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Pharmaceutical Research
Journal Prestige (SJR): 1.077
Citation Impact (citeScore): 3
Number of Followers: 142  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1573-904X - ISSN (Online) 0724-8741
Published by Springer-Verlag Homepage  [2350 journals]
  • Three-Dimensional Printing of Cell Exclusion Spacers (CES) for Use in
           Motility Assays
    • Authors: Christen J. Boyer; David H. Ballard; Jungmi W. Yun; Adam Y. Xiao; Jeffery A. Weisman; Mansoureh Barzegar; Jonathan Steven Alexander
      Abstract: Purpose Cell migration/invasion assays are widely used in commercial drug discovery screening. 3D printing enables the creation of diverse geometric restrictive barrier designs for use in cell motility studies, permitting on-demand assays. Here, the utility of 3D printed cell exclusion spacers (CES) was validated as a cell motility assay. Methods A novel CES fit was fabricated using 3D printing and customized to the size and contour of 12 cell culture plates including 6 well plates of basal human brain vascular endothelial (D3) cell migration cells compared with 6 well plates with D3 cells challenged with 1uM cytochalasin D (Cyto-D), an F-actin anti-motility drug. Control and Cyto-D treated cells were monitored over 3 days under optical microscopy. Results Day 3 cell migration distance for untreated D3 cells was 1515.943μm ± 10.346μm compared to 356.909μm ± 38.562μm for the Cyt-D treated D3 cells (p < 0.0001). By day 3, untreated D3 cells reached confluency and completely filled the original voided spacer regions, while the Cyt-D treated D3 cells remained significantly less motile. Conclusions Cell migration distances were significantly reduced by Cyto-D, supporting the use of 3D printing for cell exclusion assays. 3D printed CES have great potential for studying cell motility, migration/invasion, and complex multi-cell interactions.
      PubDate: 2018-06-04
      DOI: 10.1007/s11095-018-2431-4
      Issue No: Vol. 35, No. 8 (2018)
  • Chimeric Antigen Receptor T-Cells (CAR T-Cells) for Cancer Immunotherapy
           – Moving Target for Industry'
    • Authors: Paula Salmikangas; Niamh Kinsella; Paul Chamberlain
      Abstract: The first CD19 CAR T-cell products, Kymriah and Yescarta, are entering the US market and also being evaluated for marketing authorization in the EU. This breakthrough has expanded the interest and also investments towards novel chimeric antigen receptor (CAR) designs, both for hematological malignancies and solid tumors. At the same time, there is active development in moving from autologous products to allogeneic, off-the-shelf -products. New manufacturing technologies are also emerging for production of these complex genetically-modified cells and even decentralized manufacturing in hospitals is under consideration. However, the high potency of CAR T-cells is associated with toxicity and not all patients respond to the treatment. In addition, the number of patient and product variables impacting the clinical outcome is high. The race towards novel CAR T treatment options for cancer patients has begun, but without careful design of the constructs and overall understanding of the factors that impact the ultimate outcome in each case, the road towards commercial success may be long and winding. This review discusses the product- and patient-related variables that may pose challenges for the industry and developers both from the scientific and regulatory perspective.
      PubDate: 2018-05-31
      DOI: 10.1007/s11095-018-2436-z
      Issue No: Vol. 35, No. 8 (2018)
  • PEG-Benzaldehyde-Hydrazone-Lipid Based PEG-Sheddable pH-Sensitive
           Liposomes: Abilities for Endosomal Escape and Long Circulation
    • Authors: Manju Kanamala; Brian D. Palmer; Hamidreza Ghandehari; William R. Wilson; Zimei Wu
      Abstract: Purpose To fabricate an acid-cleavable PEG polymer for the development of PEG-cleavable pH-sensitive liposomes (CL-pPSL), and to investigate their ability for endosomal escape and long circulation. Methods PEG-benzaldehyde-hydrazone-cholesteryl hemisuccinate (PEGB-Hz-CHEMS) containing hydrazone and ester bonds was synthesised and used to fabricate a dual pH-sensitive CL-pPSL. Non-cleavable PEGylated pH-sensitive liposome (pPSL) was used as a reference and gemcitabine as a model drug. The cell uptake and endosomal escape were investigated in pancreatic cancer Mia PaCa-2 cells and pharmacokinetics were studied in rats. Results The CL-pPSL showed accelerated drug release at endosomal pH 5.0 compared to pPSL. Compared to pPSL, CL-pPSL released their fluorescent payload to cytosol more efficiently and showed a 1.4-fold increase in intracellular gemcitabine concentration and higher cytotoxicity. In rats, injection of gemcitabine loaded CL-pPSL resulted in a slightly smaller Vd (149 ± 27 ml/kg; 170 ± 30 ml/kg) and shorter terminal T1/2 (5.4 ± 0.3 h; 5.8 ± 0.6 h) (both p > 0.05) but a significantly lower AUC (p < 0.01), than pPSL, due to the lower PEGylation degree (1.7 mol%) which means a ‘mushroom’ configuration of PEG. A five-time increase in the dose with CL-pPSL resulted in a 11-fold increase in AUC and a longer T1/2 (8.2 ± 0.5 h). Conclusion The PEG-detachment from the CL-pPSL enhanced endosome escape efficiency compared with pPSL, without significantly compromising their stealth abilities.
      PubDate: 2018-05-31
      DOI: 10.1007/s11095-018-2429-y
      Issue No: Vol. 35, No. 8 (2018)
  • Development of a Simple Mechanical Screening Method for Predicting the
           Feedability of a Pharmaceutical FDM 3D Printing Filament
    • Authors: Jehad M. Nasereddin; Nikolaus Wellner; Muqdad Alhijjaj; Peter Belton; Sheng Qi
      Abstract: Purpose The filament-based feeding mechanism employed by the majority of fused deposition modelling (FDM) 3D printers dictates that the materials must have very specific mechanical characteristics. Without a suitable mechanical profile, the filament can cause blockages in the printer. The purpose of this study was to develop a method to screen the mechanical properties of pharmaceutically-relevant, hot-melt extruded filaments to predetermine their suitability for FDM. Methods A texture analyzer was used to simulate the forces a filament is subjected to inside the printer. The texture analyzer produced a force-distance curve referred to as the flexibility profile. Principal Component Analysis and Correlation Analysis statistical methods were then used to compare the flexibility profiles of commercial filaments to in-house made filaments. Results Principal component analysis showed clearly separated clustering of filaments that suffer from mechanical defects versus filaments which are suitable for printing. Correlation scores likewise showed significantly greater values with feedable filaments than their mechanically deficient counterparts. Conclusion The screening method developed in this study showed, with statistical significance and reproducibility, the ability to predetermine the feedability of extruded filaments into an FDM printer.
      PubDate: 2018-05-31
      DOI: 10.1007/s11095-018-2432-3
      Issue No: Vol. 35, No. 8 (2018)
  • Extended Pharmacokinetic Model of the Rabbit Eye for Intravitreal and
           Intracameral Injections of Macromolecules: Quantitative Analysis of
           Anterior and Posterior Elimination Pathways
    • Authors: Marko Lamminsalo; Ella Taskinen; Timo Karvinen; Astrid Subrizi; Lasse Murtomäki; Arto Urtti; Veli-Pekka Ranta
      Abstract: Purpose To extend the physiological features of the anatomically accurate model of the rabbit eye for intravitreal (IVT) and intracameral (IC) injections of macromolecules. Methods The computational fluid dynamic model of the rabbit eye by Missel (2012) was extended by enhancing the mixing in the anterior chamber with thermal gradient, heat transfer and gravity, and studying its effect on IC injections of hyaluronic acids. In IVT injections of FITC-dextrans (MW 10–157 kDa) the diffusion though retina was defined based on published in vitro data. Systematic changes in retinal permeability and convective transport were made, and the percentages of anterior and posterior elimination pathways were quantified. Simulations were compared with published in vivo data. Results With the enhanced mixing the elimination half-lives of hyaluronic acids after IC injection were 62–100 min that are similar to in vivo data and close to the theoretical value for the well-stirred anterior chamber (57 min). In IVT injections of FITC-dextrans a good match between simulations and in vivo data was obtained when the percentage of anterior elimination pathway was over 80%. Conclusions The simulations with the extended model closely resemble in vivo pharmacokinetics, and the model is a valuable tool for data interpretation and predictions.
      PubDate: 2018-05-31
      DOI: 10.1007/s11095-018-2435-0
      Issue No: Vol. 35, No. 8 (2018)
  • Synthesis, Characterization and Biocompatibility of N -palmitoyl
           L-alanine-based Organogels as Sustained Implants of Granisetron and
           Evaluation of thier Antiemetic Effect
    • Authors: Hala Bakr El-Nassan; Aliaa Nabil ElMeshad; Walaa Wadie; Rabab H. Sayed
      Abstract: Purpose To assess the gelation power of N-palmitoyl L-alanine derivatives in injectable oils and to use the best chosen organogel as parenteral implant of granisetron for the treatment of emesis. Methods Twelve N-palmitoyl L-alanine derived organogels were developed and evaluated in terms of morphology, thermal properties and in vivo performance. The ability of the selected formula to form in situ gel upon subcutaneous injection in rats and its biocompatibility were monitored over 2 weeks by histopathological examination of the injection site. Results The acid derivative (N-palmitoyl L-alanine; PA) was superior to ester derivatives. The chosen formula (PA/safflower oil 10% w/v) was successful in forming an in situ gel of granisetron when subcutaneously injected in rats, lasting for 2 weeks and proved to be biocompatible by histopathological examination. Moreover, it exerted an extended antiemetic activity by decreasing the cisplatin-induced pica for a duration of 96 h and reduced preprotachykinin A mRNA expression and Substance P level for up to 4 days (gastric tissue) or 5 days (medulla oblongata) in rats. Conclusion Granisetron organogel could be considered as a safe, sustained-release and supportive anticancer treatment in both acute and chronic emesis as well as an accompanying treatment with chemotherapeutics in cancer cases.
      PubDate: 2018-05-29
      DOI: 10.1007/s11095-018-2433-2
      Issue No: Vol. 35, No. 8 (2018)
  • Iron-Based Metal-Organic Frameworks as a Theranostic Carrier for Local
           Tuberculosis Therapy
    • Authors: Gabriela Wyszogrodzka; Przemysław Dorożyński; Barbara Gil; Wieslaw J. Roth; Maciej Strzempek; Bartosz Marszałek; Władysław P. Węglarz; Elżbieta Menaszek; Weronika Strzempek; Piotr Kulinowski
      Abstract: Purpose The purpose of the study was initial evaluation of applicability of metal organic framework (MOF) Fe-MIL-101-NH2 as a theranostic carrier of antituberculous drug in terms of its functionality, i.e. drug loading, drug dissolution, magnetic resonance imaging (MRI) contrast and cytotoxic safety. Methods Fe-MIL-101-NH2 was characterized using X-ray powder diffraction, FTIR spectrometry and scanning electron microscopy. The particle size analysis was determined using laser diffraction. Magnetic resonance relaxometry and MRI were carried out on phantoms of the MOF system suspended in polymer solution. Drug dissolution studies were conducted using Franz cells. For MOF cytotoxicity, commercially available fibroblasts L929 were cultured in Eagle’s Minimum Essential Medium supplemented with 10% fetal bovine serum. Results MOF particles were loaded with 12% of isoniazid. The particle size (3.37–6.45 μm) depended on the micronization method used. The proposed drug delivery system can also serve as the MRI contrast agent. The drug dissolution showed extended release of isoniazid. MOF particles accumulated in the L929 fibroblast cytoplasmic area, suggesting MOF release the drug inside the cells. The cytotoxicity confirmed safety of MOF system. Conclusions The application of MOF for extended release inhalable system proposes the novel strategy for delivery of standard antimycobacterial agents combined with monitoring of their distribution within the lung tissue.
      PubDate: 2018-05-18
      DOI: 10.1007/s11095-018-2425-2
      Issue No: Vol. 35, No. 7 (2018)
  • Identification of N-Terminally Truncated Derivatives of Insulin Analogs
           Formed in Pharmaceutical Formulations
    • Authors: Joanna Zielińska; Jacek Stadnik; Anna Bierczyńska-Krzysik; Dorota Stadnik
      Abstract: Purpose Isolation and identification of unknown impurities of recombinant insulin lispro (produced at IBA) formed during accelerated stability testing of pharmaceutical solutions. For comparative purposes also commercially available formulations of recombinant human insulin (Humulin S®; Lilly), recombinant insulin lispro (Humalog®; Lilly), recombinant insulin aspart (NovoRapid® Penfill®; Novo Nordisk), recombinant insulin detemir (Levemir®; Novo Nordisk) and recombinant insulin glargine (Lantus®; Sanofi-Aventis) were analyzed. Methods The impurities of insulin analogs were isolated by RP-HPLC and identified with peptide mass fingerprinting using MALDI-TOF/TOF mass spectrometry. Results The identified derivatives were N-terminally truncated insulin analog impurities of decreased molecular mass of 119, 147 and 377 Da related to the original protein. The modifications resulting in a mass decrease were detected at the N-terminus of B chains of insulin lispro, insulin aspart, human insulin, insulin glargine, insulin detemir in all tested formulations. To our knowledge it is the first time that these impurities are reported. Conclusions The following derivatives formed by truncation of the B chain in insulin analogs were identified in pharmaceutical formulations: desPheB1-N-formyl-ValB2 derivative, desPheB1 derivative, pyroGluB4 derivative.
      PubDate: 2018-05-16
      DOI: 10.1007/s11095-018-2426-1
      Issue No: Vol. 35, No. 7 (2018)
  • Kinetics and Characterization of Non-enzymatic Fragmentation of Monoclonal
           Antibody Therapeutics
    • Authors: Sahithi Ravuluri; Rohit Bansal; Nidhi Chhabra; Anurag S. Rathore
      Abstract: Purpose To understand non-enzymatic hydrolytic fragmentation of a monoclonal antibody therapeutic under temperature stressed conditions and investigating possible mechanism for the same. Methods The mAb therapeutic was incubated at 50°C in phosphate buffer at pH 6.5 and fragmentation was monitored at different ionic strengths under stressed conditions. The incubated mAb was sampled at regular time intervals by analytical Size Exclusion Chromatography (SEC). Results It was observed that 57% of the mAb product fragmented over 4 days into two fragment species – Fc-Fab and Fab with molecular weights of 97 KDa and 47 KDa, respectively, as measured by mass spectrometry (MS) and sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). The fragmentation rate was slow initially and then accelerated with time. No change in % aggregate level was observed in this duration, implying that degradation was primarily via fragmentation at high temperature. Kinetics of hydrolytic fragmentation was hypothesized and SEC data was fitted to estimate the kinetic rate constants. While degradation of the monomer into fragment species was non-Arrhenius with a negative activation energy, further degradation of Fab-Fc fragments into Fab or Fc fragments followed Arrhenius Law with an activation energy of 2.1 and 15.38 kcal/mol, respectively. Conclusion High temperature (50°C) causes mAb to cleave at the hinge region to form Fab-Fc and Fab/Fc, as confirmed by dynamic light scattering, SDS-PAGE, SEC, and MS. A kinetic model for hydrolytic fragmentation has been proposed. The results are expected to assist end users in formulation development as well as in monitoring stability of biotherapeutic products.
      PubDate: 2018-05-14
      DOI: 10.1007/s11095-018-2415-4
      Issue No: Vol. 35, No. 7 (2018)
  • Determining the Effect of pH on the Partitioning of Neutral, Cationic and
           Anionic Chemicals to Artificial Sebum: New Physicochemical Insight and
           QSPR Model
    • Authors: Senpei Yang; Lingyi Li; Tao Chen; Lujia Han; Guoping Lian
      Abstract: ABSTRACT Purpose Sebum is an important shunt pathway for transdermal permeation and targeted delivery, but there have been limited studies on its permeation properties. Here we report a measurement and modelling study of solute partition to artificial sebum. Methods Equilibrium experiments were carried out for the sebum-water partition coefficients of 23 neutral, cationic and anionic compounds at different pH. Results Sebum-water partition coefficients not only depend on the hydrophobicity of the chemical but also on pH. As pH increases from 4.2 to 7.4, the partition of cationic chemicals to sebum increased rapidly. This appears to be due to increased electrostatic attraction between the cationic chemical and the fatty acids in sebum. Whereas for anionic chemicals, their sebum partition coefficients are negligibly small, which might result from their electrostatic repulsion to fatty acids. Increase in pH also resulted in a slight decrease of sebum partition of neutral chemicals. Conclusions Based on the observed pH impact on the sebum-water partition of neutral, cationic and anionic compounds, a new quantitative structure-property relationship (QSPR) model has been proposed. This mathematical model considers the hydrophobic interaction and electrostatic interaction as the main mechanisms for the partition of neutral, cationic and anionic chemicals to sebum.
      PubDate: 2018-05-14
      DOI: 10.1007/s11095-018-2411-8
      Issue No: Vol. 35, No. 7 (2018)
  • Recrystallization and Water Absorption Properties of Vitrified Trehalose
           Near Room Temperature
    • Authors: Ryo Shirakashi; Kiyoshi Takano
      Abstract: Purpose To provide the physicochemical properties of vitrified trehalose for predicting its recrystallization. Methods Thin films of vitrified trehalose solutions were prepared at room temperature and exposed to various humid and temperature atmospheres. The in-situ amount of retained water in the vacuum-dried trehalose thin film during exposure was determined using its FTIR spectrum by quantifying the extremely infinitesimal amount of retained water in the trehalose solution. Recrystallization of the sample was also assessed by the FTIR spectrum of trehalose dihydrate. Results The effective water absorption coefficient, h meff , exponentially increased to the water activity of the trehalose sample, A w , at 25°C and 40°C at which the increasing rates are comparable. The surface energy of trehalose dihydrate, γ, was found to be lower than the value calculated from the reported equation, neglecting the effects of the activity of the solute and solvent water. Conclusions The retained water in trehalose considerably increases its affinity for water vapor, and the change in this affinity with regard to the water activity is nearly independent of temperature. The dihydrate nucleation rate of trehalose-water system is maximal when trehalose weight ratio is ~0.8 at 25°C and is slightly higher (~0.85) at 40°C.
      PubDate: 2018-05-10
      DOI: 10.1007/s11095-018-2420-7
      Issue No: Vol. 35, No. 7 (2018)
  • Comparative Study of the Dose-Dependence of OATP1B Inhibition by
           Rifampicin Using Probe Drugs and Endogenous Substrates in Healthy
    • Authors: Issey Takehara; Takashi Yoshikado; Keiko Ishigame; Daiki Mori; Ken-ichi Furihata; Nobuaki Watanabe; Osamu Ando; Kazuya Maeda; Yuichi Sugiyama; Hiroyuki Kusuhara
      Abstract: Purpose To evaluate association of the dose-dependent effect of rifampicin, an OATP1B inhibitor, on the plasma concentration–time profiles among OATP1B substrates drugs and endogenous substrates. Methods Eight healthy volunteers received atorvastatin (1 mg), pitavastatin (0.2 mg), rosuvastatin (0.5 mg), and fluvastatin (2 mg) alone or with rifampicin (300 or 600 mg) in a crossover fashion. The plasma concentrations of these OATP1B probe drugs, total and direct bilirubin, glycochenodeoxycholate-3-sulfate (GCDCA-S), and coproporphyrin I, were determined. Results The most striking effect of 600 mg rifampicin was on atorvastatin (6.0-times increase) and GCDCA-S (10-times increase). The AUC0–24h of atorvastatin was reasonably correlated with that of pitavastatin (r2 = 0.73) and with the AUC0–4h of fluvastatin (r2 = 0.62) and sufficiently with the AUC0–24h of rosuvastatin (r2 = 0.32). The AUC0–24h of GCDCA-S was reasonably correlated with those of direct bilirubin (r2 = 0.74) and coproporphyrin I (r2 = 0.80), and sufficiently with that of total bilirubin (r2 = 0.30). The AUC0–24h of GCDCA-S, direct bilirubin, and coproporphyrin I were reasonably correlated with that of atorvastatin (r2 = 0.54–0.70). Conclusion These results suggest that direct bilirubin, GCDCA-S, and coproporphyrin I are promising surrogate probes for the quantitative assessment of potential OATP1B-mediated DDI.
      PubDate: 2018-05-10
      DOI: 10.1007/s11095-018-2416-3
      Issue No: Vol. 35, No. 7 (2018)
  • Polymorphic Transformation of Indomethacin during Hot Melt Extrusion
           Granulation: Process and Dissolution Control
    • Authors: Ting Xu; Kajalajit Nahar; Rutesh Dave; Simon Bates; Kenneth Morris
      Abstract: ABSTRACT Purpose To study and elucidate the effect of the intensity and duration of processing stresses on the possible solid-state changes during a hot melt extrusion granulation process. Methods Blends of α-indomethacin and PEG 3350 (w/w 4:1) were granulated using various screw sizes/designs on the melt extruder under different temperature regimes. Differential Scanning Calorimetry and X-ray Powder Diffraction were employed for characterization. The dissolution behavior of the pure polymorphs and the resulting granules was determined using in-situ fiber optic UV testing system. An XRPD quantitation method using Excel full pattern fitting was developed to determine the concentration of each constituent (amorphous, α and γ indomethacin and PEG) in samples collected from each functioning zone and in granules. Results Analysis of in-process samples and granules revealed that higher temperature (≥130°C) and shear stress accelerated the process induced phase transitions from amorphous and/or the α form to γ indomethacin during heating stage. However, rapid cooling resulted in an increased percentage of the α form allowing isolation of the meta-stable form. Conclusions By determining the conditions that either prevent or facilitate process induced transformations of IMC polymorphs during melt granulation, a design space was developed to control the polymorph present in the resulting granules. This represents the conditions necessary to balance the thermodynamic relationships between the polymorphs of the IMC system and the kinetics of the possible transformations as a function of the processing stresses.
      PubDate: 2018-05-10
      DOI: 10.1007/s11095-017-2325-x
      Issue No: Vol. 35, No. 7 (2018)
  • Denaturation and Aggregation of Interferon-τ in Aqueous Solution
    • Authors: Ryan R. Manning; Glenn A. Wilson; Ryan E. Holcomb; Nathaniel J. Zbacnik; Auria A. Tellechea; Chelsey L. Gilley-Dunn; Ryan J. Krammes; Nathan S. Krammes; Gabriel J. Evans; Charles S. Henry; Mark Cornell Manning; Brian M. Murphy; Robert W. Payne; Derrick S. Katayama
      Abstract: Purpose To evaluate the different degrees of residual structure in the unfolded state of interferon-τ using chemical denaturation as a function of temperature by both urea and guanidinium hydrochloride. Methods Asymmetrical flow field-flow fractionation (AF4) using both UV and multi-angle laser light scattering (MALLS). Flow Microscopy. All subvisible particle imaging measurements were made using a FlowCAM flow imaging system. Results The two different denaturants provided different estimates of the conformational stability of the protein when extrapolated back to zero denaturant concentration. This suggests that urea and guanidinium hydrochloride (GnHCl) produce different degrees of residual structure in the unfolded state of interferon-τ. The differences were most pronounced at low temperature, suggesting that the residual structure in the denatured state is progressively lost when samples are heated above 25°C. The extent of expansion in the unfolded states was estimated from the m-values and was also measured using AF4. In contrast, the overall size of interferon-τ was determined by AF4 to decrease in the presence of histidine, which is known to bind to the native state, thereby providing conformational stabilization. Addition of histidine as the buffer resulted in formation of fewer subvisible particles over time at 50°C. Finally, the thermal aggregation was monitored using AF4 and the rate constants were found to be comparable to those determined previously by SEC and DLS. The thermal aggregation appears to be consistent with a nucleation-dependent mechanism with a critical nucleus size of 4 ± 1. Conclusion Chemical denaturation of interferon-τ by urea or GnHCl produces differing amounts of residual structure in the denatured state, leading to differing estimates of conformational stability. AF4 was used to determine changes in size, both upon ligand binding as well as upon denaturation with GnHCl. Histidine appears to be the preferred buffer for interferon-τ, as shown by slower formation of soluble aggregates and reduced levels of subvisible particles when heated at 50°C.
      PubDate: 2018-05-09
      DOI: 10.1007/s11095-018-2418-1
      Issue No: Vol. 35, No. 7 (2018)
  • Effect of Technically Relevant X-Ray Doses on the Structure and Function
           of Alcohol Dehydrogenase and Hen Egg-White Lysozyme
    • Authors: Lisa-Marie Schaden; Miriam Wimmer-Teubenbacher; Johannes Poms; Peter Laggner; Karl Lohner; Stephan Sacher; Johannes G. Khinast; Sharareh Salar-Behzadi
      Abstract: Purpose The effect of different irradiation doses on the structure and activity of lyophilized powders of Hen Egg-White Lysozyme (HEWL) and alcohol dehydrogenase (ADH) was investigated using these substances as models for robust and sensitive proteins, respectively. Three doses were selected to cover the ranges of radio-sterilization (25kGy), treatment of blood products (25Gy) and annual background radiation dose (approximately 2mGy). The results offer an initial screening of different irradiation doses and support the development of X-ray imaging methods as non-destructive process analytical technology (PAT) tools for detecting the visible particulate matters in such products. Methods HEWL and ADH were exposed to X-rays in the solid state. The effect of irradiation was determined directly after irradiation and after storage. Structural changes and degradation were investigated using SAXS, SDS-PAGE and HPLC-MS. Protein functionality was assessed via activity assays. Results Lower irradiation doses of 25Gy and 2mGy had no significant impact on the structure and enzyme activity. The dose of 25kGy caused a significant decrease in the enzyme activity and structural changes immediately after irradiation of ADH and after storage of irradiated HEWL at −20°C. Conclusion The results emphasize the importance of careful selection of radiation doses for development of X-ray imaging methods as PAT tools inspection of solid biopharmaceutical products.
      PubDate: 2018-05-07
      DOI: 10.1007/s11095-018-2417-2
      Issue No: Vol. 35, No. 7 (2018)
  • Label-Free, Flow-Imaging Methods for Determination of Cell Concentration
           and Viability
    • Abstract: Purpose To investigate the potential of two flow imaging microscopy (FIM) techniques (Micro-Flow Imaging (MFI) and FlowCAM) to determine total cell concentration and cell viability. Methods B-lineage acute lymphoblastic leukemia (B-ALL) cells of 2 different donors were exposed to ambient conditions. Samples were taken at different days and measured with MFI, FlowCAM, hemocytometry and automated cell counting. Dead and live cells from a fresh B-ALL cell suspension were fractionated by flow cytometry in order to derive software filters based on morphological parameters of separate cell populations with MFI and FlowCAM. The filter sets were used to assess cell viability in the measured samples. Results All techniques gave fairly similar cell concentration values over the whole incubation period. MFI showed to be superior with respect to precision, whereas FlowCAM provided particle images with a higher resolution. Moreover, both FIM methods were able to provide similar results for cell viability as the conventional methods (hemocytometry and automated cell counting). Conclusion FIM-based methods may be advantageous over conventional cell methods for determining total cell concentration and cell viability, as FIM measures much larger sample volumes, does not require labeling, is less laborious and provides images of individual cells.
      PubDate: 2018-05-30
      DOI: 10.1007/s11095-018-2422-5
  • Considerations for the Use of Polysorbates in Biopharmaceuticals
    • Abstract: Purpose Polysorbates are commonly added to protein formulations and serve an important function as stabilizers. This paper reviews recent literature detailing some of the issues seen with the use of polysorbate 80 and polysorbate 20 in protein formulations. Based on this knowledge, a development strategy is proposed that leads to a control strategy for polysorbates in protein formulations. Methods A consortium of Biopharmaceutical scientists working in the area of protein formulations, shared experiences with polysorbates as stabilizers in their formulations. Results Based on the authors experiences and recent published literature, a recommendation is put forth for a development strategy which will lead into the appropriate control strategy for these excipients. Conclusions An appropriate control strategy may comprise one or more elements of raw material, in-process and manufacturing controls. Additionally, understanding the role, if any, polysorbates play during stability will require knowledge of the criticality of the excipient, based upon its impact on CQAs due to variations in concentration and degradation level.
      PubDate: 2018-05-24
      DOI: 10.1007/s11095-018-2430-5
  • Membrane Loaded Copper Oleate PEGylated Liposome Combined with Disulfiram
           for Improving Synergistic Antitumor Effect In Vivo
    • Abstract: Purpose This work aims to create a novel Cu2+ liposome with excellent loading stability and develop synergistic effect with disulfiram (DSF) for the treatment of tumor. Methods Copper oleate was incorporated into the liposome membrane via alcohol injection method in this work. In vitro release test was applied to evaluate the release profile of the liposomes. Pharmacokinetic studies were performed in rats and the antitumor efficacy was assessed in mice bearing hepatoma xenografts. Results The copper oleate liposome (Cu(OI)2-L) was formulated and the loading efficiency were more than 85%. TEM images confirmed that the Cu(OI)2-L had a spherical morphology with an average diameter of 100 nm. Cu(OI)2-L displayed a biphasic release profile, with >70% retained drug over 8 h incubation in PBS at pH 7.4. Pharmacokinetic studies demonstrated that Cu(OI)2-L had a prolonged circulation time and increased AUC when compared to the injection of copper oleate solution. The antitumor efficacy test demonstrated an enhanced tumor inhibition rate with the treatment of Cu(OI)2-L and DSF nanoparticles, indicating an improved synergistic antitumor effect. Conclusions The Cu(OI)2-L was suitable to be employed in combination with disulfiram for tumor treatment and can also open up opportunities for targeted delivery of copper.
      PubDate: 2018-05-23
      DOI: 10.1007/s11095-018-2414-5
  • Impact of Vial Washing and Depyrogenation on Surface Properties and
           Delamination Risk of Glass Vials
    • Abstract: Purpose The proper understanding of glass delamination is important to glass manufacturers, pharmaceutical companies, and health authorities to mitigate the occurrence of glass flakes from the vial when in contact with specific drug product solutions. The surface of glass vials is altered during glass cane- and vial forming processes and is exposed to different stress conditions during drug product processing before coming in contact with the drug product solution. In this study, the impact of vial washing and depyrogenation including an evaluation of various residual water volumes on surface properties of glass vials was investigated for a defined set of vials. Methods 3D laser scanning microscopy was established as a new method for topographic analysis of curved surfaces of glass vials operating in high-throughput mode. A subset of vials was subsequently exposed to delamination stress testing and both the stressed solution and inner vial surface were analyzed by a panel of conventional and advanced analytical techniques including 3D laser scanning microscopy. Results The data showed that vial washing and depyrogenation strongly influenced surface properties, in particular those of uncoated vials. Surface characteristics such as pits increased depending on the process conditions, which especially applies to Expansion 33 vials. Even low residual water volumes of 50 μL after vial washing were sufficient to change the surface properties of the glass and weaken the surface in those positions prone to glass delamination. An increase in pits was related to a greater risk for glass delamination. Conclusions Vial processing conditions need to be assessed when aiming at minimizing the glass delamination risk during parenteral product storage.
      PubDate: 2018-05-23
      DOI: 10.1007/s11095-018-2421-6
  • Pectin and Mucin Enhance the Bioadhesion of Drug Loaded Nanofibrillated
           Cellulose Films
    • Abstract: Purpose Bioadhesion is an important property of biological membranes, that can be utilized in pharmaceutical and biomedical applications. In this study, we have fabricated mucoadhesive drug releasing films with bio-based, non-toxic and biodegradable polymers that do not require chemical modifications. Methods Nanofibrillar cellulose and anionic type nanofibrillar cellulose were used as film forming materials with known mucoadhesive components mucin, pectin and chitosan as functional bioadhesion enhancers. Different polymer combinations were investigated to study the adhesiveness, solid state characteristics, film morphology, swelling, mechanical properties, drug release with the model compound metronidazole and in vitro cytotoxicity using TR146 cells to model buccal epithelium. Results SEM revealed lamellar structures within the films, which had a thickness ranging 40–240 μm depending on the film polymer composition. All bioadhesive components were non-toxic and showed high adhesiveness. Rapid drug release was observed, as 60–80% of the total amount of metronidazole was released in 30 min depending on the film formulation. Conclusions The liquid molding used was a straightforward and simple method to produce drug releasing highly mucoadhesive films, which could be utilized in treating local oral diseases, such as periodontitis. All materials used were natural biodegradable polymers from renewable sources, which are generally regarded as safe.
      PubDate: 2018-05-22
      DOI: 10.1007/s11095-018-2428-z
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