The Role of Polysorbate 80 and HPβCD at the Air-Water Interface of IgG Solutions

Serno, Tim; Härtl, Elisabeth; Besheer, Ahmed; Miller, R.; Winter, Gerhard

doi:10.1007/s11095-012-0854-x

Cited by 39 publications

(38 citation statements)

References 46 publications

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“…On the basis of the results of this study and on previous studies performed in our lab regarding the stabilization of proteins using HPßCD, one can conclude that high‐concentration HPßCD is probably not a viable option to stabilize high‐concentration MAb formulations, and that polysorbate 80 represents a better option, so long its degradation issue is controlled. Additionally, the observed differences regarding the effect of HPßCD on the stability of IgG A and IgG B point to the different cyclodextrin interaction with the proteins, probably because of differences in structure, surface distribution of hydrophobic amino acids, and/or charge pattern.…”

Section: Discussionmentioning

confidence: 63%

Influence of Hydroxypropyl‐Beta‐Cyclodextrin on the Stability of Dilute and Highly Concentrated Immunoglobulin G Formulations

Härtl

Winter²,

Besheer³

2013

Journal of Pharmaceutical Sciences

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Section: Discussionmentioning

confidence: 63%

Influence of Hydroxypropyl‐Beta‐Cyclodextrin on the Stability of Dilute and Highly Concentrated Immunoglobulin G Formulations

Härtl

Winter²,

Besheer³

2013

Journal of Pharmaceutical Sciences

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“…Furthermore, it causes mechanical perturbation of the interface, thereby increasing the probability of intermolecular protein-protein interactions as well as desorption of aggregated species into bulk solution. 31,32 The propensity of protein molecules to accumulate at phase boundaries makes the air-liquid interfacial stress the predominant stress factor during shaking. Nevertheless, cavitation and solid-liquid interfaces are also detrimental to the physical stability of proteins.…”

Section: Discussionmentioning

confidence: 99%

What Makes Polysorbate Functional? Impact of Polysorbate 80 Grade and Quality on IgG Stability During Mechanical Stress

Grabarek

Bozic²,

Rousel

et al. 2020

Journal of Pharmaceutical Sciences

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Polysorbate 80 (PS80) is a commonly used surfactant in therapeutic protein formulations to mitigate adsorption and interface-induced protein aggregation. Several PS80 grades and qualities are available on the market for parenteral application. The role of PS80 grade on protein stability remains debatable, and the impact of (partially) degraded PS on protein aggregation is not yet well understood. In our study, a monoclonal antibody (IgG) was subjected to 3 different mechanical stress conditions in the presence of multicompendial (MC) and Chinese pharmacopeia (ChP) grade PS80. Furthermore, IgG formulations were spiked with (partly) hydrolyzed PS80 to investigate the effect of PS80 degradants on protein stability. PS80 functionality was assessed by measuring the extent of protein aggregation and particle formation induced during mechanical stress by using size-exclusion chromatography, dynamic light scattering, backgrounded membrane imaging, and flow imaging microscopy. No distinguishable differences in PS80 functionality between MC and ChP grade were observed in the 3 stress tests. However, with increasing degree of PS80 hydrolysis, higher counts of subvisible particles were measured after stress. Furthermore, higher levels of PS80 degradants at a constant PS80 concentration may destabilize the IgG. In conclusion, MC and ChP grade PS80 are equally protective, but PS80 degradants compromise IgG stability.

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“…Surfactants are often included as stabilizers against aggregation in therapeutic protein formulations, and they generally are thought to inhibit aggregation by reducing protein adsorption to various interfaces 5–8,11. Other protection mechanisms may be protein specific 4–6,12,13.…”

Section: Introductionmentioning

confidence: 99%

The Effects of Excipients on Protein Aggregation During Agitation: An Interfacial Shear Rheology Study

Liu

Wei

Schwartz

et al. 2013

Journal of Pharmaceutical Sciences

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We investigated the effects of excipients in solutions of keratinocyte growth factor 2 (KGF-2) on protein aggregation during agitation as well as on interfacial shear rheology at the air-water interface. Samples were incubated with or without agitation, and in the presence or absence of the excipients heparin, sucrose or polysorbate 80 (PS80). The effect of excipients on the extent of protein aggregation was determined by UV spectroscopy and microflow imaging (MFI). Interfacial shear rheology was used to detect the gelation time and strength of protein gels at the air-water interface. During incubation, protein particles of size ≥ 1 μm and insoluble aggregates formed faster for KGF-2 solutions subjected to agitation. Addition of either heparin or sucrose promoted protein aggregation during agitation. In contrast, PS 80 substantially inhibited agitation-induced KGF-2 aggregation but facilitated protein particulate formation in quiescent solutions. The combination of PS 80 and heparin or sucrose completely prevented protein aggregation during both non-agitated and agitated incubations. Interfacial rheological measurements showed that KGF-2 in buffer alone formed an interfacial gel within a few minutes. In the presence of heparin, KGF-2 interfacial gels formed too quickly for gelation time to be determined. KGF-2 formed gels in about 10 minutes in the presence of sucrose. The presence of PS80 in the formulation inhibited gelation of KGF-2. Furthermore, the interfacial gels formed by the protein in the absence of PS80 were reversible when PS80 was added to the samples after gelation. Therefore, there is a correspondence between formulations that exhibited interfacial gelation and formulations that exhibited agitation-induced aggregation.

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The Role of Polysorbate 80 and HPβCD at the Air-Water Interface of IgG Solutions

Abstract: The results confirm surface displacement as the stabilization mechanism of polysorbate 80, but refute the frequently held opinion, that HPβCD stabilizes proteins against aggregation at the air-water interface in a manner comparable to non-ionic surfactants.

Cited by 39 publications

References 46 publications

Influence of Hydroxypropyl‐Beta‐Cyclodextrin on the Stability of Dilute and Highly Concentrated Immunoglobulin G Formulations

Influence of Hydroxypropyl‐Beta‐Cyclodextrin on the Stability of Dilute and Highly Concentrated Immunoglobulin G Formulations

What Makes Polysorbate Functional? Impact of Polysorbate 80 Grade and Quality on IgG Stability During Mechanical Stress

The Effects of Excipients on Protein Aggregation During Agitation: An Interfacial Shear Rheology Study

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