Quality-by-Design Approach for Biological API Encapsulation into Polymersomes Using “Off-the-Shelf” Materials: a Study on L-Asparaginase

Abstract

Polymersomes are versatile nanostructures for protein delivery with hydrophilic core suitable for large biomolecule encapsulation and protective stable corona. Nonetheless, pharmaceutical products based on polymersomes are not available in the market, yet. Here, using commercially available copolymers, we investigated the encapsulation of the active pharmaceutical ingredient (API) L-asparaginase, an enzyme used to treat acute lymphoblastic leukemia, in polymersomes through a quality-by-design (QbD) approach. This allows for streamlining of processes required for improved bioavailability and pharmaceutical activity. Polymersomes were prepared by bottom-up (temperature switch) and top-down (film hydration) methods employing the diblock copolymers poly(ethylene oxide)–poly(lactic acid) (PEG45-PLA69, PEG114-PLA153, and PEG114-PLA180) and the triblock Pluronic® L-121 (poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide), PEG5-PPO68-PEG5). Quality Target Product Profile (QTPP), Critical Quality Attributes (CQAs), Critical Process Parameters (CPPs), and the risk assessment were discussed for the early phase of polymersome development. An Ishikawa diagram was elaborated focusing on analytical methods, raw materials, and processes for polymersome preparation and L-asparaginase encapsulation. PEG-PLA resulted in diluted polymersomes systems. Nonetheless, a much higher yield of Pluronic® L-121 polymersomes of 200 nm were produced by temperature switch, reaching 5% encapsulation efficiency. Based on these results, a risk estimation matrix was created for an initial risk assessment, which can help in the future development of other polymersome systems with biological APIs nanoencapsulated.

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Acknowledgments

We acknowledge support from the State of São Paulo Research Foundation (FAPESP-Brazil) projects 2013/08617-7 (Thematic project), 2014/10456-4 and 2017/03811-0 (Apolinário, A.C. PhD fellowships), and 2016/03887-4 (Oliveira, C.A. Post-Doctoral Fellowship), Coordination for the Improvement of Higher Education Personnel (CAPES, Project 001), and the National Council for Scientific and Technological Development (CNPq-Brazil, project 303334/2014-2). We are in debt with Dr. Monika S. Magón for the enlightening discussions and text reading. Additionally, we thank the BASF Brazil for Pluronic® L-121 donations.

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Correspondence to Carlota de Oliveira Rangel-Yagui.

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Apolinário, A.C., Ferraro, R.B., de Oliveira, C.A. et al. Quality-by-Design Approach for Biological API Encapsulation into Polymersomes Using “Off-the-Shelf” Materials: a Study on L-Asparaginase. AAPS PharmSciTech 20, 251 (2019). https://doi.org/10.1208/s12249-019-1465-1

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KEY WORDS

  • self-assembly
  • L-asparaginase encapsulation
  • amphiphilic block copolymers
  • polymersomes
  • biologics