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Pharmaceutical Research

Carsten Ehrhardt
November 16, 2017: Pharmaceutical Research
Linda O Narhi, Quanzhou Luo, Jette Wypych, Riccardo Torosantucci, Andrea Hawe, Kiyoshi Fujimori, Yasser Nashed-Samuel, Vibha Jawa, Marisa K Joubert, Wim Jiskoot
PURPOSE: To physicochemically characterize and compare monoclonal antibody (mAb) solutions containing aggregates generated via metal catalyzed oxidation (MCO). METHODS: Two monoclonal IgG2s (mAb1 and mAb2) and one monoclonal IgG1 (rituximab) were exposed to MCO with the copper/ascorbic acid oxidative system, by using several different methods. The products obtained were characterized by complementary techniques for aggregate and particle analysis (from oligomers to micron sized species), and mass spectrometry methods to determine the residual copper content and chemical modifications of the proteins...
November 6, 2017: Pharmaceutical Research
Abbas Hemati Azandaryani, Soheila Kashanian, Katayoun Derakhshandeh
PURPOSE: Letrozole as a steroidal anticancer drug with hydrophobic nature is usually administrated by oral route for patient treatment and the injectable formulation for this drug has not still been reported. In this study, a new letrozole incorporated folate-conjugated polymer - lipid hybrid nanoparticles - is introduced for cancer treatment. METHODS: Nanoparticles were fabricated via modified oil in water ionic gelation method using optimization parameters and then were coupled to folic acid using carbodiimide activation...
November 6, 2017: Pharmaceutical Research
Fateme Haghiralsadat, Ghasem Amoabediny, Samira Naderinezhad, Kamran Nazmi, Jantine Posthuma De Boer, Behrouz Zandieh-Doulabi, Tymour Forouzanfar, Marco N Helder
PURPOSE: To employ Doxorubicin-loaded liposomes, modified with YSA-peptide to target EphA2, to reduce adverse effects against primary bone cells and maximize toxicity against Saos-2 osteosarcoma cells. METHODS: PEGylated liposomes were prepared by thin film method using Dipalmitoylphosphatidylcholine (DPPC), cholesterol and distearylphosphatidylethanolamine-polyethyleneglycol conjugate (DSPE-mPEG) in 67.9:29.1:3 M ratios, and loaded with DOX (L-DOX) by pH-gradient method...
November 6, 2017: Pharmaceutical Research
Kuan-Hui Hsu, Karishma Gupta, Harish Nayaka, Aashrit Donthi, Siddarth Kaul, Anuj Chauhan
PURPOSE: About 70% of eye drops contain benzalkonium chloride (BAK) to maintain sterility. BAK is an effective preservative but it can cause irritation and toxicity. We propose to mitigate ocular toxicity without compromising sterility by incorporating a filter into an eye drop bottle to selectively remove BAK during the process of drop instillation. METHODS: The filter is a packed bed of particles made from poly(2-hydroxyethyl methacrylate) (pHEMA), which is a common ophthalmic material...
October 24, 2017: Pharmaceutical Research
Daniel Weinbuch, Mitchel Ruigrok, Wim Jiskoot, Andrea Hawe
PURPOSE: To investigate the effect of nanoparticulate impurities (NPIs) isolated from pharmaceutical-grade sucrose, on the stability of monoclonal antibodies (mAbs). METHODS: NPIs were purified from pharmaceutical-grade sucrose and spiked into trastuzumab, rituximab, infliximab, and cetuximab formulations. The stability of the mAbs as a function of storage time, temperature, and NPI concentration was assessed by visual inspection, flow-imaging microscopy, nanoparticle tracking analysis, size-exclusion chromatography, capillary isoelectric focusing, and intrinsic differential scanning fluorimetry...
October 24, 2017: Pharmaceutical Research
Thiago Goulart Rosa, Sofia Nascimento Dos Santos, Terezina de Jesus Andreoli Pinto, Daniele Dal Molim Ghisleni, Thereza Christina Barja-Fidalgo, Eduardo Ricci-Junior, Mohammed Al-Qahtani, Jan Kozempel, Emerson Soares Bernardes, Ralph Santos-Oliveira
PURPOSE: The purpose of this article was to develop, characterize and test (in vivo) dacarbazine microparticles that may be labeled with 99mTc and Ra-223 for both use: diagnostic and therapy of metastatic melanoma. METHODS: We developed by double emulsion solvent evaporation methodology the microparticle. The characterization has been done using, Dynamic Light Scattering (DLS) and Scanning Electron Microscopy (SEM). The labeling with 99mTc and Ra-223 has been done by the direct labeling process...
October 23, 2017: Pharmaceutical Research
Shubhajit Paul, Changquan Calvin Sun
PURPOSE: To systematically assess the dependence of friability on tablet mechanical properties, compaction pressure, and tablet porosity. METHODS: Several common excipients and their mixtures exhibiting diverse mechanical properties were analyzed. Tablet elastic modulus, hardness, brittleness, porosity, and tensile strength were determined using standard techniques and then were correlated to tablet friability both individually and as a group to derive a universal model...
October 5, 2017: Pharmaceutical Research
Naomi Rozentul, Yosef Avrahami, Moran Shubely, Laura Levy, Anna Munder, Guy Cohen, Erol Cerasi, Shlomo Sasson, Arie Gruzman
PURPOSE: A series of novel polycyclic aromatic compounds that augment the rate of glucose uptake in L6 myotubes and increase glucose-stimulated insulin secretion from beta-cells were synthesized. Designing these molecules, we have aimed at the two main pathogenic mechanisms of T2D, deficient insulin secretion and diminished glucose clearance. The ultimate purpose of this work was to create a novel antidiabetic drug candidate with bi-functional mode of action. METHODS: All presented compounds were synthesized, and characterized in house...
October 5, 2017: Pharmaceutical Research
Jace W Jones, Isabel L Jackson, Zeljko Vujaskovic, Michael D Kaytor, Maureen A Kane
PURPOSE: Biomarkers serve a number of purposes during drug development including defining the natural history of injury/disease, serving as a secondary endpoint or trigger for intervention, and/or aiding in the selection of an effective dose in humans. BIO 300 is a patent-protected pharmaceutical formulation of nanoparticles of synthetic genistein being developed by Humanetics Corporation. The primary goal of this metabolomic discovery experiment was to identify biomarkers that correlate with radiation-induced lung injury and BIO 300 efficacy for mitigating tissue damage based upon the primary endpoint of survival...
October 2, 2017: Pharmaceutical Research
Valvanera Vozmediano, Ander Sologuren, John C Lukas, Nerea Leal, Mónica Rodriguez
PURPOSE: Bilastine is an H1 antagonist whose pharmacokinetics (PK) and pharmacodynamics (PD) have been resolved in adults with a therapeutic oral dose of 20 mg/day. Bilastine has favorable characteristics for use in pediatrics but the PK/PD and the optimal dose in children had yet to be clinically explored. The purpose is to: (1) Develop an ontogenic predictive model of bilastine PK linked to the PD in adults by integrating current knowledge; (2) Use the model to design a PK study in children; (3) Confirm the selected dose and the study design through the evaluation of model predictability in the first recruited children; (4) Consider for inclusion the group of younger children (< 6 years)...
October 2, 2017: Pharmaceutical Research
Paolo Arosio
An increasing amount of findings suggests that the aggregation of soluble peptides and proteins into amyloid fibrils is a relevant upstream process in the complex cascade of events leading to the pathology of Alzheimer's disease and several other neurodegenerative disorders. Nevertheless, several aspects of the correlation between the aggregation process and the onset and development of the pathology remain largely elusive. In this context, biophysical and biochemical studies in test tubes have proven extremely powerful in providing quantitative information about the structure and the reactivity of amyloids at the molecular level...
September 28, 2017: Pharmaceutical Research
Hitesh S Purohit, Lynne S Taylor
PURPOSE: The aim of this research was to study the interplay of solid and solution state phase transformations during the dissolution of ritonavir (RTV) amorphous solid dispersions (ASDs). METHODS: RTV ASDs with polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) were prepared at 10-50% drug loading by solvent evaporation. The miscibility of RTV ASDs was studied before and after exposure to 97% relative humidity (RH)...
September 27, 2017: Pharmaceutical Research
Kati-Sisko Vellonen, Jouni Ihalainen, Marie-Christine Boucau, Fabien Gosselet, Théo Picardat, Mikko Gynther, Katja M Kanninen, Anthony R White, Tarja Malm, Jari Koistinaho, Markus M Forsberg, Marika Ruponen
PURPOSE: Alzheimer's disease (AD) may disturb functions of the blood-brain barrier and change the disposition of drugs to the brain. This study assessed the disease-induced changes in drug transporters in the brain capillaries of transgenic AD mice. METHODS: Eighteen drug transporters and four tight junction-associated proteins were analyzed by RT-qPCR in cortex, hippocampus and cerebellum tissue samples of 12-16-month-old APdE9, Tg2576 and APP/PS1 transgenic mice and their healthy age-matched controls...
September 26, 2017: Pharmaceutical Research
Steffen E Storck, Claus U Pietrzik
The accumulation of the neurotoxin beta-amyloid (Aβ) is a major hallmark in Alzheimer's disease (AD). Aβ homeostasis in the brain is governed by its production and various clearance mechanisms. Both pathways are influenced by the ubiquitously expressed low-density lipoprotein receptor-related protein 1 (LRP1). In cerebral blood vessels, LRP1 is an important mediator for the rapid removal of Aβ from brain via transport across the blood-brain barrier (BBB). Here, we summarize recent findings on LRP1 function and discuss the targeting of LRP1 as a modulator for AD pathology and drug delivery into the brain...
September 25, 2017: Pharmaceutical Research
Chenguang Pu, Qiao Wang, Hongjuan Zhang, Jingxin Gou, Yuting Guo, Xinyi Tan, Bin Xie, Na Yin, Haibing He, Yu Zhang, Yanjiao Wang, Tian Yin, Xing Tang
PURPOSE: The mechanism of PRG release from PLGA microspheres was studied and the correlation of in vitro and in vivo analyses was assessed. METHODS: PRG-loaded microspheres were prepared by the emulsion-evaporate method. The physical state of PRG and microstructure changings during the drug release period were evaluated by powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM) respectively. Pharmacokinetic studies were performed in male Sprague-Dawley rats, and the in vivo-in vitro correlation (IVIVC) was established by linear fitting of the cumulative release (%) in vitro and fraction of absorption (%) in vivo...
September 25, 2017: Pharmaceutical Research
Zhengxiong Li, Linlin Zhang, Cui Tang, Chunhua Yin
PURPOSE: The present study is aimed at designing an appropriate co-delivery system for chemotherapeutic drugs and gene drugs with high loading capacity, on-demand release behaviors, efficient endosomal escape, and enhanced nucleic localization, thereby providing efficacious antitumor activity. METHODS: Schiff-base linked imidazole dendritic mesoporous silica nanoparticles (SL-IDMSN) were developed and employed to load doxorubicin (DOX) and survivin shRNA-expressing plasmid (iSur-pDNA) to form nanocomplexes...
September 25, 2017: Pharmaceutical Research
Lærke Arnfast, Md Kamruzzaman, Korbinian Löbmann, Johanna Aho, Stefania Baldursdottir, Thomas Rades, Jukka Rantanen
PURPOSE: Many future drug products will be based on innovative manufacturing solutions, which will increase the need for a thorough understanding of the interplay between drug material properties and processability. In this study, hot melt extrusion of a drug-drug mixture with minimal amount of polymeric excipient was investigated. METHODS: Using indomethacin-cimetidine as a model drug-drug system, processability of physical mixtures with and without 5% (w/w) of polyethylene oxide (PEO) were studied using Differential Scanning Calorimetry (DSC) and Small Amplitude Oscillatory Shear (SAOS) rheometry...
September 19, 2017: Pharmaceutical Research
Daniel Steinmann, Olivier Mozziconacci, Rupesh Bommana, John F Stobaugh, Y John Wang, Christian Schöneich
PURPOSE: Comprehensive product characterization was performed for the photodegradation of protein disulfides, representatively of human growth hormone (somatotropin; hGH), in order to provide a product database, which will be useful for the general analysis of protein stability. METHODS: HGH was photo-irradiated at λ = 254 and λ > 295 nm and tryptic digests were analyzed by HPLC-MS to investigate light-induced disulfide degradation pathways. RESULTS: A total of 60 products were detected, and structures/tentative structures were assigned to the products by MS(2) and MS(3) analysis...
September 18, 2017: Pharmaceutical Research
Cynthia Bosquillon, Michaela Madlova, Nilesh Patel, Nicola Clear, Ben Forbes
PURPOSE: To evaluate the ability of human airway epithelial cell layers and a simple rat isolated perfused lung (IPL) model to predict pulmonary drug absorption in rats in vivo. METHOD: The permeability of seven compounds selected to possess a range of lipophilicity was measured in two airway cell lines (Calu-3 and 16HBE14o-), in normal human bronchial epithelial (NHBE) cells and using a simple isolated perfused lungs (IPL) technique. Data from the cell layers and ex vivo lungs were compared to published absorption rates from rat lungs measured in vivo...
September 18, 2017: Pharmaceutical Research
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