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Stabilization of chimeric BR96-doxorubicin immunoconjugate
N P Barbour1, M Paborji, T C Alexander
1Pharmaceutics Research and Development, Bristol-Myers Squibb Company, Syracuse, New York 13221, USA.
Pharmaceutical Research
|February 1, 1995
Summary
Lyophilization significantly enhances the stability of chimeric BR96-doxorubicin conjugate (BR96-DOX) for long-term storage. Adding sugars like lactose or sucrose before freeze-drying improves the drug conjugate
Area of Science:
- Pharmaceutical Sciences
- Bioconjugation Chemistry
- Drug Delivery Systems
Background:
- Chimeric BR96-doxorubicin conjugate (BR96-DOX) is an immunoconjugate targeting tumor cells.
- The conjugate utilizes an acid-labile hydrazone linker for in vivo drug release.
- In vitro studies identified acid-catalyzed hydrolysis as the primary degradation pathway.
Purpose of the Study:
- To evaluate the stability of BR96-DOX under various conditions.
- To identify methods for improving the long-term storage stability of BR96-DOX.
- To assess the efficacy of lyophilization as a stabilization technique.
Main Methods:
- Stability studies of BR96-DOX in solution at different pH and temperatures.
- Lyophilization of BR96-DOX with and without cryoprotectants (lactose, sucrose).
- Storage of lyophilized BR96-DOX under refrigeration and assessment of stability.
Main Results:
- BR96-DOX exhibited poor stability in solution, even under optimal conditions.
- Lyophilization in the presence of lactose or sucrose significantly improved BR96-DOX stability.
- Refrigerated storage of the lyophilized product further enhanced its shelf-life.
Conclusions:
- Acid-catalyzed hydrazone hydrolysis limits the solution stability of BR96-DOX.
- Lyophilization, particularly with sugar excipients, is a viable strategy for stabilizing BR96-DOX.
- This approach enables long-term storage and potential therapeutic application of the immunoconjugate.