CN105504131B - β is removed for blood purification2The preparation method of the resin of microglobulin - Google Patents
β is removed for blood purification2The preparation method of the resin of microglobulin Download PDFInfo
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- CN105504131B CN105504131B CN201610057425.5A CN201610057425A CN105504131B CN 105504131 B CN105504131 B CN 105504131B CN 201610057425 A CN201610057425 A CN 201610057425A CN 105504131 B CN105504131 B CN 105504131B
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- microballoon
- chloromethylation
- resin
- microglobulin
- preparation
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- 239000011347 resin Substances 0.000 title claims abstract description 28
- 229920005989 resin Polymers 0.000 title claims abstract description 28
- 210000004369 blood Anatomy 0.000 title claims abstract description 19
- 239000008280 blood Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000007265 chloromethylation reaction Methods 0.000 claims abstract description 34
- 229920003053 polystyrene-divinylbenzene Polymers 0.000 claims abstract description 34
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims abstract description 31
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 125000001165 hydrophobic group Chemical group 0.000 claims abstract description 17
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000000746 purification Methods 0.000 claims abstract description 14
- 239000004088 foaming agent Substances 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 239000000178 monomer Substances 0.000 claims abstract description 7
- HRQGCQVOJVTVLU-UHFFFAOYSA-N bis(chloromethyl) ether Chemical compound ClCOCCl HRQGCQVOJVTVLU-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000011148 porous material Substances 0.000 claims abstract description 3
- 239000004005 microsphere Substances 0.000 claims description 38
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 150000003973 alkyl amines Chemical class 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 10
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 10
- 239000003999 initiator Substances 0.000 claims description 10
- 239000003381 stabilizer Substances 0.000 claims description 10
- 238000010792 warming Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 5
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 5
- 239000005662 Paraffin oil Substances 0.000 claims description 5
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 235000019441 ethanol Nutrition 0.000 claims description 5
- 239000004210 ether based solvent Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000010557 suspension polymerization reaction Methods 0.000 claims description 5
- 230000008961 swelling Effects 0.000 claims description 5
- 108010010803 Gelatin Proteins 0.000 claims description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 4
- 238000004132 cross linking Methods 0.000 claims description 4
- 229920000159 gelatin Polymers 0.000 claims description 4
- 239000008273 gelatin Substances 0.000 claims description 4
- 235000019322 gelatine Nutrition 0.000 claims description 4
- 235000011852 gelatine desserts Nutrition 0.000 claims description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 2
- 229920006389 polyphenyl polymer Polymers 0.000 claims 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000011701 zinc Substances 0.000 claims 1
- 229910052725 zinc Inorganic materials 0.000 claims 1
- 238000010521 absorption reaction Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 230000002209 hydrophobic effect Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000000725 suspension Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000001179 sorption measurement Methods 0.000 description 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 8
- 102000009027 Albumins Human genes 0.000 description 4
- 108010088751 Albumins Proteins 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- 239000011592 zinc chloride Substances 0.000 description 4
- 235000005074 zinc chloride Nutrition 0.000 description 4
- 239000003463 adsorbent Substances 0.000 description 3
- 230000008081 blood perfusion Effects 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- -1 alkenyl benzol Chemical compound 0.000 description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000001951 hemoperfusion Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- FJLUATLTXUNBOT-UHFFFAOYSA-N 1-Hexadecylamine Chemical group CCCCCCCCCCCCCCCCN FJLUATLTXUNBOT-UHFFFAOYSA-N 0.000 description 1
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 description 1
- 238000004438 BET method Methods 0.000 description 1
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical group CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical group CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- PLZVEHJLHYMBBY-UHFFFAOYSA-N Tetradecylamine Chemical group CCCCCCCCCCCCCCN PLZVEHJLHYMBBY-UHFFFAOYSA-N 0.000 description 1
- 231100000570 acute poisoning Toxicity 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- SYWDWCWQXBUCOP-UHFFFAOYSA-N benzene;ethene Chemical group C=C.C1=CC=CC=C1 SYWDWCWQXBUCOP-UHFFFAOYSA-N 0.000 description 1
- 102000015736 beta 2-Microglobulin Human genes 0.000 description 1
- 108010081355 beta 2-Microglobulin Proteins 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/30—Introducing nitrogen atoms or nitrogen-containing groups
- C08F8/32—Introducing nitrogen atoms or nitrogen-containing groups by reaction with amines
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying
- B01J13/043—Drying and spraying
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/06—Making microcapsules or microballoons by phase separation
- B01J13/14—Polymerisation; cross-linking
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
- C08J9/28—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof by elimination of a liquid phase from a macromolecular composition or article, e.g. drying of coagulum
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2325/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring; Derivatives of such polymers
- C08J2325/02—Homopolymers or copolymers of hydrocarbons
- C08J2325/04—Homopolymers or copolymers of styrene
- C08J2325/08—Copolymers of styrene
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Dispersion Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- General Chemical & Material Sciences (AREA)
- External Artificial Organs (AREA)
Abstract
The present invention discloses a kind of for blood purification removing β2The preparation method of the resin of microglobulin prepares polystyrene divinyl benzene microballoon first；Polystyrene divinyl benzene microballoon and chloromethyl ether are subjected to chloromethylation again, obtain chloromethylation microballoon；Finally long chain hydrophobic group is grafted on chloromethylation microballoon.Using the present invention, using styrene and divinylbenzene as monomer, polystyrene divinyl benzene microballoon is obtained by suspension polymerisation, and the pore size inside microballoon is adjusted by using a certain amount of pore-foaming agent in the synthesis process, then as carrier, skill alkyl is connect by chloromethane reaction, aminating reaction, obtain that specific surface area is adjustable, and the microballoon with hydrophobic grouping, resin surface are smooth, intensity is high, has very high absorption property to 2 microglobulins of β in uremic patient body.Simple production process of the present invention, high income, product purity are high, while raw material easily obtains, it can be achieved that prepared by large-scale production.
Description
Technical field
The present invention relates to biomedical engineering fields, and β is removed for blood purification more particularly to one kind2Microglobulin
Resin preparation method.
Background technology
It is calculated according to the statistical data of ministry of Health of China：There is 270,000 people of hemodialysis patients in China；Liver cirrhosis patient 1,560,000；
More than 10 ten thousand/year of acute poisoning；Itself exempted from based on systemic loupus erythematosus (910,000) and rheumatoid arthritis (13,260,000)
Nearly 15,000,000 people of epidemic disease disease；In addition millions of Severe sepsis and hyperlipidemia patient, can carry out hemoperfusion treatment
Potential patient be up to 20,000,000 person-times or more.
Hemoperfusion treatment is that blood samples of patients is introduced into the perfusion device equipped with solid adsorbent by extracorporal circulatory system, with
Remove certain exogenous or endogenous toxin and metabolite, and by a kind of therapy in the defeated ex vivo of the blood purified.
Blood perfusion device fills adsorbent, utilizes the affine original such as the physical absorption of adsorbent, chemisorption and antigen-antibody
It clears except blood samples of patients exogenous and endogenous substance, poisonous substance and metabolite.
At present in the domestic market temporarily without single-minded for the blood perfusion for removing uremic patient toxicity in vivo substance
Device product, especially removes β2Microglobulin (β2- MG) specificity blood perfusion device.More simply by broad spectrum type
Resin/activated carbon perfusion device removes the toxicant in uremic patient body, to the β of uremic patient body2Microglobulin
It removes than relatively limited, only by the abundant specific surface area of resin/activated carbon, suitable aperture and aperture are adsorbed, and curative effect has
Limit.
Invention content
In order to solve the above technical problems, the present invention provides a kind of for blood purification removing β2The resin of microglobulin
Preparation method.
Technical solution is as follows：
One kind removing β for blood purification2The preparation method of the resin of microglobulin, key are：First, it prepares
Polystyrene-divinylbenzene microspheres；Polystyrene-divinylbenzene microspheres and chloromethyl ether are subjected to chloromethylation again, are obtained
Chloromethylation microballoon；Finally long chain hydrophobic group is grafted on chloromethylation microballoon.
Above-mentioned long chain hydrophobic group is the alkyl of C10~C20.
Above-mentioned long chain hydrophobic group is the alkyl of C14~C18.
The step of above-mentioned polystyrene-divinylbenzene microspheres is：It will be to styrene and divinylbenzene monomers in mass ratio
1:1~2 configuration oil phase, at the same be added to the initiator of 0.5~1wt% of styrene and divinyl benzene mixtures and 40wt% with
Under pore-foaming agent the stabilizer to 3~10wt% of styrene and divinyl benzene mixtures is added using suspension polymerization,
Oil phase is added to the polystyrene-divinylbenzene microspheres that 12~24 hours obtained superhigh cross-linking degree are stirred to react in 80 DEG C of water,
Polystyrene-divinylbenzene microspheres are cleaned up with water or acetone again, and dry.
The preparation method of above-mentioned chloromethylation microballoon is, by the polystyrene-divinylbenzene microspheres by volume 1:
2.5~4 in chloromethane ether solvents room temperature be swollen 2~4 hours after, be added polystyrene-divinylbenzene microspheres quality 0.5~1
Zinc chloride again is warming up to 35~40 DEG C and reacts 15~40 hours, chloromethylation microballoon is obtained, with ethyl alcohol or third as catalyst
Ketone cleans up, dry.
Above-mentioned initiator is benzoyl peroxide, and the pore-foaming agent is arbitrary in toluene, naphthalene, paraffin oil, benzene, dodecane
One kind or arbitrary two kinds of mixture, the stabilizer are polyvinyl alcohol or gelatin.
The step of grafting long chain hydrophobic group, is on above-mentioned chloromethylation microballoon：According to 1:2~3 mass ratio, to institute
Input swelling solvent swell in chloromethylation microballoon is stated, the alkylamine of chloromethylation microspheres quality 10~20% is added, and
So that the pH value of reaction system is maintained at 12 or more, the finished product for being grafted with long chain hydrophobic group, finished product ethyl alcohol and water is obtained by the reaction
It is cleaned and is dried, the sweller is dimethyl sulfoxide (DMSO), dichloroethanes or N, any one of N- dimethylformamides.
After putting into sweller into above-mentioned chloromethylation microballoon, in being swollen 2~4 hours under room temperature, add described
Alkylamine, and be warming up to 70~80 DEG C and react 8~12 hours, NaOH solution is gradually added dropwise during the reaction, makes reaction system
PH value be maintained at 12 or more.
Advantageous effect：It is using the present invention to remove β for blood purification2The preparation method of the resin of microglobulin, with benzene
Ethylene and divinylbenzene are monomer, obtain polystyrene-divinylbenzene microspheres by suspension polymerisation, and pass through in the synthesis process
The pore size inside microballoon is adjusted using a certain amount of pore-foaming agent, it is anti-by chloromethane reaction, amination then as carrier
Skill alkyl should be connect, obtains that specific surface area is adjustable, and the microballoon with hydrophobic grouping, resin surface is smooth, and intensity is high, to uremic
The β2-microglobulin of disease patient's body has very high absorption property.Simple production process of the present invention, high income, product purity
Height, while raw material easily obtains, it can be achieved that prepared by large-scale production.
Specific implementation mode
With reference to embodiment, the invention will be further described.
Embodiment 1：
One kind removing β for blood purification2The preparation method of the resin of microglobulin：
Step 1: first, preparing polystyrene-divinylbenzene microspheres；
It will be to styrene and divinylbenzene monomers in mass ratio 1:1 configuration oil phase, while being added to styrene and diethyl
The initiator and 5wt% pore-foaming agents below of alkenyl benzol mixture 0.5wt% is added using suspension polymerization to styrene
With the stabilizer of divinyl benzene mixtures 3wt%, oil phase is added in 80 DEG C of water and is stirred to react obtained superelevation friendship in 12 hours
The polystyrene-divinylbenzene microspheres of connection degree, then polystyrene-divinylbenzene microspheres are cleaned up with water or acetone, and do
It is dry；
The initiator is benzoyl peroxide, and the pore-foaming agent is arbitrary two in toluene, naphthalene, paraffin oil, benzene, dodecane
The mixture of kind, the stabilizer are gelatin.
Step 2: secondly, by polystyrene-divinylbenzene microspheres chloromethylation；
By the polystyrene-divinylbenzene microspheres by volume 1:2.5 in chloromethane ether solvents room temperature be swollen 2 hours
Afterwards, 0.5 times of zinc chloride of polystyrene-divinylbenzene microspheres quality is added as catalyst, it is small to be warming up to 35 DEG C of reactions 15
When, chloromethylation microballoon is obtained, is cleaned up with ethyl alcohol or acetone, it is dry.
Step 3: it is last, it is grafted long chain hydrophobic group on chloromethylation microballoon；
According to 1:2 mass ratio, the input swelling solvent swell into the chloromethylation microballoon, in being swollen 2 under room temperature
Hour, add the alkylamine of chloromethylation microspheres quality 10%, be warming up to 70 DEG C react 8 hours, during the reaction
The NaOH solution of the 20wt% of 3 times of alkylamine quality is gradually added dropwise, so that the pH value of reaction system is maintained at 12 or more, is obtained by the reaction
It is grafted with the finished product of long chain hydrophobic group, finished product ethyl alcohol and water are cleaned and dried, and the sweller is dichloroethanes.
The alkylamine is decyl amine, to obtain the microballoon for being grafted with decyl.
Embodiment 2：
One kind removing β for blood purification2The preparation method of the resin of microglobulin：
Step 1: first, preparing polystyrene-divinylbenzene microspheres；
It will be to styrene and divinylbenzene monomers in mass ratio 1:2 configuration oil phases, while being added to styrene and diethyl
The initiator and 40wt% pore-foaming agents below of alkenyl benzol mixture 1wt%, using suspension polymerization, be added to styrene and
Oil phase is added in 80 DEG C of water and is stirred to react 24 hours obtained superhigh cross-linkings by the stabilizer of divinyl benzene mixtures 10wt%
The polystyrene-divinylbenzene microspheres of degree, then polystyrene-divinylbenzene microspheres are cleaned up with water or acetone, and it is dry；
The initiator is benzoyl peroxide, and the pore-foaming agent is arbitrary in toluene, naphthalene, paraffin oil, benzene, dodecane
One kind, the stabilizer are polyvinyl alcohol.
Step 2: secondly, by polystyrene-divinylbenzene microspheres chloromethylation；
By the polystyrene-divinylbenzene microspheres by volume 1:4 in chloromethane ether solvents room temperature be swollen 4 hours after,
1 times of zinc chloride of polystyrene-divinylbenzene microspheres quality is added as catalyst, is warming up to 40 DEG C and reacts 40 hours, obtain
To chloromethylation microballoon, cleaned up with ethyl alcohol or acetone, it is dry.
Step 3: it is last, it is grafted long chain hydrophobic group on chloromethylation microballoon；
According to 1:3 mass ratio, the input swelling solvent swell into the chloromethylation microballoon, in being swollen 4 under room temperature
Hour, the alkylamine of chloromethylation microspheres quality 20% is added, 80 DEG C is warming up to and reacts 12 hours, in reaction process
In be gradually added dropwise 3 times of alkylamine quality 20wt% NaOH solution, so that the pH value of reaction system is maintained at 12 or more, react
To the finished product for being grafted with long chain hydrophobic group, finished product ethyl alcohol and water are cleaned and are dried, and the sweller is that dimethyl is sub-
Sulfone.
The alkylamine is 20 amine, to obtain the microballoon for being grafted with eicosyl.
Embodiment 3：
One kind removing β for blood purification2The preparation method of the resin of microglobulin：
Step 1: first, preparing polystyrene-divinylbenzene microspheres；
It will be to styrene and divinylbenzene monomers in mass ratio 1:1.5 configuration oil phases, while being added to styrene and two
The initiator and 20wt% pore-foaming agents below of vinyl benzene mixture 0.8wt% is added using suspension polymerization to benzene second
Oil phase is added in 80 DEG C of water and is stirred to react 16 hours obtained superelevation by the stabilizer of alkene and divinyl benzene mixtures 5wt%
The polystyrene-divinylbenzene microspheres of the degree of cross linking, then polystyrene-divinylbenzene microspheres are cleaned up with water or acetone, and
It is dry；
The initiator is benzoyl peroxide, and the pore-foaming agent is arbitrary in toluene, naphthalene, paraffin oil, benzene, dodecane
One kind or arbitrary two kinds of mixture, the stabilizer are polyvinyl alcohol or gelatin.
Step 2: secondly, by polystyrene-divinylbenzene microspheres chloromethylation；
By the polystyrene-divinylbenzene microspheres by volume 1:3 in chloromethane ether solvents room temperature be swollen 3 hours after,
0.7 times of zinc chloride of polystyrene-divinylbenzene microspheres quality is added as catalyst, is warming up to 38 DEG C and reacts 23 hours,
Chloromethylation microballoon is obtained, is cleaned up with ethyl alcohol or acetone, it is dry.
Step 3: it is last, it is grafted long chain hydrophobic group on chloromethylation microballoon；
According to 1:2.5 mass ratio, the input swelling solvent swell into the chloromethylation microballoon, in being swollen under room temperature
3 hours, add the alkylamine of chloromethylation microspheres quality 15%, be warming up to 75 DEG C react 9 hours, during the reaction
The NaOH solution of the 20wt% of 3 times of alkylamine quality is gradually added dropwise, so that the pH value of reaction system is maintained at 12 or more, is obtained by the reaction
It is grafted with the finished product of long chain hydrophobic group, finished product ethyl alcohol and water are cleaned and dried, and the sweller is N, N- dimethyl
Any one of amide.
The alkylamine is tetradecy lamine, to obtain the microballoon for being grafted with myristyl.
Embodiment 4：
The present embodiment and the difference of embodiment 3 are：The alkylamine is octadecylamine, to obtain being grafted with octadecyl
Microballoon.
Embodiment 5：
The present embodiment and the difference of embodiment 3 are：The alkylamine is hexadecylamine, to obtain being grafted with positive 16
The microballoon of alkyl.
With reference to test example, the present invention will be further described：
Using BET method, the specific surface area of resin made from embodiment 1,2,3,4,5 is measured respectively, the results are shown in Table 1.
External plasma adsorption experiment is carried out respectively to resin, using the blood plasma (β of uremic patient2- MG's is a concentration of
20mg/L), it is 1ml by resin and Plasma volumes ratio:The ratio of 20ml, resin made from embodiment 1,2,3,4,5 correspond to respectively
Number 1#, 2#, 3#, 4# and 5# after oscillation is adsorbed 2 hours in the shaking table of 60~80rpm, detect the β in blood plasma at 37 DEG C2-
The concentration of MG, albumin, the results are shown in Table 1.
Table 1, the specific surface area of each group resin, adsorption rate and adsorbance
As it can be seen from table 1 resin made from 1# and 2#, specific surface area is higher, to β2Microglobulin (β2- MG) have compared with
High adsorption rate and higher adsorbance, it is relatively low to the adsorption rate of albumin.Resin made from 3#, 4# and 5#, specific surface area is more
Height, to β2Microglobulin (β2- MG) there is higher adsorption rate and higher adsorbance, it is lower to the adsorption rate of albumin；Wherein
The specific surface area highest of resin made from 5#, to β2Microglobulin (β2- MG) adsorption rate and adsorbance highest, to albumin
Adsorption rate is minimum.
Finally, it should be noted that foregoing description is only the preferred embodiment of the present invention, the ordinary skill people of this field
Member under the inspiration of the present invention, without prejudice to the purpose of the present invention and the claims, can make table as multiple types
Show, such transformation is each fallen within protection scope of the present invention.
Claims (6)
1. one kind removing β for blood purification2The preparation method of the resin of microglobulin, it is characterised in that：First, polyphenyl is prepared
Ethylene-divinylbenzene microspheres；Polystyrene-divinylbenzene microspheres and chloromethyl ether are subjected to chloromethylation again, obtain chloromethane
Base microballoon；Finally long chain hydrophobic group is grafted on chloromethylation microballoon；
The step of polystyrene-divinylbenzene microspheres is：By styrene and divinylbenzene monomers in mass ratio 1:1~2
Oil phase is configured, while initiator and the 40wt% pores below of 0.5~1wt% of styrene and divinyl benzene mixtures is added
Agent is added the stabilizer of styrene and 3~10wt% of divinyl benzene mixtures, oil phase is added using suspension polymerization
To the polystyrene-divinylbenzene microspheres for being stirred to react 12~24 hours obtained superhigh cross-linking degree in 80 DEG C of water, then by polyphenyl second
Alkene-divinylbenzene microspheres are cleaned up with water or acetone, and dry；
The step of grafting long chain hydrophobic group, is on the chloromethylation microballoon：According to 1:2~3 mass ratio, to the chlorine
Methylate input swelling solvent swell in microballoon, adds the alkylamine of chloromethylation microspheres quality 10~20%, and make anti-
It answers the pH value of system to be maintained at 12 or more, the finished product for being grafted with long chain hydrophobic group is obtained by the reaction, finished product ethyl alcohol and water carry out
It cleans and dries, the sweller is dimethyl sulfoxide (DMSO), dichloroethanes or N, any one of N- dimethylformamides.
2. according to claim 1 remove β for blood purification2The preparation method of the resin of microglobulin, feature exist
In：The long chain hydrophobic group is the alkyl of C10~C20.
3. according to claim 2 remove β for blood purification2The preparation method of the resin of microglobulin, feature exist
In：The long chain hydrophobic group is the alkyl of C14~C18.
4. according to claim 1 remove β for blood purification2The preparation method of the resin of microglobulin, feature exist
In：The preparation method of the chloromethylation microballoon is, by the polystyrene-divinylbenzene microspheres by volume 1:2.5~4
After room temperature is swollen 2~4 hours in chloromethane ether solvents, 0.5~1 times of chlorination of polystyrene-divinylbenzene microspheres quality is added
Zinc is warming up to 35~40 DEG C and reacts 15~40 hours, obtain chloromethylation microballoon as catalyst, is cleaned with ethyl alcohol or acetone dry
Only, dry.
5. according to claim 1 remove β for blood purification2The preparation method of the resin of microglobulin, feature exist
In：The initiator is benzoyl peroxide, and the pore-foaming agent is any one in toluene, naphthalene, paraffin oil, benzene, dodecane,
Or arbitrary two kinds of mixture, the stabilizer are polyvinyl alcohol or gelatin.
6. according to claim 1 remove β for blood purification2The preparation method of the resin of microglobulin, feature exist
In：After putting into sweller into the chloromethylation microballoon, in being swollen 2~4 hours under room temperature, the alkyl is added
Amine, and be warming up to 70~80 DEG C and react 8~12 hours, NaOH solution is gradually added dropwise during the reaction, makes the pH of reaction system
Value is maintained at 12 or more.
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| CN107876031A (en) * | 2017-11-28 | 2018-04-06 | 珠海健帆生物科技股份有限公司 | A kind of uremia blood-purifying adsorbing agent and preparation method thereof |
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| CN107876031A (en) * | 2017-11-28 | 2018-04-06 | 珠海健帆生物科技股份有限公司 | A kind of uremia blood-purifying adsorbing agent and preparation method thereof |
| CN107876031B (en) * | 2017-11-28 | 2020-11-13 | 健帆生物科技集团股份有限公司 | Blood purification adsorbent for uremia and preparation method thereof |
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Denomination of invention: Used for blood purification and clearance b2-Preparation method of resin for microsphere protein Effective date of registration: 20231214 Granted publication date: 20180717 Pledgee: Societe Generale Limited by Share Ltd. Chongqing branch Pledgor: CHONGQING XIERKANG BLOOD PURIFICATION EQUIPMENT RESEARCH DEVELOPMENT CO.,LTD. Registration number: Y2023500000103 |