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WIREs Nanomed Nanobiotechnol
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Hot melt extrusion: An emerging manufacturing method for slow and sustained protein delivery

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Abstract With the rapid development of the biopharmaceutical industry, an increasing number of new therapeutic protein products (TPPs) have been approved by the FDA and many others are under pre‐clinical and clinical evaluation. A major limitation of biopharmaceuticals is their limited half‐life when administered systemically. A one‐time, implantable, sustained protein delivery device would be advantageous in order to improve the quality of life of patients. Hot melt extrusion (HME) is a mature technology that has been extensively used for a broad spectrum of applications in the polymer and pharmaceutical industry and has achieved success as evidenced by a variety of FDA‐approved commercial products. These commercial products are mostly for sustained delivery of small molecule therapeutics, leaving a significant gap for HME formulation of therapeutic proteins. With the increasing need of sustained TPP delivery, HME shows promise as a downstream processing method due to its high efficiency and economic value. Several challenges remain for the application of HME in protein delivery. Progress of HME for protein delivery, challenges encountered, and potential solutions will be detailed in this review article. This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants Biology‐Inspired Nanomaterials > Protein and Virus‐Based Structures
(a) Displayed picture of a mini‐scale commercial extruder manufactured by Thermo Scientific™. (b) Schematic of the heating tape‐based syringe‐die mini extruder, and temperature profile of the extruder. (c) Digital image of micro‐injection molding instrument. (d) Customized patterned molds, from top‐left to right: ribbon extruder, DLP mold. From bottom‐left to right: cylinder mold, small disks. Adapted with permission from P. W. Lee, Shukla, et al. (2017), “ThermoFisher Minilab HME Micro Compounder (2020),” and Wirth and Pokorski (2019)
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(a) Feasibility of HME for the preparation of protein/polymer composites. (ii) A single‐die simplified extruder, (ii) lysozyme distribution illustrated with EDX–SEM elemental mapping of sulfur (yellow/white spots) on cross‐section of implants prepared by hot‐melt extrusion, (iii) lysozyme release on day 1 from S‐HME implants vs. concentration of a PEG 400 and b‐PEG 1500 at different lysozyme loadings. Dots show n = 3 data, if not overlapping, and bars show their average. (b) PEGylation to improve protein stability during HME. (i)–(iii) SEM micrographs of PLGA with lysozyme, lysozyme and PEG6000 additive and PEGylated lysozyme, respectively, with the region examined via EDX marked in white (iv)–(vi) EDX mapping of the sulfur peak for PLGA with lysozyme, lysozyme and PEG6000 additive, and PEGylated lysozyme. (c) Enhancement of activity by moderate milling (i) and (ii) enzymatic activity of lysozyme samples and GOx samples after recovery from PLGA samples prepared via HME. (iii) Upper and bottom: TEM micrograph of Qβ and 25 Hz milled Qβ recovered after HME with PLGA (iv)–(ix) EDS maps of the nitrogen peak for PLGA processed with 10% (w/w) of unmilled lysozyme, 25 Hz milled lysozyme, 50 Hz milled lysozyme, unmilled GOx, 25 Hz milled GOx, 50 Hz milled GOx, respectively. The nitrogen signal is shown in green. (d) Improving release completeness by the addition of weekly basic base and shellac. (i) and (ii) Release profile of 10% OVA‐loaded PLGA‐based implants with/without addition of weak bases and shellac. (e) End‐point titers of anti‐Qβ IgG indicating the implanted PLGA/Qβ devices immunize as effectively as repeated Qβ administration. Adapted with permission from Duque et al. (2018), Ghalanbor et al. (2010), P. W. Lee, Maia, and Pokorski (2017), P. W. Lee, Shukla, et al. (2017), and Lee et al. (2015)
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(a) Schematic representation of HME and its downstream process, (b) various dosage forms prepared by HME. Adapted with permission from Ren et al. (2019)
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A schematic representation of two typical implantable delivery devices
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Schematic diagram of producing dual release profile dosage form by co‐extrusion. Adapted with permission from Vynckier et al. (2014)
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(A) Schematic diagram of continuous manufacturing of pharmaceutical cocrystals with a PAT assisted HME based equipment. (B) Illustration of HME coupled with FDM 3DP and digital picture of 3D printed tablets with varied drug loading levels, and SEM image of the printed tablet. Adapted with permission from Moradiya et al. (2016) and Pietrzak et al. (2015)
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(a) Trehalose limited Fab2 aggregation with a proposed “water‐substitution” mechanism. (i) Illustration schematic of the spray‐dried Fab2‐trehalose particles. (ii) Morphology of spray‐dried particles: SEM images of Fab2 spray‐dried particles before and after heat treatment for 1 h at various temperatures. (b) Protein/polymer conjugates synthesized via (i) “graft‐to” strategy and (ii) “graft‐from” strategy. (c) Schematic representation of a MOF–enzyme carrier. (d) Protein stabilization via mineral‐coated microparticles (MCM). Adapted with permission from Dutta et al. (2019), Isarov et al. (2016), P. Li et al. (2016), Lu et al. (2020), Rajagopal et al. (2019), and X. Yu et al. (2017)
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(a) Pressure‐induced phase transition of copolymers with UDOT phase diagram. (b) Low‐temperature processable polymer with the potential for protein delivery. (i) Chemical structure of PIPP78b‐PLLAx. (ii) Illustration schematic of the low‐temperature processable polymer/protein composites. (iii) Fully enzymatic activity of proteinase K is preserved after the high‐pressure process. Adapted with permission from Iwasaki et al. (2016) and Taniguchi and Lovell (2012)
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Biology-Inspired Nanomaterials > Protein and Virus-Based Structures
Implantable Materials and Surgical Technologies > Nanomaterials and Implants

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