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protein formulation,biopharmaceuticals

Stijn H S Koshari, Jean L Ross, Purnendu K Nayak, Isidro E Zarraga, Karthikan Rajagopal, Norman J Wagner, Abraham M Lenhoff
Protein-stabilizer microheterogeneity is believed to influence long-term protein stability in solid-state biopharmaceutical formulations and its characterization is therefore essential for the rational design of stable formulations. However, the spatial distribution of the protein and the stabilizer in a solid-state formulation is, in general, difficult to characterize because of the lack of a functional, simple, and reliable characterization technique. We demonstrate the use of confocal fluorescence microscopy with fluorescently labeled monoclonal antibodies (mAbs) and antibody fragments (Fabs) to directly visualize three-dimensional particle morphologies and protein distributions in dried biopharmaceutical formulations, without restrictions on processing conditions or the need for extensive data analysis...
January 17, 2017: Molecular Pharmaceutics
Matthew J Webber, Eric A Appel, Brittany Vinciguerra, Abel B Cortinas, Lavanya S Thapa, Siddharth Jhunjhunwala, Lyle Isaacs, Robert Langer, Daniel G Anderson
The covalent modification of therapeutic biomolecules has been broadly explored, leading to a number of clinically approved modified protein drugs. These modifications are typically intended to address challenges arising in biopharmaceutical practice by promoting improved stability and shelf life of therapeutic proteins in formulation, or modifying pharmacokinetics in the body. Toward these objectives, covalent modification with poly(ethylene glycol) (PEG) has been a common direction. Here, a platform approach to biopharmaceutical modification is described that relies on noncovalent, supramolecular host-guest interactions to endow proteins with prosthetic functionality...
December 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
Mark L Brader, Edward N Baker, Michael F Dunn, Thomas M Laue, John F Carpenter
Every major biopharmaceutical company incorporates a protein crystallography unit that is central to its structure-based drug discovery efforts. Yet these capabilities are rarely leveraged toward the formal higher order structural characterization that is so challenging but integral to large-scale biologics manufacturing. Although the biotech industry laments the shortcomings of its favored biophysical techniques, x-ray crystallography is not even considered for drug development. Why not? We suggest that this is due, at least in part, to outdated thinking (for a recent industry-wide survey, see Gabrielson JP, Weiss IV WF...
February 2017: Journal of Pharmaceutical Sciences
Xiaobo Chen, Fang Zeng, Tao Huang, Liang Cheng, Huan Liu, Rui Gong
Fc-based therapeutics including therapeutic full-size monoclonal antibodies (mAbs) and Fc-fusion proteins represent fastest-growing market in biopharmaceutical industrial. However, one major challenge during development of Fc-based therapeutics is how to maintain their efficacy in clinic use. Many factors may lead to failure in final marketing. For example, the stability and aggregation resistance might not be high enough for bearing the disadvantages during fermentation, purification, formulation, storage, shipment and other steps in manufacture and sale...
November 17, 2016: Current Pharmaceutical Biotechnology
Sophia G Antimisiaris
Dried reconstituted vesicles (DRV) are liposomes that are formulated under mild conditions and have the capability to entrap substantially high amounts of hydrophilic solutes (compared to other types of liposomes). These characteristics make this liposome type ideal for entrapment of labile substances, as peptide, protein, or DNA vaccines, or in general biopharmaceuticals and sensitive drugs. In this chapter, all possible types of DRV liposomes (with respect to the encapsulated molecule characteristics and/or their applications in therapeutics) are introduced, and preparation methodologies (for each type) are described in detail...
2017: Methods in Molecular Biology
Katharina Christin Bauer, Susanna Suhm, Anna Katharina Wöll, Jürgen Hubbuch
In concentrated protein solutions attractive protein interactions may not only cause the formation of undesired aggregates but also of gel-like networks with elevated viscosity. To guarantee stable biopharmaceutical processes and safe formulations, both phenomenons have to be avoided as these may hinder regular processing steps. This work screens the impact of additives on both phase behavior and viscosity of concentrated protein solutions. For this purpose, additives known for stabilizing proteins in solution or modulating the dynamic viscosity were selected...
January 10, 2017: International Journal of Pharmaceutics
Cyrus D Agarabi, Brittany K Chavez, Scott C Lute, Erik K Read, Sarah Rogstad, David Awotwe-Otoo, Matthew R Brown, Michael T Boyne, Kurt A Brorson
Linkage of upstream cell culture with downstream processing and purification is an aspect of Quality by Design crucial for efficient and consistent production of high quality biopharmaceutical proteins. In a previous Plackett-Burman screening study of parallel bioreactor cultures we evaluated main effects of 11 process variables, such as agitation, sparge rate, feeding regimens, dissolved oxygen set point, inoculation density, supplement addition, temperature, and pH shifts. In this follow-up study, we observed linkages between cell culture process parameters and downstream capture chromatography performance and subsequent antibody attributes...
November 4, 2016: Biotechnology Progress
Lauren Platts, Samuel J Darby, Robert J Falconer
The positively charged amino acids are commonly used excipients in biopharmaceutical formulations for stabilization of therapeutic proteins, yet the mechanisms for their modulation of protein stability are poorly understood. In this study, both lysine and histidine are shown to affect the thermal stability of myoglobin, bovine serum albumin, and lysozyme through a combination of mechanisms governed by their respective functional side chains and glycine, similar to arginine. This study provides evidence that at low concentrations, lysine and histidine interact with proteins by a combination of (1) direct electrostatic interactions with negatively charged side chains, (2) possible binding to high-affinity hydrophobic binding sites, and (3) glycine-mediated weak interactions with peptide backbone and polar side chains...
October 21, 2016: Journal of Pharmaceutical Sciences
Tongkai Chen, Chuwen Li, Ye Li, Xiang Yi, Simon Ming-Yuen Lee, Ying Zheng
Schisantherin A (SA) is a promising anti-Parkinsonism Chinese herbal medicine but with poor water solubility and challenges to be delivered to the brain. We formulated SA as nanocrystals (SA-NC), aiming to improve its solubility and pharmacokinetic profile and thus provide a potential therapeutic agent for the treatment of Parkinson's disease (PD). The rod-shaped SA-NC had a particle size of ∼160 nm with 33.3% drug loading, and the nanocrystals exhibited a fast dissolution rate in vitro. The intact drug nanocrystals could be internalized into Madin-Darby canine kidney (MDCK) cells, which were followed by rapid intracellular release, and most of the drug was transported to the basolateral side in its soluble form...
November 7, 2016: Molecular Pharmaceutics
Xinsheng Tian, M Reza Nejadnik, Dorrit Baunsgaard, Anette Henriksen, Christian Rischel, Wim Jiskoot
Nanoparticle tracking analysis (NTA) has attracted great interest for application in the field of submicron particle characterization for biopharmaceuticals. It has the virtue of direct sample visualization and particle-by-particle tracking, but the complexity of method development has limited its routine applicability. We systematically evaluated data collection and processing parameters as well as sample handling methods using shake-stressed protein samples. The camera shutter and gain were identified as the key factors influencing NTA results...
November 2016: Journal of Pharmaceutical Sciences
Bin Deng, Cristina Lento, Derek J Wilson
Protein therapeutics have emerged as a major class of biopharmaceuticals over the past several decades, a trend that has motivated the advancement of bioanalytical technologies for protein therapeutic characterization. Hydrogen deuterium exchange mass spectrometry (HDX-MS) is a powerful and sensitive technique that can probe the higher order structure of proteins and has been used in the assessment and development of monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs) and biosimilar antibodies. It has also been used to quantify protein-ligand, protein-receptor and other protein-protein interactions involved in signaling pathways...
October 12, 2016: Analytica Chimica Acta
Kelly Zhang, Xiaodong Liu
Mixed-mode chromatography (MMC) is a fast growing area in recent years, thanks to the new generation of mixed-mode stationary phases and better understanding of multimode interactions. MMC has superior applications in the separation of compounds that are not retained or not well resolved by typical reversed-phase LC methods, especially for polar and charged molecules. Due to the multiple retention modes that a single MMC column can offer, often MMC provides additional dimension to a separation method by adjusting the mobile phase conditions...
October 25, 2016: Journal of Pharmaceutical and Biomedical Analysis
Hideyo Inouye, Damian Houde, Deniz B Temel, Lee Makowski
Characterization of immunoglobulin solutions at high concentrations represents a significant challenge. A current trend in the biopharmaceutical industry is to manufacture highly concentrated drug products, which can be used to deliver high doses in small volumes, via subcutaneous injections. Studying a molecule's structure and properties in its final drug product formulation is ideal, but characterization is typically performed under dilute solution conditions with critical stabilizing buffer components removed because of interference effects, which can result in an incomplete understanding of the molecule's properties...
November 2016: Journal of Pharmaceutical Sciences
Lukas Brückl, Rainer Hahn, Mauro Sergi, Stefan Scheler
Particle formation by physical degradation during the compounding step of biopharmaceuticals is a common concern and found in vessels with bottom mounted stirrers. It was potentially linked to sliding bearings, however, the exact mechanism was still unclear. In this study, custom designed small scale bearings in combination with an IgG1 antibody as model protein were used for investigations of the degradation mechanism inside a bearing. Thereby, abrasion of adsorbed proteins by contact sliding was identified as prevailing protein degradation mechanism and was quantified by an increase in turbidity and by monomer loss...
September 25, 2016: International Journal of Pharmaceutics
Fernanda Andrade, Pedro Fonte, Ana Costa, Cassilda Cunha Reis, Rute Nunes, Andreia Almeida, Domingos Ferreira, Mireia Oliva, Bruno Sarmento
AIM: Explore the use of polymeric micelles in the development of powders intended for pulmonary delivery of biopharmaceuticals, using insulin as a model protein. MATERIALS & METHODS: Formulations were assessed in vitro for aerosolization properties and in vivo for efficacy and safety using a streptozotocin-induced diabetic rat model. RESULTS: Powders presented good aerosolization properties like fine particle fraction superior to 40% and a mass median aerodynamic diameter inferior of 6 μm...
September 2016: Nanomedicine
M M R Meor Mohd Affandi, Minaketan Tripathy, A B A Majeed
Categorized as a Biopharmaceutics Classification System Class II drugs, atorvastatin (ATV) exhibits low aqueous solubility and bioavailability thus presenting an obstacle and great challenge to formulation researchers. Numerous studies are available in regard to the solubility enhancement of ATV, but very few actually describe this phenomenon in terms of thermodynamics and the solute-solvent interaction. Arginine (ARG) is an amino acid that has been reported to enhance the solubility of the highly insoluble wheat protein gluten through hydrogen bonding and π electron-cation interaction...
July 2016: Journal of Advanced Pharmaceutical Technology & Research
Katharina Christin Bauer, Mathias Göbel, Marie-Luise Schwab, Marie-Therese Schermeyer, Jürgen Hubbuch
The colloidal stability of a protein solution during downstream processing, formulation, and storage is a key issue for the biopharmaceutical production process. Thus, knowledge about colloidal solution characteristics, such as the tendency to form aggregates or high viscosity, at various processing conditions is of interest. This work correlates changes in the apparent diffusion coefficient as a parameter of protein interactions with observed protein aggregation and dynamic viscosity of the respective protein samples...
September 10, 2016: International Journal of Pharmaceutics
Mie Kristensen, Hanne Mørck Nielsen
Non-injectable delivery of peptide and protein drugs is hampered by their labile nature, hydrophilicity, and large molecular size; thus limiting their permeation across mucosae, which represent major biochemical and physical barriers to drugs administered via e.g. the oral, nasal, and pulmonary routes. However, in recent years cell-penetrating peptides (CPP) have emerged as promising tools to enhance mucosal delivery of co-administered or conjugated peptide and protein cargo and more advanced CPP-cargo formulations are emerging...
April 2016: Tissue Barriers
Lungile Nomcebo Thwala, Veronique Préat, Noémi Stefania Csaba
Protein and peptide-based drugs are preferred therapeutics due to their specificity but are mainly administered by injection. Alternative routes for peptide delivery are preferred because of their ease of administration and increased patient compliance. Areas covered: This review provides a critical overview of current strategies for non-invasive mucosal delivery routes of therapeutic proteins and peptides, with emphasis on their advantages and limitations. Selected new trends and interesting novel formulations in advanced preclinical and clinical development stages for the pulmonary, nasal and the oral route are discussed for the most relevant peptide and protein drugs in terms of their specific requirements and intended therapeutic applications...
January 2017: Expert Opinion on Drug Delivery
Mohammad Amin Mohammad, Ian M Grimsey, Robert T Forbes
It is important for the formulators of biopharmaceuticals to predict the folding-unfolding transition of proteins. This enables them to process proteins under predetermined conditions, without denaturation. Depending on the apparent denaturation temperature (Tm) of lysozyme, we have derived an equation describing its folding-unfolding transition diagram. According to the water content and temperature, this diagram was divided into three different areas, namely, the area of the water-folded lysozyme phase, the area of the water-folded lysozyme phase and the bulk water phase, and the area of the denatured lysozyme phase...
July 21, 2016: Journal of Physical Chemistry. B
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