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  • 1.
    Bergström, Christel
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Box, Karl
    PION Inc, Forest Row Business Pk, Forest Row RH18 5DW, E Sussex, England.
    Holm, Rene
    Johnson & Johnson, Janssen R&D, Drug Prod Dev, Turnhoutseweg 30, B-2340 Beerse, Belgium.
    Matthews, Wayne
    GlaxoSmith Kline Med Res Ctr, Dept Prod Dev, 2G118,Gunnels Wood Rd, Stevenage, Herts, England.
    McAllister, Mark
    Pfizer Ltd, Pharmaceut Sci, Drug Prod Design, Sandwich CT13 9NJ, Kent, England.
    Mullertz, Anette
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Rades, Thomas
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Schäfer, Kerstin J.
    Boehringer Ingelheim Pharma GmBH & Co KG, Pharmaceut Dev, Birkendorfer Str 65, D-88397 Biberach, Germany.
    Teleki, Alexandra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Biorelevant intrinsic dissolution profiling in early drug development: Fundamental, methodological, and industrial aspects2019Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 139, s. 101-114Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

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

  • 2.
    Boge, Lukas
    et al.
    RISE - Research Institutes of Sweden, Biovetenskap och material, Yta, process och formulering. Chalmers University of Technology, Sweden.
    Hallstensson, Karin
    RISE - Research Institutes of Sweden, Biovetenskap och material, Yta, process och formulering.
    Ringstad, Lovisa
    RISE - Research Institutes of Sweden, Biovetenskap och material, Yta, process och formulering.
    Johansson, Jenny
    RISE - Research Institutes of Sweden, Biovetenskap och material, Kemi och material.
    Andersson, Therese
    RISE - Research Institutes of Sweden, Biovetenskap och material, Kemi och material.
    Davoudi, Mina
    Lund University, Sweden.
    Larsson, Tomas
    RISE - Research Institutes of Sweden, Biovetenskap och material, Kemi och material.
    Mahlapuu, Margit
    Promore Pharma AB, Sweden; University of Gothenburg, Sweden.
    Håkansson, Joakim
    RISE - Research Institutes of Sweden, Biovetenskap och material, Kemi och material.
    Andersson, Martin
    Chalmers University of Technology, Sweden.
    Cubosomes for topical delivery of the antimicrobial peptide LL-372019Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 134, s. 60-67Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In this study, the use of cubosomes for topical delivery of the antimicrobial peptide (AMP) LL-37 was investigated. Topical delivery of AMPs is of great interest for treatment of skin infections caused by bacteria, such as Staphylococcus aureus. AMP containing cubosomes were produced by three different preparation protocols and compared: (i) pre-loading, where LL-37 was incorporated into a liquid crystalline gel, which thereafter was dispersed into nanoparticles, (ii) post-loading, where LL-37 was let to adsorb onto pre-formed cubosomes, and (iii) hydrotrope-loading, where LL-37 was incorporated during the spontaneously formed cubosomes in an ethanol/glycerol monooleate mixture. Particle size and size distribution were analyzed using dynamic light scattering (DLS), liquid crystalline structure by small angle x-ray scattering (SAXS) and release of LL-37 by a fluorescamine assay. Proteolytic protection of LL-37 as well as bactericidal effect after enzyme exposure was investigated. The skin irritation potential of cubosomes was examined by an in vitro epidermis model. Finally, the bacterial killing property of the cubosomes was examined by an ex vivo pig skin wound infection model with Staphylococcus aureus. Data showed that a high loading of LL-37 induced formation of vesicles in case of cubosomes prepared by sonication (pre-loading). No release of LL-37 was observed from the cubosomes, indicating strong association of the peptide to the particles. Proteolysis studies showed that LL-37 was fully protected against enzymatic attacks while associated with the cubosomes, also denoting strong association of the peptide to the particles. As a consequence, bactericidal effect after enzyme exposure remained, compared to pure LL-37 which was subjected to proteolysis. No skin irritation potential of the cubosomes was found, thus enabling for topical administration. The ex vivo wound infection model showed that LL-37 in pre-loaded cubosomes killed bacteria most efficient.

  • 3. Borde, A. S.
    et al.
    Karlsson, E. M.
    Andersson, K.
    Bjorhall, K.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Abrahamsson, B.
    Assessment of enzymatic prodrug stability in human, dog and simulated intestinal fluids2012Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 80, nr 3, s. 630-637Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this study was to determine the stability of three ester prodrugs, chloramphenicol succinate, enalapril and candesartan cilexetil, in human proximal small intestinal fluid (HIF), dog proximal small intestinal fluids (DIF) and simulated intestinal fluid (FaSSIF), with the addition of pancreatin. The total protein content in the proximal jejuna] fluids was determined in HIF and DIF, respectively. Candesartan cilexetil was significantly degraded in HIF (initial t(1/2(0-5min)) 5.4 +/- 0.5 min) and in DIF (initial t(1/2(0-5min))) = 5.7 +/- 0.1 min), while chloramphenicol succinate and enalapril were stable in both media. The degradation of candesartan cilexetil was shown to be mediated by enzymes following Michaelis-Menten enzyme kinetics and was inhibited by addition of esterase inhibitors. The enzymatic capacity reflected by V-max was 4-fold higher in DIF than in HIF and correlated to its 2-fold higher protein concentration. The degradation of candesartan cilexetil in the FaSSIF-pancreatin solution was slower (t(1/2) = 207 +/- 34 min) than the degradation in both HIF and DIF. Changing the pH to the enzyme optima or increasing the amount of pancreatin, increased the degradation rate of candesartan cilexetil, but not in the magnitude as in HIF. As a result, two in vitro models, based on in vivo intestinal fluids, were developed using candesartan cilexetil as a model drug. The DIF seems to be a reasonably good model for HIF, although the degradation capacity seems to be somewhat higher, possibly due to the higher enzyme concentration in DIF. Future investigations will develop novel enzymatic based in vitro models for rapid assessment and biopharmaceutical screening tools for prodrugs.

  • 4.
    Cai, Bing
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Xia, Wei
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Bredenberg, Susanne
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Li, Hao
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Engqvist, Håkan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Bioceramic microneedles with flexible and self-swelling substrate2015Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 94, s. 404-410Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To reduce the effort required to penetrate the skin and optimize drug release profiles, bioceramic microneedle arrays with higher-aspect-ratio needles and a flexible and self-swelling substrate have been developed. Swelling of the substrate can assist in separating it from the needles and leave them in the skin as a drug depot. The preparation procedures for this bioceramic microneedle are described in the paper. Clonidine hydrochloride, the model drug, was released in a controlled manner by the microneedle device in vitro. Results showed that the microneedle array with a flexible and self-swelling substrate released the drug content faster than the array with a rigid substrate. Disintegration of the needle material and diffusion of the drug molecules are believed as the main control mechanisms of the drug release from these microneedle arrays. Ex vivo skin penetration showed that they can effectively penetrate the stratum corneum without an extra device. This work represents a progression in the improvement of bioceramic microneedles for transdermal drug delivery.

  • 5. Dahlberg, C
    et al.
    Millqvist-Fureby, A
    YKI – Ytkemiska institutet.
    Schuleit, M
    Surface composition and contact angle relationships for differently prepared solid dispersions2008Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 70, nr 2, s. 478-485Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Solid dispersions are promising drug delivery forms which offer the possibility to disperse a hydrophobic drug in a hydrophilic matrix and thereby improve the dissolution behavior and the bioavailability of the drug. One important aspect and a prerequisite in understanding the drug dissolution mechanism from solid dispersions is a better analytical monitoring of the solid dispersion surface properties, such as powder surface composition and water adsorption properties. In this paper, we have considered chemical and structural surface analysis data for solid dispersions processed by spray drying or roto-evaporation and compared these data with information obtained by contact angle measurements. Firstly, we establish the usefulness and suitability of X-ray photoelectron spectroscopy (XPS) for determination of surface chemical composition and scanning electron microscopy (SEM) for determining the structure of solid dispersions composed of different types of carriers, drugs and drug concentrations. Secondly, we measure contact angles of solid dispersions to describe wettability, to finally establish a link between the surface chemical composition, the powder structure and the wetting behavior. These experimental methods offer a rapid screening tool for the selection of carrier, drug concentration and/or process in early development. In addition, they provide a useful tool for investigating structural aspects of solid dispersions which have intrinsic relevance for drug dissolution and stability.

  • 6.
    Dahlberg, Carina
    et al.
    KTH, Skolan för kemivetenskap (CHE), Kemi, Fysikalisk kemi.
    Millqvist-Fureby, Anna
    Schuleit, Michael
    Surface composition and contact angle relationships for differently prepared solid dispersions2008Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 70, s. 478-485Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Solid dispersions are promising drug delivery forms which offer the possibility to disperse a hydrophobic drug in a hydrophilic matrix and thereby improve the dissolution behavior and the bioavailability of the drug. One important aspect and a prerequisite in understanding the drug dissolution mechanism from solid dispersions is a better analytical monitoring of the solid dispersion surface properties, such as powder surface composition and water adsorption properties. In this paper, we have considered chemical and structural surface analysis data for solid dispersions processed by spray drying or roto-evaporation and compared these data with information obtained by contact angle measurements. Firstly, we establish the usefulness and suitability of X-ray photoelectron spectroscopy (XPS) for determination of surface chemical composition and scanning electron microscopy (SEM) for determining the structure of solid dispersions composed of different types of carriers, drugs and drug concentrations. Secondly, we measure contact angles of solid dispersions to describe wettability, to finally establish a link between the surface chemical composition, the powder structure and the wetting behavior. These experimental methods offer a rapid screening tool for the selection of carrier, drug concentration and/or process in early development. In addition, they provide a useful tool for investigating structural aspects of solid dispersions which have intrinsic relevance for drug dissolution and stability.

  • 7. Dahlberg, Carina
    et al.
    Millqvist-Fureby, Anna
    RISE., SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, YKI – Ytkemiska institutet.
    Schuleit, Michael
    Furó, Istvan
    Relationships between solid dispersion preparation process, particle size and drug release - An NMR and NMR microimaging study2010Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 76, nr 2, s. 311-319Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Solid dispersion tablets prepared by either spray drying or rotoevaporation and exhibiting different grain and pore sizes were investigated under the process of hydration-swelling-gelation. H-2 and H-1 NMR microimaging experiments were used to selectively follow water penetration and polymer mobilization kinetics, respectively, while the drug release kinetics was followed by H-1 NMR spectroscopy. The obtained data, in combination with morphological information by scanning electron microscopy (SEM), reveal a complex process that ultimately leads to release of the drug into the aqueous phase. We find that the rate of water ingress has no direct influence on release kinetics, which also renders air in the tablets a secondary factor. On the other hand, drug release is directly correlated with the polymer mobilization kinetics. Water diffusion into the originally dry polymer grains determines the rate of grain swelling and the hydration within the grains varies strongly with grain size. We propose that this sets the stage for creating homogeneous gels for small grain sizes and heterogeneous gels for large grain sizes. Fast diffusion through water-rich sections of the inhomogeneous gels that exhibit a large mesh size is the factor which yields a faster drug release from tablets prepared by rotoevaporation.

  • 8.
    Dahlberg, Carina
    et al.
    KTH, Skolan för kemivetenskap (CHE), Kemi, Fysikalisk kemi. KTH, Skolan för kemivetenskap (CHE), Centra, Centrum för Industriell NMR-teknik.
    Millqvist-Fureby, Anna
    Schuleit, Michael
    Furó, István
    KTH, Skolan för kemivetenskap (CHE), Kemi, Fysikalisk kemi. KTH, Skolan för kemivetenskap (CHE), Centra, Centrum för Industriell NMR-teknik.
    Relationships between solid dispersion preparation process, particle size and drug release: an NMR and NMR microimaging study2010Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 76, nr 2, s. 311-319Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Solid dispersion tablets prepared by either spray drying or rotoevaporation and exhibiting different grain and pore sizes were investigated under the process of hydration-swelling-gelation. H-2 and H-1 NMR microimaging experiments were used to selectively follow water penetration and polymer mobilization kinetics, respectively, while the drug release kinetics was followed by H-1 NMR spectroscopy. The obtained data, in combination with morphological information by scanning electron microscopy (SEM), reveal a complex process that ultimately leads to release of the drug into the aqueous phase. We find that the rate of water ingress has no direct influence on release kinetics, which also renders air in the tablets a secondary factor. On the other hand, drug release is directly correlated with the polymer mobilization kinetics. Water diffusion into the originally dry polymer grains determines the rate of grain swelling and the hydration within the grains varies strongly with grain size. We propose that this sets the stage for creating homogeneous gels for small grain sizes and heterogeneous gels for large grain sizes. Fast diffusion through water-rich sections of the inhomogeneous gels that exhibit a large mesh size is the factor which yields a faster drug release from tablets prepared by rotoevaporation.

  • 9.
    Dahlgren, David
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Roos, Carl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lundqvist, A.
    Tannergren, C.
    Sjöblom, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Time-dependent effects on small intestinal transport by absorption-modifying excipients2018Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 132, s. 19-28Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The relevance of the rat single-pass intestinal perfusion model for investigating in vivo time-dependent effects of absorption-modifying excipients (AMEs) is not fully established. Therefore, the dynamic effect and recovery of the intestinal mucosa was evaluated based on the lumen-to-blood flux (Jabs) of six model compounds, and the blood-to-lumen clearance of 51Cr-EDTA (CLCr), during and after 15- and 60-min mucosal exposure of the AMEs, sodium dodecyl sulfate (SDS) and chitosan, in separate experiments. The contribution of enteric neurons on the effect of SDS and chitosan was also evaluated by luminal coadministration of the nicotinic receptor antagonist, mecamylamine. The increases in Jabs and CLCr (maximum and total) during the perfusion experiments were dependent on exposure time (15 and 60 min), and the concentration of SDS, but not chitosan. The increases in Jabs and CLCr following the 15-min intestinal exposure of both SDS and chitosan were greater than those reported from an in vivo rat intraintestinal bolus model. However, the effect in the bolus model could be predicted from the increase of Jabs at the end of the 15-min exposure period, where a six-fold increase in Jabs was required for a corresponding effect in the in vivo bolus model. This illustrates that a rapid and robust effect of the AME is crucial to increase the in vivo intestinal absorption rate before the yet unabsorbed drug in lumen has been transported distally in the intestine. Further, the recovery of the intestinal mucosa was complete following 15-min exposures of SDS and chitosan, but it only recovered 50% after the 60-min intestinal exposures. Our study also showed that the luminal exposure of AMEs affected the absorptive model drug transport more than the excretion of 51Cr-EDTA, as Jabs for the drugs was more sensitive than CLCr at detecting dynamic mucosal AME effects, such as response rate and recovery. Finally, there appears to be no nicotinergic neural contribution to the absorption-enhancing effect of SDS and chitosan, as luminal administration of 0.1 mM mecamylamine had no effect.

  • 10.
    Dahlgren, David
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Roos, Carl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Peters, Karsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lundqvist, A.
    AstraZeneca R&D, Gothenburg, Sweden.
    Tannergren, C.
    AstraZeneca R&D, Gothenburg, Sweden.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjöblom, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Sjöblom/Nylander: Gastrointestinal fysiologi.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Evaluation of drug permeability calculation based on luminal disappearance and plasma appearance in the rat single-pass intestinal perfusion model2019Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, s. 31-37Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The rat single-pass intestinal perfusion (SPIP) model is commonly used to investigate gastrointestinal physiology and membrane drug transport. The SPIP model can be used with the intestinal segment inside or outside the abdomen. The rats can also be treated with parecoxib, a selective cycloxygenase-2 inhibitor that has been shown to affect some intestinal functions following abdominal surgery, such as motility, epithelial permeability, fluid flux and ion transport. However, the impact of extra-abdominal placement of the intestinal segment in combination with parecoxib on intestinal drug transport has not been investigated. There is also uncertainty how well intestinal permeability determinations based on luminal drug disappearance and plasma appearance correlate in the rat SPIP model. The main objective of this rat in vivo study was to investigate the effect of intra- vs. extra abdominal SPIP, with and without, pretreatment with parecoxib. The effect was evaluated by determining the difference in blood-to-lumen Cr-51-EDTA clearance, lumen-to-blood permeability of a cassette-dose of four model compounds (atenolol, enalaprilat, ketoprofen, and metoprolol), and water flux. The second objective was to compare the jejunal permeability values of the model drugs when determined based on luminal disappearance or plasma appearance. The study showed that the placement of the perfused jejunal segment, or the treatment with parecoxib, had minimal effects on membrane permeability and water flux. It was also shown that intestinal permeability of low permeability compounds should be determined on the basis of data from plasma appearance rather than lumina] disappearance. If permeability is calculated on the basis of luminal disappearance, it should preferably include negative values to increase the accuracy in the determinations.

  • 11.
    Dahlgren, David
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjöblom, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Sjöblom/Nylander: Gastrointestinal fysiologi.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Intestinal absorption-modifying excipients: A current update on preclinical in vivo evaluations2019Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, s. 411-420Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pharmaceutical excipients in drug products are defined as pharmacologically inactive and are integral constituents of all types of oral dosage forms. However, some excipients may increase drug absorption by interacting with the mucosal membrane. If the strategy is to use an excipient with a potential to affect the processes determining the rate and/or extent of the intestinal drug absorption, it is defined as an absorption-modifying excipients (AME). These pharmaceutical excipients may act as AMEs, depending on the amounts applied, and accordingly influence bioequivalence assessment of innovative and generic drug products, as well as enable oral delivery of peptides and oligonucleotides. This review discusses the mechanisms by which AMEs increase drug absorption, and especially permeation step. The focus is on the most recent data regarding how AMEs can be evaluated in preclinical models, with an emphasis on in situ and in vivo intestinal absorption models. The in vivo predictive value of these models is reviewed for five factors of clinical relevance for the intestinal absorption performance: (a) effect and response rate of AMEs, (b) mucosal exposure time and intestinal transit of AMEs, (c) intraluminal AME dilution and prandial state, (d) mucosa] recovery and safety, and (e) variability in the effects of the AMEs. We argue that any preclinical investigations of AMEs that fail to consider these processes will ultimately be of limited clinical value and add little to our understanding of how excipients affect intestinal drug absorption.

  • 12.
    Dubbelboer, Ilse R
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Dahlgren, David
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Rat intestinal drug permeability: A status report and summary of repeated determinations2019Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, s. 364-376Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 13.
    Eriksson, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Thörn, Helena
    AstraZeneca, Phannaceut Technol & Dev Inhalat, Pepparedsleden 1, S-43183 Molndal, Sweden..
    Rubin, Katarina
    Bäckman, Per
    AstraZeneca, Phannaceut Technol & Dev Inhalat, Pepparedsleden 1, S-43183 Molndal, Sweden.;Mylan Pharma UK Ltd, Mylan Global Resp Grp, Sandwich CT13 9FF, Kent, England..
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Pulmonary absorption - estimation of effective pulmonary permeability and tissue retention of ten drugs using an ex vivo rat model and computational analysis2018Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 124, s. 1-12Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Permeation of inhaled drugs across the pulmonary epithelium can regulate the rate and extent of local drug absorption and hence the pulmonary tissue concentration. Therefore, understanding pulmonary epithelial transport could be important for successful design of novel inhaled medicines. To enhance understanding of pulmonary epithelial transport, drug transport data were generated for a set of inhaled compounds (n = 10) in the single-pass, isolated perfused rat lung model. A compartmental in silica model was used to estimate pulmonary permeability and tissue retention. The theoretical model was also used to re-analyze previously obtained historical drug transport data from the isolated perfused lung (n = 10) with re-circulating buffer. This was performed to evaluate the re-circulating model for assessing tissue retention measurements and to increase the number of data points. The tissue retention was an important parameter to estimate to be able to describe the drug transport profiles accurately of most of the investigated compounds. A relationship between the pulmonary permeability and the intrinsic (carrier-mediated transport inhibited) permeability of Caco-2 cell monolayers (n = 1-6) was also established. This correlation (R-2 = 0.76, p < .0001) suggests that intrinsic Caco-2 permeability measurements could offer early predictions of the passive transcellular permeability of lung epithelium to candidate drugs. Although, for some compounds a deviation from the correlation suggests that other transport mechanisms may coexist. The compartmental in silica model was successful in describing the pulmonary drug transport profiles of the investigated compounds and has potential for further development to investigate the effects of formulations with different features on the pulmonary overall absorption rate.

  • 14.
    Fransén, Nelly
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Björk, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Nyström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Development and characterisation of interactive mixtures with a fine-particulate mucoadhesive carrier for nasal drug delivery2007Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 67, nr 2, s. 370-376Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this study was to investigate whether mucoadhesive interactive mixtures can be created using carrier particles in a size range appropriate for nasal administration, i.e. 10–50 μm. We also used theoretical models to investigate if homogeneity measurements can be used to evaluate the formation of interactive mixtures containing carrier particles in this size range. Sodium starch glycolate (SSG) was used as carrier material and sodium salicylate (SS) as the model fine-particulate drug. The size ranges of SSG particles and amounts of SS were varied to find the smallest carrier particle size and highest amount of drug that still resulted in an interactive mixture. Visual inspection of the mixtures by scanning electron microscopy showed that interactive mixtures could be formed with carrier particles as small as 30 μm and containing up to 4% (w/w) of SS. Comparisons with theoretical models highlighted the difficulties of using homogeneity measurements to determine if interactive mixtures were formed. The measured coefficients of variation (CV) for the amount of drug in the samples were low and inferior mixtures were associated with only a slight increase. It was thus concluded that mucoadhesive interactive mixtures can be created in an appropriate size range for nasal administration, but that visual inspection of these mixtures is initially necessary to confirm the formation of an interactive mixture.

  • 15.
    Garousi, Javad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lindbo, Sarah
    KTH Royal Inst Technol, Dept Prot Technol, SE-10691 Stockholm, Sweden.
    Borin, Jesper
    KTH Royal Inst Technol, Dept Prot Technol, SE-10691 Stockholm, Sweden.
    von Witting, Emma
    KTH Royal Inst Technol, Dept Prot Technol, SE-10691 Stockholm, Sweden.
    Vorobyeva, Anzhelika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Oroujeni, Maryam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Buijs, Jos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Hober, Sophia
    KTH Royal Inst Technol, Dept Prot Technol, SE-10691 Stockholm, Sweden.
    Comparative evaluation of dimeric and monomeric forms of ADAPT scaffold protein for targeting of HER2-expressing tumours2019Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 134, s. 37-48Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ADAPTs are small engineered non-immunoglobulin scaffold proteins, which have demonstrated very promising features as vectors for radionuclide tumour targeting. Radionuclide imaging of human epidermal growth factor 2 (HER2) expression in vivo might be used for stratification of patients for HER2-targeting therapies. ADAPT6, which specifically binds to HER2, has earlier been shown to have very promising features for in vivo targeting of HER2 expressing tumours. In this study we tested the hypothesis that dimerization of ADAPT6 would increase the apparent affinity to HER2 and accordingly improve tumour targeting. To find an optimal molecular design of dimers, a series of ADAPT dimers with different linkers, -SSSG- (DiADAPT6L1), -(SSSG)(2)- (DiADAPT6L2), and -(SSSG)(3)- (DiADAPT6L3) was evaluated. Dimers in combination with optimal linker lengths demonstrated increased apparent affinity to HER2. The best variants, DiADAPT6L2 and DiADAPT6L3 were site-specifically labelled with In-111 and I-125, and compared with a monomeric ADAPT6 in mice bearing HER2-expressing tumours. Despite higher affinity, both dimers had lower tumour uptake and lower tumour-to-organ ratios compared to the monomer. We conclude that improved affinity of a dimeric form of ADAPT does not compensate the disadvantage of increased size. Therefore, increase of affinity should be obtained by affinity maturation and not by dimerization.

  • 16.
    Garousi, Javad
    et al.
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden..
    Lindbo, Sarah
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Proteinteknologi.
    Borin, Jesper
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Proteinteknologi.
    von Witting, Emma
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Proteinteknologi.
    Vorobyeva, Anzhelika
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden..
    Oroujeni, Maryam
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden..
    Mitran, Bogdan
    Uppsala Univ, Dept Med Chem, Uppsala, Sweden..
    Orlova, Anna
    Uppsala Univ, Dept Med Chem, Uppsala, Sweden..
    Buijs, Jos
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden..
    Tolmachev, Vladimir
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden..
    Hober, Sophia
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Proteinteknologi.
    Comparative evaluation of dimeric and monomeric forms of ADAPT scaffold protein for targeting of HER2-expressing tumours2019Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 134, s. 37-48Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ADAPTs are small engineered non-immunoglobulin scaffold proteins, which have demonstrated very promising features as vectors for radionuclide tumour targeting. Radionuclide imaging of human epidermal growth factor 2 (HER2) expression in vivo might be used for stratification of patients for HER2-targeting therapies. ADAPT6, which specifically binds to HER2, has earlier been shown to have very promising features for in vivo targeting of HER2 expressing tumours. In this study we tested the hypothesis that dimerization of ADAPT6 would increase the apparent affinity to HER2 and accordingly improve tumour targeting. To find an optimal molecular design of dimers, a series of ADAPT dimers with different linkers, -SSSG- (DiADAPT6L1), -(SSSG)(2)- (DiADAPT6L2), and -(SSSG)(3)- (DiADAPT6L3) was evaluated. Dimers in combination with optimal linker lengths demonstrated increased apparent affinity to HER2. The best variants, DiADAPT6L2 and DiADAPT6L3 were site-specifically labelled with In-111 and I-125, and compared with a monomeric ADAPT6 in mice bearing HER2-expressing tumours. Despite higher affinity, both dimers had lower tumour uptake and lower tumour-to-organ ratios compared to the monomer. We conclude that improved affinity of a dimeric form of ADAPT does not compensate the disadvantage of increased size. Therefore, increase of affinity should be obtained by affinity maturation and not by dimerization.

  • 17.
    Gavini, Elisabetta
    et al.
    Department of Chemistry and Pharmacy, University of Sassari.
    Rassu, Giovanna
    Department of Chemistry and Pharmacy, University of Sassari.
    Ferraro, Luca
    Department of Experimental and Clinical Medicine, Pharmacology Section, University of Ferrara.
    Beggiato, Sarah
    Department of Experimental and Clinical Medicine, Pharmacology Section, University of Ferrara.
    Alhalaweh, Amjad
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Velaga, Sitaram
    Luleå tekniska universitet, Institutionen för hälsovetenskap, Medicinsk vetenskap.
    Marchetti, Nichola
    Department of Chemistry, University of Ferrara.
    Bandiera, Pasquale
    Department of Biomedical Sciences, University of Sassari.
    Giunchedi, Paolo
    Department of Chemistry and Pharmacy, University of Sassari.
    Dalpiaz, Alessandro
    Department of Pharmaceutical Sciences, University of Ferrara.
    Influence of polymeric microcarriers on the in-vivo intranasal uptake of an anti-migraine drug for brain targeting2013Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 83, nr 2, s. 174-183Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The objective of this study was to investigate the effect of polymeric microcarriers on the in-vivo intranasal uptake of an anti-migraine drug for brain targeting. Mucoadhesive powder formulations consisted of antimigraine drug, zolmitriptan, and chitosans (various molecular weights and types) or hydroxypropyl methylcellulose (HPMC). Their suitability for nasal administration was evaluated by in-vitro and ex-vivo mucoadhesion and permeation tests. The formulations based on chitosan glutamate (CG) or HPMC were tested in-vivo because they showed good mucoadhesive properties and altered the permeation rate of the drug. The in-vivo results from intravenous infusion and nasal aqueous suspension of the drug or nasal particulate powders were compared. The plasmatic AUC values obtained within 8 h following intravenous administration appeared about three times higher than those obtained by nasal administration, independent of the formulations. Zolmitriptan concentrations in the cerebrospinal fluid obtained from nasal and intravenous administrations were respectively 30 and 90 times lower than the concentrations of the drug in the blood. Thus, nasal administration potentiated the central zolmitriptan activity allowing a reduction of the drug peripheral levels, with respect to the intravenous administration. Among nasally administered formulations, CG microparticles showed the highest efficacy in promoting the central uptake of zolmitriptan within 1 h.

  • 18. Geh, Katharina J.
    et al.
    Hubert, Madlen
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Winter, Gerhard
    Progress in formulation development and sterilisation of freeze-dried oligodeoxynucleotide-loaded gelatine nanoparticles2018Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 129, s. 10-20Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oligodeoxynucleotide (ODN)-loaded gelatine nanoparticles (GNPs) have proven their outstanding potential in the treatment of allergic diseases such as equine asthma and canine atopic dermatitis, which are appropriate models for the corresponding human diseases. To encourage the development of a marketable product, long term stability and sterility needs to be ensured. In this work, we aimed to advance freeze-drying options to stabilise ODN-loaded GNPs. Matrix-assisted laser desorption/ionisation mass spectrometry time-of-flight was implemented as a versatile tool to assess ODN stability. With this method long-term storage stability of lyophilised ODN-loaded GNPs formulated in sucrose or trehalose was achieved. Controlled nucleation was further introduced to optimise the lyophilisation approach. This allowed shortening of the process in comparison to standard freeze-drying procedures. Particle sizes, polydispersity indices, ODN stability, residual moisture and glass transition temperature were maintained upon storage. Excipient portfolio was enlarged by novel amino acid containing formulations for lyophilisates. His emerged as an excellent excipient in stabilising lyophilised ODN-loaded GNPs, whereas addition of Arg and Gly revealed to be inadequate at accelerated conditions. Lastly, gamma irradiation was evaluated as a suitable sterilisation method of ODN-loaded GNPs.

  • 19.
    Grudén, Stefan
    et al.
    LIDDS AB, Uppsala, Sweden.
    Sandelin, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    Rasanen, Veera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi. National Veterinary Institute (SVA), Department of Chemistry, Environment and Feed Hygiene, Uppsala, Sweden.
    Axén, Niklas
    LIDDS AB, Uppsala, Sweden.
    Jeansson, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Antitumoral effect and reduced systemic toxicity in mice after intra-tumoral injection of an in vivo solidifying calcium sulfate formulation with docetaxel2017Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 114, s. 186-193Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Docetaxel is a cytostatic agent approved for treatment of non-small cell lung cancer as well as other cancers. Although docetaxel is an effective cytostatic agent, its effectiveness in clinical practice is associated with a variety of acute and long term side-effects. To overcome systemic side-effects, a slow release formulation based on calcium sulfate with docetaxel for intra-tumoral administration was developed.

    Methods

    Two formulations with the calcium sulfate NanoZolid technology were generated with a twofold difference in docetaxel drug load. The formulations were injected intra-tumorally as a paste which solidified within the tumor. The effects of the two intra-tumoral injection formulations were tested in female mice (n = 60) inoculated with subcutaneous Lewis lung carcinoma cells. The two formulations were compared to systemic intraperitoneal injection of docetaxel and a placebo formulation without docetaxel. Tumor volumes were measured and systemic side-effects were evaluated using body weight and cell counts from whole blood as well as plasma concentrations.

    Results

    Both docetaxel formulations showed a significantly higher antitumor efficacy compared to placebo, which was comparable to that of systemic administration of docetaxel. Moreover, the intra-tumoral formulations with docetaxel showed reduced systemic toxicity compared to systemic treatment, including less weight loss and no decrease in blood cell counts.

    Conclusions

    The results suggest that intra-tumoral slow release calcium sulfate based formulations with docetaxel can be an alternative strategy as an efficient local antitumoral treatment with reduced systemic toxicity.

  • 20.
    Hossain, Md Shakhawath
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Swedish Drug Delivery Forum.
    Kabedev, Aleksei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Parrow, Albin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergström, Christel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Swedish Drug Delivery Forum.
    Larsson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Swedish Drug Delivery Forum.
    Molecular simulation as a computational pharmaceutics tool to predict drug solubility, solubilization processes and partitioning2019Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 137, s. 46-55Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    In this review we will discuss how computational methods, and in particular classical molecular dynamics simulations, can be used to calculate solubility of pharmaceutically relevant molecules and systems. To the extent possible, we focus on the non-technical details of these calculations, and try to show also the added value of a more thorough and detailed understanding of the solubilization process obtained by using computational simulations. Although the main focus is on classical molecular dynamics simulations, we also provide the reader with some insights into other computational techniques, such as the COSMO-method, and also discuss Flory-Huggins theory and solubility parameters. We hope that this review will serve as a valuable starting point for any pharmaceutical researcher, who has not yet fully explored the possibilities offered by computational approaches to solubility calculations.

  • 21.
    Hu, Yang
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gaillard, Pieter J.
    2-BBB Medicine B.V..
    De lange, Elizabeth C.M.
    Leiden University.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Targeted Brain Delivery of Methotrexate by Glutathione PEGylated Liposomes: How can the Formulation Make a Difference?2019Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 139, s. 197-204Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The purpose of this study was to quantitatively investigate how conjugation of GSH to different liposomal formulations influence the brain delivery of methotrexate (MTX) in rats. GSH-PEG liposomal MTX based on hydrogenated soy phosphatidylcholine (HSPC) or egg yolk phosphatidylcholine (EYPC) and their corresponding PEG control liposomes were prepared. The brain delivery of MTX after intravenously administering free MTX, four liposomal formulations or free MTX + empty GSH-PEG-HSPC liposomes was evaluated by performing microdialysis in brain interstitial fluid and blood. Compared to free MTX with a steady-state unbound brain-toplasma concentration ratio (K-p,K-uu) of 0.10, PEG-HSPC liposomes did not affect the brain uptake of MTX, while PEG-EYPC liposomes improved the uptake (K-p,(uu) 1.5, p < 0.05). Compared to PEG control formulations, GSHPEG-HSPC liposomes increased brain delivery of MTX by 4-fold (K-p,(uu) 0.82, p < 0.05), while GSH-coating on PEG-EYPC liposomes did not result in a further enhancement in uptake. The co-administration of empty GSHPEG-HSPC liposomes with free MTX did not influence the uptake of MTX into the brain. This work showed that the brain-targeting effect of GSH-PEG liposomal MTX is highly dependent on the liposomal formulation that is combined with GSH, providing insights on formulation optimization of this promising brain delivery platform.

  • 22.
    Kennedy, Patrick J.
    et al.
    Univ Porto, Inst Invest & Inovacao Saude, Porto, Portugal;Univ Porto, INEB Inst Engn Biomed, Porto, Portugal;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, Porto, Portugal;Univ Porto, ICBAS, Porto, Portugal.
    Perreira, Ines
    Univ Porto, Inst Invest & Inovacao Saude, Porto, Portugal;Univ Porto, INEB Inst Engn Biomed, Porto, Portugal.
    Ferreira, Daniel
    Univ Porto, Inst Invest & Inovacao Saude, Porto, Portugal;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, Porto, Portugal.
    Nestor, Marika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Oliveira, Carla
    Univ Porto, Inst Invest & Inovacao Saude, Porto, Portugal;Univ Porto, IPATIMUP Inst Patol & Imunol Mol, Porto, Portugal;Univ Porto, Fac Med, Porto, Portugal.
    Granja, Pedro L.
    Univ Porto, Inst Invest & Inovacao Saude, Porto, Portugal;Univ Porto, INEB Inst Engn Biomed, Porto, Portugal;Univ Porto, ICBAS, Porto, Portugal;Univ Porto, Fac Engn, Porto, Portugal.
    Sarmento, Bruno
    Univ Porto, Inst Invest & Inovacao Saude, Porto, Portugal;Univ Porto, INEB Inst Engn Biomed, Porto, Portugal;Inst Invest & Formacao Avancada Ciencias & Tecnol, CESPU, Gandra, Portugal;Inst Univ Ciencias Saude, Gandra, Portugal.
    Impact of surfactants on the target recognition of Fab-conjugated PLGA nanoparticles2018Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 127, s. 366-370Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Targeted drug delivery with nanoparticles (NPs) requires proper surface ligand presentation and availability. Surfactants are often used as stabilizers in the production of targeted NPs. Here, we evaluated the impact of surfactants on ligand functionalization and downstream molecular recognition. Our model system consisted of fluorescent poly(lactic-co-glycolic acid) (PLGA) NPs that were nanoprecipitated in one of a small panel of commonly-used surfactants followed by equivalent washes and conjugation of an engineered Fab antibody fragment. Size, polydispersity index and zeta potential were determined by dynamic light scattering and laser Doppler anemometry, and Fab presence on the NPs was assessed by enzyme-linked immunosorbent assay. Most importantly, Fab-decorated NP binding to the cell surface receptor was monitored by fluorescence-activated cell sorting. 2% polyvinyl alcohol, 1% sodium cholate, 0.5% Pluronic F127 (F127) and 2% Tween-80 were initially tested. Of the four surfactants tested, PLGA NPs in 0.5% F127 and 2% Tween-80 had the highest cell binding. These two surfactants were then retested in two different concentrations, 0.5% and 2%. The Fab-decorated PLGA NPs in 2% F127 had the highest cell binding. This study highlights the impact of common surfactants and their concentrations on the downstream targeting of ligand-decorated NPs. Similar principles should be applied in the development of future targeted nanosystems where surfactants are employed.

  • 23. Klevan, Ingvild
    et al.
    Nordström, Josefina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bauer-Brandl, Annette
    Alderborn, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    On the physical interpretation of the initial bending of a Shapiro-Konopicky-Heckel compression profile2009Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 71, nr 2, s. 395-401Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The relationship between the natural logarithm of the tablet porosity arc! the applied pressure is used to describe the compression behavior of a powder. Such a relationship, here referred to as a Shapiro-Konopicky-Heckel (SKH) profile, is usually divided into three   regions, of which the first often is non-linear. The objective of this work was to address the question of the mechanisms controlling the compression and the bending of the first region of a SKH profile for dense particles. In this paper, the first region was described by the   Shapiro General Compression Equation, from which a compression parameter was derived as a measure of the bending. The results indicate that for powders undergoing significant particle rearrangement at low applied pressures, the particle rearrangement is the major cause for the initial bending of the SKH profile. For powders showing limited particle rearrangement, the initial bending is mainly caused by the change in particle diameter due to particle fragmentation. It is concluded that the evaluation of the first region of a SKIT profile in terms of bending may be used to assess particle fragmentation. The SKH profile could hence be a useful tool to describe powder compression behavior in terms of particle fragmentation and particle deformation from one single compression analysis.

  • 24.
    Klevan, Ingvild
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Nordström, Josefina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Tho, Ingunn
    Alderborn, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    A statistical approach to evaluate the potential use of compression parameters for classification of pharmaceutical powder materials2010Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 75, nr 3, s. 425-435Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The current work aims to investigate whether a multivariate statistical approach could reveal latent structures in compression data and group powders with respect to their compression behavior in a way that is consistent with an earlier proposed classification system. Seventeen pharmaceutically relevant materials, exhibiting a wide range of mechanical properties, were used as supplied, compressed, and parameters from three commonly used powder compression models (Kawakita parameters a and b(-1), the rearrangement index ab, the Shapiro f parameter and Heckel P(y)) were retrieved. Multivariate analysis of the compression parameters was done with a Principal Component Analysis (PCA). It was found that the latent structures could be divided into three main parts; the most variation was found in the direction associated with particle rearrangement, second largest variation was found in the direction described by the particle fragmentation propensity, and the least variation was found in the direction associated with the plasticity of the particles. This work demonstrates that a combination of the selected compression parameters could be utilized to find relevant differences in compression behavior for a wide range of materials, and that this information can be presented in an efficient way by applying multivariate data analysis techniques.

  • 25. Larsson, M.
    et al.
    Hjartstam, J.
    Berndtsson, J.
    Stading, Mats
    RISE., SP – Sveriges Tekniska Forskningsinstitut, SP Sveriges tekniska forskningsinstitut, SIK – Institutet för livsmedel och bioteknik.
    Larsson, A.
    Effect of ethanol on the water permeability of controlled release films composed of ethyl cellulose and hydroxypropyl cellulose2010Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 76, nr 3, s. 428-432Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The robustness of controlled release formulations when co-ingested with alcohol is a current concern expressed by regulatory authorities, especially with regard to dose dumping. One such controlled release formulation commonly used is film coating composed of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC). The aim of this study was to investigate how the presence of ethanol in the dissolution medium affects the water permeability of such films. Film samples were prepared in various EC-HPC compositions, and the effect of different ethanol concentrations in the dissolution medium on the permeability was studied using a modified Ussing chamber and tritiated water. It was found that the effect of ethanol on the film permeability varied depending on the composition of the films. The results were interpreted in terms of swelling of the EC in the films, where the swelling increased with increasing ethanol concentration. Thus, for films with low HPC content (non-interconnected pores), the water permeability of the films increased with increasing ethanol concentration as the diffusion through the ethyl cellulose increased due to swelling. However, for films with higher HPC content (having interconnected pores through the films), the permeability decreased, likely due to the swelling of the ethyl cellulose blocking the pores. The interpretation of the results was supported by dynamic mechanic analysis and SEM analysis © 2010 Elsevier B.V.

  • 26.
    Mak, Wing Cheung
    et al.
    Hong Kong University of Science and Technology, Hong Kong, China.
    Richter, Heike
    Center of Experimental and Cutaneous Physiology, Department of Dematology, Venerology and Allergology, Charité Universitätsmedizin Berlin, Germany.
    Patzelt, Alexa
    Center of Experimental and Cutaneous Physiology, Department of Dematology, Venerology and Allergology, Charité Universitätsmedizin Berlin, Germany.
    Sterry, Wolfram
    Center of Experimental and Cutaneous Physiology, Department of Dematology, Venerology and Allergology, Charité Universitätsmedizin Berlin, Germany.
    Lai, Kwok Kei
    Hong Kong University of Science and Technology, Hong Kong, China.
    Renneberg, Reinhard
    Hong Kong University of Science and Technology, Hong Kong, China.
    Lademann, Jürgen
    Center of Experimental and Cutaneous Physiology, Department of Dematology, Venerology and Allergology, Charité Universitätsmedizin Berlin, Germany.
    Drug delivery into the skin by degradable particles2011Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 79, nr 1, s. 23-27Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recently, it was demonstrated that particles could be utilized as carrier systems for drugs into the hair follicles. In the present study, a two-component drug delivery system is presented consisting of degradable particles loaded with fluorescein isothiocyanate and a separate protease formulation for degradation. The particles were applied alone, 30 min previous to the protease application and simultaneously with the protease onto porcine skin. Subsequently, biopsies were removed, and the penetration depths of the particles were analyzed using laser scanning microscopy.

    The obtained results demonstrate that the particles alone achieved a penetration depth of around 900 μm. Similar results were obtained for the successive application of particles and protease, whereas a release of the fluorescent dye was only observed in the upper 250 μm corresponding to the penetration depth of the protease. In the case of the simultaneous application, the particles were partly dissolved before application, leading to a reduced particle size and diminished penetration depth.

    The results revealed that degradable particles are a promising tool for drug delivery into the skin.

  • 27.
    Morales, Javier O.
    et al.
    College of Pharmacy, University of Texas at Austin.
    McConville, Jason T
    College of Pharmacy, University of Texas at Austin.
    Manufacture and characterization of mucoadhesive buccal films2011Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 77, nr 2, s. 187-199Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The buccal route of administration has a number of advantages including bypassing the gastrointestinal tract and the hepatic first pass effect. Mucoadhesive films are retentive dosage forms and release drug directly into a biological substrate. Furthermore, films have improved patient compliance due to their small size and reduced thickness, compared for example to lozenges and tablets. The development of mucoadhesive buccal films has increased dramatically over the past decade because it is a promising delivery alternative to various therapeutic classes including peptides, vaccines, and nanoparticles. The "film casting process" involves casting of aqueous solutions and/or organic solvents to yield films suitable for this administration route. Over the last decade, hot-melt extrusion has been explored as an alternative manufacturing process and has yielded promising results. Characterization of critical properties such as the mucoadhesive strength, drug content uniformity, and permeation rate represent the major research areas in the design of buccal films. This review will consider the literature that describes the manufacture and characterization of mucoadhesive buccal films.

  • 28.
    Niemelä, E.
    et al.
    Abo Akad Univ, Fac Sci & Engn, Cell Biol, Turku, Finland;Univ Turku, Turku Biosci Ctr, Turku, Finland;Abo Akad Univ, Turku, Finland.
    Desai, D.
    Abo Akad Univ, Fac Sci & Engn, Pharmaceut Sci Lab, Turku, Finland.
    Niemi, R.
    Abo Akad Univ, Fac Sci & Engn, Cell Biol, Turku, Finland.
    Doroszko, Milena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Univ Turku, Inst Biomed, Turku, Finland.
    Özliseli, E.
    Abo Akad Univ, Fac Sci & Engn, Pharmaceut Sci Lab, Turku, Finland.
    Kemppainen, K.
    Abo Akad Univ, Fac Sci & Engn, Cell Biol, Turku, Finland.
    Rahman, N. A.
    Univ Turku, Inst Biomed, Turku, Finland;Med Univ Bialystok, Dept Reprod & Gynecol Endocrinol, Bialystok, Poland.
    Sahlgren, C.
    Abo Akad Univ, Fac Sci & Engn, Cell Biol, Turku, Finland;Univ Turku, Turku Biosci Ctr, Turku, Finland;Abo Akad Univ, Turku, Finland;Eindhoven Univ Technol, Dept Biomed Engn, Eindhoven, Netherlands.
    Törnquist, K.
    Abo Akad Univ, Fac Sci & Engn, Cell Biol, Turku, Finland;Minerva Fdn, Biomed, Helsinki, Finland.
    Eriksson, J. E.
    Abo Akad Univ, Fac Sci & Engn, Cell Biol, Turku, Finland;Univ Turku, Turku Biosci Ctr, Turku, Finland;Abo Akad Univ, Turku, Finland.
    Rosenholm, J. M.
    Abo Akad Univ, Fac Sci & Engn, Pharmaceut Sci Lab, Turku, Finland.
    Nanoparticles carrying fingolimod and methotrexate enables targeted induction of apoptosis and immobilization of invasive thyroid cancer2020Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 148, s. 1-9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Metastatic tumors are the main cause of cancer-related death, as the invading cancer cells disrupt normal functions of distant organs and are nearly impossible to eradicate by traditional cancer therapeutics. This is of special concern when the cancer has created multiple metastases and extensive surgery would be too dangerous to execute. Therefore, combination chemotherapy is often the selected treatment form. However, drug cocktails often have severe adverse effects on healthy cells, whereby the development of targeted drug delivery could minimize side-effects of drugs and increase the efficacy of the combination therapy. In this study, we utilized the folate antagonist methotrexate (MTX) as targeting ligand conjugated onto mesoporous silica nanoparticles (MSNs) for selective eradication of folate receptor-expressing invasive thyroid cancer cells. The MSNs was subsequently loaded with the drug fingolimod (FTY720), which has previously been shown to efficiently inhibit proliferation and invasion of aggressive thyroid cancer cells. To assess the efficiency of our carrier system, comprehensive in vitro methods were employed; including flow cytometry, confocal microscopy, viability assays, invasion assay, and label-free imaging techniques. The in vitro results show that MTX-conjugated and FTY720-loaded MSNs potently attenuated both the proliferation and invasion of the cancerous thyroid cells while keeping the off-target effects in normal thyroid cells reasonably low. For a more physiologically relevant in vivo approach we utilized the chick chorioallantoic membrane (CAM) assay, showing decreased invasive behavior of the thyroid derived xenografts and an increased necrotic phenotype compared to tumors that received the free drug cocktail. Thus, the developed multidrug-loaded MSNs effectively induced apoptosis and immobilization of invasive thyroid cancer cells, and could potentially be used as a carrier system for targeted drug delivery for the treatment of diverse forms of aggressive cancers that expresses folate receptors.

  • 29.
    Nordstrom, Josefina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Kievan, Ingvild
    Alderborn, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    A protocol for the classification of powder compression characteristics2012Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 80, nr 1, s. 209-216Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In this paper, a structured protocol for powder compression analysis as a test to assess the mechanical properties of particles in a formulation development programme is presented. First, the sequence of classification steps of the protocol is described, and secondly, the protocol is illustrated using compression data of six powders of two model substances, sodium chloride and mannitol. From powder compression data, a set of compression variables are derived, and by using critical values of these variables, the stages expressed during the compression of the powders are identified and the powders are classified into groups with respect to the expression of particle rearrangement, particle fragmentation and particle plastic deformation during compression. It is concluded that the proposed protocol could, in a satisfactorily way, describe and distinguish between the powders regarding their compression behaviour. Hence, the protocol could be a valuable tool for the formulation scientist to comprehensively assess important functionality-related characteristics of drugs and excipients.

  • 30.
    Persson, Ann-Sofie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Alderborn, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    A hybrid approach to predict the relationship between tablet tensile strength and compaction pressure using analytical powder compression2018Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 125, s. 28-37Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The objective was to present a hybrid approach to predict the strength-pressure relationship (SPR) of tablets using common compression parameters and a single measurement of tablet tensile strength. Experimental SPR were derived for six pharmaceutical powders with brittle and ductile properties and compared to predicted SPR based on a three-stage approach. The prediction was based on the Kawakita b(-1) parameter and the in-die Heckel yield stress, an estimate of maximal tensile strength, and a parameter proportionality factor alpha. Three values of alpha were used to investigate the influence of the parameter on the SPR. The experimental SPR could satisfactorily be described by the three stage model, however for sodium bicarbonate the tensile strength plateau could not be observed experimentally. The shape of the predicted SPR was to a minor extent influenced by the Kawakita b(-1) but the width of the linear region was highly influenced by alpha. An increased alpha increased the width of the linear region and thus also the maximal predicted tablet tensile strength. Furthermore, the correspondence between experimental and predicted SPR was influenced by the alpha value and satisfactory predictions were in general obtained for alpha = 4.1 indicating the predictive potential of the hybrid approach.

  • 31.
    Roos, Carl
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Dahlgren, David
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjöblom, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Effects of absorption-modifying excipients on jejunal drug absorption in simulated fasted and fed luminal conditionsInngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The pharmaceutical industry, prescribers, and patients have all traditionally preferred oral administration of drug products. In recent years there has been an increase in drug candidates with low solubility and/or low permeability, which may limit the use of oral administration. To increase the possibility of oral administration for the poorly permeating drugs, the use of absorption modifying excipients (AMEs) has been proposed, with the aim of increasing the fraction of dose absorbed. The effects of AMEs have previously been investigated in various animal models, including the single-pass intestinal perfusion (SPIP) in rats. To further improve the biorelevance and the in vivo predictiveness of the SPIP model, four compounds (atenolol, enalaprilat, ketoprofen, metoprolol) were perfused in fasted or fed state simulated intestinal fluid (FaSSIF or FeSSIF) together with the AMEs N-acetyl-cysteine, caprate, or sodium dodecyl sulphate. For the poorly permeating compounds enalaprilat and atenolol, the flux was increased the most by the addition of SDS in both FaSSIF and FeSSIF. For ketoprofen, the flux decreased in the presence of all AMEs in at least one of the perfusion media. The flux of metoprolol was not affected by any of the excipients. The changes in magnitude in the compounds’ absorptions were in general smaller in FeSSIF than in FaSSIF, possibly due to differences in colloidal structures present in FeSSIF that made the AMEs less available. The results in FeSSIF were similar to those from bolus-dosing in rat, which further suggests that the effect of AMEs on permeability is strongly affected by interactions between AMEs and colloidal structures in the intestinal lumen. The results suggest that, when investigating the effects of AMEs, the biorelevance of the SPIP method can be increased by the addition of intraluminal constituents to the perfusate.

  • 32.
    Roos, Carl
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Dahlgren, David
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjöblom, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Sjöblom/Nylander: Gastrointestinal fysiologi.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk farmaceutisk kemi. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, S-75189 Uppsala, Sweden.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Effects of absorption-modifying excipients on jejunal drug absorption in simulated fasted and fed luminal conditions2019Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, s. 387-395Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oral administration of drug products is the preferred administration route. In recent decades there has been an increase in drug candidates with low solubility and/or low permeability. To increase the possibility of oral administration for the poorly permeating drugs, the use of absorption modifying excipients (AMEs) has been proposed. These types of AMEs may also affect the regulatory assessment of a novel drug delivery system if they affect the absorption of a drug from any of the four BCS classes. The effects of AMEs have previously been investigated in various animal models, including the single-pass intestinal perfusion (SPIP) in rats. To further improve the biorelevance and the in vivo predictiveness of the SPIP model, four compounds (atenolol, enalaprilat, ketoprofen, metoprolol) were perfused in fasted or fed state simulated intestinal fluid (FaSSIF or FeSSIF) together with the AMEs N-acetyl-cysteine, caprate, or sodium dodecyl sulfate. For the highly soluble and poorly permeating compounds enalaprilat and atenolol (BCS class III), the flux was increased the most by the addition of SDS in both FaSSIF and FeSSIF. For ketoprofen (BCS class II), the flux decreased in the presence of all AMEs in at least one of the perfusion media. The flux of metoprolol (BCS class I) was not affected by any of the excipients in none of simulated prandial states. The changes in magnitude in the absorption of the compounds were in general smaller in FeSSIF than in FaSSIF. This may be explained by a reduced free concentration AMEs in FeSSIF. Further, the results in FeSSIF were similar to those from intrajejunal bolus administration in rat in a previous study. This suggests that the biorelevance of the SPIP method may be increased when investigating the effects of AMEs, by the addition of intraluminal constituents representative to fasted and/or fed state to the inlet perfusate.

  • 33.
    Roos, Carl
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Dahlgren, David
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjöblom, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk vetenskap.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Jejunal absorption of aprepitant from nanosuspensions: Role of particle size, prandial state and mucus layer.2018Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 132, s. 222-230, artikkel-id S0939-6411(18)30760-4Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The number of highly lipophilic active pharmaceutical ingredients (APIs) in pharmaceutical development has been constantly increasing over recent decades. These APIs often have inherent issues with solubility and dissolution, limiting their oral bioavailability. Traditionally, a reduction in particle size to the micrometer range has been used to improve dissolution. More recently, size reduction to the nanometer range has been introduced, which further increases the dissolution rate, but may also involve other mechanisms for increasing bioavailability. The effect of particle size on the absorption of aprepitant was investigated using the single-pass intestinal perfusion (SPIP) model in the rat jejunum. Phosphate buffer, fasted-state simulated intestinal fluid (FaSSIF), and fed-state simulated intestinal fluid (FeSSIF) were used as perfusion media to increase understanding of the processes involved and the effects of colloidal structures. The role of mucus on intestinal absorption was investigated by adding the mucolytic agent N-acetyl-cysteine (NAC). The absorption of aprepitant from the nanosuspensions was similar with all perfusion media (buffer = FaSSIF = FeSSIF), whereas food had a pronounced effect on absorption from the microsuspensions (FeSSIF > FaSSIF > buffer). The colloidal structures hence contributed to absorption from the microsuspensions. Partitioning of aprepitant from the nanosuspension into the colloidal structures decreased the amount of nanoparticles available, which offset the effect of food. The appearance flux of aprepitant in blood was non-significantly decreased for nanosuspensions of aprepitant with NAC versus without NAC in buffer (ratio of 2:1), indicating that particle deposition in the mucus may have been decreased as the layer thinned, with subsequently reduced intestinal absorption. The study also showed that the SPIP model is suitable for investigating detailed absorption mechanisms using complex perfusion media, which increase the biorelevance of the model.

  • 34.
    Roos, Carl
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Westergren, Jan
    Dahlgren, David
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Mechanistic modelling of intestinal drug absorption: the in vivo effects of nanoparticles, hydrodynamics, and colloidal structures2018Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 133, s. 70-76Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Particle size reduction is a traditional approach to increase the intestinal absorption of active pharmaceutical ingredients with poor intestinal solubility, by increasing the particle dissolution rate. However, an increase in the dissolution rate cannot always fully explain the effects of nanoformulations, and a method of assessing the potential benefits of a nanoformulation in vivo would hence be of great value in drug development. A novel mathematical model of a nanoformulation, including interlinked descriptions of the hydrodynamics, particle dissolution and diffusion of particles and colloidal structures (CS), was developed to predict the combined in vivo effects of these mechanisms on drug absorption. The model successfully described previously reported in vivo observations of nanoformulated aprepitant in rats, at various drug concentrations and in the presence or absence of CS. The increase in absorption rate was explained as a direct consequence of the increased drug concentration at the membrane, caused by the contributing effects of the diffusion of both nanoparticles and CS into which the drug had partitioned. Further simulations supported the conclusion that the model can be applied during drug development to provide a priori assessments of the potential benefits of nanoformulations.

  • 35.
    Tran, Ngo Bich Nga Nathalie
    et al.
    Charite, Germany.
    Knorr, Fanny
    Charite, Germany.
    Mak, Wing Cheung
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Kwan Yee, Cheung
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Richter, Heike
    Charite, Germany.
    Meinke, Martina
    Charite, Germany.
    Lademann, Juergen
    Charite, Germany.
    Patzelt, Alexa
    Charite, Germany.
    Gradient-dependent release of the model drug TRITC-dextran from FITC-labeled BSA hydrogel nanocarriers in the hair follicles of porcine ear skin2017Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 116, s. 12-16Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hair follicle research is currently focused on the development of drug-loaded nanocarriers for the targeting of follicular structures in the treatment of skin and hair follicle-related disorders. In the present study, a dual-label nanocarrier system was implemented in which FITC-labeled BSA hydrogel nanocarriers loaded with the model drug and dye TRITC-dextran were applied topically to porcine ear skin. Follicular penetration and the distribution of both dyes corresponding to the nanocarriers and the model drug in the follicular ducts subsequent to administration to the skin were investigated using confocal laser scanning microscopy. The release of TRITC-dextran from the particles was induced by washing of the nanocarriers, which were kept in a buffer containing TRITC-labeled dextran to balance out the diffusion of the dextran during storage, thereby changing the concentration gradient. The results showed a slightly but statistically significantly deeper follicular penetration of fluorescent signals corresponding to TRITC-dextran as opposed to fluorescence corresponding to the FITC-labeled particles. The different localizations of the dyes in the cross-sections of the skin samples evidenced the release of the model drug from the labeled nanoparticles. (C) 2016 Elsevier B.V. All rights reserved.

  • 36. Unga, Johan
    et al.
    Tajarobi, Farhad
    Norder, Ove
    Frenning, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Larsson, Anette
    Relating solubility data of parabens in liquid PEG 400 to the behaviour of PEG 4000-parabens solid dispersions2009Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 73, nr 2, s. 260-268Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The solid state behaviour of polyethylene glycol 4000 (PEG 4000) and dispersions of a homologous series of parabens (methyl- (MP), ethyl- (EP), propyl- (PP) and butyl- (BP)) were examined and compared to the paraben solubility in liquid PEG 400. Dispersions were prepared by co-melting different amounts of paraben (5-80% (w/w)) and PEG 4000 and were studied using a combination of differential scanning calorimetry (DSC) and small and wide angle X-ray diffraction (SAXD/WAXD). Depending on the concentration of parabens in the dispersions, DSC showed melting peaks from folded and unfolded forms of PEG, a eutectic melting and melting of pure parabens. The fraction of folded PEG increased and the melting temperatures of both PEG forms decreased with increasing paraben content. In an apparent phase diagram of PP-PEG dispersions a eutectic mixture appeared above 5% PP. In addition, a melting peak corresponding to the paraben appeared for dispersion containing more than 60% PP. Similar phase diagrams were shown for the other parabens. The SAXD data and a 1D correlation function analysis revealed that MP and BP were incorporated into the amorphous domains of the lamellae of solid PEG to a higher degree than EP and PP. In addition, the lamellae thickness of PEG and the fraction of amorphous domains increased more for MP and BP compared to EP and PP. BP showed the highest solubility of the parabens followed by MP, EP and PP in both liquid and solid PEG. Furthermore, the thickness of the amorphous domains of the PEG in the different parabens-PEG dispersions could be correlated to the solubility in liquid PEG 400.

  • 37. van den Brand, Dirk
    et al.
    Gorris, Mark A. J.
    van Asbeck, Alexander H.
    Palmen, Emma
    Ebisch, Inge
    Dolstra, Harry
    Hällbrink, Mattias
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Massuger, Leon F. A. G.
    Brock, Roland
    Peptide-mediated delivery of therapeutic mRNA in ovarian cancer2019Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 141, s. 180-190Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ovarian cancer is the most lethal gynecological malignancy in the developed world. In spite of intensive research, the mortality has hardly decreased over the past twenty years. This necessitates the exploration of novel therapeutic modalities. Transient protein expression through delivery of mRNA is emerging as a highly promising option. In contrast to gene therapy there is no risk of integration into the genome. Here, we explore the expression of mRNA in models of ovarian cancer of increasing complexity. The cell-penetrating peptide (CPP) PepFect 14 (PF14) was used to formulate CPP-mRNA nanoparticles. Efficient expression of a reporter protein was achieved in two-dimensional tissue cultures and in three-dimensional cancer cell spheroids. PF14 nano particles greatly outperformed a lipid-based transfection agent in vivo, leading to expression in various cell types of tumor associated tissue. Protein expression was restricted to the peritoneal cavity. Messenger RNA expression across different cell types was confirmed in primary ovarian cancer explants. As ovarian cancer is confined to the peritoneal cavity in most cases, the results create the basis for applications in which the tumor microenviron-ment is transiently modified through protein expression.

  • 38.
    von Witting, Emma
    et al.
    KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lindbo, Sarah
    KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Vorobyeva, Anzhelika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Altai, Mohamed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Oroujeni, Maryam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Hober, Sophia
    KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Selection of the optimal macrocyclic chelators for labeling with 111In and 68Ga improves contrast of HER2 imaging using engineered scaffold protein ADAPT62019Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 140, s. 109-120Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Radionuclide molecular imaging is a promising tool that becomes increasingly important as targeted cancer therapies are developed. To ensure an effective treatment, a molecular stratification of the cancer is a necessity. To accomplish this, visualization of cancer associated molecular abnormalities in vivo by molecular imaging is the method of choice. ADAPTs, a novel type of small protein scaffold, have been utilized to select and develop high affinity binders to different proteinaceous targets. One of these binders, ADAPT6 selectively interacts with human epidermal growth factor 2 (HER2) with low nanomolar affinity and can therefore be used for its in vivo visualization. Molecular design and optimization of labeled anti-HER2 ADAPT has been explored in several earlier studies, showing that small changes in the scaffold affect the biodistribution of the domain. In this study, we evaluate how the biodistribution properties of ADAPT6 is affected by the commonly used maleimido derivatives of the macrocyclic chelators NOTA, NODAGA, DOTA and DOTAGA with the aim to select the best variants for SPECT and PET imaging. The different conjugates were labeled with 111In for SPECT and 68Ga for PET. The acquired data show that the combination of a radionuclide and a chelator for its conjugation has a strong influence on the uptake of ADAPT6 in normal tissues and thereby gives a significant variation in tumor-toorgan ratios. Hence, it was concluded that the best variant for SPECT imaging is 111In-(HE)3DANS-ADAPT6-GSSC-DOTA while the best variant for PET imaging is 68Ga-(HE)3DANS-ADAPT6-GSSC-NODAGA.

  • 39. Zimmermann, A
    et al.
    Millqvist-Fureby, A
    YKI – Ytkemiska institutet.
    Ringkjøbing, Elema M
    Hansen, T
    Müllertz, A
    Hovgaard L,
    Adsorption of pharmaceutical excipients onto microcrystals of siramesine hydrochloride: Effects on physicochemical properties2009Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 71, nr 1, s. 109-116Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A common challenge in the development of new drug substances is poor dissolution characteristics caused by low aqueous solubility. In this study, microcrystals with optimized physicochemical properties were prepared by precipitation in the presence of excipients, which adsorbed to the particle surface and altered particle size, morphology, and dissolution rate. The poorly water-soluble drug siramesine hydrochloride was precipitated by the antisolvent method in the presence of each of various polymeric and surface active excipients. Powder dissolution studies of six of the resulting particle systems showed a significant increase in percent dissolved after 15 min compared to the starting material. A quantitative determination of the amount of excipient adsorbed to the surface of the drug particles proved that only a very small amount of excipient was needed to exert a marked effect on particle properties. The adsorbed amount of excipient constituted less than 1.4% (w/w) of the total particle weight, and thus powders of very high drug loads were obtained. Sodium lauryl sulphate (SLS), hydroxypropyl methylcellulose (HPMC), and hydroxypropyl cellulose (HPC), which exhibited the greatest degree of adsorption, also had the greatest effect on the physicochemical properties of the particles. X-ray Photoelectron Spectroscopy (XPS) analysis of the surface composition and scanning electron microscopy studies on particle morphology suggested that the excipients adsorbed to specific faces of the crystals.

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