WO2016155107A1 - 一种壳聚糖复合膜的制备方法 - Google Patents

一种壳聚糖复合膜的制备方法 Download PDF

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WO2016155107A1
WO2016155107A1 PCT/CN2015/079963 CN2015079963W WO2016155107A1 WO 2016155107 A1 WO2016155107 A1 WO 2016155107A1 CN 2015079963 W CN2015079963 W CN 2015079963W WO 2016155107 A1 WO2016155107 A1 WO 2016155107A1
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solution
polyvinyl alcohol
chitosan
modified polyvinyl
succinic anhydride
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PCT/CN2015/079963
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English (en)
French (fr)
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倪才华
陶蕾
张丽萍
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江南大学
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Priority to US15/322,724 priority Critical patent/US10442904B2/en
Publication of WO2016155107A1 publication Critical patent/WO2016155107A1/zh

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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
    • C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
    • C08J5/18—Manufacture of films or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/041—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
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    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C39/00—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor
    • B29C39/003—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor characterised by the choice of material
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C39/00—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor
    • B29C39/14—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor for making articles of indefinite length
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C39/00—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor
    • B29C39/22—Component parts, details or accessories; Auxiliary operations
    • B29C39/38—Heating or cooling
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L31/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an acyloxy radical of a saturated carboxylic acid, of carbonic acid or of a haloformic acid; Compositions of derivatives of such polymers
    • C08L31/06—Homopolymers or copolymers of esters of polycarboxylic acids
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    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
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    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
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    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1851—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
    • A61K49/1863—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being a polysaccharide or derivative thereof, e.g. chitosan, chitin, cellulose, pectin, starch
    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/23—Carbohydrates
    • A61L2300/232—Monosaccharides, disaccharides, polysaccharides, lipopolysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/424—Anti-adhesion agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2005/00—Use of polysaccharides or derivatives as moulding material
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2029/00—Use of polyvinylalcohols, polyvinylethers, polyvinylaldehydes, polyvinylketones or polyvinylketals or derivatives thereof as moulding material
    • B29K2029/04—PVOH, i.e. polyvinyl alcohol
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
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    • B29L2007/00—Flat articles, e.g. films or sheets
    • B29L2007/008—Wide strips, e.g. films, webs
    • 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
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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
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    • C08J2329/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal, or ketal radical; Hydrolysed polymers of esters of unsaturated alcohols with saturated carboxylic acids; Derivatives of such polymer
    • C08J2329/02—Homopolymers or copolymers of unsaturated alcohols
    • C08J2329/04—Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids
    • D—TEXTILES; PAPER
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    • D01F9/00—Artificial filaments or the like of other substances; Manufacture thereof; Apparatus specially adapted for the manufacture of carbon filaments

Definitions

  • the invention relates to a preparation method of a chitosan composite membrane.
  • Tissue adhesion during surgery is a common phenomenon and an inevitable pathophysiological process during postoperative healing.
  • Postoperative adhesions and scar tissue formation can cause serious complications such as peritoneal adhesions, tendon adhesions, soft tissue adhesions after eyelid injury, peripheral nerve adhesions, and often hinder the normal recovery of the human body.
  • Postoperative adhesions are a common phenomenon in cardiothoracic surgery, obstetrics and gynecology, and orthopedic surgery.
  • the main methods to prevent adhesions so far are: drug therapy, biological therapy, improved surgery, and the use of spacers.
  • Chitosan is a product of chitin deacetylation. It is a natural alkaline polysaccharide with good biocompatibility, antibacterial and hemostasis, tissue regeneration, cell adhesion and biodegradability. There are many studies on chitosan, and chitosan film or gel can effectively prevent postoperative adhesion and weaken the degree of fibrous adhesion.
  • polyelectrolyte composite membranes have become an important part of new membrane materials, and have been widely used in the fields of phase separation, nanofiltration, fruit preservation and biomedicine.
  • the pure chitosan membrane is brittle, degraded and lost too quickly in body fluids, and its application is limited.
  • the present invention provides a method for preparing a chitosan composite film, and the composite film synthesized by the method can effectively improve the mechanical properties of the pure chitosan film and prolong the degradation time.
  • Polyvinyl alcohol (PVA) has good biocompatibility and hydrophilicity and is the most common biomedical material for wound dressings and drug delivery.
  • PVA has good film forming properties and good compatibility with CS. The most outstanding advantage is that PVA film has excellent mechanical properties.
  • the object of the present invention is to provide a preparation method of a chitosan composite membrane, overcome the defects of the pure chitosan membrane, and improve its performance to satisfy the use as a medical anti-blocking.
  • a method for preparing a chitosan composite membrane comprising the following steps:
  • the modified polyvinyl alcohol is formulated into a 0.4 wt% aqueous solution, and then added dropwise to an acetic acid solution having a concentration of 0.4 wt% of chitosan to obtain a mixed solution;
  • reacting polyvinyl alcohol-124 with succinic anhydride in step (1) to obtain a modified polyvinyl alcohol comprises: dissolving polyvinyl alcohol-124 in a dimethyl sulfoxide solvent to form 20 wt% of polyvinyl alcohol-124.
  • the succinic anhydride is dissolved in a dimethyl sulfoxide solvent to form a 20 wt% succinic anhydride solution, according to the molar ratio of the succinic anhydride to the -OH in the polyvinyl alcohol-124 is 1:10, 1.25:10, 1.6:10, 2.0:10, 2.5:10 calculation, the succinic anhydride solution was added dropwise to the polyvinyl alcohol-124 solution, at a temperature of 75 ° C, at 800 r / min After stirring for 5 hours, the heating was stopped. After cooling to room temperature, it was slowly added dropwise to an excess of 5-10 wt% NaOH in ethanol.
  • the product was precipitated, washed repeatedly with ethanol, and dried under vacuum at 50 ° C to a constant weight to obtain a pure
  • the polyvinyl alcohol was modified and stored to obtain five modified polyvinyl alcohols, which were named SP1, SP2, SP3, SP4, and SP5, respectively.
  • the modified polyvinyl alcohol in the step (2) is respectively formulated into a 0.4 wt% aqueous solution by using SP1, SP2, SP3, SP4, and SP5, and then respectively added dropwise to an equal mass of 0.4 wt% of the shell.
  • the acetic acid solution of the polysaccharide is mixed to prepare a mixed solution.
  • the modified polyvinyl alcohol is formulated into a 0.4 wt% aqueous solution, and then added dropwise to an acetic acid solution having a concentration of 0.4 wt% of chitosan to obtain a mixed solution comprising: modifying the The polyvinyl alcohol is dissolved in deionized water to prepare a 0.4 wt% aqueous solution, and the 1 wt% aqueous acetic acid solution is used as a solvent to prepare a 0.4 wt% chitosan solution, and the diameter is A 0.45 ⁇ m needle filter was filtered to remove traces of insoluble impurities, and then the aqueous solution was added dropwise to the filtered chitosan solution, and the mixed solution was stirred at a rate of 1000 r/min until homogeneous.
  • Carboxylation modification of PVA not only hydrogen bonding between modified products and chitosan molecules, but also stronger ionic bond, which improves the stability and mechanical properties of the composite membrane in simulated body fluids. It has sufficient application strength to achieve anti-blocking purposes.
  • the pure chitosan membrane degrades too fast, is easy to be lost from the wound site, and affects the anti-adhesion effect.
  • the chitosan composite membrane of the invention since the formation of the film by polyvinyl alcohol, the degradation of chitosan is slowed and prolonged. The blocking time enhances the application effect.
  • PVA and chitosan have been shown to have good biocompatibility, small molecule succinic anhydride reacts with PVA, and after removal of unreacted small molecules, the resulting product is non-toxic and harmless, biological Good compatibility, no cytotoxicity, can meet the safety requirements of implant materials in human body.
  • the materials selected for the present invention are inexpensive and the reaction is not complicated, so the product cost is not too high and is easily accepted by most ordinary patients.
  • 1 is an infrared spectrum diagram of a modified polyvinyl alcohol in a method for preparing a chitosan composite film of the present invention
  • FIG. 2 is a nuclear magnetic resonance spectrum of a modified polyvinyl alcohol in a method for preparing a chitosan composite film of the present invention
  • FIG. 3 is a graph showing the thermal weight loss curve before and after polyvinyl alcohol modification in a method for preparing a chitosan composite membrane according to the present invention, wherein a is PVA, b is SP1, and c is SP2, d. Is SP3, e is SP4, and f is SP5;
  • chitosan 4 is a composite of chitosan obtained by mixing 0.4 wt% of chitosan acetic acid aqueous solution with 0.4 wt% of different ratio of modified polyvinyl alcohol aqueous solution in a method for preparing a chitosan composite membrane of the present invention; Infrared spectrum of the membrane;
  • thermogravimetric curve of a chitosan composite membrane in a method for preparing a chitosan composite membrane of the present invention wherein a is CS/SP1, b is CS/SP2, c is CS/SP3, and d is CS/SP4, e is CS/SP5;
  • FIG. 6 is a contact angle of a chitosan composite film in a method for preparing a chitosan composite film of the present invention
  • A is a positive control group (RPMI-1640 containing 0.64% phenol).
  • B was a negative control group (RPMI-1640 complete medium)
  • C and D were an experimental group (RPMI-1640 medium of chitosan composite membrane CS/SP1 and CS/SP5 extract).
  • the invention provides a preparation method of a chitosan composite membrane, comprising the following steps:
  • the modified polyvinyl alcohol is formulated into a 0.4 wt% aqueous solution, and then added dropwise to an acetic acid solution having a concentration of 0.4 wt% of chitosan to obtain a mixed solution;
  • a method for preparing a chitosan composite film comprising:
  • Step 1 reacting polyvinyl alcohol-124 with succinic anhydride to obtain a modified polyvinyl alcohol
  • the step may be specifically performed by dissolving polyvinyl alcohol-124 in a dimethyl sulfoxide solvent to form a 20 wt% solution of polyvinyl alcohol-124, and dissolving the succinic anhydride in a dimethyl sulfoxide solvent.
  • a 20 wt% solution of succinic anhydride is formed in which the molar ratio of the succinic anhydride to the -OH in the polyvinyl alcohol-124 is 1:10, 1.25:10, 1.6:10, 2.0:10, 2.5: 10 calculation, the succinic anhydride solution was added dropwise to the polyvinyl alcohol-124 solution, mechanically stirred at 800 ° C for 5 hours at a temperature of 75 ° C, the heating was stopped, and after cooling to room temperature, slowly drip Adding to an excess of 5-10% by weight of NaOH in ethanol solution, the product is precipitated, washed repeatedly with ethanol, and dried under vacuum at 50 ° C to a constant weight to obtain pure modified polyvinyl alcohol and preserved to obtain 5 kinds of modified poly Vinyl alcohol, named SP1, SP2, SP3, SP4, SP5.
  • Step 2 The modified polyvinyl alcohol is formulated into a 0.4 wt% aqueous solution, and then added dropwise to an acetic acid solution having a concentration of 0.4 wt% of chitosan to obtain a mixed solution;
  • the step may be specifically performed by dissolving the modified polyvinyl alcohol in deionized water, preparing a 0.4 wt% aqueous solution, and using 1 wt% aqueous acetic acid as a solvent to prepare a 0.4 wt% chitosan solution. And removing a trace amount of insoluble impurities by using a 0.45 ⁇ m diameter needle filter, and then adding the aqueous solution solution dropwise to the filtered chitosan solution, and stirring the mixed solution at a speed of 1000 r/min until homogeneous.
  • the modified polyvinyl alcohol was separately prepared into an aqueous solution of 0.4 wt% by using SP1, SP2, SP3, SP4, and SP5, and then separately added to an acetic acid solution of an equal mass of 0.4w% chitosan to be mixed. liquid.
  • Step 3 adjusting the pH of the mixed solution to 5.5 with a 0.01 wt% NaOH solution, and removing the surface bubbles after standing for 1 hour to obtain a casting solution;
  • Step 4 Pour the casting liquid into a Petri dish, and dry the Petri dish in an oven at 60 ° C to a constant weight to obtain a chitosan composite film.
  • an embodiment or “an embodiment” as used herein means that it may be included in Particular features, structures, or characteristics of at least one implementation of the invention.
  • the polyvinyl alcohol-124 is formulated into a 20 wt% dimethyl sulfoxide solution, and then the succinic anhydride is formulated into a 25 wt% dimethyl sulfoxide solution, and the molar ratio of succinic anhydride to polyvinyl alcohol in the OH is 1 :10, 1.25:10, 1.6:10, 2.0:10, 2.5:10 calculation, the succinic anhydride solution was added dropwise to the polyvinyl alcohol solution, and mechanically stirred (800r/min) for 5 hours at a temperature of 75 °C. After the heating is stopped, after cooling to room temperature, it is slowly added dropwise to an excess of 5 to 10 wt% NaOH in ethanol. The product is precipitated, washed repeatedly with ethanol, and dried under vacuum at 50 ° C to a constant weight to obtain a pure modified poly. Vinyl alcohol and preserved.
  • the modified polyvinyl alcohol was synthesized according to the formula shown in Table 1.
  • the infrared characterization was carried out by Fourier transform infrared spectroscopy. The scanning range was in the range of 4000-500 cm -1 and the resolution was 4 cm -1 .
  • the results are shown in Figure 1.
  • . 1 is an infrared spectrum of a modified polyvinyl alcohol in a method for preparing a chitosan composite film of the present invention. As shown in FIG. 1, an absorption peak of -OH in a PVA segment occurs at 3200 to 3600 cm -1 .
  • the characteristic peak at 2930 cm -1 is the asymmetric stretching vibration absorption peak of -CH 2
  • the symmetric bending vibration absorption peak of -CH 2 appears at 1450 cm -1 .
  • characteristic carboxylate appears at 1580cm-1 and the absorption peak of 1408cm -1, which table Mingding
  • the dianhydride has successfully modified PVA.
  • the sample concentration was about 10 mg/ml.
  • the structure of the modified polyvinyl alcohol was tested by 1H-NMR. Please refer to FIG. 2, which is a kind of the present invention.
  • the nuclear magnetic resonance spectrum of the modified polyvinyl alcohol in the preparation method of the chitosan composite film is shown in Fig. 2, ⁇ 2.50 is the solvent DMSO peak, ⁇ 3.50 is the water peak, and ⁇ 0 is the TMS peak.
  • the proton peaks in PVA are: ⁇ 1.10 ⁇ 1.70 is the proton peak of CH2, ⁇ 3.70 ⁇ 3.97 is the proton peak of CH, and ⁇ 4.15 ⁇ 4.70 is OH. Proton peak.
  • the proton peak of CH appears at ⁇ 4.80 ⁇ 5.20, and ⁇ 2.24 ⁇ 2.49 is the multiple peak formed by the superposition of CH 2 and CH 2 proton peaks on succinic anhydride. The appearance of the peak indicates that the succinic anhydride modification reaction can proceed smoothly.
  • FIG. 3 is a graph showing the thermogravimetric curve before and after polyvinyl alcohol modification in the preparation method of the chitosan composite membrane of the present invention, as shown in FIG. 3, which shows polyvinyl alcohol and modification thereof.
  • the thermogravimetric analysis results of polyvinyl alcohol, curves a, b, c, d, e, f are the thermal weight loss curves of PVA, SP1, SP2, SP3, SP4, SP5, respectively.
  • the weight loss of PVA is divided into three stages: the first stage is the thermal decomposition of the PVA main chain, mainly concentrated between 250 and 400 ° C; the second stage is that the residual alkyne compound after the degradation of the PVA main chain continues to degrade into carbon and For hydrocarbons, the thermal decomposition temperature starts at 400 °C.
  • the temperature at which PVA main chain thermal decomposition begins to decrease after succinic anhydride modification the decomposition quality in the second stage increases, and the thermal decomposition residual mass increases.
  • chitosan (CS, degree of deacetylation 96.4%), dissolve it in 498 ml of 1.0 wt% aqueous acetic acid solution, stir well, and remove a trace of insoluble impurities by using a 0.45 ⁇ m diameter needle filter;
  • the modified polyvinyl alcohol SP1 was dissolved in deionized water to prepare 500 ml of 0.4 wt% SP1 aqueous solution; 50 g of 0.4 wt% SP1 solution was added dropwise to the filtered 50 g of 0.4 wt% chitosan solution, and mixed.
  • SP1, SP3, SP4, SP5 were used instead of SP1, and the other four operations were the same as above, and the other four chitosan composite membranes were prepared and named as: CS/SP2, CS/SP3, CS/SP4, CS/SP5.
  • the composite film was made into a type 2 spline according to the GBT 1040.3-2006 standard, and the spline was subjected to mechanical properties test using an electronic tensile machine.
  • the test conditions were: 25 ° C, RH (air humidity) 50%, and tensile speed 5 mm/min.
  • FIG. 4 is a mixture of 0.4 wt% chitosan acetic acid aqueous solution and 0.4 wt% different ratio modified polyvinyl alcohol aqueous solution in a method for preparing a chitosan composite membrane according to the present invention.
  • the infrared spectrum of the obtained chitosan composite film is shown in Fig. 4.
  • FIG. 5 is a graph showing the thermal weight loss curve of the chitosan composite membrane in the preparation method of the chitosan composite membrane of the present invention, as shown in FIG. 5, which shows CS and SP1, SP3, and SP5.
  • FIG. 6 is a contact angle of a chitosan composite film in a method for preparing a chitosan composite film according to the present invention, as shown in FIG. 6, along with a modified polyethylene in a chitosan composite film.
  • the increase in the alcohol content and the increase in the water contact angle are related to the increase in the amount of polyelectrolyte complex formation and the decrease in the hydrophilic groups -NH3+, -COO-, -OH. Therefore, the hydrophilicity of the composite membrane can be controlled by changing the mass ratio of chitosan to modified polyvinyl alcohol in the composite system, thereby designing composite membranes with different hydrophilic and hydrophobic properties to meet different requirements for biofilm materials.
  • the membrane was cut into a square membrane with a size of 3 cm ⁇ 3 cm, and then the membrane was immersed in a 0.9 wt% NaCl solution, and placed in a 37 ° C constant temperature shaking water bath. After 6 hours, the surface moisture was wiped off with a filter paper, and the mass was judged. When the mass is basically constant, the degree of swelling reaches equilibrium, and the equilibrium swelling degree is S0. The measurements were made in parallel 3 times and averaged. The formula for calculating the equilibrium swelling degree is as follows:
  • M0 and mb are the masses of the composite film before and after swelling, respectively (g)
  • FIG. 7 is an equilibrium swelling degree of the chitosan composite membrane in the preparation method of the chitosan composite membrane of the present invention in physiological saline.
  • the composite membrane has a large degree of swelling.
  • a large amount of positively charged -NH 3+ is distributed on the molecular chain of chitosan, and the molecular chains are mutually exclusive and easy to stretch.
  • the composite membrane has a higher swelling ratio; as the SP content in the composite membrane increases, the swelling degree of the composite membrane decreases, which may be because the polyelectrolyte complex is formed as the content of the modified polyvinyl alcohol in the composite membrane increases.
  • the in vitro cytotoxicity of the composite membrane was evaluated by the MTT method.
  • 3T3 cells in logarithmic growth phase were seeded in 96-well culture plates at 2.4 ⁇ 104 Cell per well, placed in a 5% CO 2 incubator at 37° C. in RPMI-1640 medium (RPMI) containing 10% fetal bovine serum. -1640 complete medium) After 24 hours of culture, the medium was discarded.
  • 6cm 2 different composite membrane samples (CS/SP1; CS/SP5) were autoclaved and then immersed in 1ml physiological saline (37 °C) for 6h, 12h, 24h, 48h, and the extract was RPMI-1640.
  • the complete medium was diluted to 0.1 ⁇ L/ ⁇ L, and the diluted extract was used as a sample group.
  • 100 ⁇ L of RPMI-1640 complete medium, RPMI-1640 medium containing 0.64% phenol, and RPMI-1640 complete medium containing complex membrane extract were added to each well as negative control group, positive control group and experimental group, respectively.
  • Six replicate wells were set and cultured in a 37 ° C, 5% CO 2 incubator for 48 h, 20 ⁇ L LTTT was added to each well and cultured for 4 h. After all the crystals were dissolved, the absorbance was measured at 570 nm using an enzyme-linked immunosorbent assay, and the cell survival rate was calculated.
  • Figure 8 is a photomicrograph of 3T3 cells after various conditions of culture: A: positive control group (RPMI-1640 medium containing 0.64% phenol); B: negative control group (RPMI-1640 complete medium); , D: experimental group (RPMI-1640 medium of chitosan composite membrane CS/SP1 and CS/SP5 extract).
  • A positive control group (RPMI-1640 medium containing 0.64% phenol); B: negative control group (RPMI-1640 complete medium);
  • D experimental group (RPMI-1640 medium of chitosan composite membrane CS/SP1 and CS/SP5 extract).
  • the present invention discloses a method for preparing a chitosan composite membrane.
  • the method firstly uses polyvinyl alcohol (PVA) as a raw material, and reacts with succinic anhydride to make a hydroxyl moiety of the polyvinyl alcohol main chain. Conversion to carboxyl group, preparation of modified polyvinyl alcohol (SP) with different degrees of carboxylation; then using chitosan (CS) as matrix, the modified polyvinyl alcohol and chitosan are combined by polyelectrolyte interaction, using solution CS and SP chitosan composite membranes were prepared by casting method.
  • PVA polyvinyl alcohol
  • SP modified polyvinyl alcohol
  • CS chitosan
  • the performance test results of the composite membrane showed that compared with the pure chitosan membrane, the mechanical strength of the chitosan composite membrane was improved, the elongation at break increased, and the hydrophilicity was enhanced.
  • the cytotoxicity is less than grade 1, and it has potential application prospects as a medical anti-adhesive agent.

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Abstract

本发明公开了一种壳聚糖复合膜的制备方法，该方法包括如下步骤：(1)将聚乙烯醇-124与丁二酸酐反应得到改性聚乙烯醇；(2)将所述改性聚乙烯醇配成0.4wt％水溶液，然后逐滴加入到浓度为0.4wt％壳聚糖的醋酸溶液中得到混合溶液；(3)用0.01wt％的NaOH溶液调节所述混合溶液的pH值至5.5，静置1小时后去除表面气泡，得到铸膜液；(4)将所述铸膜液倒入培养皿中，将所述培养皿置于60℃烘箱中烘干至恒重，得到壳聚糖复合膜。该方法所用的材料价格低廉，反应不复杂，因此产物成本不会太高，作为医用防粘连膜应用容易为多数普通患者接受。

Description

一种壳聚糖复合膜的制备方法 技术领域
本发明涉及一种壳聚糖复合膜的制备方法。
背景技术
外科手术中的组织粘连是常见的现象，也是在术后愈合过程中不可避免的病理生理过程。术后粘连和瘢痕组织的形成会引起腹膜粘连、肌腱粘连、眼眶损伤后软组织粘连、周围神经粘连等严重的并发症，常常阻碍人体的正常康复。在心胸外科、妇产科和骨科手术中，术后粘连是一种常见的现象。到目前为止预防粘连的方法主要有：药物治疗、生物疗法、改进外科手术和采用隔离物等。
壳聚糖是甲壳质脱乙酰基后的产物，是一种天然碱性多糖，具有生物相容性好、抑菌止血、促进组织再生、细胞粘附性强和可生物降解等优点，近年来关于壳聚糖的研究较多，壳聚糖薄膜或凝胶可以有效防止术后粘连的产生，减弱纤维性粘连程度。
近年来，聚电解质复合膜成为新型膜材料的重要组成部分，在相分离、纳滤、水果保鲜及生物医药等领域具有广泛应用。但纯壳聚糖膜性脆、在体液中降解和流失过快，应用受到一定限制。
为了改善壳聚糖膜的性能，本发明提供了一种制备壳聚糖复合膜的方法，用此方法合成得到的复合膜可有效改善纯壳聚糖膜力学性能、延长降解时间的方法。聚乙烯醇(PVA)具有良好的生物相容性和亲水性，是最常见的生物医用材料，可应用于伤口敷料、药物输送]等方面。另外，PVA成膜性好，与CS有良好的相容性，最为突出的优点在于PVA膜具有优异的力学性能。目前PVA与CS复合有两种常见的方法：共混和化学交联。PVA与壳聚糖物理共混后，主要依靠分子间氢键作用形成均相体系，成膜后，在体液中易溶胀溶解，导致膜快速流失，难以起到防粘连的作用。化学交联法制备的PVA与CS复合物，虽能得到性能优良的医用材料，但化学交联剂多为戊二醛等有毒物质，或对人体健康有一定的负面影响。
发明内容
本发明目的是：提供一种壳聚糖复合膜的制备方法，克服纯壳聚糖膜的缺陷，改进其性能以满足用作医用防粘连。
本发明的技术方案是：
一种壳聚糖复合膜的制备方法，该方法包括如下步骤：
(1)将聚乙烯醇-124与丁二酸酐反应得到改性聚乙烯醇；
(2)将所述改性聚乙烯醇配成0.4wt％水溶液，然后逐滴加入到浓度为0.4wt％壳聚糖的醋酸溶液中得到混合溶液；
(3)用0.01wt％的NaOH溶液调节所述混合溶液的pH值至5.5，静置1小时后去除表面气泡，得到铸膜液；和
(4)将所述铸膜液倒入培养皿中，将所述培养皿置于60℃烘箱中烘干至恒重，得到壳聚糖复合膜。
进一步的，步骤(1)中将聚乙烯醇-124与丁二酸酐反应得到改性聚乙烯醇包括：将聚乙烯醇-124溶解在二甲亚砜溶剂中形成20wt％的聚乙烯醇-124溶液，再将丁二酸酐溶解在二甲亚砜溶剂中形成20wt％的丁二酸酐溶液，按照所述丁二酸酐与所述聚乙烯醇-124中-OH的摩尔比分别为1:10、1.25:10、1.6:10、2.0:10、2.5:10计算，将所述丁二酸酐溶液滴加至聚乙烯醇-124溶液内，在75℃的温度下，在800r/min的条件下机械搅拌5小时后停止加热，冷却至室温后，缓慢滴加到过量的含5～10wt％NaOH的乙醇溶液中，产物析出后用乙醇反复洗涤浸泡，50℃真空干燥至恒重后，得到纯净的改性聚乙烯醇并保存，得到5种改性聚乙烯醇，分别命名为SP1、SP2、SP3、SP4、SP5。
进一步的，步骤(2)中所述改性聚乙烯醇分别用SP1、SP2、SP3、SP4、SP5，将其分别配成0.4wt％的水溶液，然后分别滴加到等质量的0.4wt％壳聚糖的醋酸溶液混合制成混合液。
进一步的，步骤(2)中将所述改性聚乙烯醇配成0.4wt％水溶液，然后逐滴加入到浓度为0.4wt％壳聚糖的醋酸溶液中得到混合溶液包括：将所述改性聚乙烯醇溶于去离子水，配制0.4wt％的水溶液，将1wt％醋酸水溶液为溶剂，配制0.4wt％壳聚糖溶液，并用直径为 0.45μm的针头式滤器过滤除去微量不溶杂质，然后将所述水溶液液逐滴加入到过滤后的所述壳聚糖溶液，按速度为1000r/min搅拌混合溶液至均匀。
本发明的优点是：
1.对PVA进行羧基化改性，改性产物与壳聚糖分子间不仅有氢键作用，还有更强的离子键作用，提高了复合膜在模拟体液中的稳定性和力学性能，提供其足够的应用强度，从而达到防粘连的目的。
2.纯粹壳聚糖膜降解太快，容易从伤口部位流失，影响防粘连效果，本发明的壳聚糖复合膜中，由于聚乙烯醇参与薄膜的形成，使壳聚糖降解变缓，延长了阻隔时间，增强了应用效果。
3.本发明所选用的材料PVA和壳聚糖已经被证明生物相容性好，小分子的丁二酸酐与PVA反应、并经过去除未反应的小分子后，所得产物无毒无害，生物相容性好，无细胞毒性，可以满足人体内植入材料的安全性要求。
4.本发明所选用的材料价格低廉，反应不复杂，因此产物成本不会太高，容易为多数普通患者接受。
附图说明
为了更清楚地说明本发明实施例的技术方案，下面将对实施例描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动性的前提下，还可以根据这些附图获得其它的附图。其中，
图1为本发明的一种壳聚糖复合膜的制备方法中的改性聚乙烯醇的红外光谱图；
图2为本发明的一种壳聚糖复合膜的制备方法中的改性聚乙烯醇的核磁共振谱图；
图3为本发明的一种壳聚糖复合膜的制备方法中的聚乙烯醇改性前后的热失重曲线，其中，a为PVA、b为SP1、c为SP2、d 为SP3、e为SP4、f为SP5；
图4为本发明的一种壳聚糖复合膜的制备方法中的0.4wt％的壳聚糖醋酸水溶液与0.4wt％的不同比例改性聚乙烯醇水溶液的等质量混合后所得壳聚糖复合膜的红外图谱；
图5为本发明的一种壳聚糖复合膜的制备方法中的壳聚糖复合膜的热失重曲线，其中，a为CS/SP1、b为CS/SP2、c为CS/SP3、d为CS/SP4、e为CS/SP5；
图6为本发明的一种壳聚糖复合膜的制备方法中的壳聚糖复合膜的接触角；
图7为本发明的一种壳聚糖复合膜的制备方法中的壳聚糖复合膜在生理盐水中的平衡溶胀度；和，
图8为本发明的一种壳聚糖复合膜的制备方法中的壳聚糖复合膜的体外细胞毒性评价3T3细胞显微照片，其中，A为阳性对照组(含0.64％苯酚的RPMI-1640培养基)、B为阴性对照组(RPMI-1640完全培养基)、C和D为实验组(壳聚糖复合膜CS/SP1和CS/SP5浸提液的RPMI-1640培养基)。
具体实施方式
本发明提供一种壳聚糖复合膜的制备方法，包括以下步骤：
(1)将聚乙烯醇-124与丁二酸酐反应得到改性聚乙烯醇；
(2)将所述改性聚乙烯醇配成0.4wt％水溶液，然后逐滴加入到浓度为0.4wt％壳聚糖的醋酸溶液中得到混合溶液；
(3)用0.01wt％的NaOH溶液调节所述混合溶液的pH值至5.5，静置1小时后去除表面气泡，得到铸膜液；和
(4)将所述铸膜液倒入培养皿中，将所述培养皿置于60℃烘箱中烘干至恒重，得到壳聚糖复合膜。
为使本发明的上述目的、特征和优点能够更加明显易懂，下面结合具体实施方式对本发明作进一步详细的说明。
一种壳聚糖复合膜的制备方法，包括：
步骤一：将聚乙烯醇-124与丁二酸酐反应得到改性聚乙烯醇；
在一个实施例中，该步骤可以具体如下执行：将聚乙烯醇-124溶解在二甲亚砜溶剂中形成20wt％的聚乙烯醇-124溶液，再将丁二酸酐溶解在二甲亚砜溶剂中形成20wt％的丁二酸酐溶液，按照所述丁二酸酐与所述聚乙烯醇-124中-OH的摩尔比分别为1:10、1.25:10、1.6:10、2.0:10、2.5:10计算，将所述丁二酸酐溶液滴加至聚乙烯醇-124溶液内，在75℃的温度下，在800r/min的条件下机械搅拌5小时后停止加热，冷却至室温后，缓慢滴加到过量的含5～10wt％NaOH的乙醇溶液中，产物析出后用乙醇反复洗涤浸泡，50℃真空干燥至恒重后，得到纯净的改性聚乙烯醇并保存，得到5种改性聚乙烯醇，分别命名为SP1、SP2、SP3、SP4、SP5。
步骤二：将所述改性聚乙烯醇配成0.4wt％水溶液，然后逐滴加入到浓度为0.4wt％壳聚糖的醋酸溶液中得到混合溶液；
在一个实施例中，该步骤可以具体如下执行：将所述改性聚乙烯醇溶于去离子水，配制0.4wt％的水溶液，将1wt％醋酸水溶液为溶剂，配制0.4wt％壳聚糖溶液，并用直径为0.45μm的针头式滤器过滤除去微量不溶杂质，然后将所述水溶液液逐滴加入到过滤后的所述壳聚糖溶液，按速度为1000r/min搅拌混合溶液至均匀，其中所述改性聚乙烯醇分别用SP1、SP2、SP3、SP4、SP5，将其分别配成0.4wt％的水溶液，然后分别滴加到等质量的0.4w％壳聚糖的醋酸溶液混合制成混合液。
步骤三：用0.01wt％的NaOH溶液调节所述混合溶液的pH值至5.5，静置1小时后去除表面气泡，得到铸膜液；和
步骤四：将所述铸膜液倒入培养皿中，将所述培养皿置于60℃烘箱中烘干至恒重，得到壳聚糖复合膜。
为使本发明的上述目的、特征和优点能够更加明显易懂，下面结合附图和实施例进一步说明本发明的技术方案。但是本发明不限于所列出的实施例，还应包括在本发明所要求的权利范围内其他任何公知的改变。
首先，此处所称的“一个实施例”或“实施例”是指可包含于 本发明至少一个实现方式中的特定特征、结构或特性。在本说明书中不同地方出现的“在一个实施例中”并非均指同一个实施例，也不是单独的或选择性的与其他实施例互相排斥的实施例。
其次，本发明利用结构示意图等进行详细描述，在详述本发明实施例时，为便于说明，示意图会不依一般比例作局部放大，而且所述示意图只是实例，其在此不应限制本发明保护的范围。此外，在实际制作中应包含长度、宽度及深度的三维空间。
另外，本发明中所讲的字母简称，均为本领域固定简称，其中部分字母文解释如下：PVA：聚乙烯醇-124；CS：壳聚糖。
实施例一
改性聚乙烯醇的合成
将聚乙烯醇-124配制成20wt％的二甲亚砜溶液，再将丁二酸酐配制成25wt％的二甲亚砜溶液，按照丁二酸酐与聚乙烯醇中-OH的摩尔比分别为1:10、1.25:10、1.6:10、2.0:10、2.5:10计算，将丁二酸酐溶液滴加至聚乙烯醇溶液内，在75℃的温度下，机械搅拌(800r/min)5小时后停止加热，冷却至室温后，缓慢滴加到过量的含5～10wt％NaOH的乙醇溶液中，产物析出后用乙醇反复洗涤浸泡，50℃真空干燥至恒重后，得到纯净的改性聚乙烯醇并保存。
表1改性聚乙烯醇的合成及分析结果
样品名 丁二酸酐：聚乙烯醇OH(投料摩尔比) 产物中OH转化成COOH(％)
SP1 1.00：10 8
SP2 1.25：10 11
SP3 1.60：10 15
SP4 2.00：10 19
SP5 2.50：10 24
实施例二
改性聚乙烯醇的红外光谱分析
按表1所示配方合成得到改性聚乙烯醇后，采用傅立叶红外光谱仪对其进行红外表征，扫描范围在4000～500cm-1的波数范围内， 分辨率为4cm-1，结果请参阅图1。图1为本发明的一种壳聚糖复合膜的制备方法中的改性聚乙烯醇的红外光谱图，如图1所示，PVA链段中-OH的吸收峰出现在3200～3600cm-1波段，2930cm-1处的特征峰是-CH2的非对称伸缩振动吸收峰，而-CH2的对称弯曲振动吸收峰出现在1450cm-1处。聚乙烯醇经丁二酸酐改性后，在1750cm-1处出现酯键中C＝O的对称伸缩振动峰，在1580cm-1和1408cm-1处出现羧酸盐的特征吸收峰，这表明丁二酸酐已成功修饰PVA。另外，随着丁二酸酐投料量的增加，-OH的吸收峰峰形变宽，强度变强，且向高波数移动，这表明随着丁二酸酐投料的增加，聚乙烯醇羧基化程度增加。
实施例三
改性聚乙烯醇的核磁共振(1H-NMR)分析：
以四甲基硅烷为内标物，氘代DMSO为溶剂，样品浓度约为10mg/ml，使用1H-NMR测试改性聚乙烯醇的结构，请参阅图2，图2为本发明的一种壳聚糖复合膜的制备方法中的改性聚乙烯醇的核磁共振谱图，如图2所示，δ2.50为溶剂DMSO峰，δ3.50为水峰，δ0为TMS峰。从图中可以看到PVA中各质子峰分别为：δ1.10～δ1.70为CH2的质子峰，δ3.70～δ3.97为CH的质子峰，δ4.15～δ4.70为OH的质子峰。PVA经丁二酸酐修饰后，CH的质子峰出现在δ4.80～δ5.20处，δ2.24～δ2.49为丁二酸酐上CH2和CH2质子峰叠加后形成的多重峰，这些峰的出现说明丁二酸酐修饰反应可顺利进行。
实施例四
改性聚乙烯醇的热重分析
请参阅图3，图3为本发明的一种壳聚糖复合膜的制备方法中的聚乙烯醇改性前后的热失重曲线，如图3所示，其给出了聚乙烯醇及改性聚乙烯醇的热重分析表征结果，曲线a、b、c、d、e、f分别是PVA，SP1，SP2，SP3,SP4，SP5的热失重曲线。PVA的失重分为三个阶段：第一阶段是PVA主链的热分解，主要集中在 250～400℃之间；第二阶段是PVA主链降解后残留的端炔基化合物继续降解为碳和烃类，热分解温度始于400℃。与纯PVA的热分解行为相比，丁二酸酐修饰后PVA主链热分解开始的温度下降，第二阶段分解质量增加，且热分解残留质量增加。随着PVA羧基化程度的增加，丁二酸酯基团含量增加，热分解后生成更多的丁二酸和水，使PVA-124主链上的-OH以更不稳定的-OH2+结构存在，促进主链的热降解。
实施例五
壳聚糖复合膜的制备
称取2克壳聚糖(CS，脱乙酰度96.4％)，将其溶解在498毫升1.0wt％的醋酸水溶液中，搅拌均匀，用直径为0.45μm的针头式滤器过滤除去微量不溶杂质；另外将改性聚乙烯醇SP1溶于去离子水，配制0.4wt％的SP1水溶液500毫升；将50克0.4wt％SP1溶液逐滴加入到过滤后的50克0.4wt％壳聚糖溶液中，混合搅拌均匀，然后用0.01wt％的NaOH溶液调节共混溶液的pH至5.5，静置去除表面气泡后，得到铸膜液，将铸膜液倒入12cm×12cm的培养皿中，于60℃烘箱中烘干至恒重，得到复合膜CS/SP1。
分别用SP2、SP3、SP4、SP5代替SP1，其他操作同上，制备其余四种壳聚糖复合膜，命名为：CS/SP2、CS/SP3、CS/SP4、CS/SP5。
实施例六
壳聚糖复合膜的力学性能测试
按照GBT 1040.3-2006标准将复合膜制成2型样条，用电子拉力机对样条进行力学性能测试，测试条件：25℃，RH(空气湿度)50％，拉伸速度5mm/min。
表2壳聚糖复合膜的力学性能
Figure PCTCN2015079963-appb-000001
Figure PCTCN2015079963-appb-000002
实施例七
壳聚糖复合膜的红外光谱测试
取实施例五所得到的壳聚糖复合膜样品CS/SP1、CS/SP2、CS/SP3、CS/SP4、CS/SP5，采用傅立叶红外光谱仪对其进行红外表征，扫描范围在4000～500cm-1的波数范围内，分辨率为4cm-1。请参阅图4，图4为本发明的一种壳聚糖复合膜的制备方法中的0.4wt％的壳聚糖醋酸水溶液与0.4wt％的不同比例改性聚乙烯醇水溶液的等质量混合后所得壳聚糖复合膜的红外图谱，如图4所示，CS与改性PVA复合后，CS的O-H、N-H与酰胺基中C＝O的特征峰及SP的C-O特征峰发生偏移，这与CS与SP分子间存在氢键有关；CS中N-H弯曲振动峰向高波数偏移，与羧酸盐中的C＝O峰重合，说明-NH2以-NH3+形式存在；因此，CS与改性PVA分子中可能存在离子键作用。
实施例八
壳聚糖复合膜的热失重曲线
请参阅图5，图5为本发明的一种壳聚糖复合膜的制备方法中的壳聚糖复合膜的热失重曲线，如图5所示，其给出了CS与SP1、SP3、SP5以1：0.3的质量比混合后，复合膜的热失重曲线。从图中可以看出复合膜的热降解分为两个阶段，在100-195℃温度范围内的热降解是聚电解质离子间脱水引起的；第二阶段是主链降解。各膜的热分解与两组分单独的热分解趋势不一致，说明样品膜形成均匀结构，可以看出随着复合膜中PVA羧基化程度的增加，膜热降解最大速度时的温度由260℃降低至236℃，在550℃时膜热分解残留质量由30.67％增至41.65％，复合膜的热降解速率较为缓和，复合膜仍具有一定的热稳定结构。
实施例九
壳聚糖复合膜的接触角测试
请参阅图6，图6为本发明的一种壳聚糖复合膜的制备方法中的壳聚糖复合膜的接触角，如图6所示，随着壳聚糖复合膜中改性聚乙烯醇含量的增加，水接触角增大，这些现象与聚电解质复合物的生成量增加、亲水基团-NH3+、-COO-、-OH减少有关。因此，可以通过改变复合体系中壳聚糖与改性聚乙烯醇质量比，调控所制复合膜的亲疏水性，从而设计不同亲疏水性能的复合膜，满足对生物膜材料的不同要求。
实施例十
壳聚糖复合膜在生理盐水中的平衡溶胀度测试
将膜剪成大小为3cm×3cm的正方形膜，然后将膜分别浸入到0.9wt％NaCl溶液中，并置于37℃恒温震荡水浴锅中，6h后用滤纸拭去表面水分，称质量，当质量基本不变时溶胀度达到平衡，记平衡溶胀度为S0。平行测定3次，取平均值。平衡溶胀度的计算公式如下：
Figure PCTCN2015079963-appb-000003
m0和mb分别为溶胀前后复合膜的质量(g)
请参阅图7，图7为本发明的一种壳聚糖复合膜的制备方法中的壳聚糖复合膜在生理盐水中的平衡溶胀度。如图7所示，改性聚乙烯醇含量较少时，复合膜溶胀度较大，此时壳聚糖分子链上分布大量带正电荷的-NH3+，分子链间相互排斥，易于伸展，复合膜具有较高的溶胀比；随着复合膜中SP含量的增加，复合膜的溶胀度降低，这可能是因为随着复合膜中改性聚乙烯醇含量的增加，聚电解质复合物生成量增加，复合膜中游离的亲水性基团-NH3+、-COO-减少，从而引起复合膜吸水量下降。当复合膜中CS与改性聚乙烯醇的质量比一定时，随着PVA羧基化程度的增加，复合膜的吸水量减少，这与聚电解质复合物的大量生成有关。
实施例十一
壳聚糖复合膜的体外细胞毒性评价
用MTT法评估复合膜的体外细胞毒性。取对数生长期的3T3细胞，按照每孔2.4×104Cell接种于96孔培养板中，置于37℃、5％CO2培养箱中用含有10％胎牛血清的RPMI-1640培养基(RPMI-1640完全培养基)培养24h后弃去培养基。将6cm2不同的复合膜样品(CS/SP1；CS/SP5)经过高温灭菌后分别置于1ml生理盐水中(37℃)浸提6h、12h、24h、48h，浸提液经RPMI-1640完全培养基稀释至0.1μL/μL，稀释后的浸提液作为样品组。每孔加入100μL RPMI-1640完全培养基、含0.64％苯酚的RPMI-1640培养基、含复合膜浸提液的RPMI-1640完全培养基依次作为阴性对照组、阳性对照组和实验组，每组均设6个复孔，置于37℃、5％CO2培养箱中培养48h后，每孔加入20μLMTT并培养4h。结晶全部溶解后，采用酶联免疫检测仪于570nm测定其吸光度,并计算细胞存活率。
图8是3T3细胞经过各种条件培养处理后的显微照片：A:阳性对照组(含0.64％苯酚的RPMI-1640培养基)；B:阴性对照组(RPMI-1640完全培养基)；C，D:实验组(壳聚糖复合膜CS/SP1和CS/SP5浸提液的RPMI-1640培养基)。
可以看出阳性对照组的细胞几乎完全圆缩死亡，阴性对照组的细胞生长状态良好，细胞核饱满，立体感强，细胞贴壁生长良好，形态正常，这说明复合膜对细胞生长无影响，计算得到的细胞存活率均大于80％，满足体内安全性要求。
综上所述，本发明公开了一种壳聚糖复合膜的制备方法，本方法首先以聚乙烯醇(PVA)为原料，用丁二酸酐与之反应，使聚乙烯醇主链的羟基部分转化成羧基，制备羧基化程度不同的改性聚乙烯醇(SP)；然后以壳聚糖(CS)为基体，将改性聚乙烯醇与壳聚糖通过聚电解质的相互作用复合，采用溶液浇铸法制备了CS与SP壳聚糖复合膜。复合膜性能测试结果表明：与纯壳聚糖膜相比较，壳聚糖复合膜的力学强度提高，断裂伸长率增加，亲水性增强，细 胞毒性小于1级，作为医用防粘剂具有潜在的应用前景。
应说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围，其均应涵盖在本发明的权利要求范围当中。

Claims (4)

  1. 一种壳聚糖复合膜的制备方法，其特征在于，该方法包括如下步骤：
    (1)将聚乙烯醇-124与丁二酸酐反应得到改性聚乙烯醇；
    (2)将所述改性聚乙烯醇配成0.4wt％水溶液，然后逐滴加入到浓度为0.4wt％壳聚糖的醋酸溶液中得到混合溶液；
    (3)用0.01wt％的NaOH溶液调节所述混合溶液的pH值至5.5，静置1小时后去除表面气泡，得到铸膜液；和
    (4)将所述铸膜液倒入培养皿中，将所述培养皿置于60℃烘箱中烘干至恒重，得到壳聚糖复合膜。
  2. 根据权利要求1所述的壳聚糖复合膜的制备方法，其特征在于：步骤(1)中将聚乙烯醇-124与丁二酸酐反应得到改性聚乙烯醇包括：将聚乙烯醇-124溶解在二甲亚砜溶剂中形成20wt％的聚乙烯醇-124溶液，再将丁二酸酐溶解在二甲亚砜溶剂中形成20wt％的丁二酸酐溶液，按照所述丁二酸酐与所述聚乙烯醇-124中-OH的摩尔比分别为1:10、1.25:10、1.6:10、2.0:10、2.5:10计算，将所述丁二酸酐溶液滴加至聚乙烯醇-124溶液内，在75℃的温度下，在800r/min的条件下机械搅拌5小时后停止加热，冷却至室温后，缓慢滴加到过量的含5～10wt％NaOH的乙醇溶液中，产物析出后用乙醇反复洗涤浸泡，50℃真空干燥至恒重后，得到纯净的改性聚乙烯醇并保存，得到5种改性聚乙烯醇，分别命名为SP1、SP2、SP3、SP4、SP5。
  3. 根据权利要求2所述的壳聚糖复合膜的制备方法，其特征在于：所述改性聚乙烯醇分别用SP1、SP2、SP3、SP4、SP5，将其分别配成0.4wt％的水溶液，然后分别滴加到等质量的0.4wt％壳聚糖的醋酸溶液混合制成混合液。
  4. 根据权利要求1所述的壳聚糖复合膜的制备方法，其特征在于，步骤(2)中将所述改性聚乙烯醇配成0.4wt％水溶液，然后逐滴加入到浓度为0.4wt％壳聚糖的醋酸溶液中得到混合溶液包括：将所述改性聚乙烯醇溶于去离子水，配制0.4wt％的水溶液，将1wt％醋酸 水溶液为溶剂，配制0.4wt％壳聚糖溶液，并用直径为0.45μm的针头式滤器过滤除去微量不溶杂质，然后将所述水溶液液逐滴加入到过滤后的所述壳聚糖溶液，按速度为1000r/min搅拌混合溶液至均匀。
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