op9b00387_si_001.pdf (1.17 MB)
Scale-Up of the Manufacturing Process To Produce Docetaxel-Loaded mPEG‑b‑p(HPMA-Bz) Block Copolymer Micelles for Pharmaceutical Applications
journal contribution
posted on 2019-11-12, 02:46 authored by Jaleesa Bresseleers, Mahsa Bagheri, Gert Storm, Josbert M. Metselaar, Wim E. Hennink, Silvie A. Meeuwissen, Jan C. M. van HestAn
efficient, scalable, and good manufacturing practice (GMP) compatible
process was developed for the production of docetaxel-loaded poly(ethylene
glycol)-b-poly(N-2-benzoyloxypropyl
methacrylamide) (mPEG-b-p(HPMA-Bz)) micelles. First,
the synthesis of the mPEG-b-p(HPMA-Bz) block copolymer
was optimized through step-by-step investigation of the batch synthesis
procedures. This resulted in the production of 1 kg of mPEG-b-p(HPMA-Bz) block copolymer with a 5 kDa PEG block and
an overall molecular weight of 22.5 kDa. Second, the reproducibility
and scalability of micelle formation was investigated for both batch
and continuous flow setups by assessing critical process parameters.
This resulted in the development of a new and highly efficient continuous
flow process, which led to the production of 100 mL of unloaded micelles
with a size of 55 nm. Finally, the loading of the micelles with the
anticancer drug docetaxel was successfully fine-tuned to obtain precise
control on the loaded micelle characteristics. As a result, 100 mL
of docetaxel-loaded micelles (20 mg/mL polymer and 5 mg/mL docetaxel
in the feed) with a size of 55 nm, an encapsulation efficiency of
65%, a loading capacity of 14%, and stable for at least 2 months in
water at room temperature were produced with the newly developed continuous
flow process. In conclusion, this study paves the way for efficient
and robust large-scale production of docetaxel-loaded micelles with
high encapsulation efficiencies and stability, which is crucial for
their applicability as a clinically relevant drug delivery platform.