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protein formulation,biopharmaceuticals

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https://www.readbyqxmd.com/read/29339145/ocular-delivery-of-proteins-and-peptides-challenges-and-novel-formulation-approaches
#1
Abhirup Mandal, Dhananjay Pal, Vibhuti Agrahari, Hoang My Trinh, Mary Joseph, Ashim K Mitra
The impact of proteins and peptides on the treatment of various conditions including ocular diseases over the past few decades has been advanced by substantial breakthroughs in structural biochemistry, genetic engineering, formulation and delivery approaches. Formulation and delivery of proteins and peptides, such as monoclonal antibodies, aptamers, recombinant proteins and peptides to ocular tissues poses significant challenges owing to their large size, poor permeation and susceptibility to degradation. A wide range of advanced drug delivery systems including polymeric controlled release systems, cell-based delivery and nanowafers are being exploited to overcome the challenges of frequent administration to ocular tissues...
January 12, 2018: Advanced Drug Delivery Reviews
https://www.readbyqxmd.com/read/29315487/using-extensional-flow-to-reveal-diverse-aggregation-landscapes-for-three-igg1-molecules
#2
Leon F Willis, Amit Kumar, John Dobson, Nick Bond, David Lowe, Richard Turner, Sheena E Radford, Nikil Kapur, David J Brockwell
Monoclonal antibodies (mAbs) currently dominate the biopharmaceutical sector due to their potency and efficacy against a range of disease targets. These proteinaceous therapeutics are, however, susceptible to unfolding, mis-folding and aggregation by environmental perturbations. Aggregation thus poses an enormous challenge to biopharmaceutical development, production, formulation and storage. Hydrodynamic forces have also been linked to aggregation, but the ability of different flow fields (e.g. shear and extensional flow) to trigger aggregation has remained unclear...
January 8, 2018: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/29288093/notorious-but-not-understood-how-liquid-air-interfacial-stress-triggers-protein-aggregation
#3
Ellen Koepf, Simon Eisele, Rudolf Schroeder, Gerald Brezesinski, Wolfgang Friess
Protein aggregation is a major challenge in the development of biopharmaceuticals. As the pathways of aggregation are manifold, good understanding of the mechanisms behind is essential. Particularly, the presence of liquid-air interfaces has been identified to trigger the formation of large protein particles. Investigations of two monoclonal antibodies (IgGs) at the liquid-air interface exhibited the formation of a highly compressible film. An inhomogeneous protein distribution across the interface with areas of increased packing density was discovered by Brewster-Angle microscopy...
December 26, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/29258899/preferential-exclusion-mechanism-by-carbohydrates-on-protein-stabilization-using-thermodynamic-evaluation
#4
Nam Ah Kim, Ritu Thapa, Seong Hoon Jeong
Carbohydrates are widely used as additives for biopharmaceutical formulations, but the mechanisms by which they confer stability to and their applicability on protein stability remain undiscovered. Herein, we aimed to elucidate these mechanisms, by studying the thermodynamic changes using isothermal titration calorimetry and micro-differential scanning calorimetry. Furthermore, conventional biophysical analyses, namely circular dichroism, dynamic light scattering, and size-exclusion chromatography, were used to investigate the beneficial effects of carbohydrates on protein stability...
December 16, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/29197156/identification-of-aggregates-in-therapeutic-formulations-of-recombinant-full-length-factor-viii-products-by-sedimentation-velocity-analytical-ultracentrifugation
#5
J F Healey, E T Parker, P Lollar
BACKGROUND: The development of inhibitory anti-factor VIII (fVIII) antibodies is the most serious complication in the management of patients with hemophilia A. Studies have suggested that recombinant full-length fVIII is more immunogenic than plasma-derived fVIII and that among recombinant fVIII products, Kogenate is more immunogenic than Advate. Aggregates in biopharmaceutical products are considered a risk factor for the development of anti-drug antibodies. OBJECTIVE: To evaluate recombinant full-length fVIII products for the presence of aggregates...
December 2, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29192343/a-view-on-the-importance-of-multi-attribute-method-for-measuring-purity-of-biopharmaceuticals-and-improving-overall-control-strategy
#6
Richard S Rogers, Michael Abernathy, Douglas D Richardson, Jason C Rouse, Justin B Sperry, Patrick Swann, Jette Wypych, Christopher Yu, Li Zang, Rohini Deshpande
Today, we are experiencing unprecedented growth and innovation within the pharmaceutical industry. Established protein therapeutic modalities, such as recombinant human proteins, monoclonal antibodies (mAbs), and fusion proteins, are being used to treat previously unmet medical needs. Novel therapies such as bispecific T cell engagers (BiTEs), chimeric antigen T cell receptors (CARTs), siRNA, and gene therapies are paving the path towards increasingly personalized medicine. This advancement of new indications and therapeutic modalities is paralleled by development of new analytical technologies and methods that provide enhanced information content in a more efficient manner...
November 30, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29183741/arginine-as-an-excipient-for-protein-freeze-drying-a-mini-review
#7
Peter Stärtzel
Successful development of marketable freeze-dried protein formulations requires adequate stabilization of the active biopharmaceutical ingredient. The choice of a stabilizer must therefore be based on sound knowledge of the physical and chemical properties of the excipients and specific needs of the protein component. Amino acids, such as arginine, have exhibit cryo- and lyoprotective effects similar to those of sugars and/or polymers and may therefore be considered to be an alternative approach to these established formulation strategies...
November 25, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29141152/tm-values-and-unfolded-fraction-can-predict-aggregation-rates-for-gcsf-variant-formulations-but-not-under-predominantly-native-conditions
#8
Mathew J Robinson, Paul Matejtschuk, Adrian F Bristow, Paul A Dalby
Protein engineering and formulation optimisation strategies can be taken to minimise protein aggregation in the biopharmaceutical industry. Short-term stability measures such as the mid-point transition temperature (Tm) for global unfolding provide convenient surrogates for longer-term (eg 2-year) degradation kinetics, with which to optimise formulations on practical time-scales. While successful in some cases, their limitations have not been fully evaluated or understood. Tm values are known to correlate with chemical degradation kinetics for wild-type granulocyte colony stimulating factor (GCSF) at pH 4-5...
November 15, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29059588/enablement-of-the-direct-analysis-of-excipients-in-monoclonal-antibody-formulations-through-the-incorporation-of-a-wide-pore-c18-protein-trap-with-hydrophilic-interaction-liquid-chromatography
#9
Jason Z Huang, Shujie Lin, Zongyun Huang, Mark S Bolgar
Establishing and maintaining the correct formulation composition is essential for ensuring the stability of biopharmaceutical drug products. A barrier to the routine assessment of excipient concentration is the lack of convenient and robust methods for the direct analysis of solutions containing high protein concentrations. To address this need an HPLC method was developed utilizing a wide-pore C18 guard column to trap proteins in-line with a hydrophilic interaction liquid chromatographic column to separate excipients...
October 16, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28993217/mechanistic-pbpk-modeling-of-the-dissolution-and-food-effect-of-a-bcs-iv-compound-the-venetoclax-story
#10
Arian Emami Riedmaier, David J Lindley, Jeffrey A Hall, Steven Castleberry, Russell T Slade, Patricia Stuart, Robert A Carr, Thomas B Borchardt, Daniel A J Bow, Marjoleen Nijsen
PURPOSE: Venetoclax, a selective B-cell lymphoma-2 inhibitor, is a biopharmaceutics classification system (BCS) class IV compound. The aim of this study was to develop a physiologically-based pharmacokinetic (PBPK) model to mechanistically describe absorption and disposition of an amorphous solid dispersion (ASD) formulation of venetoclax in humans. METHODS: A mechanistic PBPK model was developed incorporating measured amorphous solubility, dissolution, metabolism and plasma protein binding...
October 6, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28939518/trimethylamine-n-oxide-tmao-is-a-counteracting-solute-of-benzyl-alcohol-for-multi-dose-formulation-of-immunoglobulin
#11
Shunsuke Yoshizawa, Shogo Oki, Tsutomu Arakawa, Kentaro Shiraki
Multi-dose formulation of biopharmaceuticals contains an antimicrobial preservative, which may facilitate aggregation of the proteins due to their hydrophobic protein binding. Here, we have investigated the effects of co-solvents on heat-induced protein aggregation in the presence of an antimicrobial preservative. Human immunoglobulin G (IgG) and benzyl alcohol were chosen because of their wide usage as a pharmaceutical protein and a preservative. Trimethylamine N-oxide (TMAO) was found to be the most effective additive in suppressing benzyl alcohol-induced IgG aggregation among the additives tested...
September 20, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28917988/a-comprehensive-screening-platform-for-aerosolizable-protein-formulations-for-intranasal-and-pulmonary-drug-delivery
#12
Martina Röhm, Stefan Carle, Frank Maigler, Johannes Flamm, Viktoria Kramer, Chrystelle Mavoungou, Otmar Schmid, Katharina Schindowski
Aerosolized administration of biopharmaceuticals to the airways is a promising route for nasal and pulmonary drug delivery, but - in contrast to small molecules - little is known about the effects of aerosolization on safety and efficacy of biopharmaceuticals. Proteins are sensitive against aerosolization-associated shear stress. Tailored formulations can shield proteins and enhance permeation, but formulation development requires extensive screening approaches. Thus, the aim of this study was to develop a cell-based in vitro technology platform that includes screening of protein quality after aerosolization and transepithelial permeation...
October 30, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28865117/development-of-a-general-defined-medium-for-pichia-pastoris
#13
Catherine B Matthews, Angel Kuo, Kerry R Love, J Christopher Love
Pichia pastoris is widely used as a host for recombinant protein production. More than 500 proteins have been expressed in the organism at a variety of cultivation scales, from small shake flasks to large bioreactors. Large-scale fermentation strategies typically employ chemically defined growth medium because of its greater batch-to-batch consistency and in many cases, lower costs compared to complex medium. For biopharmaceuticals, defined growth medium may also simplify downstream purification and regulatory documentation...
September 2, 2017: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/28818376/an-overview-on-the-strategies-to-exploit-rice-endosperm-as-production-platform-for-biopharmaceuticals
#14
REVIEW
Fumio Takaiwa, Yuhya Wakasa, Shimpei Hayashi, Taiji Kawakatsu
Cereal seed has been utilized as production platform for high-value biopharmaceutical proteins. Especially, protein bodies (PBs) in seeds are not only natural specialized storage organs of seed storage proteins (SSPs), but also suitable intracellular deposition compartment for recombinant proteins. When various recombinant proteins were produced as secretory proteins by attaching N terminal ER signal peptide and C terminal KDEL endoplasmic reticulum (ER) retention signal or as fusion proteins with SSPs, high amounts of recombinant proteins can be predominantly accumulated in the PBs...
October 2017: Plant Science: An International Journal of Experimental Plant Biology
https://www.readbyqxmd.com/read/28716374/high-throughput-quantitation-of-fc-containing-recombinant-proteins-in-cell-culture-supernatant-by-fluorescence-polarization-spectroscopy
#15
Ben Thompson, Jerry Clifford, Mike Jenns, Andrew Smith, Ray Field, Kalpana Nayyar, David C James
Measurement of recombinant protein product titer critically underpins all biopharmaceutical manufacturing process development, as well as diverse research and discovery activity. Here, we describe a simple rapid (<2 min per 96 samples) 96-well microplate-based assay that enables high-throughput quantitation of recombinant immunoglobulin G and Fc-containing IgG derivatives in mammalian cell culture supernatant over a wide dynamic range of 2.5-80 mg/L, using microplate fluorescence polarization (FP) spectroscopy...
October 1, 2017: Analytical Biochemistry
https://www.readbyqxmd.com/read/28699244/biophysical-characterization-of-layer-by-layer-synthesis-of-aptamer-drug-microparticles-for-enhanced-cell-targeting
#16
Kei X Tan, Michael K Danquah, Amandeep Sidhu, Sie Yon Lau, Clarence M Ongkudon
Targeted delivery of drug molecules to specific cells in mammalian systems demonstrates a great potential to enhance the efficacy of current pharmaceutical therapies. Conventional strategies for pharmaceutical delivery are often associated with poor therapeutic indices and high systemic cytotoxicity, and this results in poor disease suppression, low surviving rates, and potential contraindication of drug formulation. The emergence of aptamers has elicited new research interests into enhanced targeted drug delivery due to their unique characteristics as targeting elements...
July 11, 2017: Biotechnology Progress
https://www.readbyqxmd.com/read/28649842/lipo-oligomer-nanoformulations-for-targeted-intracellular-protein-delivery
#17
Peng Zhang, Benjamin Steinborn, Ulrich Lächelt, Stefan Zahler, Ernst Wagner
Here, we report novel lipo-oligoaminoamide nanoformulations for targeted intracellular protein delivery. Formulations are generated by first bioreversibly conjugating a sequence-defined amphiphilic lipo-oligomer 728 to the cargo protein via disulfide bonds, followed by formulation of the formed 728-SS-protein conjugate with different helper lipids in various compositions. The triblock oligoaminoamide 728 contains cysteines for reversible covalent protein conjugation and cross-link-stabilization of formed nanoparticles, polyethylene glycol (PEG) for shielding, and providing a hydrophilic domain, eight cationizable succinoyl tetraethylene pentamine (Stp) repeats for endosomal buffering and escape into the cytosol, and a tetra-oleic acid block for hydrophobic stabilization...
July 10, 2017: Biomacromolecules
https://www.readbyqxmd.com/read/28625725/closing-the-gap-counting-and-sizing-of-particles-across-submicron-range-by-flow-cytometry-in-therapeutic-protein-products
#18
Liling Zhang, Shuai Shi, Valentyn Antochshuk
Quantification and size distribution characterization of subvisible particles in parenteral biopharmaceutics, present as both proteinaceous and nonproteinaceous particles in the size range from 0.1 to 100 μm, are important for biopharmaceutical industry due to their potential safety and efficacy implications. Although a number of analytical techniques are available to count and size subvisible particles, characterization of particles ≤2 μm remains a significant challenge due to technical limitations of existing particle counting instruments...
June 15, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28624419/thermo-optical-protein-characterization-for-straightforward-preformulation-development
#19
Randy Wanner, Dennis Breitsprecher, Stefan Duhr, Philipp Baaske, Gerhard Winter
The determination of protein unfolding and aggregation characteristics during preformulation is of major significance for the development of biopharmaceuticals. The aim of this study was to investigate the feasibility of a new immobilization- and label-free thermo-optical approach as an orthogonal method for material and time-saving early formulation and drugability screenings. In the experimental setup used, changes in the intrinsic tryptophan fluorescence of the protein were measured during IR laser-induced heating of the samples...
June 15, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28617076/characterization-of-highly-concentrated-antibody-solution-a-toolbox-for-the-description-of-protein-long-term-solution-stability
#20
Marie-Therese Schermeyer, Anna K Wöll, Bas Kokke, Michel Eppink, Jürgen Hubbuch
High protein titers are gaining importance in biopharmaceutical industry. A major challenge in the development of highly concentrated mAb solutions is their long-term stability and often incalculable viscosity. The complexity of the molecule itself, as well as the various molecular interactions, make it difficult to describe their solution behavior. To study the formulation stability, long- and short-range interactions and the formation of complex network structures have to be taken into account. For a better understanding of highly concentrated solutions, we combined established and novel analytical tools to characterize the effect of solution properties on the stability of highly concentrated mAb formulations...
October 2017: MAbs
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