The aim of this work is to develop a scalable continuous system suitable for the formulation of polymeric nanoparticles using membrane-assisted nanoprecipitation. One of the hurdles to overcome in the use of nanostructured materials as drug delivery vectors is their availability at industrial scale. Innovation in process technology is required to translate laboratory production into mass production while preserving their desired nanoscale characteristics.
Membrane-assisted nanoprecipitation has been used for the production of Poly[(D,L lactide-co-glycolide)-co-poly ethylene glycol] diblock) (PLGA-PEG) nanoparticles using a pulsed back-and-forward flow arrangement. Tubular Shirasu porous glass membranes (SPG) with pore diameters of 1 and 0.2 μm were used to control the mixing process during the nanoprecipitation reaction.
The size of the resulting PLGA-PEG nanoparticles could be readily tuned in the range from 250 to 400 nm with high homogeneity (PDI lower than 0.2) by controlling the dispersed phase volume/continuous phase volume ratio. Dexamethasone was successfully encapsulated in a continuous process, achieving an encapsulation efficiency and drug loading efficiency of 50% and 5%, respectively. The dexamethasone was released from the nanoparticles following Fickian kinetics.
The method allowed to produce polymeric nanoparticles for drug delivery with a high productivity, reproducibility and easy scalability.
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Drug loading efficiency
Nanoprecipitation in a stirred batch-type reactor
Poly ethylene glycol
Poly[(D,L lactide-co-glycolide)-co-poly ethylene glycol] diblock
Scanning Electron Microscopy
Luque-Michel E, Imbuluzqueta E, Sebastián V, Blanco-Prieto MJ. Clinical advances of nanocarrier-based cancer therapy and diagnostics. Expert Opinion on Drug Delivery. 2016;14:1–18.
Makadia HK, Siegel SJ. Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier. Polymer. 2011;3:1377–97.
Sebastian V, Arruebo M, Santamaria J. Reaction Engineering strategies for the production of inorganic Nanomaterials. Small. 2014;10:835–53.
Noorlander CW, Kooi MW, Oomen AG, Park MV, Vandebriel RJ, Geertsma RE. Horizon scan of nanomedicinal products. Nanomedicine. 2015;10:1599–608.
Sainz V. Conniot J. Peres C, Zupančič E, Moura L, et al. Regulatory aspects on nanomedicines. Biochem Biophys Res Commun: Matos AI; 2015. http://linkinghub.elsevier.com/retrieve/pii/S0006291X15304137. Accessed 4 Nov 2015
Chan JM, Valencia PM, Zhang L, Langer R, Farokhzad OC. Polymeric Nanoparticles for Drug Delivery. In: Grobmyer SR, Moudgil BM, editors. Cancer Nanotechnol. Totowa: Humana Press; 2010. p. 163–75. http://link.springer.com/10.1007/978-1-60761-609-2_11. Acccessed 22 Feb 2015.
Faisant N, Siepmann J, Benoit JP. PLGA-based microparticles: elucidation of mechanisms and a new, simple mathematical model quantifying drug release. Eur J Pharm Sci. 2002;15:355–66.
Xu Q, Ensign LM, Boylan NJ, Schön A, Gong X, Yang J-C, et al. Impact of surface polyethylene glycol (PEG) density on biodegradable nanoparticle transport in mucus ex Vivo and distribution in Vivo. ACS Nano. 2015;9:9217–27.
Ghahremankhani AA, Dorkoosh F, Dinarvand R. PLGA-PEG-PLGA tri-block copolymers as in situ gel-forming peptide delivery system: effect of formulation properties on peptide release. Pharm Dev Technol. 2008;13:49–55.
Avgoustakis K. Pegylated poly(Lactide) and poly(Lactide-co-Glycolide) nanoparticles: preparation, properties and possible applications in drug delivery. Current Drug Delivery. 2004;1:321–33.
Vllasaliu D, Fowler R, Stolnik S. PEGylated nanomedicines: recent progress and remaining concerns. Expert Opinion on Drug Delivery. 2014;11:139–54.
Xu S, Yang F, Zhou X, Zhuang Y, Liu B, Mu Y, et al. Uniform PEGylated PLGA microcapsules with embedded Fe 3 O 4 nanoparticles for US/MR dual-modality imaging. ACS Appl Mater Interfaces. 2015;7:20460–8.
Johnson BK, Prud’homme RK. Chemical processing and micromixing in confined impinging jets. AICHE J. 2003;49:2264–82.
Johnson BK, Prud’homme RK. Mechanism for Rapid Self-Assembly of Block Copolymer Nanoparticles. Phys Rev Lett. 2003. p. 91. http://link.aps.org/doi/10.1103/PhysRevLett.91.118302. Accessed 6 Oct 2015.
De Solorzano IO, Uson L, Larrea A, Miana M, Sebastian V, Arruebo M. Continuous synthesis of drug-loaded nanoparticles using microchannel emulsification and numerical modeling: effect of passive mixing. Int J Nanomedicine. 2016;11:3397–416.
Rietscher R, Thum C, Lehr C-M, Schneider M. Semi-automated Nanoprecipitation-system—an option for operator independent, scalable and size adjustable nanoparticle synthesis. Pharm Res. 2015;32:1859–63.
Galindo-Rodríguez SA, Puel F, Briançon S, Allémann E, Doelker E, Fessi H. Comparative scale-up of three methods for producing ibuprofen-loaded nanoparticles. Eur J Pharm Sci. 2005;25:357–67.
Schubert S, Delaney Jr JT, Schubert US. Nanoprecipitation and nanoformulation of polymers: from history to powerful possibilities beyond poly(lactic acid). Soft Matter. 2011;7:1581–8.
Perevyazko IY, Delaney JT, Vollrath A, Pavlov GM, Schubert S, Schubert US. Examination and optimization of the self-assembly of biocompatible, polymeric nanoparticles by high-throughput nanoprecipitation. Soft Matter. 2011;7:5030.
Imbrogno A, Piacentini E, Drioli E, Giorno L. Preparation of uniform poly-caprolactone Microparticles by membrane emulsification/solvent diffusion process. J Membr Sci. 2014;467:262–8.
Piacentini E, Drioli E, Giorno L. Membrane emulsification technology: twenty-five years of inventions and research through patent survey. J Membr Sci. 2014;468:410–22.
Vladisavljević GT. Structured microparticles with tailored properties produced by membrane emulsification. Adv Colloid Interf Sci. 2015;225:53–87.
Piacentini E, Dragosavac M, Giorno L. Pharmaceutical Particles Design by Membrane Emulsification. Curr Pharm Des. 2016;in press.
Charcosset C, Fessi H. Preparation of nanoparticles with a membrane contactor. J Membr Sci. 2005;266:115–20.
Othman R, Vladisavljević GT. Shahmohamadi H. Holdich RG. Formation of size-tuneable biodegradable polymeric nanoparticles by solvent displacement method using micro-engineered membranes fabricated by laser drilling and electroforming. Chem Eng J: Nagy ZK; 2016. http://linkinghub.elsevier.com/retrieve/pii/S1385894716309573. Accessed 7 Jul 2016
Laouini A, Charcosset C, Fessi H, Holdich RG, Vladisavljević GT. Preparation of liposomes: a novel application of microengineered membranes - investigation of the process parameters and application to the encapsulation of vitamin E. RSC Adv. 2013;3:4985.
Laouini A, Koutroumanis KP, Charcosset C, Georgiadou S, Fessi H, Holdich RG, et al. pH-sensitive micelles for targeted drug delivery prepared using a novel membrane contactor method. ACS Appl Mater Interfaces. 2013;5:8939–47.
Limayem Blouza I, Charcosset C, Sfar S, Fessi H. Preparation and characterization of spironolactone-loaded nanocapsules for paediatric use. Int J Pharm. 2006;325:124–31.
Soleimani G, Daryadel A, Ansari Moghadam A, Sharif MR. The comparison of oral and IM dexamethasone efficacy in croup treatment. J Compr Pediatr. 2013;4:175–8.
Piacentini E, Drioli E, Giorno L. Pulsed back-and-forward cross-flow batch membrane emulsification with high productivity to obtain highly uniform and concentrate emulsions. J Membr Sci. 2014;453:119–25.
Cheng J, Teply B, Sherifi I, Sung J, Luther G, Gu F, et al. Formulation of functionalized PLGA–PEG nanoparticles for in vivo targeted drug delivery. Biomaterials. 2007;28:869–76.
Ganachaud F, Katz JL. Nanoparticles and Nanocapsules created using the ouzo effect: spontaneous emulsification as an alternative to ultrasonic and high-shear devices. ChemPhysChem. 2005;6:209–16.
Beck-Broichsitter M, Nicolas J, Couvreur P. Solvent selection causes remarkable shifts of the “ouzo region” for poly(lactide-co-glycolide) nanoparticles prepared by nanoprecipitation. Nano. 2015;7:9215–21.
Mora-Huertas CE, Fessi H, Elaissari A. Influence of process and formulation parameters on the formation of submicron particles by solvent displacement and emulsification–diffusion methods. Adv Colloid Interf Sci. 2011;163:90–122.
Aubry J, Ganachaud F, Cohen Addad J-P, Cabane B. Nanoprecipitation of Polymethylmethacrylate by solvent shifting:1. Boundaries Langmuir. 2009;25:1970–9.
Stainmesse S, Orecchioni A-M, Nakache E, Puisieux F, Fessi H. Formation and stabilization of a biodegradable polymeric colloidal suspension of nanoparticles. Colloid Polym Sci. 1995;273:505–11.
Beck-Broichsitter M, Rytting E, Lebhardt T, Wang X, Kissel T. Preparation of nanoparticles by solvent displacement for drug delivery: a shift in the “ouzo region” upon drug loading. Eur J Pharm Sci. 2010;41:244–53.
Karnik R, Gu F, Basto P, Cannizzaro C, Dean L, Kyei-Manu W, et al. Microfluidic platform for controlled synthesis of polymeric nanoparticles. Nano Lett. 2008;8:2906–12.
Vladisavljevic GT. Integrated membrane processes for the preparation of emulsions, particles and bubbles. Integr Membr Syst Process. 2015;79
Laouini A, Jaafar-Maalej C, Sfar S, Charcosset C, Fessi H. Liposome preparation using a hollow fiber membrane contactor—application to spironolactone encapsulation. Int J Pharm. 2011;415:53–61.
Khayata N, Abdelwahed W, Chehna MF, Charcosset C, Fessi H. Preparation of vitamin E loaded nanocapsules by the nanoprecipitation method: from laboratory scale to large scale using a membrane contactor. Int J Pharm. 2012;423:419–27.
Spyropoulos F, Lloyd DM, Hancocks RD, Pawlik AK. Advances in membrane emulsification. Part B: recent developments in modelling and scale-up approaches. J Sci Food Agric. 2014;94:628–38.
Piacentini E, Imbrogno A, Drioli E, Giorno L. Membranes with tailored wettability properties for the generation of uniform emulsion droplets with high efficiency. J Membr Sci. 2014;459:96–103.
Gijsbertsen-Abrahamse A. Status of cross-flow membrane emulsification and outlook for industrial application. J Membr Sci. 2004;230:149–59.
Charcosset C. Preparation of emulsions and particles by membrane emulsification for the food processing industry. J Food Eng. 2009;92:241–9.
Piacentini E, Giorno L, Dragosavac MM, Vladisavljević GT, Holdich RG. Microencapsulation of oil droplets using cold water fish gelatine/gum arabic complex coacervation by membrane emulsification. Food Res Int. 2013;53:362–72.
Imbrogno A, Dragosavac M, Piacentini E, Vladisavljević GT, Holdich RG, Giorno L. Polycaprolactone multicore-matrix particle for the simultaneous encapsulation of hydrophilic and hydrophobic compounds produced by membrane emulsification and solvent diffusion processes. Colloids Surf B: Biointerfaces. 2015;135:116–25.
Kahraman C, Yanık S, editors. Intelligent decision making in quality management. Cham: Springer International Publishing; 2016. http://link.springer.com/10.1007/978-3-319-24499-0. Accessed 14 Sept 2016
Ermer J, Ploss H-J. Validation in pharmaceutical analysis. J Pharm Biomed Anal. 2005;37:859–70.
Zhang L, editor. Nonclinical statistics for pharmaceutical and biotechnology industries. Cham: Springer International Publishing; 2016. http://link.springer.com/10.1007/978-3-319-23558-5. Accessed 14 Sept 2016
Villaverde A. Editor. Nanoparticles in translational science and medicine. Amsterdam: Elsevier, Acad. Press; 2011.
Chorny M, Fishbein I, Danenberg HD, Golomb G. Lipophilic drug loaded nanospheres prepared by nanoprecipitation: effect of formulation variables on size, drug recovery and release kinetics. J Control Release. 2002;83:389–400.
Budhian A, Siegel SJ, Winey KI. Haloperidol-loaded PLGA nanoparticles: systematic study of particle size and drug content. Int J Pharm. 2007;336:367–75.
Guhagarkar SA, Malshe VC, Devarajan PV. Nanoparticles of polyethylene Sebacate: a new biodegradable polymer. AAPS PharmSciTech. 2009;10:935–42.
Dhakar R. From Formulation Variables to Drug Entrapment Efficiency of Microspheres: A Technical Review. J Drug Deliv Ther. 2012. p. 2. http://jddtonline.info/index.php/jddt/article/view/160.
Govender T, Stolnik S, Garnett MC, Illum L, Davis SS. PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug. J Control Release Off J Control Release Soc. 1999;57:171–85.
Campos IMF, Santos TM, Cunha GMF, Silva KMMN, Domingues RZ, da Silva Cunha Júnior A, et al. Preparation and release characteristics of dexamethasone acetate loaded organochlorine-free poly(lactide- co -glycolide) nanoparticles. J. Appl. Polym. Sci. 2014;131:n/a-n/a.
Ford Versypt AN, Pack DW, Braatz RD. Mathematical modeling of drug delivery from autocatalytically degradable PLGA microspheres — a review. J Control Release. 2013;165:29–37.
Kim D-H, Martin DC. Sustained release of dexamethasone from hydrophilic matrices using PLGA nanoparticles for neural drug delivery. Biomaterials. 2006;27:3031–7.
Ritger PL, Peppas NA. A simple equation for description of solute release I. Fickian and non-fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs. J. Controlled Release. 1987;5:23–36.
Grassi M, Grassi G. Mathematical Modelling and controlled drug delivery: matrix systems. Current Drug Delivery. 2005;2:97–116.
Vega E Egea, Calpena, Espina García. Role of hydroxypropyl-&beta;-cyclodextrin on freeze-dried and gamma-irradiated PLGA and PLGA&ndash;PEG diblock copolymer nanospheres for ophthalmic flurbiprofen delivery. Int J Nanomedicine. 2012;7(1):1357–1371.
Acknowledgements and Disclosures
The People Program (CIG-Marie Curie Actions, REA grant agreement no. 321642) and the ERC Consolidator Grant program (ERC-2013-CoG-614,715, NANOHEDONISM), the Government of Aragon and the European Social Fund are gratefully acknowledged. CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008–2011 financed by the Instituto de Salud Carlos III with the assistance of the European Regional Development Fund. Program Erasmus Mundus Doctorate in Membrane Engineering-EUDIME (2011–0014) is grate fully acknowledged. The authors acknowledge the European Union, FESR, MIUR, MSE for the financial support to the project PON Olio Più - PON01_01545, within the framework PON Ricerca e Competitività 2007–2013.
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Albisa, A., Piacentini, E., Sebastian, V. et al. Preparation of Drug-Loaded PLGA-PEG Nanoparticles by Membrane-Assisted Nanoprecipitation. Pharm Res 34, 1296–1308 (2017). https://doi.org/10.1007/s11095-017-2146-y