Browsing by Subject "Viscosity"

Now showing 1 - 17 of 17

Design of co-solute formulations for stable, highly concentrated monoclonal antibody solutions with low viscosity
(2018-05-04) Hung, Jessica Joy; Johnston, Keith P., 1955-; Truskett, Thomas Michael, 1973-; Keitz, Benjamin K; Maynard, Jennifer A; Stachowiak, Jeanne C
Highly concentrated (> 200 mg/mL) monoclonal antibody (mAb) formulations with low viscosities are strongly desired for subcutaneous drug delivery for the treatment of diseases such as cancer, as well as for improved process performance and yield in the manufacture of biologic drug products using techniques such as tangential flow ultrafiltration (TFF). High solution viscosities and protein aggregation at high concentration lead to significant challenges in delivery and manufacture due to large injection forces, product loss to aggregation, and significant filter membrane fouling and flux decay. Small-molecule co-solutes such as arginine and various electrolytes have in some cases been shown to greatly reduce the viscosity of concentrated mAbs. However, the mechanism by which co-solutes modify mAb viscosity is not well understood. Herein, we investigate the effects of several amino acids and inorganic ionic co-solutes on the viscosity of mAbs up to 250 mg/mL. We relate the viscosities to measurable changes in the protein-protein interactions (PPI), mAb structure and self-association behavior as assessed through small-volume techniques such as dynamic light scattering (DLS), static light scattering (SLS) and fluorescence correlation spectroscopy (FCS) in order to develop a hierarchical understanding of the co-solute effects on the mAb behavior. We demonstrate that the viscosity reduction is correlated with the disruption of mAb self-association and attractive PPI, as directly probed by SLS, DLS, FCS and rheology. We also relate these changes in the PPI and viscosity to the physical properties of the co-solute, including the co-solute charge, size and shape. Finally, we demonstrate that the ability to mitigate aggregation and membrane fouling by the combined addition of viscosity-reducing co-solutes and selection of hollow fiber filter geometries resulted in a high-concentration transmembrane flux three-fold higher than that of conventional low co-solute buffer formulations. The reduced viscosities also led to more uniform axial transmembrane pressure and shear stress profiles, which led to reduce irreversible aggregation and solution turbidity during ultrafiltration.
Development of reference materials for cement paste and mortar : calibration of rheological measurements
(2016-05) Olivas, Alex; Ferron, Raissa; Liljestrand, Howard M. (Howard Michael); Ferraris, Chiara
This thesis presents the results of five interrelated projects conducted to advance the progress of studies in concrete workability. Specifically, work conducted towards the development and certification of Standard Reference Materials (SRMs) for cement paste and mortar rheometers are presented in this work. Other SRMs developed at NIST have served a multitude of services, but these SRMs target the concrete industry by providing a way for commercially available rheometers to be calibrated economically and with good accuracy. However, problems regarding reproducibility of the paste SRM, microbial contamination of the paste SRM, and accuracy of measurement have limited the development of the concrete SRM. Thus, this thesis includes studies that were conducted to address these issues. In Project 1, the SRM preparation method was modified to improve reproducibility. The major outcome of this project was the development and re-certification of a standard reference material for cement paste. This recertification includes new rheological characteristics and statistical analyses. The goal of Project 2 was to extend the shelf life of the SRM since it was discovered that after 10 days the rheological properties of the SRM was not stable It was found that use of biocides, such as sodium propionate, extends the stability of the SRM. In Project 3, the development and certification of a SRM for mortar is provided with rheological properties and statistical analyses. Description of a model that was developed to predict the behavior of the SRM is also provided. In Project 4, a literature review regarding why industrial rheometers experience slippage issues was conducted. Key findings were that slippage issues depends on the rheometry choice and boundary conditions (free surfaces). Project 5 presents the results of a critical analysis conducted to evaluate the effect of rheometry systems for calibrating mortar-type rheometers. Rheological behaviors of two SRMs were measured experimentally and the results were compared to a computer simulation models. Discussion on the best rheometry system to avoid slippage is provided in that project. Overall, the outcomes of the work conducted in fulfillment of this thesis serve as the initial steps towards developing a reference material for concrete rheometers.
Effect of liquid viscosity on liquid film mass transfer for packings
(2017-12) Song, Di, 1989-; Rochelle, Gary T.; Seibert, Frank; Freeman, Benny; Eldridge, Bruce; Ganesan, Venkat
The effect of liquid viscosity (μL) on liquid film mass transfer for packings was investigated in a pilot-scale column with 0.43 m (16.8 in) ID and 3 m (10 ft) maximum packing. Mass transfer area (ae) of three structured packings, one random packing, and one hybrid packings was measured by chemical absorption of CO2 into dilute (~ 0.1 mol/L) NaOH. Liquid film mass transfer coefficient (kL) of eight structured packings, one random packing, and one hybrid packing was measured by air stripping toluene from water. Liquid viscosity was varied 0.8-70 mPa·s by adding 0-89 wt % glycerol to water in one ae and nine kL experiments. In the experiments, the liquid load was varied 6-75 m3/m2·hr (2.5-30 gpm/ft2), and the gas rates were 0.6, 1, and 1.5 m/s (180, 300, and 450 ACFM). The models of ae,packing and kL were developed based on data for 39 packings from this work and the SRP air-water column database. The model of the gas film mass transfer coefficient, kG, was developed based on data for 20 packings in the SRP air-water database. The secondary (wall and end) effect of ae was corrected in the area model. A taller packing bed consistently gave smaller kL due to maldistribution. Liquid viscosity does not have a significant effect on ae. The kL depends on μL to the -0.75 power, in which the -0.4 is the direct influence on the liquid turbulence, and -0.35 is the indirect effect via diffusivity of the mass transfer species. The effect of μL on kL is the same for different packing geometry and types. To prepare for the pilot-scale area experiment with glycerol, reaction kinetic model of CO2 and hydroxide in aqueous glycerol was developed based on the wetted-wall column (WWC) experiments.
Estimation of in-situ fluid properties from the combined interpretation of nuclear, dielectric, optical, and magnetic resonance measurements
(2018-12) Lee, Hyungjoo; Torres-Verdín, Carlos; Daigle, Hugh; Heidari, Zoya; Okuno, Ryosuke; Raizen, Mark
During the last few decades, the quantification of hydrocarbon pore volume from borehole measurements has been widely studied for reservoir descriptions. Relatively less effort has been devoted to estimating in-situ fluid properties because (1) acquiring fluid samples is expensive, (2) reservoir fluids are a complex mixture of various miscible and non-miscible phases, and (3) they depend on environmental factors such as temperature and pressure. This dissertation investigates the properties of fluid mixtures based on various manifestations of their electromagnetic properties from the MHz to the THz frequency ranges. A variety of fluids, including water, alcohol, alkane, aromatics, cyclics, ether, and their mixtures, are analyzed with both laboratory experiments and numerical simulations. A new method is introduced to quantify in-situ hydrocarbon properties from borehole nuclear measurements. The inversion-based estimation method allows depth-continuous assessment of compositional gradients at in-situ conditions and provides thermodynamically consistent interpretations of reservoir fluids that depend greatly on phase behavior. Applications of this interpretation method to measurements acquired in two field examples, including one in a gas-oil transition zone, yielded reliable and verifiable hydrocarbon compositions. Dielectric properties of polar liquid mixtures were analyzed in the frequency range from 20 MHz to 20 GHz at ambient conditions. The Havriliak-Negami (HN) model was adapted for the estimation of dielectric permittivity and relaxation time. These experimental dielectric properties were compared to Molecular Dynamics (MD) simulations. Additionally, thermodynamic properties, including excess enthalpy, density, number of hydrogen bonds, and effective self-diffusion coefficient, were computed to cross-validate experimental results. Properties predicted from MD simulations are in excellent agreement with experimental measurements. The three most common optical spectroscopy techniques, i.e. Near Infrared (NIR), Infrared, and Raman, were applied for the estimation of compositions and physical properties of liquid mixtures. Several analytical techniques, including Principal Component Analysis (PCA), Radial Basis Functions (RBF), Partial Least-Squares Regression (PLSR), and Artificial Neural Networks (ANN), were separately implemented for each spectrum to build correlations between spectral data and properties of liquid mixtures. Results show that the proposed methods yield prediction errors from 1.5% to 22.2% smaller than those obtained with standard multivariate methods. Furthermore, the errors can be decreased by combining NIR, Infrared, and Raman spectroscopy measurements. Lastly, the ¹H NMR longitudinal relaxation properties of various liquid mixtures were examined with the objective of detecting individual components. Relaxation times and diffusion coefficients obtained via MD simulations for these mixtures are in agreement with experimental data. Also, the ¹H-¹H dipole-dipole relaxations for fluid mixtures were decomposed into the relaxations emanate from the intramolecular and intermolecular interactions. The quantification of intermolecular interactions between the same molecules and different molecules reveals how much each component contributes to the total NMR longitudinal relaxation of the mixture as well as the level of interactions between different fluids. Both experimental and numerical simulation results documented in this dissertation indicate that selecting measurement techniques that can capture the physical property of interest and maximize the physical contrasts between different components is important for reliable and accurate in-situ fluid identification
Highly concentrated, nanoclusters of self-crowded monoclonal antibodies for low viscosity, subcutaneous injections
(2011-05) Miller, Maria Andrea; Maynard, Jennifer Anne, 1974-; Johnston, Keith P., 1955-; Edgar, Thomas; Truskett, Thomas; Williams, III, Robert O.
Delivery of protein therapeutics is restricted to intravenous infusions due to protein-dependent problems including low solubilities, high viscosities, and physical instabilities. The ability to inject high concentrations of proteins via subcutaneous injections would increase accessibility and compliance. Large particles of a protein in a non-aqueous solvent can decrease the viscosity over a solution of equally concentrated individual protein molecules. The lower viscosity of a particle suspension is due to decreased surface area resulting in reduced electroviscous effects, solvation and deviations of the particle shape from a spherical geometry. Additional studies show that aqueous-based dispersions of antibody nanoclusters can be formed by increasing the attractive interactions between protein molecules using the excluded volume effects of extrinsic crowding agents. These novel, equilibrium, nanoclusters are maintained by a balance of highly attractive interactions and weak electrostatic repulsive interactions near the protein’s pI. These protein nanoclusters are ideal for subcutaneous delivery as they have low interactions between the colloids, are reversible in nature, and dissolve rapidly upon dilution in a buffer media. Through in vivo mouse studies, the bioavailability of a monoclonal antibody in the dispersion is prolonged and higher doses can be administered versus a solution. Overall, these studies with high concentration, low viscosity subcutaneous injections of protein therapeutics open new opportunities in biotechnology. For oral delivery of itraconzole, controlled flocculation of individual polymerically-stabilized nanoparticles is used to increase supersaturation. Flocculation of these nanoparticles is achieved by desolvating the polymer by changing the pH. The flocculated dispersions can then be easily filtered. The final amorphous powder maintains high supersaturation with simulated stomach and small intestine conditions and improves bioavailability of itraconazole, over the commercial product, Sporanox®.
The manufacture and characterization of protein nanoclusters
(2013-05) Dinin, Aileen Kathryn; Johnston, Keith P., 1955-; Maynard, Jennifer Anne, 1974-
The ability to formulate monoclonal antibodies at high concentration in a low-viscosity form is of broad interest in drug delivery, as monoclonal antibody-based drugs are now prescribed for cancer, autoimmune disorders, and many other diseases. Herein, we create highly concentrated antibody dispersions (up to 260 mg/mL) via three different methods, utilizing proline as an interacting depletant or trehalose as a non-interacting depletant. These dispersions are able to achieve viscosities an order of magnitude lower than similarly concentrated antibody solutions over a range of formulation pHs. When diluted, these antibody dispersions return to monomer. The proline acts to minimize protein zeta potential, thus reducing the electrostatic repulsion on the protein, even when formulated 3 pH units away from the antibody pI. In addition, it acts as a depletant, forcing the monomers into cluster via osmotic effects
Mass transfer area of structured packing
(2010-05) Tsai, Robert Edison; Eldridge, R Bruce; Rochelle, Gary T.; Bonnecaze, Roger T.; McGlamery, Gerald G.; Seibert, A Frank; Truskett, Thomas M.
The mass transfer area of nine structured packings was measured as a function of liquid load, surface tension, liquid viscosity, and gas rate in a 0.427 m (16.8 in) ID column via absorption of CO₂ from air into 0.1 mol/L NaOH. Surface tension was decreased from 72 to 30 mN/m via the addition of a surfactant (TERGITOL[trademark] NP-7). Viscosity was varied from 1 to 15 mPa·s using poly(ethylene oxide) (POLYOX[trademark] WSR N750). A wetted-wall column was used to verify the kinetics of these systems. Literature model predictions matched the wetted-wall column data within 10%. These models were applied in the interpretation of the packing results. The packing mass transfer area was most strongly dictated by geometric area (125 to 500 m²/m³) and liquid load (2.5 to 75 m³/m²·h or 1 to 30 gpm/ft²). A reduction in surface tension enhanced the effective area. The difference was more pronounced for the finer (higher surface area) packings (15 to 20%) than for the coarser ones (10%). Gas velocity (0.6 to 2.3 m/s), liquid viscosity, and channel configuration (45° vs. 60° or smoothed element interfaces) had no appreciable impact on the area. Surface texture (embossing) increased the area by 10% at most. The ratio of effective area to specific area (a[subscript e]/a[subscript p]) was correlated within limits of ±13% for the experimental database: [mathematical formula]. This area model is believed to offer better predictive accuracy than the alternatives in the literature, particularly under aqueous conditions. Supplementary hydraulic measurements were obtained. The channel configuration significantly impacted the pressure drop. For a 45°-to-60° inclination change, pressure drop decreased by more than a factor of two and capacity expanded by 20%. Upwards of a two-fold increase in hold-up was observed from 1 to 15 mPa·s. Liquid load strongly affected both pressure drop and hold-up, increasing them by several-fold over the operational range. An economic analysis of an absorber in a CO₂ capture process was performed. Mellapak[trademark] 250X yielded the most favorable economics of the investigated packings. The minimum cost for a 7 m MEA system was around $5-7/tonne CO₂ removed for capacities in the 100 to 800 MW range.
Modeling of Real Gas Flow Behavior in Porous Media
(1993-08) Chien, Tony; Caudle, Ben H.
Due to the highly nonlinear variation of gas density and viscosity with respect to pressure, no analytical solution to the real gas diffusivity equation has ever been presented in the literature. Analytical solutions used in gas well testing and pressure analysis are based on idealized assumptions, such as small and/or constant gas compressibility and constant hydraulic diffusivity. These solutions, though widely used and easily applied, are not accurate. This research presents a detailed investigation in the behavior of real gas flow through porous media. Starting from the most fundamental flow equation a new real gas potential is implemented to transform the nonlinear flow equation into a quasi-linear diffusivity equation. The effects of pressure-dependent fluid and rock properties such as gas viscosity, compressibility, porosity and permeability are included. Advanced analytical derivations with respect to nonconstant hydraulic diffusivity are performed, and an analytical solution method is successfully developed. Multiple-rate and multiple-well systems as well as bounded reservoirs of any shape are rigorously implemented by using the principle of superposition and an unsteady-state bounding technique. Validation of the model is favorably achieved by comparison with finite-difference simulation and type curve matching. Reservoir pressures and flowing bottomhole pressures calculated by the analytical solution presented in this study are more accurate than by those methods published in the literature. The new solution method is also applicable to a broad range of pressure changes and different flow periods. This is a significant contribution to transient pressure analysis, long-term well performance tests and production forecasts in natural gas reservoirs. Moreover, since the pressure-dependent porosity and permeability are included in this study, the general solution may be applied to abnormally pressured reservoirs and tight gas sands for improved predictions of gas reserves and flow performance.
Pahoehoe, aa, and blocky lavas
(2009-03) Barker, Daniel S.
Performance prediction of cavitating propulsors using a viscous/inviscid method
(2008-08) Sun, Hong, active 2008; Kinnas, Spyros A.
A viscous/inviscid interaction method for predicting the effect of viscosity on the performance of wetted and cavitating propulsors is presented. The emphasis is placed on steady wetted and cavitating propulsor flows. A three-dimensional low order potential based boundary element method is strongly coupled with a two dimensional integral boundary layer analysis method based on the strip theory assumption. The influence of viscosity on the outer inviscid flow is modeled through the wall transpiration model by distributing “blowing” sources on the propulsor blade and trailing wake surfaces. The boundary layer edge velocities are expressed as the sum of the inviscid edge velocity and a correction which depends only on the boundary layer variables. The influence of outer potential flow on the inner boundary layer flow is considered through the edge velocities. In the case of sheet cavitation, a “thin” cavity approach is employed and the viscous/inviscid interaction method is applied on the blade surface underneath the cavity. On the cavity surface, the friction force coefficient is forced to be zero. Numerical predictions by the present viscous/inviscid interaction method are presented for open, ducted, and water-jet propulsors. For water-jet propulsors, the flow is solved in an iterative manner by solving the rotor and stator problems separately and by considering the time-averaged effects of one component on the other. Predicted forces, pressure distributions, and boundary layer variables are compared with those predicted by other numerical methods and experimental measurements.
Relation of protein-protein interactions to rheological properties and stability of highly concentrated of monoclonal antibodies
(2018-08-16) Dear, Barton Joseph; Johnston, Keith P., 1955-; Truskett, Thomas Michael, 1973-; Lynd, Nathaniel; Stachowiak, Jeanne
Solutions of monoclonal antibodies (mAbs) at high concentration are strongly desirable for subcutaneous delivery for the treatment of many autoimmune diseases and cancer. However, at the high concentrations necessary for practical application, mAbs tend to have strongly attractive protein-protein interactions (PPI) that cause the solutions to be highly viscous and prone to aggregation. Herein, the PPI of various mAbs and other proteins at concentrations up to 250 mg/ml are tuned by the addition of the small molecule co-solutes that can screen both electrostatic and hydrophobic PPI to produce low viscosities. The effects of the co-solutes on PPI were directly measured using small angle x-ray scattering, dynamic light scattering, and shear-dependent rheology as well as indirectly through the viscosity and storage stability. MAb solutions with attractive net PPI will be shown to be generally more viscous and aggregation prone than solutions with less attractive net PPI; however, these correlations remain challenging to understand across mAbs. Alternatively, the formation of reversible oligomers, or clusters in solution, as determined by fitting SAXS structure factors with molecular dynamic simulations, or the polydispersity of DLS data, will be demonstrated to be a key factor in determining high concentration viscosity. The storage stability will be shown to be influenced by both PPI and conformational stability; therefore, co-solutes that improve both will cause yield the highest stabilities.
Sensitivity of AVO reflectivity to fluid properties in porous media
(2004-05) Stine, Jason Andrew; Tatham, R. H. (Robert H.), 1943-
The Zoeppritz equations used in a typical reflection amplitude versus source-receiver offset (AVO) study to calculate the reflection and transmission coefficients do not directly consider the fluids filling the pore space in a porous solid medium. Although they account for the effects on the density and P-wave and S wave velocities in porous solids, these equations neglect the movements of fluids with respect to the porous framework. In doing so, the effects of the permeability and viscosity of the fluids during flow are ignored. These properties may affect the energy reflected and transmitted at a boundary; therefore, they must be accounted for to give an accurate wave propagation model. Biot theory considers the propagation of elastic waves in a porous elastic solid saturated by a viscous fluid. This theory accounts for the motion of fluids in the interconnected voids of a porous solid, assuming Darcian fluid flow. Biot theory accounts for the propagation of three waves, one rotational (shear) wave and two dilational waves (P-wave and slow wave). Reflection and transmission coefficients are calculated including Biot theory, showing potentially observable differences from the coefficients calculated using the Zoeppritz equations, for different physical situations. The sensitivity of the reflection coefficients to different physical parameters is examined. The goal is to evaluate how the reflection coefficients change as individual parameters, such as viscosity or permeability, are varied, and which parameters affect the reflection coefficients the most. If the reflection coefficient does not change as a parameter is varied, there is no sensitivity to that parameter and information about that parameter cannot be extracted from the data. The sensitivity analysis is complimented by calculating partial derivatives of the expressions for the reflection coefficients with respect to individual parameters, particularly fluid parameters. With this approach, large values of the partial derivative imply large changes in reflection coefficients with respect to a physical parameter indicate the most sensitivity to that parameter in the reflection coefficient. In Biot theory, the solid properties dominate over those of the fluids alone. The fluid properties only impact the reflection coefficients in a significant manner when there is a small contrast in the solid properties across a boundary. If the contrast in solid properties is too large, any effects caused by the fluid properties are insignificant compared to the solid effects. The three shale over sandstone models have too large of a contrast in solid properties to see fluid effects. Conversely, the six models of fluid boundaries within a reservoir sand all have little to no contrast in solid properties, so the fluid effects are evident. For gas-water interfaces, the observable changes in the P-P reflectivity are estimated to be as large as 5% for a 1% change in permeability and 15% for a 1% change in viscosity. When the above criteria for observing the fluid effects are met, the P-wave has sensitivity to viscosity, sensitivity, and porosity, with the reflection coefficients giving the most sensitivity to changes in the fluid viscosity. The apparent sensitivity to porosity is mostly a response to the density change caused by the change in porosity, rather than direct effects of the porosity. Theoretical AVO reflection coefficient curves based on Biot theory are inverted using two and three term AVO inversions based on approximations of Zoeppritz reflectivity. There is significant error in the parameters extracted by the inversion for both the two- and three-term AVO inversions. The three-term Aki and Richards (2002) inversion produces inaccurate values of the physical parameters across the boundary. Standard AVO inversion algorithms based on Zoeppritz reflectivity have problems accurately calculating parameters for a porous medium where fluids can move. An intercept and gradient interpretation algorithm based on Biot theory is desirable to accurately extract physical properties in porous media. A second formulation for reflectivity in a porous elastic solid is examined. In this study the theory developed by de la Cruz and Spanos (1985) is modified from their high viscosity limits, to fit more common lighter-oil viscosity regimes. The equations of motion and boundary conditions developed as part of the Spanos theory are adapted for this application. The reflectivity problem is simplified to an eigenvalue problem, based on a number of assumptions. De la Cruz, Hube, and Spanos (1992) published their computed values of reflection coefficients for high viscosity fluids. However, the complexity of this theory makes it impractical, in this study, to follow through to calculation of reflection coefficients in a porous elastic solid
Stratovolcanoes
(2009-03) Barker, Daniel S.
A study of microemulsion viscosity with consideration of polymer and co-solvent additives
(2014-05) Dashti, Ghazal; Delshad, Mojdeh
With the dramatic increase in the worldwide demand for the crude oil and with the fact that the oil and gas resources are depleting, the enhanced oil recovery process plays an important role to increase the production from the existing hydrocarbon reservoirs. Chemical enhanced oil recovery is one of the most important techniques to unlock significant amount of trapped oil from oil reservoirs. Surface agent materials (Surfactants) are used to lower the interfacial tension (IFT) between water and oil phases to ultralow values and mobilize the trapped oil. When surfactant, water, and oil are mixed together they form a thermodynamically stable phase called microemulsion which can be characterized by ultralow interfacial tension and the ability to solubilize both aqueous and oil compounds. Another characteristic of microemulsion solution is its viscosity which plays an important role in the creation and movement of the oil bank. The microemulsion micro-structure is complex and its viscosity is difficult to predict. Various viscosity models and correlations are presented in the literature to describe microemulsion viscosity behavior, but they fail to represent the rheological behavior of many microemulsion mixtures. Most of these models are valid in the lower and higher ranges of solute where one of the domains is discontinuous. The majority of the models fail to calculate the rheology of microemulsion phase in bicontinuous domains. In this work, we present a systematic study of the rheological behavior of microemulsion systems and the effect of additives such as polymer and co-solvent on rheological properties of microemulsions. Several laboratory experiments were conducted to determine the rheological behavior of surfactant solutions. A new empirical model for the viscosity of microemulsion phase as a function of salinity is introduced. The model consists of three different correlations one for each phase type of Windsor phase behaviors. The proposed model is validated using a number of experimental results presented in this document. The proposed viscosity model is implemented in the UTCHEM simulator and the simulator results are compared with the coreflood experiments. Excellent matches were obtained for the pressure. We further improved the proposed viscosity model to incorporate the effect of polymer and co-solvent on the microemulsion viscosity.
The effects of protein-protein interactions on in vitro and in vivo behavior of protein solutions
(2017-01-09) Laber, Joshua Ryan; Maynard, Jennifer Anne, 1974-; Georgiou, George; Ehrlich, Lauren I.R.; Truskett, Thomas M.; Johnston, Keith P.
Protein-based therapeutics such as monoclonal antibodies (mAbs) and related fragments are increasingly attractive modalities to treat a variety of diseases due to the ability to engineer their biochemical and biophysical properties, streamlined manufacturing processes, minimal toxicity, and low immunogenicity/low risk of adverse side effects. Research in the methods used to deliver these treatments are limited when compared to small molecule drugs, as it is difficult to administer proteins orally and the high concentrations required for subcutaneous delivery are associated with high viscosities precluding syringe injection. Therefore, most protein therapeutics are delivered intravenously over long periods of time (>30 min) at dilute concentrations under medical supervision. Subcutaneous self-administration is a major objective in the field as it is expected to increase patient accessibility and compliance in addition to reducing pain and cost. Two common approaches under active investigation are 1) engineering the primary amino acid sequence for such traits as increased solubility and aggregation resistance, as well as 2) optimizing solution parameters for reduced viscosity via addition of excipients or optimizing manufacturing parameters. These approaches are unable to achieve stable protein solutions at concentrations sufficient for self-administration due to the dominant role of attractive forces at high concentration where even single amino acid mutations can drastically alter solution properties and thus solution optimization becomes protein-specific in nature. My overarching goals for this document are to systematically determine the dominant effects of protein-specific properties on this protein delivery technology in vitro and in vivo. Specifically, (1) investigate the role of protein-protein interactions on protein solution properties, and (2) investigate the effect of protein therapeutics can have on the immune system in vivo.
Vesicles and pumice
(2009-03) Barker, Daniel S.
Viscous lava flows
(2009-03) Barker, Daniel S.