WO2005014698A1 - Procedes de preparation de reseaux polymeriques reticules par coacervation et reticulation in situ - Google Patents

Procedes de preparation de reseaux polymeriques reticules par coacervation et reticulation in situ Download PDF

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WO2005014698A1
WO2005014698A1 PCT/CA2004/001456 CA2004001456W WO2005014698A1 WO 2005014698 A1 WO2005014698 A1 WO 2005014698A1 CA 2004001456 W CA2004001456 W CA 2004001456W WO 2005014698 A1 WO2005014698 A1 WO 2005014698A1
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cross
coacervate
dma
functional groups
polymers
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PCT/CA2004/001456
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English (en)
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Harald Stover
Xiangchun Yin
Nicholas Burke
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Mcmaster University
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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
    • C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/5089—Processes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
    • C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
    • 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
    • C08F8/00—Chemical modification by after-treatment

Definitions

  • TITLE METHODS FOR THE PREPARATION OF CROSS-LINKED POLYMER NETWORKS USING COACERVATION AND IN SITU CROSS-LINKING FIELD OF THE INVENTION
  • the present invention relates to methods for preparing cross-linked polymer networks using coacervation and in situ cross-linking, to polymer networks prepared using the methods and to the use of these networks, in particular as microspheres, microcapsules and films.
  • Cross-linked hydrophilic polymers are commonly used for the encapsulation of hydrophobic materials, as protective immunobarriers for transplantable cell cultures, and as functional and/or structural components of separation membranes. These systems are commonly prepared by cross-linking a preformed polymer such as gelatin, alginate, acrylic or other synthetic analogs, using low molecular weight reagents such as formaldehyde, glutaraldehyde, vinylic cross-linkers, multivalent salts such as calcium or ammonium salts, esterification or amidation reagents such as water soluble dicyclohexylcarbodiimide (DCC) derivatives, or photo cross-linkers.
  • a preformed polymer such as gelatin, alginate, acrylic or other synthetic analogs
  • low molecular weight reagents such as formaldehyde, glutaraldehyde, vinylic cross-linkers, multivalent salts such as calcium or ammonium salts, esterification or amidation reagents such as water soluble
  • the present invention relates to new methods and systems for forming cross-linked hydrophilic polymer networks using coacervation and in-situ cross- linking reactions and to the polymer networks prepared using these methods.
  • the new methods involve coacervation of a suitable polymer solution(s), said polymer(s) having reactive functional groups, followed by addition of a reagent which will react with those functional groups on the coacervated polymer(s), to covalently cure the polymer(s) and to provide stable polymer networks.
  • One example of this involves the thermally induced formation of a coacervate of a suitable polymer bearing reactive functional groups followed by addition of a reagent to react with those functional groups to effect covalent cross-linking and thus curing or stablization of the polymer network.
  • Another example includes the formation of complex coacervates between two polyelectrolytes bearing complementary reactive groups that are designed to accomplish two tasks: first to bring the polymers together to form a complex coacervate and second to react and cross-link the two polymers with each other.
  • one reactive polymer is made to form a complex with an oppositely charged but non-cross-linkable polymer in order to form a stable complex coacervate.
  • This coacervate is subsequently cross-linked by addition of a third polymer carrying the requisite cross-linking groups.
  • the present invention relates to a method of preparing a cross- linked polymer network, wherein said method comprises obtaining a coacervate comprising one or more polymers, said polymers comprising one or more cross- linkable functional groups, and cross-linking said polymers through said functional groups.
  • the method of preparing a cross-linked polymer network comprises combining:
  • a cross-linker comprising one or more functional groups with complementary reactivity to the one or more cross-linkable functional groups on the one or more poylmers, under conditions whereby the one or more polymers forms a coacervate before reaction of the one or more cross-linkable functional groups with the cross-linker, to form a cross-linked polymer network.
  • the cross-linker may be comprised within the one or more polymers allowing a one-step approach to formation of the cross-linked polymer network, however, two-step processes of coacervation, followed on demand by cross-linking through addition of a cross-linker, have the benefit of separating the coacervation from the subsequent cross-linking, and hence offer longer pot-life, and better control over shape and cross-link densities.
  • the one or more polymers are water soluble, avoiding the need for organic solvents in the polymer network formation
  • a coacervate takes the form of a separate and dispersable aqueous liquid phase that contains up to about 30% polymer, and that has slightly amphiphilic properties. This feature is very useful in applications where bulk or dispersed materials such as oil droplets, cells, membranes or surfaces are to be coated or impregnated with a layer of cross- linkable polymers, while maintaining a low solution viscosity.
  • Another aspect of the present invention is that the higher molecular weight of the one or more polymers, and especially of the polymer carrying electrophilic reactive groups such as epoxy, aldehyde, anhydride and acetylacetonate, makes them less bioavailable and hence less of an environmental and health concern.
  • the one or more polymers are based on modified natural polymers, i.e. chitosan and oxidized sodium alginate.
  • the present invention also includes the cross-linked polymer networks prepared using the method of the present invention. Accordingly the present invention includes a cross-linked polymer network comprising a cross-linked coacervate of one or more polymers, wherein said one or more polymers comprise one or more cross-linkable functional groups and form a coacervate.
  • the cross-linked coacervate further comprises a cross-linker comprising one or more functional groups which have reacted with the one or more cross-linkable functional groups with complementary reactivity on the one or more polymers.
  • Some applications for the material produced using the method of the invention include, but are not limited to, replacement of gelatin/formaldehyde and urea/formaldehyde capsules in industrial encapsulation, replacement of banned formaldehyde based encapsulations in cosmetic applications, coating/impregnation of non-porous and porous materials with cross-linked hydrogels and encapsulation of other aqueous phases such as cell dispersions.
  • the present invention also includes microcapsules, microspheres and films comprising the cross-linked polymer networks of the present invention.
  • Figure 1 shows an optical microscope image of uncontrolled phase separation and crosslinking upon reacting SMA-g-MPEG-70% with chitosan at pH 7.00 in 0.05 mol L "1 NaCl solution.
  • Figure 2 shows an optical microscopy image of SMA-g-MPEG-70% / PDADMAC complex coacervate.
  • Figure 3 shows the effect of PDADMAC to SMA-g-MPEG-70% ratio on coacervation yield (pH of 7.00 in 0.05 mol L "1 NaCl solution, SMA-g-MPEG, 0.5 wt %; PDADMAC, 2.0 wt %).
  • Figure 4 shows ESEM micrographs of microspheres formed by crosslinking SMA-g-MPEG-70% / PDADMAC coacervates with chitosan at pH 7.00 in 0.05 mol L "1 NaCl solution: (a) SDC-1 , (b) SDC-2, (c) SDC-3, (d) SDC-8.
  • Figure 5 shows ESEM micrographs of microspheres formed by crosslinking SMA-g-MPEG-70% / PDADMAC coacervates with PEI at pH 10.50 in 0.05 mol 1 NaCl solution: (a) SDE-1 , (b) SDE-2, (c) SDE-4, (d) SDE- 5.
  • Figure 6 shows a dependence of swelling properties of the SMA-g-MPEG- 70% / PDADMAC coacervate microspheres upon NaCl concentrations. SDC-3 coacervate microspheres were used.
  • Figure 7 shows 1 H NMR spectra of pDMA and pGMA homopolymers and copolymer DMA-co-GMA58 in chloroform-d.
  • Figure 8 shows photovoltaic cloud point curves for 0.5 wt % aqueous solutions of DMA-co-GMA and pNIPAM, with -250 mV corresponding to a transparent solution.
  • Figure 9 shows an optical microscope image of coacervate droplets in 1 wt % aqueous DMA-C0-GMA47 solution at room temperature (25 °C).
  • Figure 10 is a graph showing effects of polymer concentration on the phase separation temperatures of DMA-co-GMA solutions as measured by the cloud point method.
  • Figure 11 is a graph showing the effects of additives on phase separation temperatures of 0.5 wt % DMA-co-GMA43 solutions.
  • Figure 12 shows ESEM images of hydrogel microspheres prepared by crosslinking thermally induced coacervates (30 ml, 0.5 wt%) with ethylene diamine (1.5 ml, 2.0 wt %): (a) DMA-co-GMA32 at 60 °C, (b) DMA-co-GMA36 at
  • Figure 13 is a graph showing yields of microspheres obtained by crosslinking DMA-co-GMA (30 ml, 0.5 wt%) with ethylene diamine (1.5 ml, 2.0 wt %)at different temperatures.
  • Figure 14 shows ESEM images of hydrogel microspheres prepared by crosslinking DMA-CO-GMA43 coacervates with ethylene diamine at (a) 40 °C and (b) 70 °C. Scale bars are 250 mm.
  • Figure 15 shows ESEM images of hydrogel microspheres prepared by crosslinking DMA-co-GMA43 coacervates at 40 °C with (a) TEPA, (b) linear PEI 423, (c) branched PEI 1800. Scale bars are 250 mm.
  • Figure 16 shows ESEM images of hydrogel microspheres prepared at 40
  • Figure 17 shows ESEM images of hydrogel microspheres prepared from DMA-CO-GMA43 coacervates in presence of 1 wt % PVP at 40 °C.
  • Figure 18 shows a 1 H NMR spectrum of DMA-co-AMA-40 obtained in chloroform-d.
  • Figure 19 shows phase transition curves for 0.5 wt% DMA-co-AMA aqueous solutions as measured by the cloud point method. The vertical axis shows the photo-induced voltage due to 180° transmitted light, with -250 mV corresponding to a transparent solution.
  • Figure 20 shows an optical microscope image of coacervate droplets formed from 0.5 wt % DMA-co-AMA-30 solution (Tp, 15.7 °C) at room temperature (20 °C). Scale bar is 250 mm.
  • Figure 21 shows optical microscope images of particles prepared by crosslinking 100g of 0.5 wt % DMA-co-AMA-28 (Tp, 23.1 °C) coacervate mixture with APS (1.0 ml, 1.0 mol L “1 ) and TEMED (1.0 ml, 1.0 mol L “1 ) at 30 °C (A), and
  • Figure 22 shows microscope images of particles prepared by crosslinking
  • DMA-co-AMA-19 (Tp, 54 °C) coacervate with APS (1.0 ml, 1.0 mol L “1 ) and TEMED (1.0 ml, 1.0 mol L “1 ) at 60 °C for 2hrs.
  • A Optical micrograph of wet particles
  • B Optical micrograph of dry particles
  • C ESEM image of dry particles
  • Figure 23 shows ESEM images of microspheres formed by crosslinking DMA-co-AMA-19 (Tp, 54 °C) coacervate mixture with APS (1.0 ml, 1.0 mol L “1 ) and TEMED (1.0 ml, 1.0 mol L “1 ) at 70 °C (A), and 80 °C (B). Scale bars are 100 mm.
  • Figure 24 shows ESEM micrographs of microspheres formed by crosslinking DMA-co-AMA-19 (Tp, 54 °C) coacervate mixtures at 60 °C with (A)
  • Figure 25 shows a 13 C CP-MAS NMR spectrum of crosslinked coacervate microspheres prepared from DMA-co-AMA-19 copolymer according to the conditions in Figure 24B.
  • Figure 26 is a graph showing the cloud points of binary copolymers of
  • Figure 27 is a graph showing the decrease in cloud point with increasing BMA content, in a 3w/v% aqueous solutions of copolymers of MAA, PEGMM and BMA.
  • Figure 28 is a graph showing the decrease in cloud point with increasing GMA content, in a 0.75% w/v aqueous solution of copolymers of MAA, PEGMM and BMA.
  • Figure 29 is a graph showing the cloud point of quaternary polymers containing both BMA and GMA, in a 0.75% w/v aqueous solution. The cloud points drop roughly 0.75 degree C for each mol % BMA or GMA.
  • Figure 30 shows an optical microscope image of [50-50-0-0] / PEI coacervate in aqueous medium.
  • Figure 31 shows an optical microscope image of [50-50-0-0] / PEI / paraffin oil.
  • Figure 32 shows an optical microscope image of [47.5-47.5-5-0] / PEI / paraffin oil.
  • Figure 33 shows optical microscope images of [47.5-47.5-0-5] / PEI coacervates.
  • Figure 34 shows an optical microscope image of paraffin oil in: (A) [47.5- 47.5-0-5] / PEI and in (B) [45-45-0-10] / PEI.
  • Figure 35 shows optical microscope images of 40-40-10-10] / PEI / mineral oil before and after puncturing.
  • Figure 36 shows optical microscope images of xylene encapsulated in [47.5-47.5-0-5] / PEI.
  • Figure 37 shows (A) the encapsulation of butyl benzoate in microcapsules formed by the pH-induced coacervation of SAPA and gelatin and (E) the wrinkling of the capsules in (A) upon addition of another 1 mL of 1% SAPA solution.
  • the present invention relates to new methods/systems for forming cross- linked polymer networks via coacervation.
  • the present approach is to cure, stablize or harden the coacervate without the use of usually toxic small-molecule crosslinkers such as formaldehyde. This problem is resolved by designing polymers with "built-in" crosslinking agents.
  • An example of the method of the present invention includes the thermally induced formation of a coacervate of poly( ⁇ /,/V-dimethyacrylamide-co-glycidyl methylacrylate (DMA-co-GMA) or poly(/V,/V-dimethyacrylamide-co-allyl methylacrylate (DMA-co-AMA) followed by reaction with polyamines or free radical initiators, respectively, to provide a cross-linked polymer network.
  • DMA-co-GMA poly( ⁇ /,/V-dimethyacrylamide-co-glycidyl methylacrylate
  • DMA-co-AMA poly(/V,/V-dimethyacrylamide-co-allyl methylacrylate
  • a second example includes the formation of complex coacervates by combining two polymers having complementary charges to form a phase-separated polyelectrolyte complex followed by either reaction of complementary functional groups on the two polymers or addition of a third polymer with complementary functional groups that react with functional groups on either one of the first two polymers, to form a cross-linked polymer network.
  • This second example includes the formation of a complex coacervate between poly(styrene-a/ -maleic anhydride) partially grafted w ith methoxy poly(ethylene g lycol) (SMA-g-M PEG) a nd polydiallyldimethylammonium chloride (PDADMAC) followed by crosslinking with a polycation, for example polyamines such as polyethylenimine (PEI) and chitosan, as well as formation of complex coacervates followed by internal crosslinking between various co-polymers based on methylacrylic acid (MAA), poly(ethyleneglycol) monomethylether (PEGMM), butylmethylacrylate (BMA) and glycidylmethylacrylate (GMA) complexed with a polycation, for example polyamines such as PEI.
  • a complex coacervate between poly(styrene-a/ -maleic anhydride) partially grafted w ith me
  • the present invention relates to a method of preparing a cross- linked polymer network, wherein said method comprises obtaining a coacervate comprising one or more polymers, said polymers comprising one or more cross- linkable functional groups, and cross-linking said polymers through said functional groups.
  • the present invention also relates to a method of preparing a cross-linked polymer network, wherein said method comprises combining:
  • a cross-linker comprising one or more functional groups with complementary reactivity to the one or more cross-linkable functional groups on the one or more poylmers, under conditions whereby the one or more polymers forms a coacervate before reaction of the one or more cross-linkable functional groups with the cross-linker, to form a cross-linked polymer network.
  • one or more means at least one and not more than 5, specifically not more than 4, more specifically not more than 3, even more specifically not more than 2. It is to be understood that this term refers to the type or identity of the variable involved and not the absolute number in any given system. For example, with respect to “one or more polymers” or “one or more functional groups”, this term refers to one or more identifiable polymers or functional groups, not the absolute number of polymer molecules in the system or the absolute number functional groups on the polymer.
  • cross-linkable functional groups refers to any reactive functional group that reacts to form a covalent bond with a cross-linker.
  • cross-linker refers to any reagent that reacts to form a covalent bond with the cross-linkable functional groups on the one or more polymers so that the coacervate becomes hardened, stabilized and/or cured.
  • the cross-linker reacts with cross-linkable functional groups on adjacent or nearby monomer units so that the monomer units are held closer together and/or have restricted movement.
  • the cross-linker may be a reagent, such as a free radical initiator, that can facilitate reaction between adjacent or nearby functional groups on the polymers.
  • the cross-linker is a polymer comprising functional groups having complementary reactivity to the cross-linkable functional groups on the one or more polymers.
  • the term "complementary" as used herein with respect to functional groups means that the functional groups react with each other to form a covalent bond.
  • the "conditions whereby the one or more polymers forms a coacervate before reaction of the one or more cross-linkable functional groups with the cross- linker" will vary depending on the identity of the one or more polymers, the concentration, the pH, salt content and other reaction conditions. A person skilled in the art would be able to readily vary the reaction conditions for any given system so that suitable conditions could be identified. It is to be understood that the one or more polymers and cross-linker are typically used in the form of aqueous, buffered solutions.
  • a person skilled in the art would be able to readily identify polymers which form coacervates by subjecting the polymer to conditions which are expected to produce coacervates (for example thermal coacervation or complex coacervation conditions as described hereinbelow) and identifying whether or not a coacervate forms. If a coacervate does not form, the structure of the polymer may be modified, for example, by the addition of hydrophobic monomers or functional groups that will assist in the formation of a complex coacervate with a polymer of opposite charge.
  • the method involves the formation of a coacervate of one polymer comprising one or more cross-linkable functional groups, specifically one cross-linkable functional group, followed by reaction with a cross-linker.
  • the polymer is a stimuli- responsive polymer that will form a coacervate in response to a physical change to the system, for example a change in concentration, pH, temperature, salt content or solvent composition.
  • the present invention relates to a method of preparing a cross- linked polymer network, wherein said method comprises obtaining a coacervate comprising a stimuli responsive polymer, said polymer comprising one or more cross-linkable functional groups, and cross-linking said polymer through said functional groups.
  • the method of preparing a cross-linked polymer network comprises combining: (a) a stimuli responsive polymer, wherein said polymer comprises one or more cross-linkable functional groups and forms a coacervate in response to a stimulus; and
  • a cross-linker comprising one or more functional groups with complementary reactivity to the one or more cross-linkable functional groups on the stimuli responsive polymer, under conditions whereby the polymer forms a coacervate before reaction of the one or more cross-linkable functional groups with the cross-linker, to form a cross- linked polymer network.
  • the polymer is a thermally responsive polymer, i.e. it will form a coacervate upon a change in temperature, in particular, in response to increasing temperature.
  • This embodiment has been called Thermal Coacervation and Cross-linking (TCC) herein.
  • the polymer comprises an electrophilic reactive functional group, such as an aldehyde, epoxy group, anhydride, acetylacetonate and the like
  • the cross-linker comprises nucleophilic or other functionalities that will react with the electrophilic reactive functional group of the polymer to form cross-links.
  • the polymer is selected from copolymers of dimethylacrylamide (DMA) with a monomer comprising a reactive electrophilic functional group, such as, but not limited to glycidyl methylacrylate (GMA), allylmethacrylate (AMA) and 2- (methacryloloxy)-ethylacetoacetate (MEAA).
  • the polymer is DMA-co-GMA or DMA-co-AMA.
  • the crosslinker may be any reagent that reacts with the cross-linkable functional groups on the polymer so that the coacervate becomes cured.
  • the cross-linker may be a polyamine, for example, polyethyleneimine, chitosan, poly(aminoethylmethacrylate) (PAEM) or a copolymer comprising aminoethylmethacrylate as a comonomer.
  • the cross-linker may be a reagent that generates free radicals, for example, a reagent that will effect free radical cross-linking of the pendant allyl groups.
  • reagents include, but are not limited to redox initiation systems such as ammonium persulfate//V, ⁇ , ⁇ /',/V- tetramethylethylenediamine (TEMED).
  • TEMED ammonium persulfate//V, ⁇ , ⁇ /',/V- tetramethylethylenediamine
  • radical cross-linking it is an embodiment of the invention that the crosslinking is performed at a temperature that is between 1 and 80 °C, preferably between 5 and 40 °C, and most preferably between 10 and 20 °C above the phase transition temperature (T p) of the polymer.
  • T p phase transition temperature
  • the coacervate is formed in the presence of a suitable surfactant or colloidal stabilizer.
  • Suitable surfactants or stabilizers do not increase the phase transition temperature of the polymer.
  • examples of such surfactants or stabilizers, in particular for use with DMA copolymers include poly(vinyl pyrrolidone), cellulose ethers, and polyvinylalcohol.
  • the one or more polymers form a coacervate by complex coacervation.
  • This method is based the interaction between one or more polycations with one or more polyanions leading to coacervate formation.
  • Suitable cross-linkable functional groups are introduced into one or all of the polyelectrolytes to cause crosslinking to accompany coacervation.
  • a further cross-linker with functional groups that will react with those on one or all of the coacervated polyelectrolytes is added to effect cross-linking.
  • This method has been called Integrated Coacervation and Crosslinking (ICC) herein.
  • the present invention relates to a method of preparing a cross- linked polymer network, wherein said method comprises obtaining a coacervate comprising two or more polyelectrolytes, wherein at least one of the polyelectrolytes comprises one or more cross-linkable functional groups, and cross-linking said polymers through said functional groups.
  • the method of preparing a cross-linked polymer network comprises combining:
  • a cross-linker comprising one or more functional groups with complementary reactivity to the one or more cross-linkable functional groups on the polyelectrolytes, under conditions whereby the two or more polyelectrolytes form a coacervate before reaction of the one or more functional groups with the cross-linker, to form a cross-linked polymer network.
  • the method involves two polyelectrolytes, specifically a polycation and a polyanion, which will form a coacervate when combined in solution, specifically aqueous solution.
  • both the polycation and the polyanion contain complementary crosslinkable functional groups so that combining aqueous solutions of the two polyelectrolytes results in coacervate formation followed by simultaneous or slower covalent coupling between the complementary functional groups to form cross-linked polymers. In this latter embodiment, the need for addition of a separate cross-linker is eliminated.
  • the present invention also relates to a method of preparing a cross-linked polymer network wherein said method comprises combining a polyanion and a polycation to form a coacervate, wherein the polyanion and a polycation each comprise one or more cross-linkable functional groups complementary to the one or more functional groups on the other, and wherein the polyanion and polycation are combined under conditions whereby the coacervate forms simultaneously or before reaction of the one or more functional groups on the polyanion and polycation with each other, to form a cross-linked polymer network.
  • the polyelectrolytes may be synthetic or natural in origin.
  • Examples of synthetic polyanions include, but are not limited to, polyanions based on methacrylic acid or acrylic acid, together with other methacrylates or acrylates chosen to modify the properties of the polyanion.
  • the structure of some examples of methacrylates along with how they modify the properties of the polyanion and/or coacervate is presented in Scheme 1.
  • R H/Na (MAA, MAANa): anionic charge
  • R PEG (PEGMA): hydrophilic, colloidal stability
  • R butyl (BMA): increase hydrophobicity
  • R dodecyl (LMA): increase hydrophobicity
  • R glycidyl (GMA): cross-linker (reactive epoxide)
  • R ethyl acetoacetate (MEAA): crosslinker
  • polycarboxylic acids examples include polycarboxylic acids, polyphenols, and related copolymers incorporating some nucleophilic centres.
  • polyanion is poly(styrene-a/ ⁇ -maleic anhydride) partially grafted with methoxy poly(ethylene glycol) (SMA-g-MPEG), as well as copolymers incorporating vinylbenzoic acid, itaconic acid, and other acid containing monomers.
  • Suitable polycations include cationic nitrogen-containing moieties such as quaternary ammonium or cationic protonated amino moieties.
  • the cationic protonated amines can be primary, secondary, or tertiary amines , depending upon the particular species and the selected pH of the composition. These include gelatin, chitosan, poly(ethyleneimine), poly(allylamine) and poly(diallyldimethylammonium chloride) (PDADMAC). It has been found that when performing ICC with SMA-g-MPEG, using chitosan as the cross-linker, it is suitable for the pH of the solution to be about 7 (ranging from 6.5 to 7.5).
  • PEI When PEI is used as the cross-linker with SMA-g- MPEG, it is suitable for the pH of the solution to be about 10.5 (ranging from 10 to 11). Coacervation was found to occur quite often with PDADMAC and this polymer was chosen for several further investigations of coacervation and cross- linking.
  • PDADMAC contains quaternary ammonium salts and thus its charge is pH-insensitive, however, it is not capable of forming covalent crosslinks with electrophilic groups on the polyanions. For this reason, copolymers prepared from DADMAC and 2-aminoethyl methacrylate hydrochloride (AEM HCI) were also studied (see Scheme 2), where the AEM can act as nucleophile.
  • Poly(diallyldimethylammonium chloride) can react with polyanionic polyelectrolytes by nucleophilic attack of an anionic centre on one of the carbon centers attached to the ammonium group.
  • Other examples involve spiro-analogs of this polymers, where the two methyl groups have been connected with an ethylene or other alkyl spacer to form a pyrrolidene or other ring.
  • the polyanionic polyelectrolyte may be a polycarboxylic acid, a polyphenolic, a polymer carrying amine groups, and related copolymers incorporating some nucleophilic centres. Natural polyelectrolytes are attractive materials because they are often readily available, inexpensive and biocompatible.
  • Suitable natural polyelectrolytes include those that can be modified to introduce reactive groups that would be able to crosslink with one of the functional groups (i.e., amines, alcohols, carboxylates) found in other natural polyelectrolytes.
  • An example of one such material is sodium alginate, an anionic polysaccharide. Oxidation converts some of the diol groups into dialdehydes (Scheme 3), which can react with amino groups found on natural polycations such as gelatin or chitosan.
  • SAPA sodium alginate polyaldehyde
  • the present inventors have used this combination to encapsulate oils such as butyl benzoate.
  • Any anionic or cationic counterions can be used in association with the polyelectrolytes so long as the polymers remain soluble in water, or in a coacervate phase, and so long as the counterions are physically and chemically compatible with the essential components of the method or do not otherwise unduly impair final product performance, stability or aesthetics.
  • Non-limiting examples of such counteranions include halides (e.g., chloride, bromide, iodide), sulfate and methylsulfate.
  • Non-limiting examples of countercations include alkali metals (e.g. sodium and potassium) and quaternary ammonium cations.
  • TCC and ICC may be extended to many other polymers. For example, one could add acetoacetate, glycidyl or other crosslinking groups to alginate or gum acacia and obtain new crosslinkable polyanions based on modified natural polymers.
  • the present invention also includes novel polymers and polymer networks prepared using the methods of the invention.
  • the present invention includes a cross-linked polymer network comprising a cross-linked coacervate of one or more polymers, wherein said one or more polymers comprise one or more cross-linkable functional groups.
  • the cross-linked coacervate further comprises a cross-linker comprising one or more functional groups which have reacted with the one or more cross-linkable functional groups with complementary reactivity on the one or more polymers.
  • the polymer network is selected from:
  • DMA-co-GMA coacervate cross-linked with a polyamine for example, PEI;
  • DMA-co-AMA coacervate cross-linked with a free radical initiator for example, ammonium persulfate/TEMED;
  • SMA-g-MPEG / PDMAC coacervate crosslinked with a polyamine, for example PEI or chitosan;
  • PEI polyamine
  • AEM aminoethylmethacrylate
  • glycidylmethacrylate may be replaced with other electrophilic comonomers, for example 2-(methacryloyloxy)ethylacetoacetate
  • SAPA coacervated crosslinked with gelatin and SAPA coacervated crosslinked with chitosan.
  • DMA-co-GMA DMA-co-AMA;
  • the cross-linked polymer networks of the present invention may be used in any system requiring encapsulation, barriers, membranes or other applications involving films. These crosslinked polymers may for example be formed as a film or membrane at the interface between different liquid or solid phases, and hence may find use in encapsulation, separation, or adhesion applications. Certain networks of the present invention are particularly suited for biomaterial applications since many of the polymers used are of natural origin or are biocompatible. In a particular embodiment of the present invention, the cross-linked polymer networks are used for encapsulation. Encapsulation is achieved by forming a coacervate, a polymer-rich aqueous phase, which then coats onto the surface of oil droplets or solid particles.
  • the present invention relates to a method of forming microcapsules comprising combining material to be encapsulated with one or more polymers, wherein said one or more polymers comprises one or more cross- linkable functional groups and forms a coacervate, and cross-linking said polymers through said functional groups.
  • the cross-linking is effected by addition of a cross-linker comprising one or more functional groups with complementary reactivity to the one or more cross- linkable functional groups on the one or more polymers.
  • the cross-linker is comprised within the one or more polymers, eliminating the need for the addition of a separate cross-linker.
  • the polymer(s) and material to be encapsulated are combined with the cross-linker in the presence of a suitable surfactant or colloidal stabilizer. Suitable surfactants or stabilzers do not change the phase transition temperature of the polymer or are otherwise detrimental to the formation of a coacervate.
  • a surfactant for use with DMA copolymers is poly(vinyl pyrrolidone).
  • Materials that can be encapsulated include any hydrophobic material, including, but not limited to oils, lubricants, and hydrophobic molecules including drugs.
  • the concept may also be extended to cell-encapsulation, given the low cytotoxicity and tunable permeability expected from these networks.
  • the self-crosslinking feature may be used to form bulk crosslinked hydrogels of any shape, by injecting the coacervate into a mold followed by self-crosslinking. In principle, this could include bio-medical applications.
  • the coacervate may be coated onto other flat surfaces, or into porous solid or flexible supports and membranes, and crosslinked in place.
  • the present invention also includes microcapsules, membranes, films, microspheres and other materials prepared using the networks of the present invention.
  • Example 1 Hydrogel Microspheres Formed by Complex Coacervation of Partially MPEG-Grafted Poly(Styrene-a/f-Maleic Anhydride) with PDADMAC and Crosslinking with Polyamines (a) Materials and Methods:
  • Styrene, maleic anhydride, methoxy poly(ethylene glycol) (MPEG) (M n , 350) , butyllithium (1 .60 mol L ' 1 in hexane), polydiallyldimethylammonium chloride (PDADMAC) (40 wt % aqueous solution), Chitosan and polyethylenimine (PEI) (branched, M n , 1800) were purchased from Aldrich. Maleic anhydride was recrystallized in chloroform before use, others were used as received. 2,2'-Azobis(isobutyronitrile) (AIBN) was obtained from American Polymer Standards Laboratories and recrystallized in methanol.
  • AIBN 2,2'-Azobis(isobutyronitrile)
  • Methyl ethyl ketone (MEK), tetrahydrofuran (THF), and anhydrous diethyl ether were obtained from Caledon. THF was dried by refluxing with metallic sodium followed by distillation. The number average molecular weight and the polydispersity index of Chitosan were 1.5 x 10 4 and 2.5 respectively, measured by aqueous gel permeation chromatography as described below.
  • SMA-g-MPEG Methoxy Poly(ethylene glycol) Partially Grafted Poly(styrene-a/f-maleic anhydride)
  • SMA-g-MPEG Poly(styrene-a/f-maleic anhydride)
  • SMA was prepared by free radical polymerization as previously reported (Yin, X.; Stover, H. D. H. Macromolecules, 2003, 36, 8773-8779).
  • the number average molecular weight and polydispersity index of SMA were 1.37 x 10 4 and 2.2 respectively.
  • SMA-g-MPEG copolymers were characterized by FT-IR and 1 H NMR.
  • FT- IR spectra were measured on a Bio-RAD FTS-40 spectrometer using KBr pellets.
  • 1 H NMR spectra were recorded on a Bruker AC 200, using DMF-d as the solvent.
  • Chitosan Chitosan of low molecular weight was prepared by a free radical degradation method following a literature procedure (Bartkowiak, A.; Hunkeler, D.
  • the molecular weight of the degraded chitosan was estimated by gel permeation chromatography, consisting of a Waters 515 HPLC pump, three Ultrahydrogel columns (0 - 3k, 0 - 5k, 2k - 300k Dalton) and a Waters 2414 refractive index detector, with 0.5 mol L "1 sodium acetate / 0.5 mol L '1 acetic acid solution as eluent at a flow rate of 0.8 ml min "1 , and narrow disperse poly(ethylene glycol) as calibration standards.
  • the M n and PDI of degraded chitosan were 3.9 x 10 3 and 1.2 respectively.
  • Mondel PC-Titrator
  • PDADMAC Polydiallyldimethylammonium Chloride
  • a solution of 2.0 wt % PDADMAC was prepared in 0.05 M NaCl solution at pH 7.00. 2.8g of this solution was added to 50 g of 0.25 wt % SMA-g-MPEG-70% in 0.05 M NaCl solution at pH 7.00 under 600 RPM stirring. The mixture was maintained at pH 7.00 by adding 0.1 N NaOH during this coacervation process. After the coacervate mixture was stirred for 5 min, it was centrifuged at 3000 RPM for 10 min. The coacervate was separated by decanting the transparent supernatant phase and dried to constant weight at 65 °C. 0.070g of dry coacervate was obtained (yield, 38 %).
  • Microspheres were prepared using the same coacervation process as described above. After coacervation and while still stirring, 4.2g of 2.0 wt % chitosan in 0.05 mol L "1 NaCl solution at pH 7.00 was added to crosslink the coacervate droplets into microspheres. The crosslinking reaction was continued for 3 h. Microspheres were isolated by centrifugation at 500 RPM for 10 min, and were washed with 0.05 M NaCl solution to remove unreacted materials. They are stored in 0.05 M NaCl solution for further studies.
  • ESEM environmental scanning electron microscope
  • SMA-g-MPEG partially methoxy poly(ethylene glycol) grafted poly(styrene-a/f-maleic anhydride) copolymer
  • SMA-g-MPEG partially methoxy poly(ethylene glycol) grafted poly(styrene-a/f-maleic anhydride) copolymer
  • the primary objective for this research was to use SMA-g-MPEG copolymers as reactive polyanions to prepare coacervate microspheres.
  • the SMA-g-MPEG backbone contains both carboxylic acid and anhydride groups.
  • the carboxylic acid forms a complex with polycations to induce the coacervation, and the anhydride group can be used to subsequently crosslink the dispersed complex coacervate droplets to prepare microspheres.
  • SMA-g-MPEG-55% is only water- soluble under basic conditions, while the content of anhydride groups in SMA-g- MPEG-87% is too low for crosslinking reactions.
  • SMA-g-MPEG-70% is chosen for further studies to prepare coacervate hydrogel microspheres.
  • PDADMAC poly(diallyldimethylammonium chloride)
  • the coacervation has the highest yield at the mass ratio of 0.48 of PDADMAC / SMA-g-MPEG-70% under the studied conditions. However, no crosslinked microspheres are obtained when chitosan is added to this coacervate mixture (Table 2). As described above, coacervation has its maximum yield at the electrostatic neutralization point of the complexed polyelectrolytes. Before the coacervation reaches the maximum yield point, the SMA-g-MPEG-70% / PDADMAC coacervates should be partially negatively charged.
  • the amount of chitosan added affects the crosslinking density of the microspheres (SDC-3, SDC-7, and SDC-8 in Table 2).
  • SDC-3, SDC-7, and SDC-8 in Table 2 At a mass ratio of chitosan to PDADMAC of 1.0, no crosslinking is observed, indicating that the concentration of chitosan is too low to diffuse into the coacervates.
  • Increasing the addition amount of chitosan crosslinked coacervate microspheres are obtained. ESEM images of these microspheres are shown in Figure 7c and d.
  • the FT-IR spectrum of the coacervate displays characteristic anhydride peaks at 1780 and 1850 cm "1 . In the spectrum of crosslinked microspheres, these characteristic absorptions have disappeared.
  • PEI may substitute PDADMAC from SMA-g-MPEG-70% / PDADMAC coacervates. Meanwhile, the crosslinking reaction between amines and anhydrides takes place very quickly, leading to the similar situation as PEI complexing directly with SMA- g-MPEG, and gel precipitations.
  • PEI is an effective crosslinker for crosslinking coacervates under basic conditions, such as pH 10.50, where PEI is less than 5% ionized (Clark, S. L.; Hammond, P. T. Langmuir2000, 16, 10206-10214).
  • hydrogel microspheres contain either anionic polymers, such as polyacrylic acid, or cationic polymers, such as poly(diethylamino ethyl methacrylate).
  • anionic polymers such as polyacrylic acid
  • cationic polymers such as poly(diethylamino ethyl methacrylate).
  • the swelling of the hydrogel microsphere at different pH and salinity is mainly due to the osmotic pressure, which results from the net difference in concentration of mobile ions between the interior of the microsphere and the exterior bathing solution (Saunder, B. R.; Crowther, H. M.; Vincent, B. Macromolecules 1997, 30, 482-487; Eichenbaum, G.
  • the polymer chains in complex coacervate microspheres are oppositely charged polyelectrolytes.
  • the salt ion penetrates into coacervate microspheres, and partially shields intermolecular ionic bonds.
  • the polymer chains expand with the breakage of ionic crosslinking points, leading to the swelling of coacervate microspheres.
  • the swelling of complex coacervate microspheres upon increasing the salinity is essentially based on the breakage of electrostatic interactions instead of osmotic pressures.
  • NaCl concentrations above 0.5 mol L "1
  • most of the charge of polyelectrolytes in coacervate microspheres is screened, and the particle sizes remain roughly constant with further increasing salt concentrations.
  • Coacervate microspheres swell with increasing salinity in the bath medium. This swelling is mainly due to the interruption of electrostatic associations of complexed polyelectrolytes with the addition of salts.
  • Example 2 Hydrogel Microspheres Formed by Thermally Induced Coacervation of of Poly (N,N-Dimethylacrylamide-co-Glycidyl Methylacrylate) Aqueous Solutions
  • DMA N,N-dimethylacrylamide
  • GMA glycidyl methacrylate
  • N IPAM N- isopropylacrylamide
  • SDS sodium dodecyl sulfate
  • PVP poly(vinylpyrrolidone) (PVP) (MW, 40,000)
  • EDA ethylenediamine
  • TEPA tetraethylenepentamine
  • PEI polyethylenimine
  • AIBN 2,2'- Azobisisobutyronitrile
  • Polymerization was carried out at 70 °C for 1 hour by rolling the bottles in a thermostated reactor fitted with a set of horizontal rollers. The product was precipitated into 500 ml of diethyl ether and dried under vacuum at 40 °C to provide 3.0 g of polymer (yield, 32%).
  • Phase transition temperatures of aqueous solutions of DMA-co-GMA copolymers were measured using the cloud point method.
  • An automatic PC-Titrator (Mandel) equipped with a temperature probe and with a photometer incorporating a 1 cm path length fiber optics probe (GT-6LD, Mitsubishi) was used to trace the phase transition by monitoring the transmittance of a beam of white light.
  • the turbidity of the solution was recorded as photoinduced voltage (mV).
  • the phase transition temperature was defined as the inflection point of the mV vs. temperature curve, as determined by the maximum in the first derivative.
  • the heating rate was 1.0 °C min-1 and concentrations of polymer solutions were 0.2, 0.5, 1.0 and 2.0 wt %.
  • the DMA-co-GMA copolymers were dissolved in de-ionized water at a temperature below the phase transition temperature. The solutions were stirred, and heated above the phase separation temperature to induce coacervation. After phase equilibration, polyamine was added to crosslink the formed coacervate droplets.
  • ESEM samples were prepared by depositing a drop of aqueous microsphere suspension onto a glass-covered ESEM stub, drying under vacuum and sputter-coating with about 5 nm of gold. (b) Results and Discussion Synthesis and Properties of DMA-co-GMA Copolymers.
  • Copolymerization with glycidyl methacrylate permits both thermal coacervation and subsequent crosslinking of the resulting coacervate droplets to form hydrogel microspheres.
  • the copolymerization conversions were kept below 30% in order to limit copolymer composition drifts.
  • 1H NMR spectra of DMA and GMA homopolymers, and of a copolymer are shown in Figure 7, with peak assignments from the literature.
  • the pNIPAM solution shows the characteristically sharp liquid-solid phase transition at about 32 °C, with the complete opacity above the LCST due to scattering from the de-solvated pNIPAM particles.
  • Figure 9 presents an optical microscope image of a 1.0 wt % DMA-co- GMA47 solution at room temperature, showing the expected liquid coacervate droplets.
  • Phase transition temperatures of thermally responsive polymer solutions commonly increase with the addition of surfactants up to the critical aggregation concentration, through formation of hydrophilic polymer-surfactant complexes.
  • 4,5 Figure 11 shows that adding 0.1 wt % SDS (ca. 3.5 mM) sodium dodecyl sulfate (SDS) increases the phase transition temperature of a 0.5 wt % DMA-co-GMA43 solution by about 37 °C, by introducing charges to the copolymer.
  • SDS sodium dodecyl sulfate
  • Coacervate microdroplets are inherently unstable and will coalesce into a bulk coacervate phase in absence of a dispersing force. However, they may be crosslinked to form colloidally stable hydrogel microspheres.
  • the thermally induced DMA-co-GMA coacervate droplets described here were designed to be crosslinked by addition of diamines and polyamines to the aqueous phase after phase separation.
  • Figure 12 a-d shows the environmental scanning electron microscopy (ESEM) images of crosslinked hydrogel microspheres prepared by addition of ethylene diamine to DMA-co-GMA coacervate droplets.
  • Coacervation and crosslinking were carried out at temperatures slightly above the corresponding phase transition temperatures. Under these conditions, ethylene diamine diffuses into the coacervates and reacts with epoxy groups in the polymer chain. Crosslinking is promoted over simple functionalization by the enrichment of the polymer in the coacervate phase, and no crosslinking or gelation is observed when ethylene diamine is added at temperatures below the phase transition temperature.
  • the crosslinked microspheres are stable during work-up.
  • the conversion of epoxy groups to hydroxyl groups and the incorporation of amines renders the microspheres more hydrophilic and even ionic, and removes their temperature- responsive properties.
  • Coacervate and Microsphere Yield Figure 13 shows the yield of crosslinked microspheres as function of crosslinking temperatures.
  • the microsphere yields which reflects both the coacervate yield and the crosslinking efficiency, increases with increasing crosslinking temperatures.
  • the phase transition of DMA-CO-GMA47 aqueous solution occurs below room temperature, which allows us to easily measure the coacervate yield itself.
  • the coacervate yield of a 0.5 wt % DMA-CO-GMA47 aqueous solution at 25 °C is 26%, which roughly corresponds to the microsphere yield in that temperature range ( Figure 13). This indicates that the microsphere yield mainly depends on the coacervation process, and that crosslinking of the formed coacervate is quite efficient. Hence, the coacervation yield can be estimated through the microsphere yield.
  • This temperature-dependent coacervation yield is partly due to the compositional distribution of the copolymer.
  • N,N-dimethylacrylamide and glycidyl methacrylate monomers have different reactivity ratios, and chains generated at the beginning of the polymerization should contain more GMA, be more hydrophobic and have lower cloud point temperatures than chains generated later in the polymerization.
  • the resulting compositional distribution will broaden the temperature range over which coacervation occurs, even though polymerizations were limited to about 30% monomer conversion.
  • FIG. 14 a-b presents ESEM micrographs of microspheres prepared from 0.5 wt % DMA-co-GMA43 at 40 and 70 °C.
  • crosslinking at these higher temperatures leads to more and larger microspheres, but with less colloidal stability. This is expected, given the same dispersing force but a higher yield of more viscous and more hydrophobic coacervates.
  • the more efficient crosslinking at higher temperature may cause inter-particle more bonds that would contribute to the observed aggregation.
  • Figure 15 a-c presents the effect of polyamine size on the morphologies of crosslinked coacervate microspheres. Colloidally stable microspheres are obtained upon crosslinking with the small amines such as ethylene diamine or tetraethylenepentamine (Fig. 15a). Using linear PEI 432 leads to more aggregation, and branched PEI 1800 gives microspheres that appear more fused, plausibly due to enhanced bridging between microspheres.
  • DMA-co-GMA copolymers have been prepared by free radical copolymerizations.
  • the thermal phase separation of DMA-co-GMA aqueous solutions is a coacervation process, and the phase transition temperature decreases with increasing GMA content.
  • the DMA-co-GMA coacervate droplets can be crosslinked by adding diamines and small polyamines.
  • the yield, size and size distribution of the resulting hydrogel microspheres increases with increasing reaction temperature and polymer concentration.
  • the size and aggregation of the microspheres can be reduced by addition of PVP.
  • Example 3 Temperature-sensitive Hydrogel Microspheres Formed by Liquid-Liquid Phase Transitions of Aqueous Solutions of Poly (N,N- Dimethylacrylamide-co-Allyl Methacrylate) (a) Materials and Methods
  • N N-dimethylacrylamide (DMA, 99w%), allyl methacrylate (AMA, 98 wt %), and N, N, N'.N'-tetramethylethylenediamine (TEMED) were obtained from Aldrich.
  • Tetrahydrofuran (THF), acetone, and pentane were obtained from Caledon Laboratories. All chemicals were used as received.
  • Molecular weights of copolymers were determined using a gel permeation chromatograph consisting of a Waters 515 HPLC pump, three ultrastyragel columns (500-20k, 500-30k, 5k-600k Daltons) and a Waters 2414 refractive index detector, using THF as solvent at a flow rate of 1 ml min-1 , and narrow disperse polystyrene as calibration standards.
  • 1 H NMR spectra of the copolymers were recorded on a Bruker AC 200, using chloroform-d as the solvent.
  • Cloud Point Measurement The cloud points of aqueous solutions of DMA-co-AMA copolymers were measured using an automatic PC-Titrator (Mandel) equipped with a temperature probe and with a photometer incorporating a 1 cm path length fiber optics probe (GT-6LD, Mitsubishi). The turbidity of the solution was recorded as photoinduced voltage (mV). The phase transition temperature was defined as the inflection point of the mV vs. temperature curve, as determined by the maximum in the first derivative. The heating rate and the concentration of polymer solutions were 1.0 °C min-1 and 0.5 wt % respectively.
  • ESEM samples were prepared by depositing a drop of aqueous microsphere suspension onto a glass-covered ESEM stub, drying under vacuum and sputter-coating with an about 5 nm thick layer of gold.
  • Transmission electron microscope (TEM) images of microspheres were obtained using a JEOL 1200EX microscope, the microspheres were embedded in Spurr epoxy resin and microtomed to about 100 nm thickness.
  • DMA-co-AMA Copolymers Poly(N,N-dimethylacrylamide-co-allyl methacrylate) (DMA-co-AMA) copolymers were prepared by copolymerizing DMA with AMA in THF at 55 °C. Conversions were kept below 30% to keep the copolymer compositions close to the comonomer ratios, as well as to prevent crosslinking through the pendant allyl groups.
  • DMA-co-AMA Poly(N,N-dimethylacrylamide-co-allyl methacrylate) copolymers were prepared by copolymerizing DMA with AMA in THF at 55 °C. Conversions were kept below 30% to keep the copolymer compositions close to the comonomer ratios, as well as to prevent crosslinking through the pendant allyl groups.
  • Figure 18 shows a typical 1 H NMR spectrum of a DMA-co-AMA copolymer, with peak assignments made according to literature. 7,8,9 The peak areas for the protons g, h, f, e of the AMA units scale according to 1:2:2:3, confirming that the allyl groups of AMA remain almost unreacted during the copolymerization process.
  • copolymer compositions shown in Table 5 were estimated from the ratio of peak areas for protons g of the AMA units (1H) vs. protons a plus c of the DMA units (7H).
  • FIG. 19 shows the phase transitions of dilute DMA-co-AMA solutions upon heating, with the corresponding phase transition temperatures shown in Table 5.
  • a 0.5 wt % solution of DMA-co-AMA-14 containing 14 mol% AMA shows a phase transition temperature (Tp) of 72 °C.
  • Tp phase transition temperature
  • the Tp decreases with increasing AMA content, with DMA-co-AMA-30 having a Tp of 15.7 °C, and DMA-co-AMA-40 not being water- soluble even at 0 °C.
  • FIG. 20 shows an optical microscope image of a 0.5 wt % DMA-co-AMA-30 solution at room temperature, showing the corresponding liquid coacervate droplets. These droplets are not colloidally stable and coalesce within several minutes in the absence of stirring. The phase transition is reversible upon cooling.
  • Hydrogel microspheres were formed by free radical crosslinking of the thermally induced
  • DMA-co-AMA coacervate droplets through the pendant allyl groups This crosslinking can involve addition of radicals to allylic double bonds, or coupling to allylic radicals.
  • Hydrogel microspheres were formed by crosslinking the thermally induced coacervates of all tested copolymer compositions at temperature just above the Tp.
  • Figure 21A illustrates the hydrogel microspheres formed from DMA-co-AMA-28 at 30 °C.
  • the coacervate phase is a highly concentrated polymer solution and the polymer chains are severely entangled, allowing for efficient radical crosslinking.
  • Example 2 The DMA-co-GMA copolymer reported in Example 2, did not show such gel precipitation upon heating above their Tp, but instead only liquid-liquid phase separations even at elevated temperatures. It appears that the more hydrophobic allyl methacrylate promotes further desolvation and collapse of the copolymer chain upon heating.
  • microsphere size and size distribution increase with reaction temperature (Table 6), likely due to loss of colloidal stability of the coacervate.
  • the crosslinked coacervate microspheres maintain their spherical shapes in aqueous suspension even upon cooling below the phase transition temperature of the corresponding copolymers.
  • Figure 22A and B show room temperature optical images of wet and dry crosslinked coacervate microspheres prepared from DMA-co-AMA-19 (Tp, 54 °C).
  • TEM Transmission electron microscopy
  • FIG. 13 C CP-MAS NMR spectroscopy was used to characterize the crosslinked microspheres formed from DMA-co-AMA-19, and specifically to try to determine the conversion of allyl groups during the crosslinking reaction.
  • Figure 25 shows the spectrum of the crosslinked microspheres formed by reacting DMA-co-AMA-19 coacervate with 4 ml of 1.0 mol L-1 APS/TEMED at 60 °C for 2 hrs.
  • the carbonyl carbons of the ester and amide groups appear at 175ppm, the vinyl carbons at 133 and 119 ppm, and the methylene oxy carbon of AMA at 66 ppm.
  • (DMA-co-AMA) copolymers prepared by free radical polymerizations show continuous solution/coacervate/gel precipitate phase transitions upon heating.
  • the polymer first separates from the solution as a liquid coacervate at temperatures slightly above the corresponding transition temperatures, and forms gel precipitates at high temperatures.
  • the phase transition temperature depends on the AMA content in the copolymers.
  • Novel thermo-sensitive hydrogel microspheres were prepared by thermally induced coacervation of DMA-co-AMA aqueous solution followed by radical crosslinking.
  • the size and size distributions of the microspheres increase with increasing reaction temperatures, which are attributed to the increase in the coacervate amount, and a decrease in the colloidal stability of the coacervate droplets.
  • the amount of initiator added affects the crosslinking efficiency, and hence the morphology of the microspheres.
  • the formed coacervate microspheres are thermo-responsive indicating that such materials will find applications in protein separation and protein delivery.
  • TEM images of microspheres were obtained using a JEOL 1200EX microscope, the microspheres were embedded in Spurr epoxy resin and microtomed to about 100 nm thickness.
  • Solid state 13 C cross-polarization magic angle spinning (CP-MAS) NMR spectroscopy was carried out on a Bruker AC 300 at 10 kHz spinning rate.
  • Example 4 Integrated Coacervation and Crosslinking of Copolymers Based On EVJethacryliG Acid (MAA), Po.y(ethySeneg.yeoI) Mono ethygether Monomethacrylate (PEGMM), Butylmethacrylate (BMA) and Glycidylmethacrylate (GMA)
  • MAA EVJethacryliG Acid
  • PGMM ethygether Monomethacrylate
  • BMA Butylmethacrylate
  • MAA methacrylic acid
  • PEGM poly(ethyleneglycol) monomethylether monomethacrylate
  • BMA butylmethacrylate
  • GMA glycidylmethacrylate
  • PEC polyelectrolyte complexes
  • PEI polyethyleneimine
  • BMA (optional) increases the hydrophobicity of the copolymer, increasing its coacervation efficiency.
  • GMA provides electrophilic sites that can crosslink with amino groups on the PEI, and potentially also with carboxylate groups on the anionic copolymer. In addition, GMA adds hydrophobicity to the PEC prior to crosslinking.
  • the composition of the copolymer has to be chosen to balance the different requirements for ICC with PEI.
  • Synthesis Initial copolymerizations were carried out in conventional two-neck round- bottom flasks fitted with a condenser. Typical procedure for the preparation of a binary 25:75 mole% poly(MMA-co-PEGMM) copolymer: 0.87g MAA and 9.13g PEGMA were dissolved in 110ml tetrahydrofuran (THF) together with 0.137g of 2,2'-azobis-isobutyronitrile (AIBN) radical initiator. The solution was purged with argon for 20 minutes, and then heated to 65°C for 21 hours under stirring.
  • THF tetrahydrofuran
  • AIBN 2,2'-azobis-isobutyronitrile
  • the cooled reaction mixture was then precipitated into 600 ml of cold diethylether (containing -10% hexanes for polymers containing more than 10% BMA) and stored in a freezer overnight. The supernatant was decanted and polymer dried under vacuum at 50°C to constant weight.
  • Aqueous solutions of MMA-PEGMM copolymers have an LCST phase diagram: they show cloud points upon heating. This cloud point is affected by the acid/ether ratio, degree of ionization, hydrophobic co-monomer content, salinity.
  • the cloud points of the copolymers are important for three reasons: • they reflect the hydrophobic/hydrophilic balance of the copolymer - this balance influences the water content of the coacervate and hence of the capsule walls.
  • Figure 26 shows the cloud points of binary copolymers of MAA and PEGMM at 3% w/v in aqueous solution at pH 3.
  • the graph reveals a minimum in the LCST curve near the 1 :1 stoichiometric ratio of acid / ether functional groups.
  • the polymers were additionally characterized by acid-base titration with
  • Figure 27 shows the decrease in cloud point with increasing BMA content, in a 3w/v% aqueous solutions.
  • Figure 28 shows the decrease in cloud point with increasing GMA content, in a 0.75% w/v aqueous solution.
  • Figure 29 shows the cloud point of quaternary polymers containing both
  • PEC polyelectrolyte complexes
  • liquid, polymer-rich complex coacervate is desirable, for two reasons:
  • this complex coacervate is amphiphilic due to the presence of hydrophobic backbone segments and optionally, hydrophobic comonomers. Being a liquid phase itself, it can assemble at the interface between a dispersed oil phase and the continuous water phase, to minimize the systems interfacial tension.
  • a polymer-rich, liquid complex coacervate is ideal for covalent crosslinking between the PEI and electrophiles on the copolymer.
  • this crosslinking takes place after the coacervate phase has formed and assembled at the interface, leading to crosslinked hydrogel capsules containing hydrophobic fill.
  • Figures 31 and 32 show optical microscopy images of paraffin oil suspensions containing [50-50-0-0] / PEI and [47.5-47.5-5-0] / PEI. Both the binary and ternary copolymer form complex coacervates that assemble around the oil droplets. Ho significant difference between the two systems is apparent, though it is expected that the BMA containing coacervate will be more polymer- rich.
  • ICC Integrated Coacervation and Crosslinking
  • This present system is designed to replace the classical gelatin / gum arabic compositions, that usually require aldehyde crosslinking to toughen the capsule walls.
  • Example 5 Preparation of sodium alginate polyaldehyde (SAPA - sodium 2,3-dialdehyde alginate) Preparation of SAPA (according to Hyun-Ah Kang, Moon Sik Shin, Jin-Won Yang, Polymer Bulletin, 2002, 47, 429-435 - see Scheme 3): 7.5 g sodium alginate was dissolved in a mixture of 200 ml H 2 O and 50 ml 1-propanol to produce a 3 % w/v sodium alginate solution. To this solution was added 1.908 g sodium periodate and the mixture stirred in the dark for 24 hour at room temperature.
  • SAPA sodium 2,3-dialdehyde alginate
  • the pH-induced coacervation of SAPA and gelatin can be used to encapsulate oils such as paraffin oil, xylene and butyl benzoate.
  • Figure 37A shows the encapsulation of butyl benzoate. Addition of another 1 mL of 1% SAPA solution after the capsules formed resulted in wrinkled and raisin like capsules (Figure 37E).
  • Table 1 The composition of SMA-g-MPEG copolymers as estimated fromH NMR.

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Abstract

La présente invention a trait à un procédé de préparation de réseaux polymèriques réticulés par coacervation et réticulation in situ, ainsi que des réseaux polymèriques obtenus par le procédé et les utilisations desdits réseaux, notamment sous forme de microsphères, microcapsules et de films.
PCT/CA2004/001456 2003-08-08 2004-08-09 Procedes de preparation de reseaux polymeriques reticules par coacervation et reticulation in situ WO2005014698A1 (fr)

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CN102370612A (zh) * 2010-08-24 2012-03-14 吴志宏 壳聚糖-单甲氧基聚乙二醇凝胶给药系统及其制备方法
CN103261246A (zh) * 2010-11-18 2013-08-21 索维公司 用于制备一种偏二氯乙烯聚合物胶乳的方法
CN104628975A (zh) * 2014-12-18 2015-05-20 东华大学 一种药用两亲性共聚物网络及其制备方法
WO2016005689A1 (fr) * 2014-07-10 2016-01-14 Isp Investments Inc. Utilisation d'un homopolymere amine pour l'encapsulation d'ingredients, procede de synthese d'un homopolymere d'aema, et procede d'encapsulation d'ingredients
WO2016070270A1 (fr) * 2014-11-03 2016-05-12 HYDRO-QUéBEC Polymere réticule à base d'un copolymère aléatoire et d'un agent réticulant polyamine volatil, et ses procédés de fabrication
CN107925085A (zh) * 2015-08-10 2018-04-17 株式会社可乐丽 非水电解质电池用粘结剂组合物、以及使用其的非水电解质电池用浆料组合物、非水电解质电池负极及非水电解质电池
CN109293951A (zh) * 2017-07-25 2019-02-01 中国科学院化学研究所 一种含有响应性荧光多糖衍生物的均相溶液及其制备方法和用途
CN109851815A (zh) * 2019-01-28 2019-06-07 西北工业大学 基于聚合物纳米微球氢键交联的纳米复合水凝胶的制备方法
CN110511459A (zh) * 2019-09-02 2019-11-29 北京化工大学 一种纤维骨架材料浸胶液、制备方法及浸渍方法
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CN112691623A (zh) * 2020-12-09 2021-04-23 石河子大学 一种超支胺化多孔微球的制备及应用
US20210198533A1 (en) * 2017-07-26 2021-07-01 University Of Massachusetts Crosslinkable polymer composition
US11260359B2 (en) 2019-01-11 2022-03-01 Encapsys, Llc Incorporation of chitosan in microcapsule wall
JP2022520646A (ja) * 2019-02-15 2022-03-31 アキュイティー ポリマーズ、インコーポレイテッド 治療薬を含有する生体適合性ポリマーコーティング
CN114316309A (zh) * 2021-12-28 2022-04-12 上海瑞凝生物科技有限公司 一种聚乙二醇-聚赖氨酸水凝胶微球及其制备方法
WO2023017794A1 (fr) * 2021-08-10 2023-02-16 株式会社日本触媒 Composé à teneur en oxyde de polyalkylène

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KR20170078808A (ko) * 2014-11-03 2017-07-07 하이드로-퀘벡 랜덤 코폴리머 및 휘발성 폴리아민 가교화제 기반의 가교된 폴리머 및 그의 제조방법
WO2016070270A1 (fr) * 2014-11-03 2016-05-12 HYDRO-QUéBEC Polymere réticule à base d'un copolymère aléatoire et d'un agent réticulant polyamine volatil, et ses procédés de fabrication
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