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Production of Lysozyme-PLGA-Loaded Microparticles for Controlled Release Using Hot-Melt Extrusion

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Abstract

Biopharmaceuticals are usually administered intravenously with frequent dosing regimens which may decrease patient compliance. Controlled-release formulations allow to reduce the frequency of injections while providing a constant dosing of the biopharmaceutical over extended periods. These formulations are typically produced by emulsions, requiring high amounts of organic solvents and have limited productivity. Hot-melt extrusion (HME) is an alternative technology to produce controlled drug delivery systems. It is a continuous solvent-free process, leading to a small ecological footprint and higher productivity. However, it may induce thermolabile compounds’ degradation. In this work, the impact of the formulation and extrusion temperature on lysozyme’s bioactivity and release profile of poly(lactic-co-glycolic acid) (PLGA)-based extended release formulations were evaluated using a design-of-experiments (DoE) approach. The lysozyme-loaded PLGA microparticles were produced by HME followed by milling. It was observed that the in vitro release (IVR) profile was mainly affected by the drug load; higher drug load led to higher burst and total lysozyme release after 14 days. HME temperature seemed to decrease lysozyme’s activity although this correlation was not statistically significant (p value = 0.0490). Adding polyethylene glycol 400 (PEG 400) as a plasticizer to the formulation had no significant impact on the lysozyme release profile. The burst release was effectively mitigated with the inclusion of a washing step. Washing the microparticles with water reduced the burst release by 80% whereas washing them with a poly(vinyl alcohol) (PVA) aqueous solution eliminated it. In conclusion, HME is demonstrated to be suitable in producing controlled-release microparticles of small biopharmaceuticals.

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Funding

The authors would like to thank Hovione for supporting this work.

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Authors and Affiliations

  1. Hovione Farmaciência S.A., R&D Drug Product Development, Estrada do Lumiar, Campus do Lumiar, Edifício R, 1649-038, Lisbon, Portugal

    Susana Farinha, Cláudia Moura & João Henriques

  2. Universidade de Lisboa, Instituto Superior Técnico, CeFEMA, Av. Rovisco Pais, 1, 1049-001, Lisbon, Portugal

    Susana Farinha & Maria Diná Afonso

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  1. Susana Farinha
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  2. Cláudia Moura
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Correspondence to João Henriques.

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Farinha, S., Moura, C., Afonso, M.D. et al. Production of Lysozyme-PLGA-Loaded Microparticles for Controlled Release Using Hot-Melt Extrusion. AAPS PharmSciTech 21, 274 (2020). https://doi.org/10.1208/s12249-020-01816-8

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