| Autor: |
Kanthe AD; Sterile Product Development, Bristol Myers Squibb, New Brunswick, New Jersey 08901, United States.; Department of Chemical Engineering, The City College of New York, New York, New York 10031, United States., Carnovale MR; Pharma Solutions R&D, International Flavors and Fragrances, Wilmington, Delaware 19803, United States., Katz JS; Pharma Solutions R&D, International Flavors and Fragrances, Wilmington, Delaware 19803, United States., Jordan S; Pharma Solutions R&D, International Flavors and Fragrances, Wilmington, Delaware 19803, United States., Krause ME; Sterile Product Development, Bristol Myers Squibb, New Brunswick, New Jersey 08901, United States., Zheng S; Sterile Product Development, Bristol Myers Squibb, New Brunswick, New Jersey 08901, United States., Ilott A; Sterile Product Development, Bristol Myers Squibb, New Brunswick, New Jersey 08901, United States., Ying W; Sterile Product Development, Bristol Myers Squibb, New Brunswick, New Jersey 08901, United States., Bu W; NSF's ChemMatCARS, Center for Advanced Radiation Sources, University of Chicago, Chicago, Illinois 606371, United States., Bera MK; NSF's ChemMatCARS, Center for Advanced Radiation Sources, University of Chicago, Chicago, Illinois 606371, United States., Lin B; NSF's ChemMatCARS, Center for Advanced Radiation Sources, University of Chicago, Chicago, Illinois 606371, United States., Maldarelli C; Department of Chemical Engineering, The City College of New York, New York, New York 10031, United States.; Levich Institute, The City College of New York, New York, New York 10031, United States., Tu RS; Department of Chemical Engineering, The City College of New York, New York, New York 10031, United States. |
| Abstrakt: |
Protein adsorption on surfaces can result in loss of drug product stability and efficacy during the production, storage, and administration of protein-based therapeutics. Surface-active agents (excipients) are typically added in protein formulations to prevent undesired interactions of proteins on surfaces and protein particle formation/aggregation in solution. The objective of this work is to understand the molecular-level competitive adsorption mechanism between the monoclonal antibody (mAb) and a commercially used excipient, polysorbate 80 (PS80), and a novel excipient, N -myristoyl phenylalanine- N -polyetheramine diamide (FM1000). The relative rate of adsorption of PS80 and FM1000 was studied by pendant bubble tensiometry. We find that FM1000 saturates the interface faster than PS80. Additionally, the surface-adsorbed amounts from X-ray reflectivity (XRR) measurements show that FM1000 blocks a larger percentage of interfacial area than PS80, indicating that a lower bulk FM1000 surface concentration is sufficient to prevent protein adsorption onto the air/water interface. XRR models reveal that with an increase in mAb concentration (0.5-2.5 mg/mL: IV based formulations), an increased amount of PS80 concentration (below critical micelle concentration, CMC) is required, whereas a fixed value of FM1000 concentration (above its relatively lower CMC) is sufficient to inhibit mAb adsorption, preventing mAb from co-existing with surfactants on the surface layer. With this observation, we show that the CMC of the surfactant is not the critical factor to indicate its ability to inhibit protein adsorption, especially for chemically different surfactants, PS80 and FM1000. Additionally, interface-induced aggregation studies indicate that at minimum surfactant concentration levels in protein formulations, fewer protein particles form in the presence of FM1000. Our results provide a mechanistic link between the adsorption of mAbs at the air/water interface and the aggregation induced by agitation in the presence of surfactants. |
