期刊
BIOTECHNOLOGY JOURNAL
卷 16, 期 6, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/biot.202000212
关键词
drug delivery; lyophilization; nanomedicine; polymeric micelles; tumor targeting
资金
- European Union [H2020-MSCA-ITN-2014 642028]
- German Research Foundation [DFG: GRK2375, 331065168, SFB1066, LA2937/4-1]
- German Federal Ministery of Education and Research [BMBF: PP-TNBC: 16GW0319K]
- European Research Council [864121]
- Phospholipid Research Center (Heidelberg, Germany) [RBA-2019-076/1-1]
- Projekt DEAL
- European Research Council (ERC) [864121] Funding Source: European Research Council (ERC)
A freeze-drying methodology was developed for drug-containing CCPM, demonstrating that trehalose-protected CPC634 could be rapidly reconstituted with identical critical quality attributes, providing proof-of-concept for future commercialization.
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 degrees 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.
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