Effect of Formulation Variables on the Stability of a Live, Rotavirus (RV3-BB) Vaccine Candidate using in vitro Gastric Digestion Models to Mimic Oral Delivery.

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Kumar, P; Pullagurla, SR; Patel, A; Shukla, RS; Bird, C; Kumru, OS; Hamidi, A; Hoeksema, F; Yallop, C; Bines, JE; ...Date
2020-10-07Source Title
Journal of Pharmaceutical SciencesPublisher
Elsevier BVUniversity of Melbourne Author/s
Bines, JulieAffiliation
Paediatrics (RCH)Metadata
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Kumar, P., Pullagurla, S. R., Patel, A., Shukla, R. S., Bird, C., Kumru, O. S., Hamidi, A., Hoeksema, F., Yallop, C., Bines, J. E., Joshi, S. B. & Volkin, D. B. (2020). Effect of Formulation Variables on the Stability of a Live, Rotavirus (RV3-BB) Vaccine Candidate using in vitro Gastric Digestion Models to Mimic Oral Delivery.. J Pharm Sci, https://doi.org/10.1016/j.xphs.2020.09.047.Access Status
Open AccessAbstract
In this work, two different in vitro gastric digestion models were used to evaluate the stability of a live attenuated rotavirus vaccine candidate (RV3-BB) under conditions designed to mimic oral delivery in infants. First, a forced-degradation model was established at low pH to assess the buffering capacity of formulation excipients and to screen for RV3-BB stabilizers. Second, a sequential-addition model was implemented to examine RV3-BB stability under conditions more representative of oral administration to infants. RV3-BB rapidly inactivated at < pH 5.0 (37 °C, 1 h) as measured by an infectivity RT-qPCR assay. Pre-neutralization with varying volumes of infant formula (Enfamil®) or antacid (Mylanta®) conferred partial to full protection of RV3-BB. Excipients with sufficient buffering capacity to minimize acidic pH inactivation of RV3-BB were identified (e.g., succinate, acetate, adipate), however, they concomitantly destabilized RV3-BB in accelerated storage stability studies. Both effects were concentration dependent, thus excipient optimization was required to design candidate RV3-BB formulations which minimize acid-induced viral inactivation during oral delivery while not destabilizing the vaccine during long-term 2-8 °C storage. Finally, a statistical Design -of-Experiments (DOE) study examining RV3-BB stability in the in vitro sequential-addition model identified key formulation parameters likely affecting RV3-BB stability during in vivo oral delivery.
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