Quality-by-Design Approach for Biological API Encapsulation into Polymersomes Using “Off-the-Shelf” Materials: a Study on L-Asparaginase
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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.
KEY WORDSself-assembly L-asparaginase encapsulation amphiphilic block copolymers polymersomes biologics
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.
- 2.Apolinário AC, Almeida Pachioni-Vasconcelos J, Pessoa A, Rangel-Yagui CO. Polymersomes versus liposomes: the “magic bullet” evolution. Quim Nova. 2017;4(7):810–7.Google Scholar
- 5.Blackman LD, Varlas S, Arno MC, Houston ZH, Fletcher NL, Thurecht KJ, et al. Confinement of therapeutic enzymes in selectively permeable polymer vesicles by polymerization-induced self-assembly (PISA) reduces antibody binding and proteolytic susceptibility. ACS Cent Sci. 2018;4(6):718–23.PubMedPubMedCentralCrossRefGoogle Scholar
- 16.European Medicines Agency (EMA), 2012. ICH guideline Q11 on development and manufacture of drug substances (chemical entities and biotechnological/biological entities) pp. 29. November 2012. https://www.ema.europa.eu/documents/scientific-guideline/ich-guideline-q11-development-manufacture-drug-substances-chemical-entities-biotechnological/biological-entities_en.pdf (Accessed 10 Sept 2018).
- 17.European Medicines Agency (EMA), 2017. ICH guideline Q11 on development and manufacture of drug substances (chemical entities and biotechnological/biological entities)—questions and answers, pp. 20. 1 September 2017. https://www.ema.europa.eu/documents/other/ich-guideline-q11-development-manufacture-drug-substances-chemical-entities-biotechnological/biological-entities-questions-answers-adopted_en.pdf (Accessed 10 Sept 2018).
- 18.FDA, 2017. FDA guidance for industry (draft): drug products, including biological products, that contain nanomaterials guidance for industry drug products, including biological products, that contain nanomaterials (December 2017). https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM588857.pdf (Accessed 1 Oct 2018).
- 19.Flühmann B, Ntai I, Brorchard G, Simoens S, Mühlebach S. Nanomedicines: the magic bullets reaching their target? Eur J Pharm Sci. 2018; In press article.Google Scholar
- 23.Hirst, N.C., 2008. Solvency effects on polymer surfactant interactions. Thesis. Cardiff University Wales, UK.Google Scholar
- 24.ICH, 2005. International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline: quality risk management Q9 https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf (Accessed 15 Oct 2018).
- 25.ICH, 2008. International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline: pharmaceutical quality systems (Q10) https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4/Q10_Guideline.pdf (Accessed 15 Oct 2018).
- 26.ICH, 2009. International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline: pharmaceutical development Q8(R2) https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf (Accessed 15 Oct 2018).
- 35.Place AE, Stevenson KE, Vrooman LM, Harris MH, Hunt SK, Brien JEO, et al. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised , open-label phase 3 trial. Lancet. 2015;16(16):1677–90.PubMedCrossRefGoogle Scholar
- 49.Meglič HS, Kotnik T. Electroporation-Based Applications in Biotechnology. In: Miklavčič D. (eds) Handbook of Electroporation. Springer: Cham; 2017. p. 2153–2169Google Scholar