WO2020087896A1

WO2020087896A1 - Medical degradable polyurethane having antibacterial activity and application thereof

Info

Publication number: WO2020087896A1
Application number: PCT/CN2019/084743
Authority: WO
Inventors: 张文芳
Original assignee: 凯斯蒂南京医疗器械有限公司
Priority date: 2018-10-28
Filing date: 2019-04-28
Publication date: 2020-05-07

Abstract

Disclosed in the present invention are a medical degradable polyurethane having antibacterial activity and an application thereof, particularly, a medical degradable polyurethane containing chitosan or a derivative thereof, a preparation method for the polyurethane, and an application of the polyurethane in implant biological material. Medical degradable polyurethanes having antibacterial activity, different molecular weights and degradation properties can be designed and synthesized according to the requirements of regenerative medicine and medical devices implanted in the body.

Description

Medical degradable polyurethane with antibacterial activity and use thereof

Technical field

The invention belongs to the technical field of degradable biological materials, and in particular relates to a medical degradable polyurethane with antibacterial activity of chitosan or its derivatives and uses thereof.

Background technique

Polyurethane materials are widely used in medical and health care, especially in recent years. Polyurethane materials are widely implanted in patients as medical devices and artificial organs. However, inflammatory reactions often occur after implantation. The infection caused by this situation is usually difficult to rely on traditional antibacterial measures for treatment, causing great pain to the patient and greatly reducing the success rate of surgery. Therefore, research and development of polyurethane materials with excellent antibacterial properties is the majority of scientific research work The goal of the fight. The material is modified by introducing antibacterial groups, and the antibacterial groups of antibacterial agents are introduced into the polyurethane material through physical modification, chemical modification or composite modification, and the purpose of finally maintaining the antibacterial surface of the material is currently commonly used. Research methods.

Many domestic and foreign literature studies have reported that polyurethane materials have good mechanical properties, biocompatibility, blood compatibility and easy processing, etc., in the field of drug sustained-release carriers, medical surgical materials, tissue engineering scaffolds, etc. The promising biodegradable medical material is an excellent component of composite scaffolds. Many domestic and foreign literatures have disclosed solutions for preparing degradable polyurethanes, such as 1,6-hexamethylene diisocyanate (HDI) as the hard segment, polycarbonate diol (PCDL) as the soft segment, and lysine ethyl Polyester synthesized by ester hydrochloride (Lys-OEt) as a chain extender; L-lysine is used as a raw material to convert carboxyl groups on L-lysine to ester groups to synthesize L-lysine di Polyurethane obtained by copolymerizing isocyanate (LDI) with different molecular weight polyethylene glycol (PEG) or hydroxyethylpiperazine (HEP); poly (ε-caprolactone) glycol with molecular weight of 2000 (PCL ) React with LDI to form prepolymer, and then react with chain extender 1,4-butanediol (BDO) to synthesize polyurethane (PU), etc.

More typical patent documents such as 200580014001.0 disclose a degradable polyurethane prepared by one-step method, mainly used to generate polyurethane elastomers with low modulus, and the reaction product is difficult to control, and the molecular weight of the obtained product is wide; general industrial production High-performance polyurethanes mostly use a two-step method. First, polyester or polyether polyol is first reacted with diisocyanate to form a prepolymer, and then diol or diamine chain extension is used to generate polyurethane. The resulting elastomer has a regular molecular structure and mechanical properties. It is better, the repeatability is good, and the product performance is easy to control. For this reason, the present invention uses a two-step method to prepare a high-performance polyurethane with antibacterial properties and controllable elongation at break.

As a natural polymer flocculant, chitosan and its derivatives have been recognized and studied for their bactericidal effect, especially in the field of medicine. The results are different from the changes in environmental conditions. The main reason for the analysis is that the effective gene N of chitosan may be related to lipids and eggs on the bacterial cell membrane. The white matter complex reacts, denatures the protein, changes the permeability of the cell membrane, or forms a negatively charged environment with the bacterial cell wall (especially the gram-positive bacteria cell wall is thick, compact, and rich in phosphoric acid), chitosan The integrity of the cell wall is damaged, or the cell wall tends to dissolve until the cell dies.

The results show that chitosan with a relative molecular weight of 1500 has the strongest inhibitory effect on bacteria and the strongest anti-tumor activity of chitosan hexasaccharide. Chitosan contains hydroxyl and amino groups and can be chemically modified, such as quaternary ammonium groups Grafting, sulfonation, phosphorylation, alkylation, hydroxyethylation, loading of natural active substances, loading of metals or oxides, etc. to change the properties of chitosan, such as the preparation of carboxymethyl chitosan, improve water solubility Sex and bacteriostasis, with good film-forming properties.

Many documents have reported methods of introducing chitosan antibacterial agents into polyurethanes, such as physical modification, chemical modification, and composite modification. Compounds obtained by blending TPU or PUP with chitosan, such as glycerin as a plasticizer The agent and polyurethane prepolymer are modifiers. In the internal mixer, water-soluble chitosan is modified. Another example is the use of surface light grafting to modify chitosan. Synthesis of azide-p-benzoic acid is first carried out. Nitro-p-benzoic acid introduces an azide group into the natural antibacterial agent chitosan and the hydrophilic modifier polyethylene glycol to synthesize azide chitosan and azide polyethylene glycol. Then chitosan and polyethylene glycol were grafted onto polyurethane by light grafting to make the surface of the polyurethane have antibacterial properties and anti-adhesion; there are also reports in the literature on the preparation of chitosan-based water-based by chemical grafting method. Polyurethane resin, but using chitosan or its derivatives as chain extenders, the degradable medical polyurethane prepared by the two-step method has not been reported.

The invention first synthesizes the polyurethane prepolymer through a two-step method, and then directly cross-links with chitosan to obtain a degradable polyurethane with antibacterial effect. This polyurethane has both degradability, good antibacterial properties and better mechanics. Performance and Young's modulus have very broad prospects for application in implanted medical products.

Summary of the invention

The technical problem to be solved by the present invention is to provide a medical degradable polyurethane with antibacterial activity and its use. The polyurethane prepolymer is synthesized by a two-step method, and then cross-linking reaction with chitosan directly to obtain an antibacterial effect. Degradable polyurethane, this polyurethane has both degradability, good antibacterial properties, good mechanical properties and Young's modulus, and has a very broad expected application prospect in implanted medical products.

The invention discloses a medical degradable polyurethane with antibacterial activity, using chitosan or its derivatives as chain extenders, wherein the content of molecular chain fragments of chitosan or its derivatives in the macromolecule of polyurethane is 0.05- 50%.

Among them, the medical degradable polyurethane with antibacterial activity adopts chitosan or its derivatives as chain extenders, and the viscosity average molecular weight range of chitosan is: 1000-200,000, and the molecular chain fragments of chitosan or its derivative components The content in the polyurethane macromolecule is 0.05-30%, and the degree of deacetylation in chitosan or its derivatives is greater than 50%.

The medical degradable polyurethane with antibacterial activity according to the present invention, wherein the soft segment is a polymer formed by polymerizing one or more of GA, LA, PDO, CL and PEG, and the hard segment is selected from diisocyanate, hard The segment is specifically selected from 1,6-hexamethylene diisocyanate, isophorone diisocyanate, and lysine polyisocyanate (which may contain a carboxyl group, or it may be a carboxyl group grafted with a hydroxyl group to form an ester group to form a certain lysine ester di (Isocyanate) or lysine triisocyanate, cis-cyclohexane diisocyanate, trans-cyclohexane diisocyanate, 1,4-butane diisocyanate, butane diisocyanate, 1,2-ethane diisocyanate, 1,3-propane diisocyanate, 4,4'-methylene-bis (cyclohexyl isocyanate), isophorone diisocyanate, 2,4,4-trimethyl 1,6-hexane diisocyanate One or two.

The medical degradable polyurethane with antibacterial activity according to the present invention, wherein the soft segment is one or more than two polymers of GA, LA, PDO, CL and PEG, and the hard segment is selected from isocyanate (diisocyanate or triisocyanate) ), Specifically selected from 1,6-hexamethylene diisocyanate, isophorone diisocyanate, lysine diisocyanate or its carboxyl derivative (such as lysine ester diisocyanate, such as lysine fatty acid Ester diisocyanate, in which the number of carbon atoms of fatty acids is 1-30, such as methyl lysine diisocyanate, ethyl lysine diisocyanate, propyl lysine diisocyanate, butyl lysine diisocyanate, lysine Amino acid 18 fatty acid ester diisocyanate), lysine triisocyanate, 1,4-butane diisocyanate, butane diisocyanate, 1,2-ethane diisocyanate, 1,3-propane diisocyanate Kind or two.

The medical degradable polyurethane with antibacterial activity according to the present invention is prepared by a two-step method to control the degradation time and elastic modulus of polyurethane. The specific preparation method is as follows:

(1) Synthesis of degradable polyurethane with various degradation times and physical properties

The soft segment is selected from one or two polymers of GA, LA, PDO, CL, glycol and PEG (molecular weight 200-2000), and the hard segment is selected from one of diisocyanate or triisocyanate, preferably lysine Acid isocyanate and one of its carboxyl derivatives (such as LDI, LTI), IPDI, HDI or 1,3-propane diisocyanate, the chain extender is selected from chitosan or carboxymethyl chitosan One (viscosity average molecular weight 200-100,000, deacetylation degree greater than 50%), the synthesis scheme is as follows:

Put the soft segment compound or composition and catalyst in the vacuum reaction bottle according to the feeding amount, put it in an oil bath at 70-140 ° C and react for 4-24h to obtain a linear polymer, and then weigh the appropriate proportion of isocyanate to react 0.5 -12h, dissolve with appropriate solvent or directly add chitosan or its derivatives as chain extender, evacuate and seal the bottle mouth, put it in an oil bath at 50-120 ℃ and react for 1-24h to obtain the final product,

(2) The soft segment is selected from PPDO, PCL, PEG, PLA, PGA, PLGA, or any two copolymers or blends thereof, such as PDO and PGA copolymers, PDO and PCL copolymers, PLGA and PCL The copolymer, chain extender is selected from chitosan or its derivatives, the synthesis scheme is as follows:

Anhydrous PPDO (molecular weight 1000-200,000), PEG (molecular weight 200-2000), PCL (molecular weight 1000-200,000), PLA (molecular weight 1000-200,000), PGA (molecular weight 1000-200,000), PLGA (molecular weight 1000-200,000), PDO and PGA copolymer (molecular weight of 1000-200,000) or copolymer of PCL and PDO (molecular weight of 1000-50,000), add the catalyst to the vacuum reaction bottle, add the appropriate proportion of LDI or LTI, Put it in an oil bath at 30-160 ℃ for 4-24h, dissolve it with an appropriate solvent or directly add chitosan or its derivatives, put it in a vacuum reaction bottle, evacuate and seal the bottle mouth, put it in 50-150 Reaction in an oil bath at ℃ for 2-24h to obtain the final product;

Wherein the catalyst is selected from one of stannous octoate, organic zinc or organic bismuth salt, and the dosage is 0.001-10wt% of the total feed amount; the organic solvent is selected from fatty alcohol, DMSO, DMF, 1, 4-di One of oxane, ethyl acetate, ethyl octanoate, n-butanol, isobutanol, xylene and toluene; the diol is selected from glycol or triol, specifically selected from ethylene glycol, Diethylene glycol, tetraethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8- One or two of octanediol, 1,9-nonanediol, 1,10-decanediol, and glycerin.

The medical degradable polyurethane with antibacterial activity according to the present invention, wherein the implanted medical product further includes a contrast agent, the contrast agent is selected from: commonly used radioactive contrast agents (positive and negative contrast agents) and the like , Also includes zirconium, barium, iodine, manganese, iron, lanthanum, cerium, praseodymium, etc. combined or complex form of ionic form, preferably a contrast agent containing barium or iodine, preferably zirconium dioxide, barium sulfate and iodine preparations One kind.

The medical degradable polyurethane with antibacterial activity according to the present invention can be added with therapeutically active substances, such as small molecule compounds, plant extracts, polypeptides, proteins and various medicines, according to clinical needs.

Chitosan or its derivatives in medical degradable polyurethane with antibacterial activity according to the present invention, wherein chitosan derivatives refer to various chemical modifications of the hydroxyl and amino groups in chitosan, specifically including quaternary ammonium groups Polymer compound obtained by modification of grafting, sulfonation, phosphorylation, alkylation, hydroxyethylation, loading of natural active material, loading of metal or oxide.

The chitosan or its derivative in medical degradable polyurethane with antibacterial activity according to the present invention can be used as a drug carrier, and can be directly mixed with drugs after being made into various drug preparations or microspheres according to the conventional preparation process. It can be made into microspheres first, and then loaded with active molecules, active factors, stem cells or drugs during use.

The lysine isocyanate and its carboxyl derivative of the present invention, wherein the lysine diisocyanate may contain a carboxyl group or may be grafted with a compound containing a hydroxyl group to form an ester group, such as lysine methyl ester diisocyanate and lysine Ethyl acid diisocyanate, lysine propyl diisocyanate, lysine butyl diisocyanate, lysine carboxyl and any of the 20 common amino acids to form an ester bond compound, such as lysine arginine, Lysine prolyl ester, lysine tyrosine ester, lysine histidine ester, or lysine triisocyanate, preferably lysine diisocyanate, lysine methyl ester diisocyanate, lysine ethyl ester One of diisocyanate and propyl lysine.

The medical degradable polyurethane with antibacterial activity according to the present invention can be used as a medical material to prepare implants or interventional instruments, the medical implant material can be used alone, and can be compounded with other polymer materials to form a composite, It can be used for implantation equipment and its coating, implantable artificial organ and its coating, contact artificial organ and its coating, stent and its coating, interventional catheter and its coating, artificial skin, tissue engineering stent and The coating materials of organ assisting devices, when used as medical implants or intervention materials, need to be further purified to remove residual toxic monomers, catalysts or organic solvents.

The chitosan or its derivative in medical degradable polyurethane with antibacterial activity according to the present invention can be made into a composite with metal materials or non-metallic materials such as polymer materials, and made by various processes suitable for blood vessels, Vein, esophagus, biliary tract, trachea, bronchus, small intestine, large intestine, urethra, ureter, or other implantable medical device products close to the tubular body channel, such as vascular stent, tracheal stent, bronchial stent, urethral stent, esophageal stent, biliary stent, Ureteral stent (double J tube), ureteral narrow stent, stent for small intestine, stent for large intestine, larynx implant, bypass catheter or ileostomy etc.

Specific applications include: implant equipment, implantable artificial organs, contact artificial organs, stents, interventional catheters, and organ assist devices, including bone plates, nails, bone needles, bone rods, spinal internal fixation equipment, and ligatures , Patella, bone wax, bone repair materials, cerebral aneurysm clips, silver clips, vascular anastomosis clips (plastic), plastic materials, heart or tissue repair materials, intraocular filling materials, birth control rings, nerve patches; implantation Specific artificial organs include: artificial esophagus, artificial blood vessel, artificial vertebral body, artificial joint, artificial urethra, artificial valve, artificial kidney, artificial breast, artificial skull, artificial jaw, artificial heart, artificial tendon, artificial cochlea, artificial anus closure Touch; artificial organs specifically include: artificial larynx, artificial skin, artificial cornea; stent vessels include: stent, prostate stent, biliary stent, esophageal stent and ureteral stent; organ assist devices include: implanted hearing aids, artificial liver Support device; extracorporeal circulation and blood treatment equipment: pump, blood storage filter, micro-embolic filter, blood filter, filter (Ultrafiltration), air bubble remover, pump tube, blood circuit; hemodialysis device, hemodiafiltration device, hemofiltration device, blood purification line, dialysis blood circuit, blood channel plastic pump tube, arteriovenous puncture device, multi-layer Flat-plate dialyzer, hollow fiber dialyzer, hollow fiber filter, adsorber, plasma separator, blood detoxification (perfusion perfusion) device, blood purification extracorporeal circulation blood circuit (pipe), intraoperative autologous blood reinfusion machine; intervention equipment : Intravascular catheters: intravascular contrast catheters, balloon dilatation catheters, central venous catheters, trocar peripheral catheters, micro-floating catheters, arteriovenous pressure measuring catheters; guide wires and sheaths, including: hard guide wires, soft head guides Wire, renal artery guide wire, micro guide wire, push guide wire, ultra-sliding guide wire, arterial sheath, venous vascular sheath, micro-puncture vascular sheath; embolization equipment, including: filters, spring emboli, embolization microspheres, platinum micro Emboli, occluder, intravenous (IV), central venous (CV), vascular access, pulmonary thermal buffer balloon, angiography, angioplasty balloon, urology, special catheter, pacemaker guide Insulation, artificial blood vessels, heart valves, heart assist devices, left ventricular assist devices, intra-aortic balloon counterpulsation, total artificial heart, artificial kidney, hemodialysis, artificial lung, blood oxygen exchanger, blood perfusion, blood filtration, Blood rinsing, artificial pancreas, breast fillings, wound dressings, facial reconstruction materials, surgical adhesives, controlled drug release, artificial tubing, used to enhance the flow and excretion of body fluids, birth control pills, penile prosthesis, etc.

Further: the polyurethane disclosed in this invention with antibacterial activity using chitosan or its derivatives as chain extenders can be made into composite materials with polymer materials according to the physical and chemical performance requirements of implanted medical devices, such as: polylactic acid, Polycaprolactone, polyparadioxanone and its copolymers (PPDO, PLA-PDO) polyparadioxanone (PPDO), polytrimethylene carbonate, polylactic acid-trimethylene carbonate Ester copolymer, polycaprolactone-trimethylene carbonate copolymer, polyglycolic acid, polylactic acid-glycolic acid copolymer, polyether ether ketone, polyvinylpyrrolidone and / or polyethylene glycol, polyvalerolactone, Poly-ε-decalactone, polylactide, polyglycolide, copolymers of polylactide and polyglycolide, poly-ε-caprolactone, polyhydroxybutyric acid, polyhydroxybutyrate, polyhydroxy Valerate, polyhydroxybutyrate-co-valerate, poly (1,4-dioxane-2,3-dione), poly (1,3-dioxane- 2-ketone), polydioxanone, polyanhydrides (such as polymaleic anhydride), polyhydroxymethacrylate, fibrin, polycyanoacrylate, polycaprolactone Methacrylate, poly-β-maleic acid, polycaprolactone butyl acrylate, multi-block polymers from oligomeric caprolactone diol and oligomeric dioxanone diol, poly Ethylene glycol and polybutylene terephthalate)), polypivalolactone, polyglycolic acid trimethyl carbonate, polycaprolactone-glycolide, poly (γ-ethyl glutamate), Poly (DTH-imino carbonate), poly (DTE-co-DT-carbonate), poly (bisphenol A-imino carbonate), polyorthoester, polyglycolic acid trimethyl carbonate, polycarbonate Trimethylester, polyiminocarbonate, poly (N-vinyl) -pyrrolidone, polyvinyl alcohol, polyesteramide, ethanolated polyester, polyphosphate, polyphosphazene, poly [p-carboxyphenoxy) propane ], Polyhydroxyvaleric acid, polyanhydride, polyethylene oxide-propylene oxide, flexible polyurethane, polyurethane with amino acid residues in the main chain, polyether ester (such as polyethylene oxide), polyolefin oxalate, polyortho acid Ester and its copolymers, carrageenan, fibrinogen, starch, collagen, protein-containing polymers, polyamino acids, synthetic polyamino acids, zein, so The biodegradable polymer material has a viscosity average molecular weight of 500 to 1,000,000, preferably a polylactic acid-based material, and more preferably PLGA (LA: GA ratio is 1-3: 1) according to the needs of stent degradation, for example: LA: GA ratio 75:25; 65:35 and 50:50, etc., the polymer viscosity average molecular weight is 50,000-500,000, preferably the polymer viscosity average molecular weight is 50,000-150,000, in order to improve the flexibility of the product, you can also add non-toxic increase Plasticizer, tributyl citrate (TBC), acetyl tributyl citrate (ATBC), trioctyl trimellitate, tri (810) trimellitate, triglyceride trimellitate, homobenzene Tetraoctyl tetraacid, diethylene glycol dibenzoate, diethylene glycol dibenzoate, dipropylene glycol dibenzoate, dioctyl terephthalate, dioctyl terephthalate, sebacic acid One or more of di-n-hexyl acid and epoxy soybean oil.

The polyurethane material with antibacterial activity according to the present invention can be added with commercially available or published polypeptides, proteins and active ingredients, including anti-proliferation, anti-migration, anti-angiogenesis, anti-inflammatory, etc. according to clinical needs. Physiologically active drugs such as sirolimus, everolimus, pimecrolimus, meflandin, ifosfamide, ifosfamide, phentermine, anti-inflammatory, cell growth inhibitory, cytotoxic or antithrombotic Nitrogen mustard, bendamustine, somatostatin, tacrolimus, roxithromycin, daunorubicin, ascomycin, bafaromycin, romustine, cyclophosphamide, estramustine Stin, dacarbazine, erythromycin ethosin, medicin, salinomycin, concanavalin, clarithromycin, oleancin, vinblastine, vincristine, vindesine, vinblastine Repin, etoposide, teniposide, nimustine, carmustine, busulfan, procarbazine, trioxofan, temozolomide, cetepa, doxorubicin, arubicin , Epirubicin, mitoxantrone, idarubicin, bleomycin, mitomycin C, dactinomycin, methotrexate, fludarabine, fludarabine-5′-dihydrophosphate, cladribine, mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine, carbohydrate Betacitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, rosuvastatin, atorvastatin, pravastatin, pitavastatin, dofomycin, cerivastatin, simvastatin Statin, lovastatin, fluvastatin, acridine, irinotecan, topotecan, hydroxyurea, mitifosin, pentostatin, aldesleukin, retinoic acid, asparaginase, perga Parmase, Anatozole, Exemestane, Letrozole, Formestane, Aluminium Lumitide, Bromocriptine, Bromocriptine, Wild Ergoline, Ergoline, Ergoline, Ergoline , Ergot toxin, ergot alkaloids, ergot alkaloids, ergot alkaloids, ergotamine, ergot isamine, ergot waring, ergot isconiline, ergot cryptotin, ergocryptine, ergot alkaloids, ergot Nitrile, ergocarbazide, ergosterol, lysergic acid, doxorubicin, azithromycin, spiramycin, cefaxam, 8-α-ergoline, di Ergoline, ergot alkaloids, 1-allyl ergot urea, 1-allyl tert ergot urea, lysergic acid amide, lysergic acid diethylamine, isolysergic acid, isolysergic acid amide, isolysergic acid diethylamine , Messergide, thalidomide, (5-isoquinolinesulfonyl) homopiperazine, cyclosporine, smooth muscle cell proliferation inhibitor 2ω, ergot benzyl ester, methyl ergot alkaloid, dimethyl ergot alkaloid , Pergolide, ergocarbazone and tergolyst, celecoxib, epothilone A and B, mitoxantrone, azathioprine, mycophenolate mofetil, antisense c-myc, antisense b- myc, betulinic acid, camptothecin, muscarinic acid, melanocyte promoting hormone, active protein C, interleukin 1-β-inhibitor, β-lapaquinone, podophyllotoxin, betulin, ghost 2-ethylhydrazine of acetic acid, moraztim, pegylated interferon alpha-2b, lengrastim, filgrastim, dacarbazine, baliximab, daclizumab, Selectin, cholesterol ester transporter inhibitors, cadherins, cytokine inhibitors, cyclooxygenase-2 inhibitors, thymosin α-1, fumaric acid and its esters, calcipotriol, Carboxyl alcohol, Lappaol, Nuclear factor kB, Angiopeptin, Ciprofloxacin, Fluoxetine, Monoclonal antibody to inhibit muscle cell proliferation, Bovine basic fibroblast growth factor antagonist, Probucol, Prostate Element, 1,11-dimethoxycoumarin-6-one, 1-hydroxy-11-methoxycoumarin-6-one, scopolamine, colchicine, nitric oxide donor, Tamoxifen, phosphoestrol, medroxyprogesterone, estradiol cypionate, estradiol benzoate, tranilast, verapamil, staurosporine, β-estradiol, α- Estradiol, estriol, estrone, ethinylestradiol, tyrosine kinase inhibitors, cyclosporine A, paclitaxel and their derivatives, synthetic and tricarbon dioxide macrocyclic oligomers obtained from natural sources And its derivatives, monobuprofen, acetophenone, diclofenac, clonazoic acid, dapsone, o-carbamoyl-phenoxy-acetic acid, lidocaine, ketoprofen, mefenamic acid , Oncostatin, Avastin, Hydroxychloroquine, Auranofin, Sodium gold thiosuccinate, Oxaciro, Celecoxib, β-sitosterol, Adenosylmethionine, Metecaine, Poly B2 Monododecyl ether, vanillylnonamide, levomenthol, benzocaine, aescin, alite, colchicine, cytochalasin AE, indanocine, nocodazole, pyridoxine Roxicam, Meloxicam, chloroquine phosphate, penicillamine, S100 protein, subtilisin, vitreous binding protein receptor antagonists, azelastine, guanidinyl cyclase stimulator, metalloproteinase 1 and 2 tissue inhibitors , Free nucleic acid, nucleic acid incorporated into viral transmitters, deoxyribonucleic acid and ribonucleic acid fragments, plasminogen activator inhibitor 1, plasminogen activator inhibitor 2, antisense oligonucleotide, vascular endothelial growth Factor inhibitors, insulin-like growth factor 1, active agents from the antibiotic group, penicillins, antithrombotic agents, desulfurization and N-reacetylated heparin, tissue plasminogen activator, GpIIb / IIIa platelet membrane receptors , Factor Xa inhibitor antibody, heparin, hirudin, r-hirudin, D-phenylalanine-proline-arginine-chloromethanone (D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone) , Acetylcholinesterase inhibitor, thioprotease inhibitor Agents, prostacyclin, valprost, interferon alpha, beta and gamma, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators, protamine, 2-methyl Sodium salt of thiazolidine-2,4-dicarboxylic acid, prourokinase, streptokinase, warfarin, and urokinase, vasodilators, platelet-derived growth factor antagonists, brocloquantel, nifedipine, fertility Phenols, vitamins B1, B2, B6 and B12, folic acid, modomin, tea polyphenols, epicatechin gallate, gallate catechin gallate, leflunomide, anakinra, ena Cipro, procainamide, retinoic acid, quinidine, pyripramine, pyripramine, flecainide, propafenone, sotalol, amiodarone, natural or synthetic steroids, betulin Mycosin, Maguire glycoside A, sulfasalazine, etoproside, triamcinolone, episporomycin, eosin, mansolin, quesinin, hydrocortisone acetate, beta Misong, dexamethasone, non-steroidal anti-inflammatory substances, antifungal drugs, antiprotozoal agents, natural terpenoids, 4, 7- Base ring parsnip oxalic acid, dryland chrysanthemum terpene B1, B2, B3 and B7, earth fritillin saponin, dysentery cholecystokinin A, B and C, anti-dysentery cholecystein C, bruceiside N and P, isodeoxy Dichokinin, chrysophanolide A and B, glyceryl theophylline A, B, C and D, carrageenin A and B, bismuth chloride chloride, 12-β-hydroxypregnane diene- 3,20-Diketone, Castanosporin B, Huanghuacainin C, Pseudochaetenyl terpene, Total order safflower terpenes A and B, Taxus A and B, Raconol), Tripterygium lactone, ursolic acid, glycyrrhizic acid A, isogermanial irisaldehyde, variegated maytansinol, guanqiuweisu A, magnetoside, trigolin, aristolochic acid, aminopterin , Hydroxamine, Pulsatilla, Protocursin, Berberine, Cerberin Chloride, Poisonous Toxin, Tetrandrine, Cudrania Isoflavone A, Curcuma, Dihydroacupuncture, Ginkgo Biloba, Ginkgo Biloba, Ginkgo acid and the like, and salts, hydrates, solvates, enantiomers, racemic compounds, enantiomeric mixtures, diastereomeric mixtures, and mixtures thereof of the above active agents.

detailed description

In order to make the technical problems, technical solutions and advantages to be solved by the present invention clearer, the following will describe in detail with reference to specific embodiments.

Option 1: Synthesis of degradable polyurethanes with multiple degradation times and elastic modulus

Note: The raw materials used in this example are processed in advance to a moisture content of less than 100 ppm and are ready for use.

Example:

Option 1: Weigh 1g 1.3-propanediol and 59g CL into the test tube, add a drop of T-9 (0.01-0.1wt%) as a catalyst, then add a magnetic stirrer, vacuum / nitrogen cycle 3 At the same time, the tube mouth was sealed under vacuum and placed in an oil bath at 120-140 ° C for 24 hours to obtain a linear polymer. Then weigh 7g L-lysine methyl ester diisocyanate and 5g chitosan (molecular weight 2000-10000), put into a test tube, evacuate and seal the tube. Place in an oil bath at 70-90 ° C for 4-6h to obtain the final product. (The resulting product: molecular weight between 50,000 and 60,000, Young's modulus is large, and the elasticity is poor)

Option 2: Weigh 1g 1.3-propylene glycol and 35g CL into test tubes, add one drop of T-9 (0.1-0.6wt%) as a catalyst, and then add a magnetic stirrer, vacuum / nitrogen filling cycle 3 At the same time, the tube mouth was sealed under vacuum and placed in an oil bath at 110-140 ° C for 18-24 hours to obtain a linear polymer. Then weigh 5.7g L-lysine ethyl ester diisocyanate and 2.4g chitosan (molecular weight 5000-20000), put into a test tube, evacuate and seal the tube. Put it in an oil bath at 70-80 ° C for 3-5 hours to obtain the final product. (Product obtained: molecular weight between 60,000 and 90,000, Young's modulus is relatively large, and elasticity is average)

Scheme 3: Weigh 1g PEG200 and 19g CL respectively into a test tube, add a drop of T-9 (0.01-0.05wt%) as a catalyst, then add a magnetic stir bar, evacuate / nitrogen cycle 3 times, and The test tube mouth was sealed under vacuum, placed in a 140 ° C oil bath and reacted for 24 hours to obtain a linear polymer. Then weigh 5.8g L-lysine diisocyanate and 1.9g chitosan (molecular weight 10000-12000), put into a test tube, evacuate and seal the tube. Put in an oil bath at 70 ° C for 4h to obtain the final product. (The resulting product: molecular weight of 90,000-140,000, Young's modulus is large, and elasticity is good)

Scheme 4: Weigh 1g GA and 26g CL respectively into a test tube, add a drop of T-9 (0.01-0.05wt%) as a catalyst, and then add a magnetic stirrer, vacuum / nitrogen cycle 3 times, And the tube mouth was fusion-sealed under vacuum, placed in an oil bath at 130-140 ℃ for 24 hours to obtain linear polymer. Then weigh 1g L-lysine diisocyanate and 0.2g chitosan (molecular weight 50000-72000), put into a test tube, evacuate and seal the tube. Put it in an oil bath at 70-100 ℃ for 2-4h to get the final product. (The resulting product: molecular weight of 12-15 million, with high mechanical properties and Young's modulus)

Scheme 5: Weigh 1g PPDO (molecular weight 3000-5000) and 10 grams CL in a test tube, add a drop of T-9 (0.001-0.005wt%) as a catalyst, then add a magnetic stirrer, vacuum / charge Nitrogen was circulated 3 times, and the mouth of the test tube was sealed under vacuum and placed in an oil bath at 120-140 ° C for 18-24 hours to obtain a linear polymer. Weigh 3.7g L-lysine diisocyanate and 1.5g chitosan (molecular weight 1000-3000), put it in a test tube, evacuate and seal the tube. Put in an oil bath at 70 ° C for 4h to obtain the final product. (Product obtained: molecular weight between 50,000 and 60,000, Young's modulus is average, and elasticity is average)

Scheme 6: Weigh 0.1g 1.3-propanediol and 19g GA, 10g LA into a test tube, add a drop of T-9 (0.003-0.008wt%) as a catalyst, then add a magnetic stirrer, vacuum / Nitrogen-filled cycle 3 times, and seal the test tube mouth under vacuum, put it in an oil bath at 110-130 ° C and react for 18-24h to obtain linear polymer. Then weigh 2.7g L-lysine diisocyanate and 0.1g chitosan (molecular weight 5000-10000), put into a test tube, evacuate and seal the tube. Put it in an oil bath at 70-100 ℃ for 2-4h to get the final product. (Product obtained: molecular weight between 60,000 and 70,000, Young's modulus is average, elasticity is average)

Scheme 7: Weigh 0.01g 1.3-propylene glycol and 1.4g CL and 9g PDO into the test tube, add a drop of T-9 (0.01-0.1wt%) as a catalyst, then add a magnetic stirrer, vacuum / Nitrogen-filled cycle 3 times, and the tube mouth was sealed under vacuum, placed in an oil bath at 130-140 ° C and reacted for 15-24h to obtain a linear polymer. Then weigh 10g L-lysine diisocyanate and 3g carboxymethyl chitosan (molecular weight 5000-10000), put into a test tube, evacuate and seal the tube. Put in an oil bath at 70-90 ° C for 4-6h to obtain the final product. (Product obtained: molecular weight between 70,000 and 90,000, Young's modulus is average, and elasticity is better)

Scheme 8: Weigh 1gGA and 39g CL respectively into a test tube, dropwise add stannous octoate (0.01-0.5wt%) as a catalyst, then add a magnetic stir bar, evacuate / nitrogen cycle 3 times, and Under vacuum conditions, the test tube mouth was fusion-sealed and placed in an oil bath at 12-140 ° C for 24-36 hours to obtain linear polymer. Then weigh 9g L-lysine diisocyanate and 1.5g chitosan (molecular weight 100,000-120,000), put into a test tube, evacuate and seal the tube. Put in an oil bath at 70 ° C for 4h to obtain the final product. (Products obtained: molecular weights of 21-270,000, Young's modulus is average, and elasticity is better)

Scheme 9: Weigh 1g 1.3-propylene glycol and 65g CL in a test tube respectively, add stannous octoate (0.01-0.1wt%) as a catalyst, and then add a magnetic stirrer, vacuum / nitrogen-filled cycle 3 times , And seal the test tube mouth under vacuum, put it in a 140 ℃ oil bath and react for 24h to obtain linear polymer. Then weigh 6gIPDI and 5g chitosan (molecular weight 150,000-200,000), put into a test tube, evacuate and seal the tube. Place in an oil bath at 70-120 ° C for 4-8h to obtain the final product. (The resulting product: molecular weight of 350,000 to 500,000, Young's modulus is large, elasticity is poor)

Scheme 10: Weigh 1g 1.3-propylene glycol and 59g CL in a test tube, add a drop of T-9 (0.001-0.1wt%) as a catalyst, and then add a magnetic stirrer, vacuum / nitrogen cycle 3 At the same time, the test tube mouth was sealed under vacuum and placed in a 140 ° C oil bath for 24 hours to obtain linear polymer. Then weigh 6g HDI and 0.4g chitosan (molecular weight 2000-5000), put into a test tube, evacuate and seal the tube. Put it in a 70 ° C oil bath for 4-8h to get the final product. (Product obtained: molecular weight between 60,000 and 70,000, Young's modulus is relatively large, and elasticity is average)

Scheme 11: Weigh 1g 1.3-propylene glycol, 15g PLGA and 39g CL in a test tube, add a drop of T-9 (0.00-0.1wt%) as a catalyst, then add a magnetic stirrer, vacuum / Nitrogen filling was circulated three times, and the mouth of the test tube was fusion-sealed under vacuum, placed in a 140 ° C oil bath and reacted for 24 hours to obtain a linear polymer. Then weigh 6g LTI and 1.3g chitosan (molecular weight 50,000-70,000), put into a test tube, evacuate and seal the tube. Put in an oil bath at 70 ° C for 4h to obtain the final product. (Product obtained: molecular weight between 170,000 and 200,000, Young's modulus is large and elasticity is good)

Scheme 12: Weigh 1g of PDO and 59g of CL respectively into a test tube, add a drop of T-9 (0.001-0.1wt%) as a catalyst, and then add a magnetic stirrer, vacuum / nitrogen cycle 3 times, And the tube mouth was fusion-sealed under the condition of evacuation, placed in an oil bath at 140 ℃ for 24 hours to obtain linear polymer. Then weigh 4.5g BDI and 3.5g chitosan (viscosity average molecular weight 30000-50000), put into a test tube, evacuate and seal the tube. Put in an oil bath at 70 ° C for 4h to obtain the final product. (Products obtained: molecular weights between 130,000 and 150,000, Young's modulus is relatively large, and elasticity is average)

Scheme 13: Weigh 1g of 1.3-propanediol and 39g of PDO into a test tube, add a drop of T-9 (0.01-0.1wt%) as a catalyst, and then add a magnetic stirrer, vacuum / nitrogen cycle At the same time, the test tube mouth was sealed under vacuum and placed in an oil bath at 120-140 ° C for 18-24 hours to obtain a linear polymer. Weigh 5gH ₁₂ MDI and 1.5g chitosan again, put it in a test tube, evacuate and seal the tube. Put it in an oil bath at 70-90 ℃ for 4-8h to get the final product. (The resulting product: molecular weight of 15-16 million, Young's modulus is relatively large, the elasticity is generally)

Scheme 14: Weigh 5gGA and 0.1gPEG400 respectively into a test tube, dropwise add stannous octoate (0.001-0.1wt%) as a catalyst, then add a magnetic stir bar, evacuate / nitrogen cycle 3 times, and pump The test tube mouth was sealed under vacuum and placed in an oil bath at 140 ° C for 24 hours to obtain a linear polymer. Weigh 2gLTI and 0.3g chitosan again, put it in a test tube, evacuate and seal the tube. Put it in an oil bath at 70-90 ℃ for 4-8h to get the final product. (The resulting product: molecular weight of 70,000 to 110, 000, Young's modulus is large, and the elasticity is good)

Example 15

Weigh 1gLA, 9gGA, 1g1, 3 propylene glycol, stannous octoate (0.03wt% of the total) as a catalyst, then add a magnetic stir bar, vacuum / nitrogen cycle 3 times, and seal under vacuum. Test tube mouth, put in an oil bath at 110 ℃ for 12 hours to obtain linear polymer, weigh 3g L-lysine ethyl ester diisocyanate and 0.6g carboxymethyl chitosan (molecular weight 50,000-70,000), put Into a vacuum reaction bottle, evacuation / nitrogen filling cycle 3 times to evacuate and seal the bottle mouth, put in an oil bath at 70 ℃ for 4h to obtain the final product (the resulting product: molecular weight of 15-190000, Young's mold Larger volume, better elasticity)

Example 16

Weigh 10g poly (hexamethylene carbonate) glycol (viscosity average molecular weight 2000-3000), organic bismuth salt (0.05wt% of the total) as a catalyst, then add a magnetic stir bar, 130 ℃ oil bath React for 12h in the pot, weigh 3g of L-lysine propyl diisocyanate into a vacuum reaction bottle, evacuate / nitrogen cycle 3 times to evacuate and seal the bottle mouth, and react in an oil bath at 80-100 ℃ 2 -4 hours, add 0.6g of chitosan (molecular weight of 3-50000) and put it in an oil bath at 110 ° C for 12-18h. Take the vacuum reaction flask and cool to room temperature to obtain the final product (the resulting product: molecular weight is 13 -15 million, Young's modulus is larger and elasticity is better).

Example 17

Weigh GA (8g), LA (12g) and BDO (0.8g), dry in a vacuum reaction bottle at 80 ℃ high vacuum dehydration, 140-150 ℃ 24-36h to stop the reaction, add LDI (8.8g) and caprylic acid Stannous (0.02wt% of total amount) reacted at room temperature for 2-4h, added 20ml DMF to dissolve the material, added 2g chitosan (molecular weight 50,000-70,000), heated to 50-70 ℃ and reacted for 4-8h . (The resulting product: molecular weight of 200,000-250,000, Young's modulus is large, and elasticity is good).

Examples of the application and test of antibacterial polyurethane developed by the present invention are as follows:

1. Preparation of microspheres

The medical degradable polyurethane developed with the antibacterial activity developed by the method disclosed by the present invention can be used as a drug carrier, can be directly mixed with drugs and prepared into various drug preparations or microspheres according to conventional preparation processes, and can also be used to make micro The medicine is attached after the ball, and the preparation process and scheme are as follows:

1. Preparation of antibacterial microspheres:

The preparation process can be as follows:

The polyurethane material of the present invention is dissolved in an organic solvent (such as ethyl acetate, dichloromethane or chloroform solution), and the formulated concentration is 1-30%. Take 1 portion and slowly add a dispersant such as carboxymethyl chitosan solution In 5-20 parts of (0.1-5%), PVA (0.1-5% solution) or its salt solution, stir to evaporate the organic solvent to form microspheres, and obtain microspheres with uniform particle size after sieving and filtration.

The microspheres are repeatedly washed with water for injection, and an appropriate amount of excipient is added to obtain the filled microspheres that can be injected.

2. Preparation of drug-loaded microspheres

Take the polyurethane material of the present invention and paclitaxel (the weight percentage with the polyurethane material is 0.01: 0.1-50) dissolved in an organic solvent (such as ethyl acetate, dichloromethane or chloroform solution), the formulated concentration is: 1-30%, Take 1 part and slowly add a dispersant such as carboxymethyl chitosan solution (0.1-5%), small molecule chitosan acid solution, PVA (0.1-5% solution) or its salt solution, 5-20 parts, The volatile organic solvent was stirred to form microspheres, and after screening and filtering, a sustained-release microsphere with paclitaxel loaded with uniform particle size was obtained.

2. Preparation of antibacterial coating:

The antibacterial and anti-adhesion coating for the long-term indwelling central venous catheter is prepared as follows:

The antibacterial polyurethane material in Examples 1, 2 or 10 of the present invention is formulated with an organic solvent (preferably one of ethyl acetate, dichloromethane or chloroform) into a 0.1-10% solution, sprayed or dipped in Insert the vein indwelling part, dry it and polish it.

3. Antibacterial antithrombotic coating of vascular stent graft

The preparation process is as follows:

(1) Weave, engrave, etch or cut the degradable metal materials into the required patterns or slats, the diameter of the bracket is 1mm and the length is 2cm;

(2) Polish the scaffold prepared in (1), soak it in 30% hydrofluoric acid by mass for 15 min, wash it with 75% ethanol, and dry it;

(3) Dissolve the polymer (polyurethane obtained in Example 2) in chloroform solvent, dip or spray on the bracket;

(4) The composite material prepared in (3) is dipped or sprayed with a hydrophilic coating (such as an aqueous solution made of chitosan, hyaluronic acid, collagen, cellulose, etc.), dried, polished, and polished. Into a stent graft.

4. Using 3D printing technology to prepare porous bionic antibacterial bone filling material

A 3D printer with two feeding devices is selected, one feeding device is added with PMMA (powder particle size 30-80um) bone cement mixed solution, and the other feeding device is added with the composite material of antibacterial polyurethane material and PVP of the present invention. Chloroform is configured as a solution with a percentage concentration of 10-30%), print out the stent of the set size and shape, wash it with water for injection and dry it.

5. Experimental study on the properties and degradation of materials prepared by different experimental examples

Example 29 The polyurethane obtained by the above reaction was dissolved with chloroform, laid into a 0.5 mm thick film, cut into a 1 cm × 5 cm film block, tested for fracture productivity and simultaneously placed in PBS solution, incubated at 37 degrees, and observed degradation experiments , The results are as follows:

6. This example provides the antibacterial application effects of the materials obtained in Examples 1 to 3.

After the materials obtained in 1 to 3 in this example were sterilized with ethylene oxide, 2 g was placed in 50 ml of PBS solution, incubated at 37 ° C for 15 days, and set aside.

Escherichia coli (8099) and Staphylococcus aureus (ATCC 6538) were used as representative strains of Gram-negative and Gram-positive bacteria, and the antibacterial effect of the samples was determined by the absorption method. The bacteria were inoculated in nutrient broth and cultured at 37 ° C for 24 hours. The concentration of the bacterial solution was adjusted to the usual concentration. 0.1 ml of bacterial solution was inoculated into the PBS solution of the degraded material and incubated at 37 ° C for 24 hours. After that, 20 ml of soybean casein digested lecithin polysorbate (SCDLP) medium was added to rinse the sample, and the number of bacteria was counted by the plate counting method. Use pure cotton gauze as a control sample. According to the equation to determine the bacteriostatic value, it can be seen from the experimental results that the antibacterial material prepared by the present invention has a good antibacterial effect.

The antibacterial effects of the materials obtained in Examples 1 to 3 are as follows:

The above is the preferred embodiment of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principles of the present invention, several changes, improvements, modifications, retouching and In combination, these improvements and retouches should also be considered as the scope of protection of the present invention.

Claims

A medical degradable polyurethane with antibacterial activity, characterized in that chitosan or its derivatives are used as chain extenders, wherein the content of molecular chain fragments of chitosan or its derivatives in the polyurethane macromolecule is 0.05- 50%.
The medical degradable polyurethane with antibacterial activity according to claim 1, characterized in that chitosan or its derivatives are used as chain extenders, and the viscosity average molecular weight range of chitosan is: 1000-20 million, chitosan The content of molecular chain fragments of its derivative components in the polyurethane macromolecule is 0.05-30%, and the degree of deacetylation in chitosan or its derivatives is greater than 50%.
The medical degradable polyurethane with antibacterial activity according to claim 1 or 2, characterized in that the soft segment is a polymer obtained by polymerizing one or more of GA, LA, PDO, CL and PEG, hard The segment is selected from diisocyanates, specifically selected from 1,6-hexamethylene diisocyanate, isophorone diisocyanate, lysine diisocyanate, lysine triisocyanate, cis-cyclohexane diisocyanate, trans -Cyclohexane diisocyanate, 1,4-butane diisocyanate, butane diisocyanate, 1,2-ethane diisocyanate, 1,3-propane diisocyanate, 4,4'-methylene-bis (cyclo One or both of hexyl isocyanate), isophorone diisocyanate, and 2,4,4-trimethyl 1,6-hexane diisocyanate.
The medical degradable polyurethane with antibacterial activity according to claim 1 or 2, wherein the soft segment is one or more than two polymers of GA, LA, PDO, CL and PEG, and the hard segment is selected from Isocyanate (diisocyanate or triisocyanate), specifically selected from 1,6-hexamethylene diisocyanate, isophorone diisocyanate, lysine diisocyanate or its carboxyl derivative (such as lysine ester diisocyanate , Such as lysine fatty acid ester diisocyanate, wherein the number of carbon atoms of fatty acids is 1-30, specifically such as lysine methyl ester diisocyanate, lysine ethyl ester diisocyanate, lysine propyl ester diisocyanate, lysine Butyric acid diisocyanate, lysine stearyl fatty acid diisocyanate), lysine triisocyanate, 1,4-butane diisocyanate, butane diisocyanate, 1,2-ethane diisocyanate, 1,3 -One or two of propane diisocyanate.
The medical degradable polyurethane with antibacterial activity according to claim 1 or 2, characterized in that, in order to control the degradation time and elastic modulus of the polyurethane, a two-step method is used for preparation, the specific preparation method is as follows:

(1) Synthesis of degradable polyurethane with various degradation times and physical properties

The soft segment is selected from one or two polymers of GA, LA, PDO, CL, glycol and PEG (molecular weight 200-2000), and the hard segment is selected from one of diisocyanate or triisocyanate, preferably lysine One of acid isocyanate and its carboxyl derivative (such as LDI, LTI), IPDI, HDI or 1,3-propane diisocyanate, the chain extender is specifically selected from chitosan or carboxymethyl chitosan One (viscosity average molecular weight 200-100,000, deacetylation degree greater than 50%), the synthesis scheme is as follows:

Put the soft segment compound or composition and catalyst in the vacuum reaction bottle according to the feeding amount, put it in an oil bath at 70-140 ° C and react for 4-24h to obtain a linear polymer, and then weigh the appropriate proportion of isocyanate to react 0.5 -12h, dissolve with appropriate solvent or directly add chitosan or its derivatives as chain extender, evacuate and seal the bottle mouth, put it in an oil bath at 50-120 ℃ and react for 1-24h to obtain the final product,

(2) The soft segment is selected from PPDO, PCL, PEG, PLA, PGA, PLGA, or any two copolymers or blends thereof, such as PDO and PGA copolymers, PDO and PCL copolymers, PLGA and PCL The copolymer, chain extender is selected from chitosan or its derivatives, the synthesis scheme is as follows:

Anhydrous PPDO (molecular weight 1000-200,000), PEG (molecular weight 200-2000), PCL (molecular weight 1000-200,000), PLA (molecular weight 1000-200,000), PGA (molecular weight 1000-200,000), PLGA (molecular weight 1000-200,000), PDO and PGA copolymer (molecular weight of 1000-200,000) or copolymer of PCL and PDO (molecular weight of 1000-50,000), add the catalyst to the vacuum reaction bottle, add the appropriate proportion of LDI or LTI, Put it in an oil bath at 30-160 ℃ for 4-24h, dissolve it with an appropriate solvent or directly add chitosan or its derivatives, put it in a vacuum reaction bottle, evacuate and seal the bottle mouth, put it in 50-150 Reaction in an oil bath at ℃ for 2-24h to obtain the final product;

The catalyst is selected from one of stannous octoate, organic zinc or organic bismuth salt, and the dosage is 0.001-10wt% of the total feed amount; the organic solvent is selected from fatty alcohol, DMSO, DMF, 1, 4-diox One of hexacyclic, ethyl acetate, ethyl octanoate, n-butanol, isobutanol, xylene and toluene; the diol is selected from glycol or triol, specifically selected from ethylene glycol, dihydric alcohol Glycol, tetraethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octane One or two of diol, 1,9-nonanediol, 1,10-decanediol, and glycerin.
The medical degradable polyurethane with antibacterial activity according to claim 1 or 2, characterized in that it can be used as a medical implant material to prepare implant or interventional instruments, the medical implant material can be used alone, and can be compounded with other polymers The materials are blended into a composite, which can be used for implantation equipment and its coating, implantable artificial organ and its coating, contact artificial organ and its coating, stent and its coating, interventional catheter and its coating The coating materials of layers, artificial skin, tissue engineering scaffolds and organ assist devices, when used as medical implant or intervention materials, need to be further purified to remove residual toxic monomers, catalysts or organic solvents.
The medical degradable polyurethane with antibacterial activity according to claim 6, wherein the medical implant material includes a contrast agent, the contrast agent is selected from common radioactive contrast agents and the like, and further includes zirconium and barium , Iodine, manganese, iron, lanthanum, cerium, praseodymium, and other ionic forms in the form of combination or complexation.
The medical degradable polyurethane with antibacterial activity according to claim 1 or 2, characterized in that an active substance having a therapeutic effect is added to the medical degradable polyurethane, and the active substance includes small molecule compounds and plant extracts , Peptides, proteins and various drugs.
The medical degradable polyurethane with antibacterial activity according to claim 1, characterized in that the chitosan derivative means that the hydroxyl and amino groups in the chitosan undergo various chemical modifications, specifically including quaternary ammonium group grafting , Sulfonation, phosphorylation, alkylation, hydroxyethylation, loaded with natural active substances, loaded with metal or oxide modified polymer compound.
The use of a medical degradable polyurethane with antibacterial activity is characterized in that it can be used as a drug carrier, can be directly mixed with drugs, and can be made into various drug preparations or microspheres according to the conventional preparation process, or it can be made into microspheres first. Afterwards, active molecules, active factors, stem cells or drugs are attached during use.