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WO2008116261A1 - Production de particules - Google Patents

Production de particules Download PDF

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Publication number
WO2008116261A1
WO2008116261A1 PCT/AU2008/000423 AU2008000423W WO2008116261A1 WO 2008116261 A1 WO2008116261 A1 WO 2008116261A1 AU 2008000423 W AU2008000423 W AU 2008000423W WO 2008116261 A1 WO2008116261 A1 WO 2008116261A1
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WIPO (PCT)
Prior art keywords
fluid
solvent
polymer
droplets
size
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PCT/AU2008/000423
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English (en)
Inventor
Justin John Cooper-White
Elisabeth Rondeau
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University of Queensland UQ
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University of Queensland UQ
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Priority claimed from AU2007901625A external-priority patent/AU2007901625A0/en
Application filed by University of Queensland UQ filed Critical University of Queensland UQ
Publication of WO2008116261A1 publication Critical patent/WO2008116261A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/12—Powdering or granulating
    • C08J3/14—Powdering or granulating by precipitation from solutions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F6/00—Post-polymerisation treatments
    • C08F6/06—Treatment of polymer solutions

Definitions

  • This invention relates to a method of forming particles that are substantially polymer based, the particles formed and a device for forming the particles.
  • the particles derived from this process scheme are typically a few hundred micrometres in diameter with very little deviation in size.
  • the production of polymer beads via two-step processes does not realize the full potential of continuous microfluidics-based synthesis.
  • the invention provides in one aspect a method of producing particles in a micrometers to nano meters in size from any synthetic or biologically derived polymer that can be solvated within a liquid that is at least partially miscible with another liquid.
  • the method may further include the step of fixing the size of the droplets to form polymer particles of a predetermined size and/or morphology by cross linking the polymer.
  • the first fluid forms a dispersed phase and the second fluid is a continuous phase.
  • the size of the droplets or dispersed phase is controlled by varying the flow rate of the second fluid or continuous phase.
  • the mutual binary solubilities of the first solvent in the second solvent should ensure sufficient interfacial tension or viscosity difference to allow the generation of droplets of the first fluid in the second fluid.
  • the first solvent should be partially miscible in the second solvent.
  • the solubility may be as low a 1% of the first solvent in the second solvent and no greater than 99%. This solubility is preferably 5 to 15% of the first solvent in the second solvent and more preferably 5 to 10% of the first solvent in the second.
  • a conduit is a flowpath of liquid which is with or without clearly defined physical walls or boundaries,
  • the flowpath may be induced by the motion of the associated apparatus.
  • the method of the invention may be conducted in an apparatus which imparts sufficient shear on the first fluid to cause the flow of first fluid into the second fluid to form droplets In the second fluid.
  • This shear is equivalent to those experienced under laminar flow regimes.
  • the flowpath or conduit is a channel of a microfluidic device.
  • the conduit is sufficiently dimensioned particularly in length to enable the required amount of the first fluid to migrate into the second fluid.
  • the first fluid and second fluid preferably flow through the conduit in co-current flow. While the first fluid and second fluids are preferably liquids, a second fluid which is a gas is within the scope of the invention.
  • the dimensions of the conduit, Ie length and width are fixed.
  • the method of the invention is able to vary the size of the resulting droplets by varying the flow rate of the continuous phase second fluid and hence increasing the shear and rate of migration of the first solvent from the dispersed phase in the continuous phase.
  • the preferred step of fixing the size of the droplets and crosslinking the polymer particles, in one form involves contacting the droplets with a third fluid.
  • the third fluid preferably contains a cros ⁇ linking agent, The droplets may be contacted with the third fluid once the droplets have reached a size to form particles of the predetermined size.
  • the third fluid is introduced into the conduit to mix with the first fluid prior to introduction of the second fluid into the conduit.
  • the crosslinking agent is preferably miscible in the first solvent and substantially immiscible in the second solvent.
  • the first and third fluid is homogeneously mixed before introduction of the second fluid into the conduit.
  • the method may further comprise the step of applying a coating to the polymer particle produced by the method above. Additionally the cross linking step may be omitted with the polymer droplets progressing directly to the coating step.
  • a fluid containing a coating polymer and a solvent for the coating polymer is introduced into a conduit carrying polymer droplets or particles.
  • the polymer Is at least partially miscible in the solvent and miscible with the fluid (continuous phase) carrying the polymer droplets or particles to be coated. While the continuous phase will contain some of the first fluid which has diffused into the second solvent, it will nevertheless be substantially the second solvent.
  • a fourth fluid comprising a fourth solvent and a coating polymer is introduced into the conduit after the polymer particle has been cross linked.
  • the coating polymer is at least partially miscible in the fourth solvent and miscible in the continuous phase carrying the polymer particles in the conduit.
  • the fourth solvent is the same or substantially the same as the second solvent and so the coating polymer will be miscible in the fourth solvent.
  • a method of producing layered polymer particles comprising:
  • first fluid in the second fluid subjecting the first fluid in the second fluid to shear under laminar conditions to form droplets of the first fluid, the first solvent being partially miscible in the second solvent and the polymer being substantially immiscible in the second solvent, and
  • the first fluid to shear until an amount of the first fluid migrates into the second fluid to reduce the size of the droplets; introducing the formed droplets to a coating fluid comprising a carrier solvent and a coating polymer, the coating polymer being at least partially miscible in the carrier solvent and miscible in the second solvent or continuous phase, and
  • the first fluid comprising a polymer and a first solvent is introduced into a flowpath
  • the introduction of the second fluid comprising a second solvent to the flowpath causes the formation of droplets of the first fluid in the second fluid
  • the first fluid and second fluid flows along the flowpath for a sufficient period for the amount of the first fluid to migrate into the second fluid to reduce the size of the droplets, preferably to a predetermined size.
  • the reduced size droplets of first polymer travel along the flowpath a sufficient distance for the coating polymer to coat the first polymer and form layered polymer particles.
  • the first polymer is preferably cross linked once the droplets have reached a predetermined size to form polymer particles of first polymer. These polymer particles continue in the continuous phase to the coating step.
  • the carrier solvent for the coating polymer is miscible in the second solvent and preferably is the same solvent or substantially the same solvent as the second solvent or continuous phase.
  • the coating polymer is preferably immiscible in the first solvent. After the first polymer have been coated with the coating polymer, further carrier solvent may be added to the conduit to prevent deposition of the coated polymer particles on the conduit wall.
  • a micro fluidic device can be constructed to facilitate the production of coated polymer particles as a continuous process.
  • the continuous phase containing the first polymer particles or droplets or coated polymer particles may be changed to allow a coating polymer/carrier solvent combination which will allow the coating polymer to be layered onto an already coated polymer particles in accordance with the invention.
  • a polymer particle having a size of 10-800 nm and preferably 10-100 nm.
  • the polymer particle is preferably crosslinked and non-agglomerated.
  • a coated polymer particle comprising a core of a first polymer having a particle size in the range of 10- 800nm, preferably 10-IOOnm, and at least one layer of a second polymer layered over the core.
  • a device for producing a polymer particle comprising a microfluidio device having a first inlet for a first fluid and a second inlet for a second fluid and a fluidic conduit for contacting the first and second fluids, the fluidic conduit being a suitable length and width such that the resulting particles formed when a substantial amount of the first fluid is transferred from the droplet to the second fluid, are less than 800 nm and preferably in the range of 10- 10Onm at the exit of the device,
  • the fluidic device is formed from a material which can be wet by the contact of the second fluid and the conduits are less than 1000 microns.
  • the microfluidic device may be provided with a third inlet for the addition of a third fluid.
  • the third inlet preferably enables the first fluid to mix with a third fluid from the third inlet prior to contacting the second fluid entering from the second inlet.
  • Figure 1 is a schematic view of a microfluidic device used to carry out the method of the invention
  • Figure 2 is a schematic view of the mixing, section of microfluidic device of figure 1,
  • Figures 3(a) and 3(b) are schematic views of the first and second embodiments of the invention.
  • Figure 4 is a graphical representation of the shear viscosity against shear rate over a range of polymer concentrations
  • Figure 5 is a flow diagram focusing on droplet formation in the mixing junction where droplets are formed
  • Figure 6(a) is a schematic diagram illustrating droplet shrinkage as it progresses through the flowpaths of the microfluidic device
  • FIG(b) and 6(c) are expanded views from figure 6(a) where indicated.
  • Figure 7(a) are TEM images of Na-alginate nanoparticles produced in accordance with the invention.
  • Figure 7(b) is a particle size distribution graph of alginate in DMC produced o ⁇ -chip, using a very low concentrated Na-atgi ⁇ ate solution (0.002%).
  • Figure 8(a) and (b) illustrates upstream mixing of cross-linking agent and polymer solution in accordance with a second embodiment of the fixing stage of the method of the invention
  • Figure 9 are TEM images of alginate particles cross linked on a chip
  • FIG. 10(a) illustrates DMC droplet shrinkage in alginate solution
  • Figure 10(b) is a graph of relative volume variation with time of the DMC droplet in the alginate solution
  • Figure 11 is a schematic diagram of the solvent migration in droplet shrinkage
  • Figure 12 is a schematic diagram of a microfluidic device for producing layered nanoparticles
  • Figures 13(a) and 13(b) are expanded views of sections A and B in figure 12,
  • Figure 14 is a schematic diagram of two microfluidic devices for producing multi layered ⁇ anoparticles , (a) using the same continuous phase solvent throughout and (b) having provision for changing the continuous phase solvent,
  • Figure 15 (a) is TEM images of PLGA nanoparticles produced in accordance with the invention.
  • Figure 15(b) is a particle size distribution graph of PLGA produced by bulk emuisification method
  • the invention allows for the production of nanoparticles from any synthetic or biologically derived polymer that can be ⁇ olvated within fluid that is at least partially miscible with another fluid.
  • the invention also allows the production of layered nanoparticles in which layers of synthetic or biologically derived polymer are built up over the initially formed nanoparticle or polymer droplet.
  • the selection of a suitable solvent may be facilitated by considering solvent-polymer interaction parameters for the polymers or polymers of interest. Thus, a solvent which affords a sufficiently low and similar Interaction parameter for the selected polymer is likely to function as a solvent for that polymer. It will be appreciated that such solve ⁇ t- polymer interaction parameters vary with temperature and it may be possible to improve the "solvating power" of a given solvent simply by raising its temperature.
  • a suitable common solvent for a given polymer may also be identified through simple trial and error.
  • solvent-polymer interaction parameters may also be used as a guide in determining whether a material is likely to function as a solvent or a non-solvent for a given polymer.
  • high interaction parameters are indicative of non-solvent properties
  • low interaction parameters are indicative of good solvent properties.
  • Suitable common solvents particular classes of various organic compounds have been found useful, including aliphatic and aromatic acids, aliphatic, aromatic and cyclic alcohols, aldehydes, primary and secondary amines, aromatic and ethoxylated amines, diamines, amides, esters and diesters, ethers, ketones and various hydrocarbons and heterocycles.
  • aromatic acids aliphatic, aromatic and cyclic alcohols, aldehydes, primary and secondary amines, aromatic and ethoxylated amines, diamines, amides, esters and diesters, ethers, ketones and various hydrocarbons and heterocycles.
  • aromatic acids will be useful as a solvent for a given polymer and, further, not all solvents useful to dissolve a polymer such as polyethylene will necessarily be useful to dissolve a polymer such as polyvinylchloride.
  • suitable common solvents, or non-solvents as the case may be, that may be used to prepare the porous polymer blend structures include, but are not limited to, dimethyl oxalate (DMO) 1 ethylene carbonate (EC), N-methyl acetamide (NMA), dimethyl sulfoxide (DMSO), acetic acid (AA), 1 ,4-dioxane (DO), dimethyl carbonate (DMC) 1 chloroform, dichloromethane (DCM), naphthalene, sulfalene, trimethylurea, ethylene glycol or other glycols and polyglycols, N-methyl pyrrolidone (NMP) 1 ethylene carbonate, hexane, trifiuoroethanol (TFE) 1 ethanol, acetic acid, and water, and combinations thereof.
  • DMO dimethyl oxalate
  • EC ethylene carbonate
  • NMA N-methyl acetamide
  • DMSO dimethyl sulfoxide
  • DO
  • suitable polymers in general can be broadly classified as thermoplastic polymers. Suitable polymers will also exhibit at least a limited degree of cross-linking provided that they can still be dissolved in the solvent.
  • Suitable polymers include, but are not limited to, low density polyethylene, high density polyethylene, polypropylene, polystyrene, polyacrylic acid and copolymers of polyacrylic acid and polystyrene, polyurethane, polyvinylchloride, polyvinylflouride, acrylo ⁇ itrile- butadiene-styrene te ⁇ olymers, styrene-acrylonitrile copolymers, styrene butadiene copolymers, poly(4-methyl-pentene-1), polybutylene, polyvinylidene chloride, polyvinyl butyral, polyvinyl imidazole, chlorinated polyethylene, polyethylene oxide, ethylene-vinyl acetate copolymers, polyvinyl acetate, polyvinyl alcohol, polymethylmethacrylate, polymethyl-acrylate, ethylene-acrylic acid copolymers, ethylene-acrylic acid metal salt copolymers, chloros
  • polycarbonates polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, poly(hydroxyalkanoates), polyacetyls, polycyanoacrylates, polyetheresters, poly(esters), poly(dioxanone)s, poly(alkylene alkylat ⁇ )s, copolymers of polyethylene glycol and polyorthoester, poly(hydroxy acids), poly(lacto ⁇ es), poly(amides), poly(ester-amides), poly(amino acids), poly(anhydrides), poly(ortho-esters), poly(carbo ⁇ ates), poly(phosphazines), poly(thioesters), polysaccharides, proteins, glycloproteins, proteoglycans, growth factors, d ⁇ a, and mixtures, blends and copolymers thereof.
  • the method of the invention is particularly suitable for making polymer na ⁇ oparticles or layered nanoparticles that may be used in pharmaceutical, nutraceutical and tissue engineering applications.
  • Polymers used in these applications will generally be biocompatible and are preferably biodegradable.
  • such polymers should also promote cell growth and allow retention of differentiated cell function, possess physical characteristics allowing for large surface to volume ratios, have sound mechanical properties and have an ability to be formed into complex shapes, such as for bone or cartilage substitutes.
  • the polymers used can be conjugated with pharmaceutical and nutraceutical compounds and coated to assist delivery of the compounds to treatment or absorption sites in a patient.
  • a further parameter to consider when selecting a polymer for use in pharmaceutical, nutraceutical or tissue engineering applications is the biodegradation kinetics of the polymer.
  • the biodegradation kinetics of the polymer match the healing rate or residence time to the absorption site associated with the specific in vivo application.
  • suitable polymers that may be used to make polymer nanoparticles or layered nanoparticles for use in these applications include, but are not limited to, aliphatic or aliphatic-co-aromatic polyesters including poly( ⁇ -hydroxye ⁇ ters) and copolymers thereof such as polyglycolic acid (PGA), polylactic acid (PLA), poly(lactic- co-glycollc acid) (PLGA), PLGA-co-poly-L-Lysine (PLGA-co-PLL), and all stereo- isomeric forms thereof; polydioxanone; polyalkanoates such as poly(hydroxy butyrat ⁇ ) (PHB), poly(hydroxy valerate) (PHV) and copolymers thereof (PHBV); and polyethylene oxide/polyethylene terephthalate as disclosed by Reed et al., in Trans.
  • PGA polyglycolic acid
  • PLA polylactic acid
  • PLGA poly(lactic- co-glycollc acid)
  • suitable polymers include biodegradable and biocompatible polycaprolactones, and copolymers of polyesters, polycarbonates, polyanhydrides, poly(ortho esters), and copolymers of polyethylene oxide/polyethylene terphthalate.
  • Bisphenol-A based polyphosphoesters have also been suggested for use in biodegradable porous polymer design.
  • Such polymers include poly(bis ⁇ henol-A phenylphosphate), poly(bi ⁇ phenol-A ethylphosphate), ⁇ oly(bisphenol-A ethylphosphonate), poly(bisphenol-A phenylphosphonate), poly[bis(2- ethoxy)hydrophosphonic terephthalate], and copolymers of bisphenol-A based poly(phosphoesters).
  • these polymers have been suggested in US Pat. No. 5,686,091 , the known cytotoxicity of bisphenol-A makes them less preferred candidates for implantation.
  • polymers suitable for use in pharmaceutical, nutraceutical or tissue engineering applications include polymers of tyrosine-derived diphenol compounds. Methods for preparing the tyrosine-derived diphenol monomers are disclosed in US Pat. Nos. 5,587,507 and 5,670,602.
  • the preferred diphenol monomers are des-aminotyrosyl- tyrosine (DT) esters. These monomers have a free carboxylic acid group that can be used to attach a pendent chain.
  • various alkyl ester pendent chains are employed, for example, ethyl ester, butyl ester, hexyl ester, octyl ester and benzyl ester pendant chians.
  • the tyrosine-derived diphenol compounds are used as monomeric starting materials for polycarbonates, polyiminocarbonates, polyarylates, polyurethanes, polyethers, and the like.
  • Polycarbonates, polyiminocarbonates and methods of their preparation are disclosed in US Pat. Nos. 5,099,060 and 5,198,507.
  • Polyarylates and methods of their preparation are disclosed in US Pat. No. 5,216,115.
  • Block copolymers of polycarbonates and polyarylates with poly(alkyle ⁇ e oxides) and methods of their preparation are disclosed in US Pat. No. 5,658,995.
  • Strictly alternating poly(alkylene oxide ether) copolymers and methods of their preparation are disclosed in WO99/24490.
  • polymers suitable for use in pharmaceutical, ⁇ traceutical or tissue engineering applications include the polycarbonates, polyimino-carbonates, polyarylates, polyurethanes, strictly alternating poly(alkylene oxide ethers) and poly(alkylene oxide) block copolymers polymerised from dihydroxy monomers prepared from ⁇ -, ⁇ - and ⁇ - hydroxy acids and derivatives of tyrosine.
  • the preparation of the dihydroxy monomers and methods of their polymerisation are disclosed in International Patent Application No. PCT/US98/036013.
  • Polycarbonates, polyimino carbonates, polyarylates, poly(alkylene oxide) block copolymers and polyethers of the diphenol and dihydroxy tyrosine monomers that contain iodine atoms or that contain free carboxylic acid pendent chains may also be employed.
  • Iodine-containing polymers are radio-opaque. These polymers and methods of preparation are disclosed in WO99/24391. Polymers containing free carboxylic acid pendent chains and methods of preparation are disclosed in US patent application Ser. No. 09/56,050, filed April 7, 1998.
  • Algi ⁇ ic acid sodium salt and calcium chloride were obtained from Sigma Chemicals (USA).
  • Anhydrous dimethyl carbonate was obtained from Aldrich Chemicals (USA).
  • the cross-linker solution was prepared by dissolving calcium chloride (2N) powder in Millipore water.
  • a video-based optical angle measuring instrument (Data Physics OCA 15+) was used to determine the wetting properties and the values of surface and interfacial tension for all solutions.
  • a controlled stress magnetic bearing rheometer (ARG2, TA Instruments) controlled was used for the rheological characterization of all polymer solutions with a cone-plate geometry (60 mm, 2°).
  • the channel network used in the present work consists of two parts: a sheath-flow junction, where droplets are formed and flow through a square spiral or serpentine channel, in which the droplets shrink and harden.
  • a schematic of two different microchannel patterns with two different total lengths for the second zone (70 cm (1a) and or 45 cm (1b)) Is presented in Figure 1.
  • Typical dimensions of the channel at the droplet formation zone are shown in Figure 2.
  • the microcha ⁇ nels were either 100 ⁇ m or 200 ⁇ m deep. Masters were prepared with SU-8 photoresist (MicroChem USA) in bas- relief on silicon wafers.
  • Microchannels were fabricated using a Dow Corning Sylgard Brand 184 Silicone Elastomer with a standard soft-lithography method which allows rapid replication of the integrated microchannel prototypes.
  • Gastight microsyringes were filled with the liquids and mounted on motor-driven syringe pumps (PHD 2000 Harvard, Instech), which can synchronously operate two syringes at various flow rates.
  • the PDMS device was linked to the dispenser syringes through polyethylene tubing (I. D. 0.58 mm/O.D. 0.965 mm). Particles in the continuous phase were collected from the device in a vial containing cross-linker solution to complete the reaction, to prevent the particles from re-dissolving, and to avoid nanoparticles coalescence.
  • the first method Figure 3(b) is a two-step process: condensed nanoparticles are generated in the microfluidic device and are subsequently collected in a hardening solution where they cross-link.
  • the second approach Figure 3(a) consists of performing the whole synthesis of cross-linked nanoparticles in a one step process on a single device. We will describe these two processes one after the other In order to analyse and discuss distinctly the different phenomena occurring in each processing method.
  • FIGS 6a, 6b, and 6c The apparatus for the processes is shown in Figures 6a, 6b, and 6c which visualize droplet shrinking through the flow, for example a 0.5 % (w/w) alginate solution.
  • the channel design figure 6a shows polymer A being added co-currently with either a first solvent or a cross linking agent B with an organic solvent stream C being subsequently added to the flow path.
  • the channel design consists of a counter- current spiral, such that anti-clockwise particle trajectories (positions 1 , 2, 3) represent flow towards the centre of the device and clock-wise particle trajectories (positions 4 and 5) represent flow towards the outside of the device and towards the exit.
  • Example 1 two-step process
  • droplets were initially generated by shearing a stream of the dispersed phase with the flow of the continuous phase 2 via a flow-focusing geometry.
  • the size of the droplets is mainly governed by the properties of the polymer solution 1 and the flow rates of the continuous 2 and droplet phases (Q 0 and Qd respectively).
  • the droplets generated at position 3 continue to shrink as the solution passes along path 4 as the first solvent diffuses from the polymer solution.
  • the polymer droplets are then proceed to a particle collection step 5 where the droplets are collected in a solution 6 containing a cross linking agent such as calcium chloride
  • the relationship between drop size and variations in the balance of viscous and interfacial forces Is generally characterized by expressing the variation in droplet size as a function of a dime ⁇ sionless Reynolds number (Re) and a Capillary number (Ca).
  • the Capillary number is calculated using the average linear fluid velocity at the end of the constriction:
  • ⁇ is the polymer solution viscosity (mPa)
  • v d is the average velocity of the dispersed phase
  • ⁇ d is the interfacial tension between the alginate solution and dimethyl carbonate (DMC) (mN/m).
  • DMC dimethyl carbonate
  • Ca describes the relative importance of viscosity and surface tension, which often dominate other forces.
  • the coherence or break-up of the interface will depend strongly on Ca, hence on the velocity of the moving interface.
  • region (S) This area is surrounded by a domain where the two immiscible liquids flow together as a continuous stream (region (S)) and a domain where the break-up occurs in a random manner (region (I)). Similar flow diagrams were determined for solutions of higher alginate concentrations. When the dispersed phase is more viscous, the break-up is stable over a larger range of Ca-Re space: region (I) is shifted toward a lower value of Qd (Ca). For the 0.3 wt. % to 0.5 wt. % alginate solutions, only plug- shaped droplets are obtained, regardless of the values of Q 6 and Qd, (A) and (B) becoming one domain.
  • the carrier fluid (continuous phase) must wet the walls of the microchannel preferentially over the aqueous polymer phase, so that the droplets remain separated from the walls by a thin layer of the continuous phase at all times. This can be easily verified by measuring and comparing the contact angle values for DMC and for the different polymer solutions on a PDMS surface.
  • the contact angle is ⁇ 47° for DMC 1 but ranges from 114° to 116" for alginate solutions (0.1 %, 0.3 and 0.5 % in water (w/w)). In line with these differences in contact angle, we observed that the isolated polymeric droplets were stable and did not leave any residue behind as they are transported through the channels.
  • the polymeric droplets shrink when flowing downstream.
  • the droplets formed at the sheath focusing point figure 6 ⁇ b) are about 200 ⁇ m in diameter. They appeared to be approximately 10 ⁇ m before exiting the device. Once reaching this length scale, the size and shape of the particles were difficult to visualize with high accuracy with the high speed camera.
  • Figure 7 shows images of isolated Ca-alginate nanoparticles produced via the process of the invention, whose sizes is about 200nm.
  • the hardening of the hydrogel nanoparticles occurs solely within the microfluidic device.
  • Figure 3a the same design for the device Is used.
  • Figures 8(a) and 8(b) the design allows reactive mixtures to be processed in a mixing region 8 upstream of the microdroplet creation site ⁇ .
  • the cross-linking reaction occurs simultaneously with the droplet formation by the addition of a cross linking agent 6 with the polymer solution 1 into the flow path and further downstream at position 7 (in figure 3a, competes with the solvent exchange process between the drop phase and the continuous phase.
  • the competing kinetics of the chemical reaction and of the water diffusing out of the droplets will determine the size and composition of the particles produced on the chip.
  • the chemical reaction of the sodium alginate and the CaCb polycations is immediate and as the gelation starts, the viscosity increases which can prevent droplet generation at the sheath-flow point.
  • the length of the channel in the mixing zone can be adjusted to control the duration of the reaction prior to droplet formation, as can the relative stoichiometry of the alginate; CaCI ⁇ mixture,
  • Adequate mixing is a significant challenge when dealing with pressure-driven laminar microflow ⁇ , as mixing occurs only through diffusion when two streams are injected into a channel at low Reynolds number (laminar). Rapid mixing of chemicals and reagents in microchannels can be difficult to achieve.
  • the sodium alginate solution and the CaCIz solution are individually inserted at the same flow rate in the device and they mix within the channel to form the dispersed phase.
  • Table 1 and figure 8(b) show the different residence times in the mixing zone, depending on the flow rate of the dispersed phase (Q d ) and also on the length of the channel in the mixing zone. This length can be adjusted.
  • the flow rate for the dispersed phase is determined by the conditions required to form the droplets upstream. In Table 1, m2(1 mm) in figure 8(b) is small compared to mi.
  • the disperse phase in this simple-step method results from a mixture of the alginate solution and the cross-linker solution.
  • the two solutions are assumed to be homogeneously mixed together at this point and the cross-linking reaction certainly may even have occurred to a certain extent prior to droplet formation, which leads to an increase in the viscosity of the polymer dispersed phase.
  • the mixing of the alginate solution with the cross-linking solution also results in a decrease in the overall polymer concentration, and therefore the viscosity.
  • the same alginate solutions were utilized in this method as used in method 1.
  • the viscosity of the dispersed phase was obviously low enough for the production of droplets even in the presence of cross- linkers for the time prior to formation.
  • the droplets After the droplets are formed, they flow downstream in the microchannel, as isolated micro-reactors carried by the continuous phase. Inside each individual droplet, the cross-linking reaction consumes available calcium, which eventually leads to the hardening of the polymer droplet.
  • the solvent diffusion at th ⁇ interface of the two phases The water diffuses out of the polymeric droplet to the DMC, modifying the reaction conditions. Not only does the total polymer concentration now vary but so does the concentration of the calcium ions in the droplet and their diffusion into the gel network during the hardening of the particles. Further, the modification of the structure of the beads affects the diffusion of solvent through the interface as the interface is becoming more solid. This prevents the particles shrinking as much as they do in the two stage process.
  • the cross-linked particles are collected in a CaCb solution to ensure a maximum cross- linking and to prevent coalescence of the Ca-alginate particles.
  • Figure 9 shows TEM Images of alginate particles cross-linked on chip. The particle sizes range Is approximately 800 nm. The particles obtained via method 1 of figure 3a are larger than the ones obtained via method 2 from figure 3b, due to the solidification of the droplets influencing the diffusion of solvent and therefore the shrinking process.
  • the solubility of pure water in pure DMC is 3 wt, % at room temperature.
  • the exchange of solvent 12 (water) from the polymer solution within the miscible interface or envelope with DMC is due to the laminar flow 13 around the droplet (diffusion controlled mixing), it is at very slow, near equilibrium, rates. This can be thought of as a pseudo equilibrium process . Due to the slow extraction of water from the droplet 10, the polymer does not effectively see the nonsolvent (DMC) 11 until there is very little solvent remaining.
  • the invention was performed using an emulsification technique.
  • PLGA solutions were prepared in DMC 1 with concentrations ranging from 0.001 to 0.005 % (w/w).
  • the polymer solution was added into water, under stirring at 1500 rpm with a motorized rotor. These stirring rates were in the laminar flow regime.
  • the PLGA solution was dispensed using a 3Og needle, in order to create a fine thread, which was then broken up under shear to create droplets/particles. The resulting mixture is stirred for another 30 minutes at the same speed before collecting and spinning down the suspended particles.
  • the Dynamic Light scattering data figure 15b of the TEM images shown in figure 15a show PLGA particles having a particle size varying between 0.20 ⁇ m to Q.29 ⁇ m.
  • Figure 16 a and 16b is a graph of the volume loss of a pendant droplet of PLGA 0.001% (in DMC) when immerged in water as a function of time.
  • FIG. 12 An apparatus for the production of layered polymer particles is shown in Figure 12.
  • a microfluidic device as shown in figure 1(b) is used to shrink the polymer droplets,
  • the polymer droplets are not cross linked and pass directly to the layering stage shown in figure 13(b), where polymer droplets are coated and solidified to produce a layered nanoparticle.
  • the particles are formed in accordance with Example 2 according to figure 13(a) are then passed in a continuous phase to a second device or second stage of the same device.
  • figure 13(a) is the same as figure 8(a).
  • a second polymer solution 21 of polymer in a solvent is added to the flowpath of this second stage or second microfluidic device.
  • the solvent is preferably the same solvent as the continuous phase.
  • the second polymer dissolved in this solvent diffuses to the surface of the first polymer particle 20 to coat the particle.
  • Additional solvent 22 which is the same solvent as the continuous phase or miscible in the continuous phase is preferably introduced into the conduit downstream of the coating section to prevent deposition of polymer onto the conduit walls.
  • the layered polymer droplets then pass through the serpentine path where the droplets are shrunk or solidified and collected at the exit of the second stage or second device.
  • a microfluidic apparatus for the application of multiple coating layers is shown in Figure 14 in which multiple microfluidic devices are shown adjacent each other.
  • the right side devices are shown adjacent each other.
  • addition inlets are provided in all coating stages to allow the introduction of a second continuous phase.
  • This second continuous phase Is added after the deposition of the latest external polymer layer and enables the continuous phase carrying the layered polymer particles to be changed between consecutive layer depositions.
  • the layering polymer needs to be miscible in the continuous phase, the ability to change the continuous phase increase the range of polymer types which can be used as a coating layer.
  • the applicant has successfully used the present invention to make nanoparticles from alginate, agarose, gelatine and synthetic polymers block copolymers.
  • the process of the invention will allow for the production of nanoparticles from any synthetic or biologically derived polymer that can be solvated within a liquid that is partially miscible with another liquid.
  • the size of the nanoparticles can be explicitly controlled by the relative solvency of the two liquids, the properties of the polymer solution, including polymer concentration, configuration and Ionic state, and solvent conditions, processing conditions, including solution flow rates and initial droplet size, and device geometry.
  • the method and apparatus of the invention enables the nanoparticles, nanodroplets or layered particles of synthetic or biologically derived polymers to be coated with single or multiple layers of polymers to produce multilayer polymer particles.

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  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nanotechnology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
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Abstract

L'invention porte sur un procédé de fabrication de nanoparticules à partir de tout polymère synthétique ou d'origine biologique pouvant être solvaté dans un liquide étant au moins partiellement miscible avec un autre liquide. Le procédé comprend l'étape consistant à introduire un premier fluide comprenant un polymère dans un premier solvant dans un second fluide comprenant un second solvant. Le premier solvant est partiellement miscible dans le second solvant, et le polymère est sensiblement non miscible dans le second solvant. Le premier fluide dans le second fluide est soumis à un cisaillement dans des conditions laminaires pour former des gouttelettes du premier fluide dans le second jusqu'à ce qu'une quantité du premier fluide migre dans le second fluide pour réduire la taille des gouttelettes. La taille des particules résultantes peut être prédéterminée.
PCT/AU2008/000423 2007-03-27 2008-03-27 Production de particules Ceased WO2008116261A1 (fr)

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CN103936986A (zh) * 2014-05-04 2014-07-23 哈尔滨工业大学 一种利用微流控技术控制银纳米粒子修饰的聚邻苯二胺微纳米结构形貌的方法
IT202100006866A1 (it) 2021-03-22 2022-09-22 Kyme Nanoimaging Srl Un processo per la preparazione di nanostrutture di idrogel mediante gelificazione ionotropica in microfluidica
US11608486B2 (en) 2015-07-02 2023-03-21 Terumo Bct, Inc. Cell growth with mechanical stimuli
US11613727B2 (en) 2010-10-08 2023-03-28 Terumo Bct, Inc. Configurable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system
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CN102245682B (zh) * 2008-10-07 2016-03-16 纳米桥股份有限公司 纳米复合材料和通过纳米沉淀制备该纳米复合材料的方法
WO2010040218A1 (fr) * 2008-10-07 2010-04-15 Nanoledge Inc. Matériaux nanocomposites et procédé de fabrication par nanoprécipitation
US11613727B2 (en) 2010-10-08 2023-03-28 Terumo Bct, Inc. Configurable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system
US11773363B2 (en) 2010-10-08 2023-10-03 Terumo Bct, Inc. Configurable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system
US11746319B2 (en) 2010-10-08 2023-09-05 Terumo Bct, Inc. Customizable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system
US11708554B2 (en) 2013-11-16 2023-07-25 Terumo Bct, Inc. Expanding cells in a bioreactor
US11667876B2 (en) 2013-11-16 2023-06-06 Terumo Bct, Inc. Expanding cells in a bioreactor
US11795432B2 (en) 2014-03-25 2023-10-24 Terumo Bct, Inc. Passive replacement of media
CN103936986A (zh) * 2014-05-04 2014-07-23 哈尔滨工业大学 一种利用微流控技术控制银纳米粒子修饰的聚邻苯二胺微纳米结构形貌的方法
US11667881B2 (en) 2014-09-26 2023-06-06 Terumo Bct, Inc. Scheduled feed
US12065637B2 (en) 2014-09-26 2024-08-20 Terumo Bct, Inc. Scheduled feed
US11608486B2 (en) 2015-07-02 2023-03-21 Terumo Bct, Inc. Cell growth with mechanical stimuli
US11965175B2 (en) 2016-05-25 2024-04-23 Terumo Bct, Inc. Cell expansion
US12077739B2 (en) 2016-06-07 2024-09-03 Terumo Bct, Inc. Coating a bioreactor in a cell expansion system
US11685883B2 (en) 2016-06-07 2023-06-27 Terumo Bct, Inc. Methods and systems for coating a cell growth surface
US11634677B2 (en) 2016-06-07 2023-04-25 Terumo Bct, Inc. Coating a bioreactor in a cell expansion system
US11999929B2 (en) 2016-06-07 2024-06-04 Terumo Bct, Inc. Methods and systems for coating a cell growth surface
US11702634B2 (en) 2017-03-31 2023-07-18 Terumo Bct, Inc. Expanding cells in a bioreactor
US11629332B2 (en) 2017-03-31 2023-04-18 Terumo Bct, Inc. Cell expansion
US11624046B2 (en) 2017-03-31 2023-04-11 Terumo Bct, Inc. Cell expansion
US12234441B2 (en) 2017-03-31 2025-02-25 Terumo Bct, Inc. Cell expansion
US12359170B2 (en) 2017-03-31 2025-07-15 Terumo Bct, Inc. Expanding cells in a bioreactor
WO2022200257A1 (fr) 2021-03-22 2022-09-29 Kyme Nanoimaging Srl Procédé de préparation de nanostructures d'hydrogel par gélification ionotropique en microfluidique
IT202100006866A1 (it) 2021-03-22 2022-09-22 Kyme Nanoimaging Srl Un processo per la preparazione di nanostrutture di idrogel mediante gelificazione ionotropica in microfluidica
US12043823B2 (en) 2021-03-23 2024-07-23 Terumo Bct, Inc. Cell capture and expansion
US12152699B2 (en) 2022-02-28 2024-11-26 Terumo Bct, Inc. Multiple-tube pinch valve assembly
US12209689B2 (en) 2022-02-28 2025-01-28 Terumo Kabushiki Kaisha Multiple-tube pinch valve assembly
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