Excipient Effects on Humanized Monoclonal Antibody Interactions with Silicone oil Emulsions

Britt, Keith A.; Schwartz, Daniel K.; Wurth, Christine; Mahler, Hanns‐Christian; Carpenter, John F.; Randolph, Theodore W.

doi:10.1002/jps.23318

Cited by 51 publications

(66 citation statements)

References 20 publications

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“…The zeta potentials of emulsified silicone oil microdroplets in water ranged from −73 to −85 mV. The highly negative zeta potential confirmed that the silicone oil emulsions were colloidally stable, as shown previously …”

Section: Resultssupporting

confidence: 83%

“…Concerns about the stability of proteins in siliconized prefilled syringes arose in the 1980s when clouding and visible precipitates were observed in disposable insulin syringes that contained silicone oil . A wide variety of proteins has been shown to adsorb readily to silicone oil microdroplets and proteins may undergo structural perturbations upon adsorption at the silicone oil–water interface . Furthermore, silicone oil may induce protein aggregation and promote particle formation in formulations .…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Analysis of the Potency of Silicone Oil Microdroplets as Immunological Adjuvants in Protein Formulations

Chisholm

Nguyen

Soucie

et al. 2015

Journal of Pharmaceutical Sciences

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Subvisible particles in a therapeutic protein product may act as adjuvants to promote unwanted immune responses against the protein. Silicone oil is used as a lubricant in prefilled syringes, and microdroplets of silicone oil are often detected in protein formulations expelled from prefilled syringes. In order to test the adjuvant potency of silicone oil microdroplets, antibody responses in mice to subcutaneous injections of formulations of ovalbumin (OVA) that contained silicone oil microdroplets were measured. These responses were compared against responses to oil-free OVA formulations and to OVA formulations that contained microparticulate aluminum hydroxide (“alum”), the common vaccine adjuvant. When administered with high concentrations of silicone oil microdroplets, OVA formulations elicited strong anti-OVA IgG1 and IgG2a antibody responses. These responses were equivalent to those observed when alum microparticles were added to OVA formulations, suggesting that silicone oil can act as a potent adjuvant. However, when OVA formulations were prepared with lower levels of silicone oil that had been obtained directly from commercial siliconized syringes, the anti-OVA antibody response was not enhanced significantly compared to responses against OVA alone.

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Section: Resultssupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

In Vivo Analysis of the Potency of Silicone Oil Microdroplets as Immunological Adjuvants in Protein Formulations

Chisholm

Nguyen

Soucie

et al. 2015

Journal of Pharmaceutical Sciences

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, accelerated stability studies and forced degradation studies are needed to determine the stability profile of a protein drug by subjecting the protein to various stresses including elevated or changing temperatures, freezing, thawing, agitation, oxidative environment, light, and the presence of different interfaces and pH changes. (Britt et al, 2012; Cordes et al, 2012; Miller et al, 2013; Wang et al, 2013a) The design of successful forced degradation and accelerated stability studies depends on having the appropriate analytical tools to detect, quantify, and characterize any degradants, impurities and side products generated during these studies.…”

Section: Introduction To Comparability Assessmentsmentioning

confidence: 99%

Protein comparability assessments and potential applicability of high throughput biophysical methods and data visualization tools to compare physical stability profiles

et al. 2014

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In this review, some of the challenges and opportunities encountered during protein comparability assessments are summarized with an emphasis on developing new analytical approaches to better monitor higher-order protein structures. Several case studies are presented using high throughput biophysical methods to collect protein physical stability data as function of temperature, agitation, ionic strength and/or solution pH. These large data sets were then used to construct empirical phase diagrams (EPDs), radar charts, and comparative signature diagrams (CSDs) for data visualization and structural comparisons between the different proteins. Protein samples with different sizes, post-translational modifications, and inherent stability are presented: acidic fibroblast growth factor (FGF-1) mutants, different glycoforms of an IgG1 mAb prepared by deglycosylation, as well as comparisons of different formulations of an IgG1 mAb and granulocyte colony stimulating factor (GCSF). Using this approach, differences in structural integrity and conformational stability profiles were detected under stress conditions that could not be resolved by using the same techniques under ambient conditions (i.e., no stress). Thus, an evaluation of conformational stability differences may serve as an effective surrogate to monitor differences in higher-order structure between protein samples. These case studies are discussed in the context of potential utility in protein comparability studies.

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“…Silicone oil has been implicated in the generation of aggregates and particulates of mAbs (Britt et al, 2012;Thirumangalathu et al, 2009). Both of these studies investigated the impact of formulation excipients on the interaction of mAbs with silicone oil emulsions.…”

Section: Silicone Oil Interactions With Proteins and Mabs In Prefillementioning

confidence: 99%

Development of delivery device technology to deal with the challenges of highly viscous mAb formulations at high concentration

Shire¹

2015

Monoclonal Antibodies

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Excipient Effects on Humanized Monoclonal Antibody Interactions with Silicone oil Emulsions

Cited by 51 publications

References 20 publications

In Vivo Analysis of the Potency of Silicone Oil Microdroplets as Immunological Adjuvants in Protein Formulations

In Vivo Analysis of the Potency of Silicone Oil Microdroplets as Immunological Adjuvants in Protein Formulations

Protein comparability assessments and potential applicability of high throughput biophysical methods and data visualization tools to compare physical stability profiles

Development of delivery device technology to deal with the challenges of highly viscous mAb formulations at high concentration

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