CN109485747A - Water-soluble chitosan antibacterial derivative and preparation method thereof - Google Patents
Water-soluble chitosan antibacterial derivative and preparation method thereof Download PDFInfo
- Publication number
- CN109485747A CN109485747A CN201710817411.3A CN201710817411A CN109485747A CN 109485747 A CN109485747 A CN 109485747A CN 201710817411 A CN201710817411 A CN 201710817411A CN 109485747 A CN109485747 A CN 109485747A
- Authority
- CN
- China
- Prior art keywords
- chitosan
- monomethyl ether
- glycol monomethyl
- polyethylene glycol
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229920001661 Chitosan Polymers 0.000 title claims abstract description 146
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 230000000844 anti-bacterial effect Effects 0.000 title abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 76
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 41
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 41
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims abstract description 32
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine group Chemical group NC(=N)N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims abstract description 23
- 230000001588 bifunctional effect Effects 0.000 claims abstract description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 4
- 230000003115 biocidal effect Effects 0.000 claims description 44
- 239000000126 substance Substances 0.000 claims description 25
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 19
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 15
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000000502 dialysis Methods 0.000 claims description 14
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 11
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 10
- 239000008367 deionised water Substances 0.000 claims description 10
- 229910021641 deionized water Inorganic materials 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- 229920000151 polyglycol Polymers 0.000 claims description 5
- 239000010695 polyglycol Substances 0.000 claims description 5
- SXGZJKUKBWWHRA-UHFFFAOYSA-N 2-(N-morpholiniumyl)ethanesulfonate Chemical compound [O-]S(=O)(=O)CC[NH+]1CCOCC1 SXGZJKUKBWWHRA-UHFFFAOYSA-N 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 230000004913 activation Effects 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 238000005057 refrigeration Methods 0.000 claims description 2
- 238000009777 vacuum freeze-drying Methods 0.000 claims description 2
- 239000007853 buffer solution Substances 0.000 claims 3
- 150000004676 glycans Chemical class 0.000 abstract description 3
- 229920001282 polysaccharide Polymers 0.000 abstract description 2
- 239000005017 polysaccharide Substances 0.000 abstract description 2
- 125000003277 amino group Chemical group 0.000 abstract 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 abstract 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 23
- 238000003756 stirring Methods 0.000 description 8
- 230000008859 change Effects 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 6
- 239000007987 MES buffer Substances 0.000 description 5
- 230000006196 deacetylation Effects 0.000 description 5
- 238000003381 deacetylation reaction Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- 229920002101 Chitin Polymers 0.000 description 4
- 241000191967 Staphylococcus aureus Species 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 3
- 238000004566 IR spectroscopy Methods 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000012456 homogeneous solution Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- -1 Amino, carboxyl Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000005611 electricity Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000010148 water-pollination Effects 0.000 description 2
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- 241000243818 Annelida Species 0.000 description 1
- 241000238421 Arthropoda Species 0.000 description 1
- 238000009631 Broth culture Methods 0.000 description 1
- 241001478240 Coccus Species 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001720 carbohydrates Chemical group 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000002242 deionisation method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
- C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
- C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
- A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
- A01N47/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=CX2 groups, e.g. isothiourea
- A01N47/44—Guanidine; Derivatives thereof
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Environmental Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Dentistry (AREA)
- Plant Pathology (AREA)
- Pest Control & Pesticides (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Materials Engineering (AREA)
- Molecular Biology (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Materials For Medical Uses (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了一种水溶性壳聚糖抗菌衍生物及其制备方法，所述水溶性壳聚糖抗菌衍生物包括壳聚糖骨架和对壳聚糖骨架上的氨基进行改性的双功能基团，所述双功能基团为胍基和羰基聚乙二醇单甲醚。本发明在壳聚糖的侧链上同时修饰上胍基和短链聚乙二醇，赋予壳聚糖良好的抗菌性能和更高的生物安全性。本发明的制备方法，壳聚糖首先与羧基聚乙二醇单甲醚进行反应，充分改善了壳聚糖的水溶性，同时大大提高生物安全性；再与三氧化硫脲进行反应，有效避免了第一步若接枝胍基，其中的氨基参与后续反应，从而有效保留了胍基带有的丰富正电荷，保证了水溶性壳聚糖抗菌衍生物中的正电荷密度，使所得水溶性壳聚糖抗菌衍生物的抗菌效果更佳。
The invention discloses a water-soluble chitosan antibacterial derivative and a preparation method thereof. The water-soluble chitosan antibacterial derivative comprises a chitosan skeleton and a bifunctional group that modifies amino groups on the chitosan skeleton. The bifunctional group is guanidine group and carbonyl polyethylene glycol monomethyl ether. In the present invention, guanidine group and short-chain polyethylene glycol are simultaneously modified on the side chain of chitosan, which endows chitosan with good antibacterial performance and higher biological safety. In the preparation method of the present invention, chitosan is first reacted with carboxyl polyethylene glycol monomethyl ether, which fully improves the water solubility of chitosan and greatly improves biological safety; and then reacts with thiourea trioxide to effectively avoid In the first step, if the guanidine group is grafted, the amino group participates in the subsequent reaction, thereby effectively retaining the rich positive charge of the guanidine group, ensuring the positive charge density in the water-soluble chitosan antibacterial derivative, and making the obtained water-soluble shell The antibacterial effect of polysaccharide antibacterial derivatives is better.
Description
Technical field
The present invention relates to anti-biotic material fields, and in particular to a kind of water soluble chitosan antibiotic derivative and its preparation side
Method.
Background technique
Chitin is the natural reproducible resource abundant of nature reserves second, can be from the ectoskeleton of arthropod, true
It is isolated in bacterium, insect and annelid.Chitin is through deacetylated processing until that can be dissolved into dilute acid soln
For transparent aqueous solution, polymer at this time is chitosan.Compared with chitin, it is opposite that a large amount of free amino assigns chitosan
Higher dissolubility, lower crystallinity, so that its application space be made to have certain promotion.In addition, in addition to good
Outside biodegradability and biocompatibility, chitosan also has certain anti-inflammatory and drug is promoted to be saturated in biofilm surface
The effect of absorption, therefore the industries such as medicine, food, chemical industry and environmental protection can be widely used in.However due to chitosan knot
Structure is regular, partially crystallizable, is insoluble in water, also significantly limits its application extensive and deep in the above numerous areas.
Due to there is the hydroxyl and amino that largely are easy to be modified in chitosan molecule, control and hydroxyl or amino can be passed through
Reaction condition, carry out such as acylation, carboxylated, etherificate, alkylation, esterification, hydrolysis react
[J.Adv.Drug.Deliv.Rev.2001,50,591.] introduces other groups and destroys chitosan crystalline texture, change its physics
Chemical property, to obtain can adapt to more areas needs, the water-solubility chitosan derivative with more specific functions.
Polyethylene glycol (PEG) is the polymer being most widely used in polyethers high molecular material.Due to having obtained the U.S.
The approval of Food and Drug Administration (FDA), can be used for the numerous areas such as biological medicine.PEG can in human body
It is dissolved in tissue fluid, good biocompatibility has no toxic side effect.It, can be with when PEG and the combination of other hydrophobic polymer chains sections
Improve the hydrophilicity of material.In the application of PEG, end group type, which directly determines, which material to carry out chemical bond company with
Or reaction.Commercialized PEG end group is generally hydroxyl, it can be made to be converted into other functional groups by terminal groups modification, such as
Amino, carboxyl etc., it is easier to carry out chemical bond and even react, to have broader practice prospect in biomedicine field.Ji
Et al. amino modified in chitosan is become into pendant carboxylic group, then alanine-polyethyleneglycol block copolymer is grafted to shell and is gathered
Carbohydrate side chain, obtain temperature, pH Dual Sensitive environmental response polymer [Ji H, et.al., J.Mater.Chem, 2011,21,
5484.]。
On the other hand, guanidine radicals is the strongest bioactivity organic base of electropositive of current nature discovery, in physiological pH
Under the conditions of can protonate, can form positively charged group in wider pH range.Guanidino functionalities have anti-inflammatory, decompression
The bioactivity such as reducing blood lipid, antiviral and antitumor, while there is strong basicity, stiff stability and be easily formed hydrogen chain.Guanidine radicals chemical combination
Object is widely present in natural products, and dissolubility is strong, there is very strong alkalinity and electropositive, so that there is good antibacterial property energy,
It is widely used in the fields such as medicine, agricultural, building, clothes, chemical industry.And the amino reactivity with higher on chitosan,
Therefore guanidinated modified its performance similar with guanidine compound of imparting is carried out to chitosan by amino, and then improves chitosan
Bacteriostasis property, there are many reports both at home and abroad for the research of this respect [Hu Y., et.al., Carbohyd.Polym.2007,
67,66；BioresourTechnol,2010,101,5693；Zhai X.,et.al.,J.Appl.Polym.Sci.2011,
121,3569.].But the hydrophilic modification of either chitosan or positive electricity are modified, these work all only carry out chitosan single
One functionalization improves the antibiotic property of chitosan, reduces its biological safety；Or improve biological safety and antibiotic property
But it is not obviously improved, this has seriously affected it and has further applied.
This seminar is in patent CN 201710556550.5 by using guanidine radicals and amino acid difunctional to chitosan
It is modified, while ensure that water-soluble and antibiotic property, has taken into account biological safety.On this Research foundation, the present invention
People continues to explore the preparation method of difunctional modification of chitosan derivative, can keep good water-soluble same
When, more efficiently, neatly regulate and control the antibiotic property and its biological safety of sample.
Summary of the invention
Based on background above technology, the present invention provides a kind of water soluble chitosan antibiotic derivative and preparation method thereof,
Successfully short chain polyalkylene glycol (PEG) and guanidinated reagent are grafted in chitosan molecule, obtained a kind of bifunctional group
Modified water soluble chitosan antibiotic derivative being capable of efficient, spirit under the premise of effectively keeping chitosan derivatives water-soluble
The antibiotic property and its biological safety of ground living balance sample, make it be more suitable for industrialized production, meet market needs.
In order to achieve the above objectives, the invention adopts the following technical scheme:
A kind of water soluble chitosan antibiotic derivative changes including chitosan skeleton and to the amino on chitosan skeleton
Property bifunctional group, the bifunctional group be guanidine radicals and carbonyl poly glycol monomethyl ether.
Guanidine radicals and amino acid is used to carry out modification phase to chitosan with this seminar patent CN 201710556550.5
Than the polyethylene glycol segment of carboxy polyethylene glycol monomethyl ether is more flexible for regulatory molecule hydrophily, and explores and try in early period
Middle discovery is tested, is adjusted to the modified sequence of bifunctional group first to carry out the modification of carboxy polyethylene glycol monomethyl ether to connect guanidine radicals again, effectively
The amino avoided in the guanidine radicals of first step grafting participates in subsequent reactions, to ensure that in water soluble chitosan antibiotic derivative
The density of positive charge, gained water soluble chitosan antibiotic derivative antibacterial effect is more preferably.
Preferably, the water soluble chitosan antibiotic derivative has following structure formula:
Wherein, x, y, m, n are natural number, and m+n is related to the molecular weight of the chitosan of selection, 6 < m+n < 6000；N and choosing
The deacetylation of chitosan is related, 0.50 < n/ (m+n) < 0.99；X and the molecular weight for selecting carboxy polyethylene glycol monomethyl ether
Correlation, 10 < x < 200；Y is related to carbonyl poly glycol monomethyl ether grafting rate, 0.10 < y/ (m+n) < 0.50.
The present invention also provides the preparation methods of above-mentioned water soluble chitosan antibiotic derivative, comprising the following steps:
S1, chitosan are reacted with carboxy polyethylene glycol monomethyl ether, obtain poly ethyldiol modified chitosan；
S2, poly ethyldiol modified chitosan and AminoiminomethanesulAcidc Acidc carry out guanidine radicals modified-reaction, obtain the water soluble shells
Glycan antibiotic derivative.Selecting AminoiminomethanesulAcidc Acidc to carry out, guanidine radicals is modified, and compared with cyanamide is modified, reaction condition is more mild, instead
Answer temperature lower, it is easily controllable.
Chitosan is reacted with carboxy polyethylene glycol monomethyl ether first, then is reacted with AminoiminomethanesulAcidc Acidc, can be made
The product that each step obtains is single without influencing subsequent reactions；The amino participation avoided in the guanidine radicals of first step grafting is subsequent anti-
It answers, has been effectively retained the abundant positive charge having in guanidine radicals, thus will not be because of further reaction and by the positive electricity ammonia in guanidine radicals
Base consumes, and ensure that the density of positive charge in water soluble chitosan antibiotic derivative, gained water soluble chitosan antibacterial are derivative
Object antibacterial effect is more preferably.
Preferably, it is dry by dialysis and vacuum refrigeration after chitosan is reacted with carboxy polyethylene glycol monomethyl ether in S1
It is dry to obtain poly ethyldiol modified chitosan；It is modified anti-to carry out guanidine radicals for poly ethyldiol modified chitosan and AminoiminomethanesulAcidc Acidc in S2
Ying Hou obtains poly ethyldiol modified chitosan by dialysis and vacuum freeze drying.It is highly preferred that the dialysis uses retention
Molecular weight is the bag filter of 8000-14000Da, uses deionized water as dialyzate.
Dialysis treatment can completely remove small molecule by-product and impurity, purified product.Using the method for freeze-drying
Sample is handled, bacteria resistance function or life caused by traditional sample drying course modified function group is decomposed because of alternating temperature have both been avoided
Object safety decline, meanwhile, freeze-drying makes sample have three-dimensional macroporous network structure, is conducive to the fast of solvent in course of dissolution
Speed penetrates into improve the solution rate of sample.
It is highly preferred that the detailed process that chitosan is reacted with carboxy polyethylene glycol monomethyl ether in S1 are as follows: first by carboxylic
Base poly glycol monomethyl ether, n-hydroxysuccinimide (NHS) and 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide hydrochloride
Salt (EDCHCl) is added in 2- (N- morpholino) ethane sulfonic acid (MES) buffer and carries out activated carboxylic；Then, carboxyl is living
Mixed solution after change, which is added in the dilute acid soln of chitosan, to be reacted, and reaction temperature control is at 0-35 DEG C, reaction time 12-
72 hours；It is eventually adding hydroxylamine hydrochloride and terminates reaction.Preferably, the amount of the substance of hydroxylamine hydrochloride and carboxy polyethylene glycol monomethyl ether
Ratio be 1:1.
Preferably, the ratio between amount of substance of NHS, EDCHCl and carboxy polyethylene glycol monomethyl ether is 1:1:0.2-2；Carboxyl
The ratio between amount of substance of poly glycol monomethyl ether and chitosan is 0.1-10:1.
Preferably, the temperature of activated carboxylic is 0-35 DEG C, and activation time is 0.5-3 hours.
Preferably, using the dilute acid soln of chitosan described in MES buffer, wherein diluted acid is hydrochloric acid or acetic acid, acid
Concentration be 0.1-0.5M, the mass percent of chitosan is 0.1%-50%.
Preferably, the concentration of MES buffer is 10-100mM, pH 4.5-7.5.
Preferably, the number-average molecular weight of chitosan is 103-106Da, deacetylation 50-99%；Carboxy polyethylene glycol list
The number-average molecular weight of methyl ether is 550-8000Da.
Preferably, the detailed process that chitosan poly ethyldiol modified in S2 is reacted with AminoiminomethanesulAcidc Acidc are as follows: prepare
The aqueous solution of poly ethyldiol modified chitosan, is heated to 20-80 DEG C, and in 10-90 minutes addition AminoiminomethanesulAcidc Acidcs, the reaction was continued
10-60 minutes.
Preferably, the mass percent of the aqueous solution of poly ethyldiol modified chitosan is 0.1-50%；AminoiminomethanesulAcidc Acidc
It is 0.1-10:1 with the ratio between the poly ethyldiol modified amount of substance of chitosan.
Chemical reaction process of the present invention is as follows:
Wherein, x, y, m, n are natural number, 6 < m+n < 6000；0.50<n/(m+n)<0.99；10<x<200；0.10<y/
(m+n)<0.50。
Beneficial effects of the present invention
Water soluble chitosan antibiotic derivative provided by the invention, not only improves the dissolubility of chitosan, and due to
The introducing of guanidino functionalities and mild polyethylene glycol segment, while ensure that the bacteriostasis antibiosis performance and bio-safety of product
Property.Due to hydrophily, the introducing of electropositive side chain, the crystallinity of product weakens water-soluble enhancing, so that its use scope be made to become
Width can be used under acidity to weak basic condition.In addition, water soluble chitosan antibiotic derivative of the invention can as biology
Degradable material, good anti-bacterial effect, cytotoxicity are low, biological safety is high, are a kind of green safe antibacterial products.
The preparation method of water soluble chitosan antibiotic derivative provided by the invention, easy to operate, mild condition, master used
Wanting raw materials of chitosan is gained after source natural polymer chitin extremely abundant is deacetylated.Required equipment is simple, is suitble to work
Industry metaplasia produces, and is a kind of modified anti-biotic material of natural polysaccharide of high-quality, great market development and application prospect.
Detailed description of the invention
Fig. 1 is the nuclear magnetic resonance spectroscopy result of chitosan poly ethyldiol modified prepared by 1 step of embodiment (1)；
Fig. 2 is Fu of chitosan and water soluble chitosan antibiotic derivative poly ethyldiol modified prepared by embodiment 1
In leaf infrared spectroscopy；
Fig. 3 is water soluble chitosan antibiotic derivative various concentration aqueous solution prepared by embodiment 1 to golden yellow grape
The inhibiting rate result of coccus；
Fig. 4 is water soluble chitosan antibiotic derivative various concentration aqueous solution prepared by embodiment 1 to human liver cell
L-02 cell proliferation inhibition rate result.
Specific embodiment
The present invention is specifically described below by embodiment, it is necessary to which indicated herein is that the present embodiment is served only for pair
The present invention is further described, and should not be understood as limiting the scope of the invention, and the person skilled in the art in the field can
To make some nonessential modifications and adaptations according to the content invented above.In the absence of conflict, the reality in the present invention
The feature applied in example and embodiment can be combined with each other.
Embodiment 1:
(1) preparation of poly ethyldiol modified chitosan
Weigh 0.16 gram-molecular weight 2 × 105The chitosan of Da deacetylation 99% be added to 10mLMES buffer (25mM,
PH=4.90 it in), and instills 0.1mL HCl and stirs half an hour at room temperature, be completely dissolved chitosan, to obtain quality volume
The uniform solution that percent concentration is 1.6%；Then by room temperature activate 1 hour carboxy polyethylene glycol monomethyl ether, NHS and
Mixed solution (the MES buffer solution that solvent is 25mM pH=4.90) 20mL of EDCHCl is added in above-mentioned reaction solution, in room
Persistently be stirred to react 24 hours under temperature, wherein chitosan, carboxy polyethylene glycol monomethyl ether, NHS, EDCHCl substance amount it
Than for 1:1:2:2；It is added and is reacted with the termination of the hydroxylamine hydrochloride of the amount of the substances such as carboxy polyethylene glycol monomethyl ether after reaction, with
Reaction solution is transferred in the bag filter that molecular cut off is 8000-14000Da afterwards, bag filter both ends are tightened and are placed in deionization
Dialysis treatment in water, it is primary to change water every 6 hours, after dialyzate is put into -20 DEG C of freeze overnights after changing water 6 times, is put into vacuum
Freeze drier is until poly ethyldiol modified water soluble chitosan can be obtained to constant weight for sufficiently drying.
(2) preparation of water soluble chitosan antibiotic derivative
It weighs water soluble chitosan obtained in 1.00 grams (1) to be added in 50mL deionized water, it is small to stir half at room temperature
When, so that water soluble chitosan is completely dissolved, to obtain the homogeneous solution that mass percent is 2%；55 are increased to temperature
DEG C, AminoiminomethanesulAcidc Acidc is slowly added into water soluble chitosan solution, the ratio between AminoiminomethanesulAcidc Acidc and the amount of substance of chitosan are
3:1 feeds intake the used time 30 minutes, continues heating stirring 30 minutes after feeding intake, reaction solution is then transferred to molecular cut off
Bag filter both ends to be tightened and are placed in dialysis treatment in deionized water in the bag filter of 8000-14000Da, water was changed every 6 hours
Once, it after dialyzate is put into -20 DEG C of freeze overnights after changing water 6 times, is put into vacuum freeze drier until sufficiently drying extremely
Constant weight can obtain water soluble chitosan antibiotic derivative.
Embodiment 2:
(1) preparation of poly ethyldiol modified chitosan
Weigh 0.10 gram-molecular weight 106The chitosan of Da deacetylation 80% is added to 100mLMES buffer (10mM pH
=7.50) in, and 0.4mL CH is instilled3COOH stirs half an hour at room temperature, is completely dissolved chitosan, to obtain mass body
The uniform solution that product percent concentration is 0.1%；Then the carboxy polyethylene glycol list first that 3 hours are activated in bath will be mixed in ice water
Above-mentioned reaction is added in mixed solution (the MES buffer solution of solvent 10mM, the pH=7.50) 20mL of ether, NHS and EDCHCl
In liquid, it is persistently stirred to react 72 hours at 0 DEG C, wherein the object of chitosan, carboxy polyethylene glycol monomethyl ether, NHS, EDCHCl
The ratio between amount of matter is 20:2:1:1；It is added after reaction whole with the hydroxylamine hydrochloride of the amounts of substances such as carboxy polyethylene glycol monomethyl ether
It only reacts, then reaction solution is transferred in the bag filter that molecular cut off is 8000-14000Da, bag filter both ends are tightened
It is placed in dialysis treatment in deionized water, it is primary to change water every 5 hours, changes after water 8 times dialyzate being put into -20 DEG C of freeze overnights
Afterwards, vacuum freeze drier is put into until sufficiently poly ethyldiol modified water soluble chitosan can be obtained to constant weight for drying.
(2) preparation of water soluble chitosan antibiotic derivative
It weighs water soluble chitosan obtained in 0.10 gram (1) to be added in 100mL deionized water, it is small to stir half at room temperature
When, so that water soluble chitosan is completely dissolved, to obtain the homogeneous solution that mass percent is 0.1%；It is increased to temperature
80 DEG C, AminoiminomethanesulAcidc Acidc, the ratio between AminoiminomethanesulAcidc Acidc and the amount of substance of chitosan are slowly added into water soluble chitosan solution
It for 10:1, feeds intake the used time 90 minutes, continues heating stirring 60 minutes after feeding intake, reaction solution is then transferred to retention molecule
Amount is to tighten bag filter both ends in the bag filter of 8000-14000Da and be placed in dialysis treatment in deionized water, every 10 hours
It is primary to change water, after dialyzate is put into -20 DEG C of freeze overnights after changing water 5 times, is put into vacuum freeze drier until sufficiently dry
It is dry to obtain water soluble chitosan antibiotic derivative to constant weight.
Embodiment 3:
(1) preparation of poly ethyldiol modified chitosan
The chitosan for weighing 5.00 gram-molecular weight 1000Da deacetylations 50% is added to 10mLMES buffer (100mM
PH=4.50 in), half an hour is stirred at room temperature, is completely dissolved chitosan, to obtain quality concentration of volume percent and be
50% uniform solution；Then 0.5 hour carboxy polyethylene glycol monomethyl ether, NHS and EDCHCl will be activated at 35 DEG C
Mixed solution (the MES buffer solution that solvent is 100mM pH=4.50) 50mL is added in above-mentioned reaction solution, continues at 35 DEG C
It is stirred to react 12 hours, wherein the ratio between amount of substance of chitosan, carboxy polyethylene glycol monomethyl ether, NHS, EDCHCl is 1:
10:5:5；It is added and is reacted with the termination of the hydroxylamine hydrochloride of the amount of the substances such as carboxy polyethylene glycol monomethyl ether after reaction, then will
Reaction solution is transferred in the bag filter that molecular cut off is 1000Da, and bag filter both ends are tightened and are placed in deionized water at dialysis
Reason, it is primary to change water every 10 hours, after dialyzate is put into -20 DEG C of freeze overnights after changing water 5 times, is put into vacuum freeze drier
Until sufficiently poly ethyldiol modified water soluble chitosan can be obtained to constant weight for drying.
(2) preparation of water soluble chitosan antibiotic derivative
It weighs water soluble chitosan obtained in 5.00 grams (1) to be added in 10mL deionized water, it is small to stir half at room temperature
When, so that water soluble chitosan is completely dissolved, to obtain the homogeneous solution that mass percent is 50%；To water solubility at 20 DEG C
AminoiminomethanesulAcidc Acidc is slowly added in chitosan solution, the ratio between AminoiminomethanesulAcidc Acidc and the amount of substance of chitosan are 1:10, and feed intake use
When 10 minutes, continue heating stirring 10 minutes after feeding intake, it is 1000Da's that reaction solution, which is then transferred to molecular cut off,
In bag filter, bag filter both ends are tightened and are placed in dialysis treatment in deionized water, it is primary to change water every 5 hours, will after changing water 8 times
After dialyzate is put into -20 DEG C of freeze overnights, be put into vacuum freeze drier until sufficiently it is dry can be obtained to constant weight it is water-soluble
Chitosan anti-bacteria derivative.
Embodiment 4:
The nuclear magnetic resonance spectroscopy of poly ethyldiol modified chitosan
The resulting poly ethyldiol modified chitosan of step (1) in 50mg embodiment 1 is dissolved in the deuterated water of 0.6mL, with
Tetramethylsilane (TMS) does internal standard, at 25 DEG C of room temperature, on Varian UNITY INOVA-400MHz nuclear magnetic resonance chemical analyser
Measure the micro-structure and chemical composition of water soluble chitosan.Acquired results are as shown in Figure 1.
Peak intensity at 2.0ppm is weaker, shows that the poly ethyldiol modified chitosan of gained is deacetylated more thoroughly.3.65ppm
Neighbouring monomethyl ether polyethylene glycol methylene CH2CH2The appearance of proton hydrogen chemical shifts shows by 1 step of embodiment (1)
Polyethylene glycol segment is successfully grafted in chitosan molecule by preparation method.
Embodiment 5:
The FTIR spectrum of poly ethyldiol modified chitosan and water soluble chitosan antibiotic derivative
The chitosan that takes the 2.0mg in sufficiently dry embodiment 1 poly ethyldiol modified respectively, 2.0mg water soluble shells are poly-
Sugared antibiotic derivative and 100.0mg potassium bromide spectroscopic pure are put into agate mortar common finely ground, are uniformly mixed, then will be ground
Mixture be put into mold, the tabletting in hydraulic press obtains translucent KBr piece, with this KBr built-in testing infrared spectroscopy, sweeps
Retouching range is 4000-400cm-1.Acquired results are as shown in Figure 2.
Compared with the infrared spectroscopy of water soluble chitosan, guanidine radicals is in 1651cm in water soluble chitosan antibiotic derivative-1With
And 1539cm-1The stretching vibration peak of place's C=N key is remarkably reinforced, and shows through the preparation method in embodiment step (2), incited somebody to action
Guanidine radicals is modified into poly ethyldiol modified chitosan molecule, and corresponding water soluble chitosan antibiotic derivative has been obtained.
Embodiment 6:
Inhibition of the water soluble chitosan antibiotic derivative to staphylococcus aureus
With aqua sterilisa compound concentration be respectively 0.02 by water soluble chitosan antibiotic derivative obtained in embodiment 1,
0.20, the aqueous solution of 2.00mg/mL respectively takes 5mL and is added thereto through pancreas peptone soybean broth culture to logarithmic phase and dense
Degree is 105The staphylococcus aureus bacterium solution 0.1mL of CFU/mL, the sample-bacterium solution stood after taking sufficiently effect after ten minutes are mixed
Conjunction liquid 0.1mL, which is spread evenly across on the MH agar plate of diameter 90mm, to be placed in 37 DEG C of incubators overnight.Through 5mL1 × PBS
The MH agar plate of (0.01M, pH=7.2-7.4) processed equivalent bacterium solution coating is as control.To being grown on agar plate
Bacterium colony counted, and be calculate by the following formula sample to the bacteriostasis rate of staphylococcus aureus.Acquired results as shown in figure 3,
The result shows that can be in wider concentration range according to water soluble chitosan antibiotic derivative aqueous solution prepared by 1 step of embodiment
There is the inhibiting effect of relatively strong (> 95%) to staphylococcus aureus.
Embodiment 7:
Water soluble chitosan antibiotic derivative Evaluation of Biocompatibility
By PRIM 1640 cell of the water soluble chitosan antibiotic derivative obtained in embodiment 1 without fetal calf serum
Culture medium is configured to the solution that concentration is respectively 0.04,0.40,4.00,12.00mg/mL, respectively takes 0.05mL that every hole is added and contains
5000 people through PRIM 1640 (containing 10% fetal calf serum, 1% penicillin, streptomysin) cell culture medium culture to logarithmic phase
In the 96 hole polystyrene culture plates of liver cell L-02, the final concentration of water soluble chitosan antibiotic derivative is made to be respectively 0.01,
0.10,1.00,3.00mg/mL.The cell suspension of 1 × PBS of 0.05mL (0.01M, pH=7.2-7.4) effect is as a control group.
Culture plate is placed in 5%CO2, continue culture 24 hours in 37 DEG C of incubator after, absorb culture medium in each hole and add equivalent
Fresh culture, and CCK-8 solution 0.01mL is added in every hole, is measured after culture 2-4 hours by multi-mode micropore board detector
The light absorption value in each hole at 450nm, and it is calculate by the following formula cell survival rate.Acquired results are as shown in Figure 4, the results showed that through water-soluble
Property the processing of chitosan anti-bacteria derivative L-02 cell survival rate it is higher, the water soluble shells of 1 preparation are poly- through the embodiment of the present invention
The biological safety of sugared antibiotic derivative is preferable.
Obviously, described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based on this
Embodiment in invention, every other reality obtained by those of ordinary skill in the art without making creative efforts
Example is applied, the scope of the present invention is belonged to.
Claims (10)
1. a kind of water soluble chitosan antibiotic derivative is modified including chitosan skeleton and to the amino on chitosan skeleton
Bifunctional group, which is characterized in that the bifunctional group be guanidine radicals and carbonyl poly glycol monomethyl ether, have following structure
Formula:
Wherein, x, y, m, n are natural number, 6 < m+n < 6000,0.50 < n/ (m+n) < 0.99,10 < x < 200；0.10<y/(m+n)
<0.50。
2. a kind of preparation method of water soluble chitosan antibiotic derivative as described in claim 1, which is characterized in that including with
Lower step:
S1, chitosan are reacted with carboxy polyethylene glycol monomethyl ether, obtain poly ethyldiol modified chitosan；
S2, poly ethyldiol modified chitosan and AminoiminomethanesulAcidc Acidc carry out guanidine radicals modified-reaction, obtain the water soluble chitosan
Antibiotic derivative.
3. according to the method described in claim 2, it is characterized in that, chitosan and carboxy polyethylene glycol monomethyl ether carry out instead in S1
Ying Hou obtains poly ethyldiol modified chitosan by dialysis and vacuum freeze drying；
After poly ethyldiol modified chitosan and AminoiminomethanesulAcidc Acidc carry out guanidine radicals modified-reaction in S2, by dialysis and vacuum refrigeration
It is dried to obtain poly ethyldiol modified chitosan；
Preferably, the bag filter that the dialysis is 8000-14000Da using molecular cut off, uses deionized water as dialysis
Liquid.
4. according to the method described in claim 2, it is characterized in that, chitosan and carboxy polyethylene glycol monomethyl ether carry out instead in S1
The detailed process answered are as follows: first by carboxy polyethylene glycol monomethyl ether, n-hydroxysuccinimide and 1- (3- dimethylamino-propyl)-
3- ethyl-carbodiimide hydrochloride is added in 2- (N- morpholino) ethane sulfonic acid buffer and carries out activated carboxylic；Then, by carboxylic
Mixed solution after base activation, which is added in the dilute acid soln of chitosan, to be reacted, and reaction temperature is controlled at 0-35 DEG C, reaction
Between 12-72 hours；It is eventually adding hydroxylamine hydrochloride and terminates reaction；
Preferably, n-hydroxysuccinimide, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride and the poly- second of carboxyl
The ratio between amount of substance of glycol monomethyl ether is 1:1:0.2-2；The ratio between carboxy polyethylene glycol monomethyl ether and the amount of substance of chitosan
For 0.1-10:1；
It is highly preferred that the ratio of the amount of the substance of hydroxylamine hydrochloride and carboxy polyethylene glycol monomethyl ether is 1:1.
5. according to the method described in claim 4, activation time is it is characterized in that, the temperature of activated carboxylic is 0-35 DEG C
0.5-3 hours.
6. according to the method described in claim 4, it is characterized in that, preparing institute using 2- (N- morpholino) ethane sulfonic acid buffer
The dilute acid soln of chitosan is stated, wherein diluted acid is hydrochloric acid or acetic acid, and sour concentration is 0.1-0.5M, the mass percent of chitosan
For 0.1%-50%.
7. the method according to claim 4 or 6, which is characterized in that the concentration of 2- (N- morpholino) ethane sulfonic acid buffer
For 10-100mM, pH 4.5-7.5.
8. according to the method described in claim 4, it is characterized in that, the number-average molecular weight of chitosan is 103-106Da, it is deacetylated
Degree is 50-99%；The number-average molecular weight of carboxy polyethylene glycol monomethyl ether is 550-8000Da.
9. according to the method described in claim 2, it is characterized in that, chitosan and AminoiminomethanesulAcidc Acidc poly ethyldiol modified in S2
The detailed process reacted are as follows: the aqueous solution for preparing poly ethyldiol modified chitosan is heated to 20-80 DEG C, at 10-90 points
AminoiminomethanesulAcidc Acidc is added in clock, and the reaction was continued 10-60 minutes.
10. according to the method described in claim 9, the mass percent of the aqueous solution of poly ethyldiol modified chitosan is 0.1-
50%；The ratio between AminoiminomethanesulAcidc Acidc and the poly ethyldiol modified amount of substance of chitosan are 0.1-10:1.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710817411.3A CN109485747B (en) | 2017-09-12 | 2017-09-12 | A kind of water-soluble chitosan antibacterial derivative and preparation method thereof |
| PCT/CN2018/101849 WO2019052321A1 (en) | 2017-09-12 | 2018-08-23 | Water-soluble chitosan antimicrobial derivative and preparation method therefor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710817411.3A CN109485747B (en) | 2017-09-12 | 2017-09-12 | A kind of water-soluble chitosan antibacterial derivative and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109485747A true CN109485747A (en) | 2019-03-19 |
| CN109485747B CN109485747B (en) | 2020-12-11 |
Family
ID=65688097
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710817411.3A Active CN109485747B (en) | 2017-09-12 | 2017-09-12 | A kind of water-soluble chitosan antibacterial derivative and preparation method thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN109485747B (en) |
| WO (1) | WO2019052321A1 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110386997A (en) * | 2019-08-19 | 2019-10-29 | 中国科学院理化技术研究所 | A biocompatible chitosan derivative with antibacterial function and its preparation method |
| CN110409192A (en) * | 2019-08-26 | 2019-11-05 | 安徽农业大学 | A kind of nano carboxy chitosan in-situ coating fabric and preparation method thereof |
| CN110483846A (en) * | 2019-08-20 | 2019-11-22 | 湖南工业大学 | A kind of preparation process of fire-retardant biomass-based antibacterial film |
| CN112300408A (en) * | 2020-10-26 | 2021-02-02 | 广州大学 | A flexible and highly stretchable temperature-sensitive and moisture-sensitive hydrogel and its preparation method and application |
| CN114225098A (en) * | 2021-11-24 | 2022-03-25 | 中国科学院理化技术研究所 | A medical dressing with antibacterial properties and promoting wound healing |
| CN114288464A (en) * | 2021-11-24 | 2022-04-08 | 中国科学院理化技术研究所 | Antibacterial healing-promoting hydrogel dressing and preparation method and application thereof |
| CN114634959A (en) * | 2022-04-02 | 2022-06-17 | 中国科学院兰州化学物理研究所 | Difunctional bionic lubricant and preparation method and application thereof |
| CN115141284A (en) * | 2022-08-22 | 2022-10-04 | 安庆市嘉欣医疗用品科技股份有限公司 | Macromolecular derivative, preparation method and application thereof |
| CN116239797A (en) * | 2022-12-21 | 2023-06-09 | 江阴奔翔生物科技有限公司 | Preparation method and application of injectable hydrogel |
| CN116554363A (en) * | 2023-04-18 | 2023-08-08 | 珠海市自然之旅生物技术有限公司 | Torone-chitosan derivative and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008038864A1 (en) * | 2006-09-27 | 2008-04-03 | Genic Co., Ltd. | Low toxic, biocompatible film using chitosan and polyethylene glycol |
| CN103524750A (en) * | 2013-10-25 | 2014-01-22 | 扬州大学 | Polyethylene glycol chitosan self-assembled nanoparticles and preparation method thereof |
| CN104672346A (en) * | 2014-12-15 | 2015-06-03 | 四川吉百瑞生物医疗科技有限公司 | Preparation method of guanidyl chitosan quaternary ammonium salt |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004073034A2 (en) * | 2003-02-12 | 2004-08-26 | University Of Maryland College Park | Controlled electrochemical deposition of polysaccharides, films and hydrogel and materials formed therefrom |
| CN101033264B (en) * | 2007-04-24 | 2010-05-19 | 武汉大学 | Chitosan biguanide hydrochloride and its preparation method and use |
| WO2010021930A1 (en) * | 2008-08-16 | 2010-02-25 | Synedgen, Inc. | Prevention and treatment of mrsa infections with chitosan-derivatives |
-
2017
- 2017-09-12 CN CN201710817411.3A patent/CN109485747B/en active Active
-
2018
- 2018-08-23 WO PCT/CN2018/101849 patent/WO2019052321A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008038864A1 (en) * | 2006-09-27 | 2008-04-03 | Genic Co., Ltd. | Low toxic, biocompatible film using chitosan and polyethylene glycol |
| CN103524750A (en) * | 2013-10-25 | 2014-01-22 | 扬州大学 | Polyethylene glycol chitosan self-assembled nanoparticles and preparation method thereof |
| CN104672346A (en) * | 2014-12-15 | 2015-06-03 | 四川吉百瑞生物医疗科技有限公司 | Preparation method of guanidyl chitosan quaternary ammonium salt |
Non-Patent Citations (2)
| Title |
|---|
| GUIPING MA等: ""Photo-polymeriable chitosan derivative prepared by Michael reaction of chitosan and polyethylene glycol diacrylate (PEGDA)"", 《INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES》 * |
| YING HU等: ""Synthesis,characterization and antibacterial activity of guanidinylated chitosan"", 《CARBOHYDRATE POLYMERS》 * |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110386997B (en) * | 2019-08-19 | 2021-09-07 | 中国科学院理化技术研究所 | A kind of biocompatible chitosan derivative with antibacterial function and preparation method thereof |
| CN110386997A (en) * | 2019-08-19 | 2019-10-29 | 中国科学院理化技术研究所 | A biocompatible chitosan derivative with antibacterial function and its preparation method |
| CN110483846A (en) * | 2019-08-20 | 2019-11-22 | 湖南工业大学 | A kind of preparation process of fire-retardant biomass-based antibacterial film |
| CN110483846B (en) * | 2019-08-20 | 2021-04-06 | 湖南工业大学 | Preparation process of flame-retardant biomass-based antibacterial film |
| CN110409192A (en) * | 2019-08-26 | 2019-11-05 | 安徽农业大学 | A kind of nano carboxy chitosan in-situ coating fabric and preparation method thereof |
| CN110409192B (en) * | 2019-08-26 | 2021-08-20 | 安徽农业大学 | A kind of nano carboxyl chitosan in-situ coated fabric and preparation method thereof |
| CN112300408A (en) * | 2020-10-26 | 2021-02-02 | 广州大学 | A flexible and highly stretchable temperature-sensitive and moisture-sensitive hydrogel and its preparation method and application |
| CN114225098A (en) * | 2021-11-24 | 2022-03-25 | 中国科学院理化技术研究所 | A medical dressing with antibacterial properties and promoting wound healing |
| CN114288464A (en) * | 2021-11-24 | 2022-04-08 | 中国科学院理化技术研究所 | Antibacterial healing-promoting hydrogel dressing and preparation method and application thereof |
| CN114634959A (en) * | 2022-04-02 | 2022-06-17 | 中国科学院兰州化学物理研究所 | Difunctional bionic lubricant and preparation method and application thereof |
| CN114634959B (en) * | 2022-04-02 | 2024-02-02 | 中国科学院兰州化学物理研究所 | A bifunctional bionic lubricant and its preparation method and application |
| CN115141284A (en) * | 2022-08-22 | 2022-10-04 | 安庆市嘉欣医疗用品科技股份有限公司 | Macromolecular derivative, preparation method and application thereof |
| CN116239797A (en) * | 2022-12-21 | 2023-06-09 | 江阴奔翔生物科技有限公司 | Preparation method and application of injectable hydrogel |
| CN116554363A (en) * | 2023-04-18 | 2023-08-08 | 珠海市自然之旅生物技术有限公司 | Torone-chitosan derivative and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109485747B (en) | 2020-12-11 |
| WO2019052321A1 (en) | 2019-03-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109485747A (en) | Water-soluble chitosan antibacterial derivative and preparation method thereof | |
| Nataraj et al. | Crosslinked chitosan films with controllable properties for commercial applications | |
| CN107746433B (en) | A kind of preparation method of cellulose-based antibacterial material dialdehyde cellulose-lysine | |
| CN110386997B (en) | A kind of biocompatible chitosan derivative with antibacterial function and preparation method thereof | |
| CN111153815B (en) | A kind of antibacterial polyphenol material and application | |
| Teng | From chitin to chitosan | |
| CN106905443B (en) | The preparation method and applications of guanidinated chitosan | |
| CN107344971A (en) | Poly-lysine modified chitosan and preparation method thereof | |
| CN103554369B (en) | A kind of preparation method of the double stimuli responsive hydrogel with cyclodextrin | |
| CN113248632A (en) | Multifunctional traditional Chinese medicine organic acid grafted chitosan quaternary ammonium salt broad-spectrum antibacterial agent and preparation method thereof | |
| CN110003359A (en) | A kind of hydrophily high substituted degree modification of chitosan preparation method and applications | |
| CN106995502B (en) | Bifunctional group-modified chitosan derivatives and preparation method thereof | |
| CN113201082A (en) | Chitosan-chlorin e6 antibacterial agent and preparation method thereof | |
| CN108929387A (en) | A kind of preparation method of chitosan-g- antibacterial peptide polymer | |
| CN109553700A (en) | Acylated chitosan oligosaccharide derivative of a kind of no cytotoxicity N- biguanides O- and preparation method thereof | |
| CN110183546B (en) | A kind of water-soluble antibacterial derivative of curdlan and preparation method thereof | |
| CN109517091A (en) | The preparation method and applications of guanidinated chitosan | |
| CN118791648B (en) | Thiophene group-containing chitosan and preparation method and application thereof | |
| CN110358098A (en) | A kind of PEG bridging mannose-modified chitosan derivatives and preparation method thereof | |
| CN101029094B (en) | A kind of preparation method of chitosan hydrochloride | |
| CN107304234B (en) | Double-modified carboxymethyl chitosan derivative and preparation method thereof | |
| CN102120823B (en) | The synthesis of water solublity zein and the utilization in pharmaceutical preparation | |
| CN110938156B (en) | Amphiphilic chitosan, preparation method thereof and amphiphilic chitosan-based nano microcapsule applying amphiphilic chitosan | |
| CN116376123A (en) | Injectable glucan-based hydrogel, glucan-based hydrogel loaded with paris polyphylla saponin I, and preparation method and application thereof | |
| CN110229249B (en) | Preparation method of quaternized chitosan-carboxyl-terminated xanthone composite antibacterial material |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |