| LDR | | 00000nam u2200205 4500 |
| 001 | | 000000431927 |
| 005 | | 20200224110927 |
| 008 | | 200131s2019 ||||||||||||||||| ||eng d |
| 020 | |
▼a 9781085791939 |
| 035 | |
▼a (MiAaPQ)AAI13886449 |
| 040 | |
▼a MiAaPQ
▼c MiAaPQ
▼d 247004 |
| 082 | 0 |
▼a 620.5 |
| 100 | 1 |
▼a Snell, Jared Richard. |
| 245 | 14 |
▼a The Effect of Nanobubble and Nanodroplet Interfaces on Protein Stability and Aggregation in Therapeutic Protein Formulations. |
| 260 | |
▼a [S.l.]:
▼b University of Colorado at Boulder.,
▼c 2019. |
| 260 | 1 |
▼a Ann Arbor:
▼b ProQuest Dissertations & Theses,
▼c 2019. |
| 300 | |
▼a 165 p. |
| 500 | |
▼a Source: Dissertations Abstracts International, Volume: 81-03, Section: B. |
| 500 | |
▼a Advisor: Randolph, Theodore W. |
| 502 | 1 |
▼a Thesis (Ph.D.)--University of Colorado at Boulder, 2019. |
| 506 | |
▼a This item is not available from ProQuest Dissertations & Theses. |
| 506 | |
▼a This item must not be sold to any third party vendors. |
| 506 | |
▼a This item must not be added to any third party search indexes. |
| 520 | |
▼a 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. |
| 590 | |
▼a School code: 0051. |
| 650 | 4 |
▼a Chemical engineering. |
| 650 | 4 |
▼a Nanoscience. |
| 690 | |
▼a 0542 |
| 690 | |
▼a 0565 |
| 710 | 20 |
▼a University of Colorado at Boulder.
▼b Chemical and Biological Engineering. |
| 773 | 0 |
▼t Dissertations Abstracts International
▼g 81-03B. |
| 773 | |
▼t Dissertation Abstract International |
| 790 | |
▼a 0051 |
| 791 | |
▼a Ph.D. |
| 792 | |
▼a 2019 |
| 793 | |
▼a English |
| 856 | 40 |
▼u http://www.riss.kr/pdu/ddodLink.do?id=T15491511
▼n KERIS
▼z 이 자료의 원문은 한국교육학술정보원에서 제공합니다. |
| 980 | |
▼a 202002
▼f 2020 |
| 990 | |
▼a ***1008102 |
| 991 | |
▼a E-BOOK |