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The Effect of Nanobubble and Nanodroplet Interfaces on Protein Stability and Aggregation in Therapeutic Protein Formulations
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | The Effect of Nanobubble and Nanodroplet Interfaces on Protein Stability and Aggregation in Therapeutic Protein Formulations. |
| 개인저자 | Snell, Jared Richard. |
| 단체저자명 | University of Colorado at Boulder. Chemical and Biological Engineering. |
| 발행사항 | [S.l.]: University of Colorado at Boulder., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 165 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-03B. Dissertation Abstract International |
| ISBN | 9781085791939 |
| 학위논문주기 | Thesis (Ph.D.)--University of Colorado at Boulder, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-03, Section: B.
Advisor: Randolph, Theodore W. |
| 이용제한사항 | This item is not available from ProQuest Dissertations & Theses.This item must not be sold to any third party vendors.This item must not be added to any third party search indexes. |
| 요약 | Interfaces presented by subvisible particulate contaminants may reduce protein stability potentially compromising the efficacy and safety of therapeutic protein formulations. However, minimal guidelines are provided for the characterization and control of particulates smaller than 10 쨉m in therapeutic protein formulations. In this work we investigated generation of nanobubbles and bis(2-ethylhexyl) phthalate (DEHP) droplets in therapeutic protein formulations and their effect on protein stability and aggregation.Nanobubbles generated upon reconstitution of lyophilized protein formulations not only serve as a source of subvisible particles but also reduce protein stability, promoting aggregation and particle formation. We show that Interluekin-1 receptor antagonist (IL-1ra) adsorbs readily to the nanobubble air-water interface resulting in significant changes in nanobubble surface charge. Further, incubating IL-1ra in nanobubble suspensions resulted in rapid particle formation and monomer loss. These results suggest nanobubbles generated during reconstitution of lyophilized protein formulations may compromise protein stability. To develop a strategy for minimizing nanobubble formation and its associated protein aggregation we evaluated the mechanism responsible for nanobubble formation upon reconstitution of lyophilized protein formulations. We hypothesized that nanobubble formation was dependent on nano-sized voids which may originate from small ice crystals generated within the freeze concentrated liquid during freezing. Correlations between nanobubble concentrations following reconstitution of lyophilized formulations and excipient crystallinity in the lyophilized solid suggests excipient crystallization could contribute to nano-void formation. Inhibiting excipient crystallization was an effective strategy for minimizing nanobubble generation in lyophilized formulations. This strategy for decreasing nanobubble formation also reduced the formation of insoluble protein particle during reconstitution.Finally, we showed that DEHP droplets shed from polyvinyl chloride (PVC) IV bags could serve as a source of subvisible particulate contaminants in therapeutic protein formulations diluted and administered using these products. Intravenous immunoglobulin (IVIG) adsorbed readily to droplets of emulsified DEHP. Adsorbed protein formed viscoelastic films at the DEHP-water interface which may contribute increased aggregation rates observed in rotated samples of IVIG containing DEHP. Activation of the complement system by IVIG formulations containing DEHP droplets suggests DEHP droplets could contribute to the frequency of infusion reactions following administration of therapeutic protein formulations. |
| 일반주제명 | Chemical engineering. Nanoscience. |
| 언어 | 영어 |
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