Lyophilization stabilizes clinical-stage core-crosslinked polymeric micelles to overcome cold chain supply challenges

Tarun Ojha, Qizhi Hu, Claudio Colombo, Jan Wit, Michiel van Geijn, Mies J. van Steenbergen, Mahsa Bagheri, Hiltrud Königs-Werner, Eva Miriam Buhl, Ruchi Bansal, Yang Shi, Wim E. Hennink, Gert Storm, Cristianne J.F. Rijcken*, Twan Lammers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background: CriPec technology enables the generation of drug-entrapped biodegradable core-crosslinked polymeric micelles (CCPM) with high drug loading capacity, tailorable size, and drug release kinetics. Docetaxel (DTX)-entrapped CCPM, also referred to as CPC634, have demonstrated favorable pharmacokinetics, tolerability, and enhanced tumor uptake in patients. Clinical efficacy evaluation is ongoing. CPC634 is currently stored (shelf life > 5 years) and shipped as a frozen aqueous dispersion at temperatures below −60°C, in order to prevent premature release of DTX and hydrolysis of the core-crosslinks. Consequently, like other aqueous nanomedicine formulations, CPC634 relies on cold chain supply, which is unfavorable for commercialization. Lyophilization can help to bypass this issue. Methods and results: Freeze-drying methodology for CCPM was developed by employing CPC634 as a model formulation, and sucrose and trehalose as cryoprotectants. We studied the residual moisture content and reconstitution behavior of the CPC634 freeze-dried cake, as well as the size, polydispersity index, morphology, drug retention, and release kinetics of reconstituted CPC634. Subsequently, the freeze-drying methodology was validated in an industrial setting, yielding a CPC634 freeze-dried cake with a moisture content of less than 0.1 wt%. It was found that trehalose-cryoprotected CPC634 could be rapidly reconstituted in less than 5 min at room temperature. Critical quality attributes such as size, morphology, drug retention, and release kinetics of trehalose-cryoprotected freeze-dried CPC634 upon reconstitution were identical to those of non-freeze-dried CPC634. Conclusion: Our findings provide proof-of-concept for the lyophilization of drug-containing CCPM and our methodology is readily translatable to large-scale manufacturing for future commercialization.

Original languageEnglish
JournalBiotechnology journal
DOIs
Publication statusAccepted/In press - 23 Jan 2021

Keywords

  • UT-Hybrid-D
  • lyophilization
  • nanomedicine
  • polymeric micelles
  • tumor targeting
  • drug delivery

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