Lyophilization stabilizes clinical-stage core-crosslinked polymeric micelles to overcome cold chain supply challenges.
drug delivery
lyophilization
nanomedicine
polymeric micelles
tumor targeting
Journal
Biotechnology journal
ISSN: 1860-7314
Titre abrégé: Biotechnol J
Pays: Germany
ID NLM: 101265833
Informations de publication
Date de publication:
Jun 2021
Jun 2021
Historique:
revised:
15
01
2021
received:
31
08
2020
accepted:
21
01
2021
pubmed:
24
1
2021
medline:
8
6
2021
entrez:
23
1
2021
Statut:
ppublish
Résumé
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. 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. 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.
Sections du résumé
BACKGROUND
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
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
CONCLUSIONS
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.
Identifiants
pubmed: 33484630
doi: 10.1002/biot.202000212
pmc: PMC7611944
mid: EMS137163
doi:
Substances chimiques
Micelles
0
Polymers
0
Sucrose
57-50-1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2000212Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : SFB1066
Organisme : Deutsche Forschungsgemeinschaft
ID : LA2937/4-1
Organisme : H2020 European Research Council
ID : 864121
Organisme : H2020 Marie Skłodowska-Curie Actions
ID : 642028
Organisme : Bundesministerium für Bildung und Forschung
ID : 16GW0319K
Organisme : ERANET-EuroNanoMed-III
ID : NSC4DIPG
Organisme : European Research Council
ID : 864121
Pays : International
Organisme : Deutsche Forschungsgemeinschaft
ID : 331065168
Organisme : Phospholipid Research Center
ID : RBA-2019-076/1-1
Informations de copyright
© 2021 The Authors. Biotechnology Journal published by Wiley-VCH GmbH.
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