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WO2022200257A1 - Procédé de préparation de nanostructures d'hydrogel par gélification ionotropique en microfluidique - Google Patents

Procédé de préparation de nanostructures d'hydrogel par gélification ionotropique en microfluidique Download PDF

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Publication number
WO2022200257A1
WO2022200257A1 PCT/EP2022/057317 EP2022057317W WO2022200257A1 WO 2022200257 A1 WO2022200257 A1 WO 2022200257A1 EP 2022057317 W EP2022057317 W EP 2022057317W WO 2022200257 A1 WO2022200257 A1 WO 2022200257A1
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channel
polymer
process according
microfluidic device
polyanionic
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Inventor
Enza TORINO
Paolo Antonio Netti
Alfonso Maria PONSIGLIONE
Alessio SMERALDO
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Kyme Nanoimaging Srl
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Kyme Nanoimaging Srl
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes

Definitions

  • the present invention refers to the field of bioengineering since it concerns the productions of nanoparticles made of polymers by means of a process consisting of nanoprecipitation-mediated ionotropic gelation in the presence or not of a crosslinking agent followed by polymer electrostatic coupling which is carried out in a microfluidic device.
  • NP Polymer nanoparticles
  • NP Polymer Nanoparticles
  • This nanocarrier has a yolk-shell structure with a radioluminescent yolk based on Gd203: Eu nanospheres, an up conversion luminescent in a silica shell, and a coating constituted by HA/CS combination for pH-triggered drug release.
  • Nanomed. 12, 2211-2222 (2017) disclose the production of core-shell polymer nanoparticles for multimodal imaging applications through a complex coacervation process driven by temperature and high pressure homogenization.
  • the nanovectors made of a CS-core and a HA shell, are designed to entrap a contrast agent for MRI, boosting its performances, together with an additional optical tracer.
  • TPP tripolyphosphate
  • H-CHS hyaluronic acid-chitosan
  • microfluidic method for the preparation of divinyl sulfone crossedlinked hyaluronic acid nanoparticles entrapping a Gd-DTPA MRI contrast agent in the presence of a cross linking agent.
  • the microfluidic method allows for a fine control of the nanoparticle properties enabling the production of monodisperse particles and does not require time-consuming and expensive purification steps.
  • US patent application, publication n. 2010022680 discloses a microfluidic system having zig zag or multiple channels that converge into a mixing apparatus, used to prepare PLGA-PEG nanoparticles by injecting 50 mg/ml PLGA-PEG solution in acetonitrile in the polymeric stream using a syringe pump at varying flow rates.
  • US patent application, publication n. 2016158383 discloses a method in a microfluidic device with groove protrusions for making polymer conjugate nanoparticles, in particular an acetylated carboxymethylcellulose polymer conjugated to polyethylene glycol and docetaxel.
  • the aim of the present invention is the use of a new microfluidic approach to produce hydrogel or semi-hydrogels nanoparticles by combining two polyelectrolytes and by implementing an ionotropic gelation process, followed by a complex coacervation process, in a microfluidic platform.
  • the inventors of the present invention overcame some drawbacks of the known procedures based on microemulsion preparation or batch-mode processes, such as the lack of control over size, polydispersity, productivity, purification/recovery steps.
  • the technical problem is solved by implementing the ionotropic gelation process in the microfluidic device.
  • Ionotropic gelation is based on the ability of polyelectrolytes, like Hyaluronic Acid (HA) and Chitosan (CS) as so their derivatives (alginate/chitosan/fucoidan, chitosan to which both azide and lactose moieties are introduced,
  • polyelectrolytes like Hyaluronic Acid (HA) and Chitosan (CS) as so their derivatives (alginate/chitosan/fucoidan, chitosan to which both azide and lactose moieties are introduced
  • Anions form meshwork structure through their combination with the polyvalent cations and induce gelation by binding to the anion blocks or viceversa.
  • a crosslinker bonds to the charged groups of the polyelectrolyte and relies only on electrostatic interaction avoiding toxicity of reagents.
  • the use of a nanoprecipitation- mediated ionotropic gelation in a microfluidic device allows the use of a one-step process to combine and complex two polymers at once, with the use of a single cross-liker.
  • the nanoprecipitation-mediated ionotropic gelation allows avoiding the use of an oil phase, thus overcoming some of the limitations of emulsion-based processes, i.e. the need for extensive purification and post-processing steps.
  • nanoprecipitation-mediated ionotropic gelation allows the complexation of two polymers in a continuous and controllable one-step process, thus overcoming some of the limitations of batch processes, i.e. the use of multiple-step processes as well as the process scalability and parameters' control issues. Furthermore, the nanoprecipitation-mediated ionotropic gelation followed by polymer electrostatic coupling in microfluidics allows the attainment of more versatile, tunable and complex nanostructures.
  • the combination of two polymers can provide a more controllable drug-delivery profile, a better interaction with biological media, a more efficient encapsulation, and in particular, the possibility to simultaneously encapsulate multiple small molecules, agents or drugs with different properties.
  • the combination of two polymers with different characteristics favours the formation of a more structured and complex environment, characterized by compartments that enable the entrapment of both hydrophilic and hydrophobic substances. Such a results cannot be obtained with a single-polymer encapsulation.
  • Purposive selection is made on process parameters such as flow rate, flow rate ratio, concentration ratio, temperature, photoactivation media, pH of crosslinking solutions, mixing time, mass ratio, concentrations and molecular weights in order to affect size and shape, grade of crosslinking and surface charge intensity of nanoparticles.
  • the technical problem is solved by providing a process for the preparation of nanoparticles entrapping active agents and acting as carriers through nanoprecipitation-mediated ionotropic gelation followed by polymer electrostatic coupling.
  • the nanoparticles obtained consist of at least one polycationic polymer and at least one polyanionic polymer.
  • Object of the present invention is a process for the preparation of nanoparticles consisting of at least one polycationic polymer and at least one polyanionic polymer entrapping active agents and acting as carriers, by nanoprecipitation-mediated ionotropic gelation followed by polymer electrostatic coupling carried out in a microfluidic device comprising at least one channel and the process comprising the following steps: a)preparing a first polycationic solution by mixing at least one polycationic polymer in a concentration between 0.005 and 0.5 % w/v in an aqueous buffer or organic solvent; b)preparing a second polyanionic solution by mixing at least one polyanionic polymer in a concentration between 0.0001 and 0.01 % w/v in an aqueous buffer or organic medium; c)injecting the solution as obtained in step a) in at least one first channel of the microfluidic device; d)contemporarily with step c) injecting the solution as obtained in step b) in at least one second channel
  • nanoparticles consisting of at least one polycationic polymer and at least one polyanionic polymer entrapping active agents, obtained by the above process, and the use of said particles as carriers for active ingredients. Further features will be clear from the following detailed description with reference to the experimental data provided and the attached figure.
  • figure Figure 1 shows in graph the relaxivity for different formulations of Gd-DTPA-loaded nanoparticles (NPs) in water compared to the corresponding free Gd-DTPA in water.
  • microfluidic process means a process carried out in a microfluidic device provided with micro-channels wherein the flow of starting solutions at specific flow rates, towards one or more outlets of the device, allows obtaining precipitation of particles of nanometric size.
  • active agent means imaging agents.
  • Imaging agents can be fluorophores for optical imaging, metal- compound for Magnetic Resonance Imaging, radiotracers for Positron Emission Tomography, colloidal systems, such as gold or quantum dots.
  • active agent means drugs, macromolecules such as peptides, chemotherapeutic, immunotherapeutic and anti-inflammatory drugs, siRNA, miRNA, DNA and their derivatives.
  • biomaterials are polyelectrolytes or hydrophilic and hydrophobic polymers.
  • hydrophilic polymers can be Water Soluble Polymers and/or Natural Water Soluble Polymers, wherein solubility of the polymers can be also reached with the use of a co-solvent.
  • Soluble Polymers with or without the co-solvent can be selected from the group consisting of: Poly(ethylene glycol) (PEG), Polyvinyl pyrrolidone (PVP), Polyvinyl alcohol (PVA), Polyacrylic acid (PAA) Polyacrylamides, N-(2-Hydroxypropyl) methacrylamide (HPMA), Divinyl Ether-Maleic Anhydride (DIVEMA), Polyphosphates and Polyphosphazenes, polyactic acid (PLLA) and poly(lactic-co-glycolic acid) (PLGA).
  • PEG Poly(ethylene glycol)
  • PVP Polyvinyl pyrrolidone
  • PVA Polyvinyl alcohol
  • PAA Polyacrylic acid
  • HPMA N-(2-Hydroxypropyl) methacrylamide
  • DIVEMA Divinyl Ether-Maleic Anhydride
  • Polyphosphates and Polyphosphazenes Polyactic acid (PLLA) and poly(lactic
  • Natural Water Soluble Polymers can be selected from the group consisting of: Xanthan Gum, Pectins, Chitosan Derivatives, Dextran, Carrageenan, Guar Gum, Cellulose Ethers (Sodium CMC, HPC, HPMC), Hyaluronic acid (HA), Albumin and Starch or Starch Based Derivatives.
  • Nanoprecipitation-mediated ionotropic gelation process has been implemented by using chitosan (CS) and hyaluronic acid (HA) in a custom-made microfluidic device for nanoparticles production, because said biomaterials show biocompatibility, biodegradability and no toxic properties. Nanoparticles can be tuned to possess different morphological structures that can be customized depending on the specific goal, simply by controlling the flow rates.
  • CS chitosan
  • HA hyaluronic acid
  • the production through the microfluidic process allows greater control of the process parameters for better optimization of the production at the minimal costs.
  • Object of the present invention is a process for the preparation of nanoparticles consisting of at least one polycationic polymer and at least one polyanionic polymer entrapping active agents and acting as carriers, by nanoprecipitation-mediated ionotropic gelation followed by polymer electrostatic coupling carried out in a microfluidic device comprising at least one channel, the process comprising the following steps: a)preparing a first polycationic solution by mixing at least one polycationic polymer in a concentration between 0.005 and 0.5 % w/v in an aqueous buffer or organic solvent; b)preparing a second polyanionic solution by mixing at least one polyanionic polymer in a concentration between
  • step a) in at least one first channel of the microfluidic device; d)contemporarily with step c) injecting the solution as obtained in step b) in at least one second channel of the microfluidic device; e)collecting the final product as precipitate and the confluence point of the channel(s); wherein the flow rate in the first channel is between 0.01 and 100 pL/min, the flow rate in the second channel is between 0.1 and 1000 pL/min, the weight ratio between polycationic polymer and polyanionic is between 0.001 to 10 (g/g).
  • the first channel is a main central (middle) channel
  • the second channel is a secondary side channel of the microfluidic device.
  • a cross-linking agent is added in step a) and/or step b)
  • the cross-linking agent is added in a concentration between 0.001 and 4 % w/v, more preferably, between 0.001 and 0.02% w/v.
  • a further cross-linking agent is added to the polyanionic solution.
  • steps a) and/or b) other excipients can be added to the solutions such as surfactant or salts.
  • the organic solvent is selected from the group consisting of: acetic acid, acetone or ethanol.
  • the aqueous buffer is water.
  • the aqueous buffer is water.
  • the organic solvent is acetone or ethanol.
  • Steps a) and b) can be inverted.
  • the flow rate in the middle channel is between 0.0001 and 10000 pL/min and the flow rate in the side channel is between 0.001 and 100000 pL/min.
  • the rate between polycationic polymer and polyanionic polymer is measured at the junction between channels.
  • the microfluidic device can be parallelized in series to form from 2 to 1000 units and multiple of them.
  • the polycationic polymer is chitosan, poloxamer, poly(amidoamine), poly(ethylenimine), poly(allylamine hydrochloride), poly(o ⁇ -1-lysine), more preferably is chitosan.
  • the polyanionic polymer is hyaluronic acid, poly(lactic acid), poly(lactic-co-glycolic acid), poly(vinyl alcohol), poly(glycolic acid), poly(acrylic acid), sodium alginate, chondroitin sulphate, heparin, dextran, more preferably is hyaluronic acid.
  • the cross-linking agent is tripolyphosphate (TPP).
  • TPP tripolyphosphate
  • the flow rate ratio defined as the ratio between the flow rate of the middle channel and the flow rate of the side channels, is 0.5 or viceversa.
  • the flow rate in the middle channel is between 0.01 pL/min and 500 pL/min.
  • the flow rate in at least one side channel is between 0.01 pL/min and 600 pL/min.
  • the weight ratio between polycationic polymer and polyanionic polymer measured at the junction between channels is 0.05 and 10 (g/g).
  • the microfluidic device has a geometry selected from the group consisting of: geometry with three inlets-T- junction, geometry with three inlets-Y-junction, geometry with five inlets-Y-junction, geometry with three inlets-Y-junction, geometry with four inlets-YT-junction.
  • the most preferred geometry of the microfluidic device is the geometry with three inlets-Y-junction.
  • nanoparticles consisting of at least one polycationic polymer and at least one polyanionic polymer entrapping active agents and acting as carriers, obtained by a process by nanoprecipitation-mediated ionotropic gelation followed by polymer electrostatic coupling carried out in a microfluidic device comprising at least one channel and the process comprising the following steps: a)preparing a first polycationic solution by mixing at least one polycationic polymer in a concentration between 0.005 and 0.5 % w/v in an aqueous buffer or organic solvent; b)preparing a second polyanionic solution by dissolving in an in an aqueous buffer or organic solvent at least one polyanionic polymer in a concentration between 0.0001 and 0.01 % w/v; c)injecting the solution as obtained in step a) in a first channel of the microfluidic device; d)and contemporarily injecting the solution as obtained in step b) in a second channel of the microflui
  • microfluidic device geometry ranges from three inlets-T-junction, three inlets-Y-junction, five inlets-Y- junction, three inlets-Y-junction, and four inlets-YT- junction.
  • a three inlets-Y-junction geometry is used for the microfluidic device.
  • the rate between polycationic polymer and polyanionic polymer is measured at the junction between said channels.
  • polymer nanoparticles entrapping active agents and acting as carriers consisting of at least one polycationic polymer and at least one polyanionic polymer are obtained by a process of nanoprecipitation-mediated ionotropic gelation, in the presence of at least one crosslinking agent added to step a) and/or to step b).
  • the at least one cross-linking agent is added in a concentration between 0.001 and 4 % w/v, more preferably between 0.001 and 0.02 % w/v
  • the nanoparticles have a mean size (diameter) comprised between 10 and 800 nm.
  • the nanoparticles have a mean size (diameter) comprised between 40 and 150 nm, even more preferably the nanoparticles have a mean size (diameter) of 50 nm.
  • the nanoparticles have a polydispersity index comprised between 0.05 and 1.
  • the nanoparticles have a polydispersity index comprised between 0.05 and 0.2, even more preferably the nanoparticles have a polydispersity index of 0.1.
  • the polycationic and polyanionic polymers are selected from the group consisting of Poly(ethylene glycol) (PEG), Polyvinyl pyrrolidone (PVP), Polyvinyl alcohol (PVA), Polyacrylic acid (PAA) Polyacrylamides, N-(2-Hydroxypropyl) methacrylamide (HPMA), Divinyl Ether-Maleic Anhydride (DIVEMA), Polyphosphates and Polyphosphazenes; Xanthan Gum, Pectins, Chitosan Derivatives, Dextran, Carrageenan, Guar Gum, Cellulose Ethers, Sodium Carboxymethyl cellulose (CMC), Hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), Hyaluronic acid (HA), Albumin and Starch or Starch Based Derivatives, alginate, heparin.
  • PEG Poly(ethylene glycol)
  • PVP Polyvinyl pyrrolidone
  • PVA
  • the nanoparticles are of hyaluronic acid and chitosan formed through a nanoprecipitation-mediated ionotropic gelation via chitosan -tripolyphosphate crosslinking followed by hyaluronic acid- chitosan complex electrostatic coupling.
  • active ingredients are preferably imaging agents, more preferably selected from the group consisting of fluorophores for optical imaging, metal-chelates for Magnetic Resonance Imaging, radiotracers for Positron Emission
  • Hyaluronic acid with a low or high molecular weight is preferred.
  • Chitosan with a low molecular weight and sodium tripolyphosphate (TPP) are preferred.
  • Commercially available Gadolinium based CAs is used since it is a well- known, low-risk Contrast Agent (CA).
  • Optical dye is used as a model optical tracer.
  • the middle and side streams include two different polymers that leads to NPs formation through a nanoprecipitation-mediated ionotropic gelation via CS-TPP crosslinking followed by HA-CS complex electrostatic coupling.
  • the starting step consists in the preparation of polycationic and polyanionic solutions. The first one is obtained by mixing CS (concentration range from 0.005 to 0.5 % w/v) in an acetic acid buffer (1% v/v) while the second one is obtained dissolving HA (concentration range from 0.001 to 0.01 % w/v) and TPP (concentration range from 0.001 to 0.02 % w/v) in water. Both solutions are stirred at 300 rpm for 30 min.
  • Polycationic solution (CS) is injected in the middle channel while polyanionic solution (HA+TPP) in the two side channels, wherein the flow rate in the middle channel is between 0,0001 and 1000 mL/min, the flow rate at the side channel is between 0,0001 and 1000 mL/min, the ratio between polycationic polymer and polyanionic polymer, or vice versa, measured at the junction between channels is between 0,001 to 99.
  • An additional advantage of the proposed process consists of the opportunity to obtain a relaxivity boost of the encapsulated CAs for MRI by changing the structural parameter of the hydrogel matrix.
  • Examples of the changes in the nanoarchitectures and process parameters is briefly reported in Tables from 2 to 4, where both morphological and structural characteristics of the nanoparticles are controlled through fine tuning of the flow rate ratio, weight ratio of the polymers and flow rate regimes.
  • the relaxation enhancement is reported in Figure 1 and in Table 5, where a comparison of the longitudinal relaxation rate between different nanoparticles formulations and the free Gd-base contrast agent is showed.
  • ATT0488 fluorophore has been introduced in the polyanionic solution (35 pg/mL) in order to demonstrate that NPs are able to encapsulate, at the same time, two diagnostic agents and so, theoretically, even a drug.
  • ATT0488 amount has been evaluated through spectrofluorimetric measurements and it shows an estimated concentration from fluorescence signal of 7 pmol.

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  • Pharmacology & Pharmacy (AREA)
  • Physics & Mathematics (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
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Abstract

Est divulgué, un procédé de préparation de nanoparticules polymères piégeant des principes actifs consistant en une gélification ionotrope médiée par nanoprécipitation en présence d'un agent de réticulation suivi d'un couplage électrostatique polymère dans un procédé en une étape réalisé dans un dispositif microfluidique.
PCT/EP2022/057317 2021-03-22 2022-03-21 Procédé de préparation de nanostructures d'hydrogel par gélification ionotropique en microfluidique Ceased WO2022200257A1 (fr)

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IT102021000006866 2021-03-22
IT102021000006866A IT202100006866A1 (it) 2021-03-22 2021-03-22 Un processo per la preparazione di nanostrutture di idrogel mediante gelificazione ionotropica in microfluidica

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Citations (6)

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WO2005103106A1 (fr) 2004-04-23 2005-11-03 Eugenia Kumacheva Procede de production de particules polymeres ayant une taille, une forme, une morphologie et une composition selectionnees
US20100022680A1 (en) 2006-06-23 2010-01-28 Massachusetts Institute Of Technology Microfluidic Synthesis of Organic Nanoparticles
WO2008116261A1 (fr) 2007-03-27 2008-10-02 The University Of Queensland Production de particules
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