-86000 Poitiers, France..
    Bouchene, Salim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    de Monte, Michele
    Univ Tours, Ctr Etude Pathol Resp, Fac Med, INSERM UMR EA6305 1100, F-37032 Tours, France..
    Guilleminault, Laurent
    Univ Tours, Ctr Etude Pathol Resp, Fac Med, INSERM UMR EA6305 1100, F-37032 Tours, France..
    Montharu, Jerome
    Univ Tours, Ctr Etude Pathol Resp, Fac Med, INSERM UMR EA6305 1100, F-37032 Tours, France..
    Cabrera, Maria
    Univ Tours, Ctr Etude Pathol Resp, Fac Med, INSERM UMR EA6305 1100, F-37032 Tours, France..
    Gregoire, Nicolas
    INSERM U1070, Pole Biol Sante, F-86073 Poitiers 9, France.;Univ Poitiers, Fac Med & Pharm, F-86073 Poitiers 9, France..
    Gobin, Patrice
    INSERM U1070, Pole Biol Sante, F-86073 Poitiers 9, France.;CHU Poitiers, Lab Toxicol & Pharmacocinet, F-86000 Poitiers, France..
    Diot, Patrice
    Univ Tours, Ctr Etude Pathol Resp, Fac Med, INSERM UMR EA6305 1100, F-37032 Tours, France..
    Couet, William
    INSERM U1070, Pole Biol Sante, F-86073 Poitiers 9, France.;Univ Poitiers, Fac Med & Pharm, F-86073 Poitiers 9, France.;CHU Poitiers, Lab Toxicol & Pharmacocinet, F-86000 Poitiers, France..
    Vecellio, Laurent
    Univ Tours, Ctr Etude Pathol Resp, Fac Med, INSERM UMR EA6305 1100, F-37032 Tours, France..
    Pharmacokinetics of Colistin Methansulphonate (CMS) and Colistin after CMS Nebulisation in Baboon Monkeys2015In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 32, no 10, p. 3403-3414Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to compare two different nebulizers: Eflow rapidA (R) and Pari LC starA (R) by scintigraphy and PK modeling to simulate epithelial lining fluid concentrations from measured plasma concentrations, after nebulization of CMS in baboons. Three baboons received CMS by IV infusion and by 2 types of aerosols generators and colistin by subcutaneous infusion. Gamma imaging was performed after nebulisation to determine colistin distribution in lungs. Blood samples were collected during 9 h and colistin and CMS plasma concentrations were measured by LC-MS/MS. A population pharmacokinetic analysis was conducted and simulations were performed to predict lung concentrations after nebulization. Higher aerosol distribution into lungs was observed by scintigraphy, when CMS was nebulized with Pari LCA (R) star than with Eflow RapidA (R) nebulizer. This observation was confirmed by the fraction of CMS deposited into the lung (respectively 3.5% versus 1.3%).CMS and colistin simulated concentrations in epithelial lining fluid were higher after using the Pari LC starA (R) than the Eflow rapidA (R) system. A limited fraction of CMS reaches lungs after nebulization, but higher colistin plasma concentrations were measured and higher intrapulmonary colistin concentrations were simulated with the Pari LC StarA (R) than with the Eflow RapidA (R) system.

  • 45.
    Matsson, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Pedersen, Jenny M
    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.
    Bergström, Christel A S
    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.
    Identification of novel specific and general inhibitors of the three major human ATP-binding cassette transporters P-gp, BCRP and MRP2 among registered drugs2009In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 26, no 8, p. 1816-1831Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To study the inhibition patterns of the three major human ABC transporters P-gp (ABCB1), BCRP (ABCG2) and MRP2 (ABCC2), using a dataset of 122 structurally diverse drugs. METHODS: Inhibition was investigated in cellular and vesicular systems over-expressing single transporters. Computational models discriminating either single or general inhibitors from non-inhibitors were developed using multivariate statistics. RESULTS: Specific (n = 23) and overlapping (n = 19) inhibitors of the three ABC transporters were identified. GF120918 and Ko143 were verified to specifically inhibit P-gp/BCRP and BCRP in defined concentration intervals, whereas the MRP inhibitor MK571 was revealed to inhibit all three transporters within one log unit of concentration. Virtual docking experiments showed that MK571 binds to the ATP catalytic site, which could contribute to its multi-specific inhibition profile. A computational model predicting general ABC inhibition correctly classified 80% of both ABC transporter inhibitors and non-inhibitors in an external test set. CONCLUSIONS: The inhibitor specificities of P-gp, BCRP and MRP2 were shown to be highly overlapping. General ABC inhibitors were more lipophilic and aromatic than specific inhibitors and non-inhibitors. The identified specific inhibitors can be used to delineate transport processes in complex experimental systems, whereas the multi-specific inhibitors are useful in primary ABC transporter screening in drug discovery settings.

  • 46.
    Nordquist, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Roxhed, Niclas
    Griss, Patrick
    Stemme, Göran
    Novel microneedle patches for active insulin delivery are efficient in maintaining glycaemic control: an initial comparison with subcutaneous administration2007In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 24, no 7, p. 1381-1388Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Good glycaemic control is essential to minimize the risk for diabetes-induced complications. Also, compliance is likely to be higher if the procedure is simple and painless. This study was designed to validate painless intradermal delivery via a patch-like microneedle array.

    MATERIALS AND METHODS: Diabetes was induced by an intravenous injection of streptozotocin (50 mg/kg bw) in adult male Sprague Dawley rats. Plasma insulin and blood glucose were measured before, during and after subcutaneous or intradermal (microneedles) infusion of insulin (0.2 IU/h) under Inactin-anaesthesia.

    RESULTS: Before insulin administration, all animals displayed a pronounced hyperglycaemia (19 +/- 1 mM; 359 mg/dl). Administration of insulin resulted in a reduced plasma glucose independently of administration route (subcutaneous 7.5 +/- 4.2, n = 9, and intradermal 11 +/- 1.8, n = 9 after 240 min), but with less errors of the mean in the intradermal group. In the intradermal group, plasma insulin was increased in all latter measurements (72 +/- 22, 81 +/- 34, and 87 +/- 20 microIU/ml), as compared to the first measurement (26 +/- 13). In the subcutaneous group, plasma insulin was elevated during the last measurement (to 154 +/- 3.5 microIU/ml from 21 +/- 18).

    CONCLUSION: This study presents a novel possibility of insulin delivery that is controllable and requires minimal training. This treatment strategy could improve compliance, and thus be beneficial for patients' glycaemic control.

  • 47.
    Overgaard, Rune Viig
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Holford, Nick
    Rytved, Klaus A.
    Madsen, Henrik
    PKPD model of interleukin-21 effects on thermoregulation in monkeys - Application and evaluation of stochastic differential equations2007In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 24, no 2, p. 298-309Article in journal (Refereed)
    Abstract [en]

    Purpose. To describe the pharmacodynamic effects of recombinant human interleukin-21 (IL-21) on core body temperature in cynomolgus monkeys using basic mechanisms of heat regulation. A major effort was devoted to compare the use of ordinary differential equations (ODEs) with stochastic differential equations (SDEs) in pharmacokinetic pharmacodynamic (PKPD) modelling. Methods. A temperature model was formulated including circadian rhythm, metabolism, heat loss, and a thermoregulatory set-point. This model was formulated as a mixed-effects model based on SDEs using NONMEM. Results. The effects of IL-21 were on the set-point and the circadian rhythm of metabolism. The model was able to describe a complex set of IL-21 induced phenomena, including 1) disappearance of the circadian rhythm, 2) no effect after first dose, and 3) high variability after second dose. SDEs provided a more realistic description with improved simulation properties, and further changed the model into one that could not be falsified by the autocorrelation function. Conclusions. The IL-21 induced effects on thermoregulation in cynomolgus monkeys are explained by a biologically plausible model. The quality of the model was improved by the use of SDEs.

  • 48.
    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: II. Vesicles formed from mixtures of amphiphilic drugs and oppositely charged surfactants2001In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 18, no 11, p. 1585-1591Article in journal (Refereed)
    Abstract [en]

    URPOSE:

    The aim of this study was to control the release of charged drugs from gels by adding surfactants that can interact with the drug and polymer matrix.

    METHODS:

    The in vitro release from gels was measured by using 6-mL gel holders immersed in 250 mL of simulated tear fluid and detecting the ultraviolet absorbance on-line. Gels were characterized by using a controlled rate rheometer, and surfactant aggregates were characterized by using cryo-transmission electron microscopy.

    RESULTS:

    The diffusion coefficient of alprenolol was 2.8 x 10(-6) cm2/s in a lipophilically modified poly(acrylic acid) gel without surfactants present and 0.14 x 10(-6) cm2/s when formulated with 1% sodium dodecyl sulfate. For fluvastatin, the diffusion coefficient changed from 3.0 x 10(-6) cm2/s to 0.07 x 10(-6) cm2/s in the presence of 0.2% benzyldimethyldodecyl-ammonium bromide. Alprenolol, betaxolol, metoprolol, diphenhydramine, and fluvastatin formed vesicles with oppositely charged surfactants in physiologic salt conditions.

    CONCLUSIONS:

    In this article we show that it is feasible to control the release of charged drugs from gels by using surfactants. Vesicles are generally formed when surface active drugs are mixed with oppositely charged surfactants in physiologic conditions. The strongest effects on the release rate are seen for lipophilically modified polymer gels in which the drug and the oppositely charged surfactant form vesicles, but systems with micelles also give a slower release.

  • 49.
    Persson, Anita Maria
    et al.
    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.
    Rosén, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Multivariate data analysis of factors affecting the in vitro dissolution rate and the apparent solubility for a model basic drug substance in aqueous media2010In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 27, no 7, p. 1309-1317Article in journal (Refereed)
    Abstract [en]

    Purpose. To evaluate the usefulness of a miniaturized rotating disk equipment for the determination of factors influencing the in vitro dissolution rate, G, of a model basic drug substance (terfenadine) in different aqueous media, using experimental design and multivariate data analysis. The apparent solubility, S, was included in the chemometric study.

    Methods. The dissolution rate was determined with a miniaturized rotating disk apparatus and the solubility by shake-flask methodology. Media were based on acetate, phosphate or maleate buffers. The later used in fasted state simulated intestinal fluid (FaSSIF-V2). The chemometric analyses included fractional factorial design, principal component analysis (PCA) and orthogonal partial least squares (OPLS). Quantifications were made with a RP-HPLC-DAD system.

    Results. The most influential factor for both G and S of terfenadine in the different media was pH. Apart from the ionic strength and sodium chloride concentration in the acetate medium, the effects of the other variables were insignificant implying no wetting effect of the surfactants.

    Conclusions. The miniaturized rotating disk equipment was suitable to use, in conjunction with the chemometric analyses, in the evaluation of the factors affecting the in vitro dissolution rate. The apparent solubility was found to be influenced by the same factors as G.

  • 50.
    Persson, Eva M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gustafsson, Ann-Sofie
    Carlsson, Anders S
    Nilsson, Ralf G
    Knutson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Forsell, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hanisch, Gunilla
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, Bertil
    The effects of food on the dissolution of poorly soluble drugs in human and in model small intestinal fluids2005In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 22, no 12, p. 2141-2151Article in journal (Refereed)
    Abstract [en]

    Purpose  This study was conducted to determine the effect of food on drug solubility and dissolution rate in simulated and real human intestinal fluids (HIF). Methods  Dissolution rate obtained via the rotating disk method and saturation solubility studies were carried out in fed and fasted state HIF, fed dog (DIF), and simulated (FeSSIF) intestinal fluid for six aprotic low solubility drugs. The intestinal fluids were characterized with respect to physical–chemical characteristics and contents. Results  Fed HIF provided a 3.5- to 30-times higher solubility compared to fasted HIF and FeSSIF, whereas fed DIF corresponded well (difference of less than 30%) to fed HIF. The increased solubility of food could mainly be attributed to dietary lipids and bile acids. The dissolution rate was also 2 to 7 times higher in fed HIF than fasted HIF. This was well predicted by both DIF and FeSSIF (difference of less than 30%). Conclusions  Intestinal solubility is higher in fed state compared to fasted state. However, the dissolution rate does not increase to the same extent. Dog seems to be a good model for man with respect to dissolution in the small intestine after intake of a meal, whereas FeSSIF is a poorer means of determining intestinal saturation solubility in the fed state.

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